ASCO Education

This episode features Dr. Quyen Chu, Chief of the Division of Surgical Oncology at Louisiana State University. A prominent surgeon, humanitarian and writer, Dr. Chu shares his life stories, from fleeing Vietnam as a young child, to finding his calling, and giving back through work in impoverished U.S. communities and war-torn regions, including Iraq, Kurdistan and Vietnam. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 01/04/22 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] PAT LOEHRER: Hi. I'm Pat Loehrer and director of the Center for Global Oncology and Health Equity, Indiana University. And welcome to another episode of Oncology Etc. DAVE JOHNSON: And hello. I'm Dave Johnson at University of Texas Southwestern in Dallas. Pat, great to have another session today. PAT LOEHRER: It's good to see you again, Dave. I'm really excited about our guest today. And I think both of you and I were talking about this book that came to mind when we thought about having Quyen here. But it's a book by Abraham Verghese entitled My Own Country. And we hope to have Abraham on in another session of ours. You know, Abraham's story of growing up in Africa, and moving to the United States, and moving to the South in Tennessee in a time of HIV was really an extraordinary journey for him. DAVE JOHNSON: Yeah, an amazing story, settling in East Tennessee in the Appalachian Mountains, and then going to the Northeast to do additional training, and then returning to that part of the country during the height of the AIDS epidemic-- really a remarkable story. For those who have not read it, we both recommend it very highly. Today's guests we're incredibly excited about both. Dave and I met Quyen Chu in the Leadership Development program for ASCO. He was in the first class. He's currently the professor of Surgery and chief of the Division of Surgical Oncology and holds the Edward and Frieda Green Professorship in Surgical Oncology at LSU in Shreveport. He earned his MB degree at Brown Medical School in Providence, trained in general surgery in Massachusetts at Springfield and at St. Elizabeth's Medical Center, and then did his fellowship training at Brown University under the mentorship of Dr. Hal Wanebo, who was a wonderful surgeon and very active in ECOG in the Southeast group. Dave and I knew him. He's authored-- or co-authored more than 178 publications, a number of book chapters, a couple of books, including translating one of the surgical textbooks into Vietnamese. He has been an extraordinary human being. And one of the things we want to explore is his journey from childhood until now. In 2013, he was appointed by President Barack Obama to the board of Vietnam Education Foundation. He has worked in impoverished areas in Louisiana but also in the war-ravaged parts of the world, including Iraq, Kurdistan, Vietnam. He is truly a special breed of humanists who-- I think he looks back at his roots. he sees the bright possibilities of the future and reflects on what he can do to make a difference. It's just a great pleasure to have you, Quyen, to join us today. QUYEN CHU: Thank you very much, Pat, for that great introduction. It is very heartwarming, and I look forward to this podcast. DAVE JOHNSON: So Quyen, why don't we start a little bit-- I mean, Pat's mentioned your background. Tell us a little about how you got here and about your family and their journey from Vietnam to the United States. QUYEN CHU: Sure. I immigrated to the United States in 1975 right after the fall of Saigon at the end of the Vietnam War. My father was a South Vietnamese officer in the army, which means that he fought alongside with the Americans so that when the Americans pulled out, South Vietnam fell. And so because he was an officer, we were-- basically had no choice but to leave the country. Otherwise, he would be in a re-education camp, which might mean that we would never see him again. So we left Vietnam in '75. I was seven. We left on a ship, and then we also left-- then we transitioned to boats, and then we went to the Philippines for several months. And then we finally got sponsored by a church in Florida. So then we stayed at Eglin Air Force Base for several months before we actually went to our home in Florida. I grew up there and basically was-- grew up in a very impoverished area. It was-- basically it's a rat-infested home that we lived in. My father was an officer. He was a captain. But coming over to the United States, you have to learn English. You have to try to get a better education. And he finally realized that he had to support a family of six, and he took on being a barber. So he was a barber for most of his-- the rest of his career, really, raising a family of six. And I was there just to do the very best that we could. Throughout it at all, we knew that we were in the right place. And we knew that America doesn't give everything out for free, but we also know that it's a great, great land of opportunity. The philosophy is that if you apply yourself, do the very best, follow the rules and regulations or laws, you know, abide by their laws, that you can do great things. And that is a great opportunity. So that was embedded in me and my sisters, and those philosophies have stood the test of time thus far. PAT LOEHRER: You know, I read a little piece when-- you told a story about arriving here in Florida and a police car pulling up to your house. Can you relate that story? QUYEN CHU: It's the memory that I will never forget. And in fact, I remember it every Thanksgiving. So it was around Thanksgiving. We really didn't know what it was. We just moved into a new house. And it's funny because when we drove by the new house, we saw the garage. And we felt, oh, my god, we're going to live in that garage. This is great. This garage is going to be our house. This is great. There's so much space. And I remember when we asked the driver, the driver goes no, no, no, no, that's where you park your car. The whole house is yours. And we were just amazed. But anyway, so around Thanksgiving, we saw-- a police car drove up to our parkway. And I saw, and I was scared. And then I called out my dad. And I said, Dad, there's a police car here. What did we do wrong? And he was so scared. And he said, Son, you know, I will take care of this. So the police came and knocked on the door. And when my dad opened the door, he claps his hand, and he just bow, just like this, several times to the policemen and say, we're-- in broken English, we're sorry. We know English. We did not mean to break any laws. Forgive us. And the police just smiled. And he says, no, no, no, no. We're here to greet you as a new neighbor. And it's Thanksgiving, and we want to give you a turkey. Then he waved to the other police to come over, and then the other police came out with a big old turkey. And they hand it to us, and they said, welcome to the neighborhood. And we were so happy. My mom-- just about to cry. And we felt that, hey, this is now our new home, and we felt that this is not going to be a strange land, that we're going to create a life for ourselves here. DAVE JOHNSON: It's a remarkable story, Quyen. That type of story just makes it even more special. You mentioned that you had several siblings. Where do you fall in the hierarchy? And what are your siblings doing? QUYEN CHU: So I'm a second-oldest. So my oldest sister-- she went to Cornell, and she is now a full professor of biochemistry at Union College. My younger sister, who's a year younger than me-- she graduated from Dartmouth, and she is now working at industry and also, in the medical field. She holds a PhD from Columbia. And then my youngest sister graduated from Oberlin College, and she is now working in the hotel business. So we're very blessed. We feel very excited about the opportunities. And we look back at our lives every Christmas when we get together as a family, and we reflect back at the lives that we've gotten. And we also feel bad about family members who couldn't make it over here and wonder what their lives would have been like had they come over here. And then we also wonder what life for us would have been like had we not come over here. And through it all, we felt that we really, really hit the jackpot in life and that all of us were very, very lucky to have this life that we have. PAT LOEHRER: I can't imagine the pride that your parents have of all of you and how much pride you have for him. I mean, it's extraordinary. Can you just because I've never-- none of us have been through this, what you've been through. But what was it like being seven years old in the middle of this war in Vietnam? What memories do you have of that? QUYEN CHU: Yeah. I remember when I was playing with my cousins. And of course, in Vietnam, we live under a house full of cousins, aunts, and the extended family. I remember leaving them, and I felt very lonely in America. Of course, each family has its own separate family. And I just felt like it was not-- it was very lonely. But we did have very nice neighbors. We did have great people that really was very supportive. Of course, as a young seven-year-old, the neighbor's daughter was around my age. She was cute, so, of course, I'd find every reason to visit them and say hi to them. But other than that, it was a very nice place to grow up. They have their challenges, obviously. What I remember as a second grader-- I saw all the boys. To me, I thought they were all brothers because they were all Caucasian. They all have blond hair. I couldn't tell the difference who's who, but I thought they were all related. But they were very nice, of course. There were curiosity between us. I've never seen African-Americans until I came over here. And I befriended a Hispanic guy, as well as an African-American, as well as my best friend. To this day his name I still remember. It's Jeff. He was very friendly. Of course, I experienced some racism, but I think that's expected because I look very different. There were a lot of mixed messages coming out of the Vietnam War. But I think that through it all, the challenges, I realized, that there are more good people than there are bad people and that people who were bad-- probably because they were insecure, or they just didn't know me. And then there were those who did finally get to know me. They turned out to be great people. I've learned throughout my 53 years on this earth that people have so many things in common that when we do have conflict, it's probably stemmed from insecurities rather than pure hatred. DAVE JOHNSON: Yeah. You went to undergraduate at Dartmouth. Is that right? QUYEN CHU: Yes. sir. DAVE JOHNSON: So I seem to recall-- maybe you told us this in the LDP program, but you had an interesting experience when you showed up on campus at Dartmouth. QUYEN CHU: Yeah. DAVE JOHNSON: Can you relate a little bit of that to us, as well? QUYEN CHU: Sure. So, again, coming from a family where your dad is a barber, I had limited means. So I basically had, I think, one tote bag that I packed together. I took a Greyhound two day's trip to Dartmouth. And I got there on the campus. It was a beautiful green campus. And I was a little bit hesitant, a little bit reserved because there were a lot of Caucasians and whatnot. And I was a little bit, you know, introvert somewhat. And when I got there, I saw a Frisbee flew by me. And I grab it, and then the guy goes, hey, you want to come and play with us? And I'm like, well, sure. And next thing you know, we hit it off like a bunch of 18-year-old kids-- no worries in our mind, just glad to be on campus. And we hit it off. And I realized that, hey, you know, my reservations were basically based on my own biases rather than the reality. And then I've realized that the reality is that a lot of the kids there are just like me-- just want to find friends, just want to hang out, just want to have a good education. And they weren't being judgmental about anything, and that made me really-- it felt really good. DAVE JOHNSON: Frisbee diplomacy, I guess, is we should call it. Maybe we should throw a Frisbee to Putin. I don't know. QUYEN CHU: That's right. PAT LOEHRER: Tell us a little bit about your journey to become a surgeon. QUYEN CHU: OK. So my dad and mom instilled with me the importance of education. They told me, now listen, you have a choice-- either be in the same rut as us now, or get a good education and get out of this rut. So I really didn't have any choice but to study hard. And I studied hard, and I got an opportunity to go to Dartmouth. I felt very, very lucky with that. They gave me a full scholarship. They believed in me. They saw something in me that I was very happy that they saw. And then I applied to medical school at my sophomore year at Dartmouth, and I got in. I was very excited about that. And I started off wanting to be a pediatrician, but then I realized that what I had to turn in my sheet of the patients that I saw, everything had to do with procedures and techniques. I wrote down there I did a spinal tap, I did a chest tube, I helped intubate, I did all of that. And it was really my pediatric mentor who says, it sounds like you should be a surgeon, not a pediatrician. And that kind of got me thinking about it. And then I rotated a service with Dr. Wanebo and really fell in love with surgery. It was tough. It was rough. But I felt that this is my calling. I felt very fortunate looking back at only the number-- maybe they admitted 100 students. And I felt very fortunate that I was among those. And I knew that it was an opportunity that I did not want to waste, that I did not want to take for granted. I wanted to do everything I can to make sure that I learn as much as I can and hoping that in the future, I would give back to the country, the community that gave me a life. DAVE JOHNSON: Yeah, my mentors suggested that I should be a forest ranger as opposed to a physician. [LAUGHS] PAT LOEHRER: Yeah I think I shared before I got, on one of my medical-school applications, they not only rejected me, but they said, good luck in whatever career you decide to go into. [LAUGHTER] I was going to be a pediatrician, too, but I envisioned all these kids just laughing and having a great time. But they were all crying, and the parents didn't like me either. And so I decided to find a different life. You have had this extraordinary journey of giving back, as I mentioned at the onset, and not only going back to Vietnam but also, going to Iraq and going to many other countries here. And about five years ago, you received the ASCO Humanitarian Award, which was so deserving for you. DAVE JOHNSON: Very deserving. PAT LOEHRER: But tell us a little bit about these efforts. What has pulled you or driven you to do so much of your humanitarian efforts around the world? QUYEN CHU: Well, first of all, I want to credit my wife Trina, who's been there for me. She's basically the backbone of my life, allowing me the opportunity to pursue my passion. She's a lawyer. She put her career in the back seat so that I can have a successful career. So I want to make sure that I acknowledge her sacrifice and her love. Because of her love and her understanding, I was able to pursue my passion, which is giving back. My colleague, Dr. Gazi Zibari is from Kurdistan. And one day, he showed me pictures of the Kurds, and he gave me the history of the struggle the Kurds. And it was reminiscent of the struggles of the Vietnamese, so it resonates with me. And I said to him one day, hey, listen, when you do go, I would love to join you. And so I did. And from that point on, I returned, I think, four or five additional times. We did not return last year or so because of COVID, but we're planning to return again to Kurdistan and Iraq. But it was an opportunity for me to really give back what I wanted to do all along, which is to render care to the less-fortunate individuals of our lives. I also went to Vietnam, Nicaragua, Honduras, and also on those different mission trips. And, you know, Dr. Zibari and I have gone together for many of these trips. And we come to realize, you know, what-- the great thing to do is capacity building. In other words, we should visit these countries not just once but several times to make sure that the surgeons there feel comfortable with the procedures that we taught them and that, hopefully, that they will also teach the other surgeons the procedures, the techniques that we taught them. And we were very pleased when we went back to see that these surgeons were very adept in what they were doing-- Whipples, liver resection. They were doing phenomenal things. In fact, I think the greatest sense of pride in me was to see a young surgeon in Kurdistan who did a laparoscopic right-liver resection bloodless. We felt very proud because-- I was looking at Dr. Zibari, and I said, you know what-- I can't even do that. And it's amazing to see how they have not only learned our skills, but they exceeded us. And isn't that what we all want, that our mentees to be better than us? And so to me, that was a great sense of pride. At the end, the young man came up to me and says, mentor, I hope I did it right. Did I make any mistake? And I chuckled. And I said, no. I could not have done what you've done. You have done amazingly. And he was so happy. He was so proud. He says, I'm so glad that I make you proud of me, Dr. Chu. So to me, that's probably the greatest thing is to see your mentee better than you and still see that respect that you got from them. DAVE JOHNSON: We're really happy you mentioned that because one of the themes of our podcast has been mentor and mentor relationships. And you had a remarkable relationship with Dr. Wanebo. Would you like to expand on that somewhat or tell us about that relationship? QUYEN CHU: Sure. Dr. Wanebo-- I always joke around. I said, Dr. Wanebo, you're a gifted surgeon with an internal-medicine demeanor. He is just so nice. He never loses his cool. And the great thing about him is that every time I have an idea, he would always push me to pursue it. There's never been a, no, it can't be done. No, that's not how-- you will never get it done-- never like that. It's always, this is a great idea, Quyen. Why don't you pursue it. And in fact, he would give me deadlines and say, why don't you get back to me in two weeks and see where we go with that. I remember visiting him in his very busy clinic. And his PA would always trying to brush me aside because they were so busy. And he would always say, no, no, no, come on, Quyen. What do you have for me? What do you need? He would always make time, even in this busy clinic, to help mentor me. And then whenever I'd write a paper or abstracts, he would look at it. He would fix it, and he would send it back to me and ask me to work on it. So he's been a great mentor, just a great person all around. PAT LOEHRER: Quyen, if you could think about a young professional or young student right now and give them some advice, what would it be? QUYEN CHU: I think the best advice is that you pursue your passion. I know it sounds so trite, but pursue your passion. Seek out mentors who believe in you, and avoid those naysayers because I think that young people have so many insecurities. And they're great people. They're so naive, and they're so fresh. They're not tainted with all of the flaws of the world. And I always worry that when they encounter negative people, it fills their mind with negativity. And that, to me, is not very constructive. So I would advise young people to seek out optimistic, idealistic people to be mentors. And then I think the rest will follow. And they will learn what can be done, what can't be done. Obviously, you need a mentor to advise them so that they don't fall into your trappings of making major mistakes. But I think that mentors should be someone who is inspiring, who is positive, who can tell them that, hey, you can do it. And if you fail somewhat, it's not the end of the world. Seek out your passion, and never give up. DAVE JOHNSON: That's great advice, Quyen. I have just one more question I wanted to ask and perhaps should have asked a bit earlier. How did you end up in Louisiana? QUYEN CHU: That's a great question. So at the end of my fellowship, I had opportunities to stay up north. Then I got a call from my previous partner to say, hey, listen, I'm in Shreveport. Why don't you come by. In fact, it's funny because when I heard the word "Shreveport," it sounds, to me, Chinese. And I said, why would I want to go to China to practice? I didn't know where it was. And then they said, no, no, this is in Louisiana. And I really thought about, nah, I don't want to go. But my wife said, listen, why don't you just go down there and take a look so that at least you won't offend the person who asked you to come down. So I went down there for an interview. And it really resonates with me about the needs, that patients there did not have, in my opinion, good surgical oncology care. There was a huge need. I saw the mortality for esophagus, gastric cancer. They were high. I saw a lot of cancers that were neglected. And the chair there, Dr. Turnage, was wonderful. And he said, listen, Quyen. Nobody's going to compete against you. We just got a huge need. I think that you would find a niche here, that you can really, really develop a practice here, and then I can mentor you for the academic part. So I thought about it. And then I talked to Trina, my wife. And I said, this is what I wanted to do. I wanted to give back. I didn't want to be just another spoke on the wheel. I wanted to make a difference. I think I can do this here. And so we took a chance, and I think that we're very happy with that decision we made. PAT LOEHRER: Well, Quyen, I just, as I reflect on this and think about that leadership-development program, there are many different kinds of leaders, but I can't think of a person who serves as a better example as a servant leader than you. You have given of yourself in so many ways. In this particular past few years. Where there's been so much angst and polarization in this country, and even consideration of isolationism and not having immigrants come into the country, I hope people listen to this, the podcast, and realize what the impact was of a man and a woman who decided to bring their kids over here. And he became a barber, which is not that prestigious of a job, if you will. But his impact on this country is huge. Mark Twain had a little quote. He said, "The two most important days of your life are the day that you were born and the day you find out why." And when you guys were born in Vietnam, you had no clue what was going on, but you are one of the fortunate people who know why you're here, and that's to make a difference. And I just want to tell you that you have. Thank you so much for your time with us today. DAVE JOHNSON: Yeah, it's been great. QUYEN CHU: Thank you very much. DAVE JOHNSON: Quyen, this has been marvelous, and we're both great admirers of yours. And I could not agree more with Pat about the impact that you've had. One thing we like to do with our guest at the end is ask you if there's something you've read recently, or a documentary, or something, a movie or something you've seen that you would recommend to us and to our listeners. Is there something special that you've read recently or maybe seen that you'd like to recommend? QUYEN CHU: Yes. So there's a book by Mr. David Epstein called Range. It's a phenomenal book. It's a book that contrasts Malcolm Gladwell's philosophy about 10,000 hours to be an expert. Mr Epstein took a different approach. He took the approach that you have to be a generalist. In other words, you have to do many things in life before you can hone in on one particular skill set to become an expert in that. So to me, that book, Range, is a fascinating book. I'm midway through. And it's just-- it's a beautifully written book, and it just gives a different perspective of life. I've always loved books that give a different perspective for a particular topic. And I would highly recommend our readership to read Range by David Epstein. DAVE JOHNSON: Yeah. I also read that, and it is a fabulous book. I couldn't agree more. QUYEN CHU: Yeah. DAVE JOHNSON: Well, we've come to the end of our session. And I really want to take this opportunity to thank our listeners and thank Quyen for joining us. It's been a marvelous session. QUYEN CHU: I appreciate it. Thank you, David, and thank you, Pat. DAVE JOHNSON: Thanks for tuning in. This is an ASCO educational podcast, where we will talk about anything and everything, really. We really will. So if our listeners have any ideas for our topic or guests that you'd like to hear, please email us at education@asco.org. Thanks, again, and remember that November 9 is National Louisianan Day. And Pat, just so you know, November 16 is National Indiana Day. I'm sure you already knew that. PAT LOEHRER: I love it. Every day's Indiana Day. DAVE JOHNSON: No, every day is Texas Day. PAT LOEHRER: Thanks, guys. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

Adjuvant immunotherapy is a game-changer for early lung cancer, but it is not the best choice for every patient. Hosted by Dr. Rami Manochakian (Mayo Clinic), Drs. Karen Kelly (University of California Davis) and Howard West (City of Hope Cancer Center) explore considerations in shared decision making and personalizing therapy through patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 12/15/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. RAMI MANOCHAKIAN: Hello, and welcome to ASCO Education Podcast on new therapies for lung cancer. My name is Dr. Rami Manochakian. I'm a thoracic medical oncologist at Mayo Clinic Florida. Today, I have the pleasure to speak with two very well known, nationally and internationally, thoracic medical oncologists specializing in the fields of lung cancer. I have Dr. Karen Kelly, who is a professor of medicine and associate director for clinical research at the University of California Davis Comprehensive Cancer Center. And I am also joined by Dr. Jack West, who's a medical oncologist as well as associate clinical professor in medical oncology at the City of Hope Comprehensive Cancer Center. In October of this year, the FDA approved atezolizumab for adjuvant treatment of stage II to IIIA non-small cell lung cancer following a resection and platinum-based chemotherapy. This is the first adjuvant immunotherapy approved for lung cancer and has the potential to improve cure rates. In this podcast episode, we'll discuss how to implement this new therapy in the care of real-world patients. We're going to start the conversation today with a patient case. We have a 64-year-old woman who is a 15-pack-year smoking history, quit several years ago in the 1980s, and was found on a screening CT to have lung adenocarcinoma. She underwent a full workup that included a negative EBUS and ultimately underwent a surgical resection with right upper lobectomy. Surgical pathology showed a 3.2-centimeter invasive adenocarcinoma with some additional lepidic noninvasive AIS, and two out of eight N1 nodes were positive. The final staging was a pT2aN1 stage IIB disease. She had a molecular testing that included NGS that showed an EGFR activating mutation in exon-- 21-L858R substitution with no other driver mutation. And PD-L1 was checked, and it was 2%. And we'll start with the first questions. And I'll start with Dr. Kelly, and then we'll ask Dr. West also to give his opinion. Given the currently available treatment and the new approvals, all the research evidence and guidelines that we have as of now, 2021, how would you manage this patient? KAREN KELLY: Well, I think that that is a great question. And of course, for this patient, who does have that EGFR L858R mutation, that is a very important finding to have. And I applaud the ability to get the NGS sequencing, because that is important here, for patients today, based upon ADAURA results, which was the randomized trial after resection for patients with early-stage disease who got chemo or not, randomized to osimertinib versus placebo. And so I think for this patient with that EGFR mutation, my driver in my treatment plan after adjuvant chemotherapy-- and I do want to make that important distinction here that, even though ADAURA did allow patients to not have chemotherapy, we are strong believers in evidence-based medicine that has shown that adjuvant chemotherapy has improved survivals and cure rates in this patient population. So after, I would begin with giving adjuvant chemotherapy for four cycles, cisplatinum-based. And then, based upon ADAURA, offer this patient osimertinib. I do not believe that this is a patient that would benefit from a immunotherapy regimen. And I'm going to let Dr. West talk about that component of this case-- that immunotherapy, I believe, would be contraindicated. RAMI MANOCHAKIAN: Excellent. Dr. West? JACK WEST: I would say that some in the audience may know that I've had some issues with the design of ADAURA and had been critical of it at the time of its release. And I think it is always a little challenging when we have disease-free survival results, but not overall survival in a curative setting, because I believe our goal here should be to improve survival. And it's not clear, particularly with a treatment that is still ongoing, whether this is really just forestalling progression and going to translate to a survival benefit. So that comes up with ADAURA. But that said, we are now in a situation where we have a remarkable improvement in disease-free survival with ADAURA that gave the adjuvant osimertinib for patients with a tumor harboring an EGFR mutation. And we don't yet have mature data for overall survival. I think we need to work with what we have, and that is giving the patient the benefit of the doubt and presume, until we see otherwise, that the remarkable improvement in disease-free survival will, we hope, translate to an improvement in overall survival. So certainly, for patients with node-positive disease, I would definitely favor at least offering, if not clearly recommending, osimertinib. I would talk about the caveats that we don't yet have overall survival, but I would say that, based on what we know, with the limitations, I would be encouraged and would favor that. And the important challenge, I would say, is what to do when you have potentially competing options, like adjuvant immunotherapy, specifically-- now in FDA approval for adjuvant-- atezolizumab, based on IMpower010 results that we first saw at ASCO in 2021 and have learned more about. And the results are also very impressive for at least a subset of patients, specifically those with stage II to IIIA disease and who have PD-L1-positive disease. I would note that, when looking at subset analysis of IMpower010, the benefit is much more impressive in the subset of patients whose tumor has PD-L1 expression in the high range, 50% or higher, where the hazard ratio for disease-free survival is 0.43. And in contrast, for the patients with low PD-L1, that hazard ratio for DFS is 0.87. And of course, we don't yet have overall survival for this trial either. So I would say that there is, arguably, a question of what you would do if someone has PD-L1-positive disease and an EGFR mutation. But I would note that we have seen in advanced disease that patients with a driver mutation-- say, particularly, EGFR-- are overwhelmingly more likely to benefit from targeted therapy against EGFR than immunotherapy. And if anything, it seems that PD-L1 expression for patients with an EGFR mutation or an ALK rearrangement doesn't necessarily mean the same thing as it would for someone with wild-type disease. It just is not nearly as strongly predictive of benefit, and the benefit with targeted therapy is far greater. RAMI MANOCHAKIAN: Thank you to both of you. Really, I think you brought both a great point. I like what Dr. West said about we need to give the benefit of the doubt. We need to deal with what we have, because right now we don't have the OS benefit, talking about, obviously, the ADAURA, or even the IMpower. And discuss with patients. Discuss what we're doing. Include them in the treatment decision and plan, and tell them this is why we're considering this and not. It appears that everyone feels that this patient, obviously, would not be the best candidate for adjuvant atezolizumab. Rather, very possibly get an adjuvant targeted-therapy osimertinib. Speaking about adjuvant atezolizumab, I want to ask, who else you would not recommend, maybe, adjuvant atezolizumab to? And I'll start with Dr. Kelly again. KAREN KELLY: So I think that we have learned a lot about other driver mutations based upon what we know about EGFR. And EGFR really has been the prototype for all the other mutations. And pretty much, they align with the findings with EGFR, particularly those of ALK, ROS1, and then we get into RET. And we can also talk about HER2. And I think the difference here, between that category and that group of oncogenic drivers, is that they're characterized by being in patients who are never smokers. And so in my opinion, this group of patients that have those additional mutations-- either ALK, RET, ROS1. I would say, also, HER2-- those never-smoking, oncogenic-driven aberrations, really, would probably fall, in my opinion, into the same category that I don't think that they would be the best for atezolizumab. I also base that on retrospective data from the IMMUNOTARGET data that came out in advanced disease, with monotherapy looking at a retrospective large series, multi-institutional, that showed that there really wasn't a benefit for mono-immunotherapy. Now, I will say that, of course, we do have oncogenes that are smoking-related-- that being KRAS G12C, now, remembering that not all KRAS are smoking-related. But something like KRAS G12C. BRAF, typically, as well. Half of the MET oncogenes are in patients who are smokers. So I think if you're a smoker and you have an oncogene, then I think that it would be reasonable. Again, based upon retrospective data-- I would say even based upon my own data from California-- we have found similar results. Even when you give immunotherapy with chemotherapy in patients with oncogenic drivers, they just don't have a benefit from immunotherapy. And I think we can logically make sense of that. They are more simplistic tumors. They don't have high tumor mutational burden. They don't have high PD-L1, for the most part. They're typically more characterized as being cold. So I think it does make sense that this group of oncogenic-driven cancers, particularly those in never-smokers are really more cold tumors and don't respond. So I would add these others to the list that we do have data on, and that, of course, is EGFR. RAMI MANOCHAKIAN: Dr. West, your thought? Especially, it looks like we're heading one way or the other to say that every patient with early-stage needs NGS testing. JACK WEST: I think that we are in a challenging place where the principles are ahead of the actual data that we have. I think that we have been struggling with this for a few years now with things like the PACIFIC trial, where we've had very impressive data for not just disease-free survival, but now overall survival. But that was a pretty broad, inclusive population. It included patients with an EGFR mutation, ALK rearrangement, and didn't really specify otherwise. And so the question is, do we broadly interpret that, well, if they were eligible for the trial and the trial is positive, they should be treated this way? Or do we make, I think, very logical inferences from stage IV disease that not only do these patients often not seem to benefit at all from immunotherapy, but that we could put ourselves in the challenging situation of giving immunotherapy and then having their cancer progress, and needing to give them a targeted therapy where there could be a harmful interaction between the osimertinib that we want to start and the immunotherapy that is still in their bloodstream? And so that's a real challenge. So I think that we need to, now, do some extrapolation. And because of that, it does make sense to want to have this information to individualize the recommendations for the patient. And it's not a big leap, based on what we know about ALK, to presume that these patients are not going to be big beneficiaries or, likely, beneficiaries at all from immunotherapy. I agree with Dr. Kelly about ROS1 and some of the other never-smoking-related driver mutations. I think it is important to say that we shouldn't paint all driver mutations with the same brush. We have seen from IMMUNOTARGET that KRAS and BRAF are not in the same category, and so we need to think of these individually. But I do believe that this information is going to be really helpful to make an informed, thoughtful decision for the individual patient in the exam room with us about whether they personally are likely to be beneficiaries of immunotherapy, targeted therapy, or whether they should withhold all of those. KAREN KELLY: Can I make one additional statement? I just want to add to what Dr. West said, particularly raising awareness about the harm factor. I think, as physicians, we're very focused on wanting to help the patients in terms of, when we look at these biomarkers, let's look at them and give you what works for them. But we have to remember now, with the oncogenic drivers, that we can potentially harm them if we give them immunotherapy. So I think we have to remember, now, the harm factor really comes to the forefront when we talk about immunotherapy and oncogenic drivers and the critical importance of knowing. Yes, we want to know if we can give osimertinib to those patients who are EGFR-positive. But in the same breath, we want to say, oh, immunotherapy would be harmful. So I think that's a little bit of a switch that we have to, as physicians, remember to have that really important conversation about why we don't want to give them immunotherapy. I will say, many of my patients with EGFR or ALK or ROS-- they come in, and they want immunotherapy. And you really have to spend time explaining to them why they are not the best candidates for immunotherapy. RAMI MANOCHAKIAN: Great point, great point. And just one very quick question before I move two Case 2. Are you both testing for NGS for every early-stage cancer patient that comes to your clinic? JACK WEST: I'll say that I would be most inclined to do that for a patient where it's likely to have an impact in the more immediate future. I would not say that I feel that this is a mandate for someone with a less-than-2-centimeter nodule, node-negative disease. You can argue that it would be nice to have this information at the time of relapse. But I think that, in general, you'd want to biopsy to confirm progression, relapse, disease, and the most important biology is what it is at the time of relapse and not what was resected two years earlier. So to me, if it is potentially going to have ramifications for immediate management, so certainly for a node-positive cancer, I would say so. I think it's debatable about whether to do this in someone who has a significant smoking history and a squamous cancer, because the pre-test probability is not high. So I don't want to be too heavy-handed about that, but I would say it makes a lot of sense to think and act beyond the narrow indications that we have now just for looking at EGFR as well as PD-L1. KAREN KELLY: Yes, I think to the point of harm. I think that we do need to be doing NGS testing in these patients that, I would say, meet the eligibility criteria from the 010 trial, in terms of adenocarcinoma. I do agree with Jack that a small 2-centimeter tumor-- I wouldn't be checking that. But if you meet the eligibility requirements, and you're thinking along those lines for that patient, then I definitely would do the NGS, not only-- as I said, because you don't really want to harm a patient. If you don't know that they have RET or ROS, you could potentially harm them if you gave them immunotherapy. So I think that is my point. We've got to remember. Now we have to think about helping our patients, but also not harming the patients. RAMI MANOCHAKIAN: Excellent. Thank you. I'm going to move on to Case 2 briefly. This is more of a case of a patient that is a good representative of a patient who meet the eligibility for the IMpower trial that led to the approval of atezo. 71-year-old male who presented with chest pain. Workup showed a mass, a 4-centimeter left-lower-lung mass. A full workup, including PET and EBUS showed that lymph nodes were negative. Also underwent left-lower lobectomy, and his staging was stage IIB, T2b, N1, with two hilar lymph node were positive. So again, very similar to the first case. A little just different size. NGS testing here did not reveal an actionable mutation, and PD-L1 was high, at a 60%. So simple question, Dr. Kelly. Is this patient a candidate for adjuvant atezo? What benefit would you expect to see? I know we touched base on it a little bit in the first case. And then, how would you talk to your patient about potential side effects? KAREN KELLY: So I think that this is the ideal patient for adjuvant atezolizumab, based, of course, on that very high PD-L1 of greater than 50%. That's where the data and the driver of the positive results really came from with that hazard ratio of 0.43. Remember that, in the subset analysis of the 1 to 49, the hazard ratio was 0.8 or higher. So it was really driven by the high PD-L1 status. So I think that this is a perfect patient to receive the adjuvant atezolizumab. When I talk to patients about side effects, I begin always with saying that we now have enormous data points about the side effects of all of the immunotherapy drugs, based upon stage III disease and stage IV disease and other diseases. And these agents are, overall, well tolerated, but they do have some risk of serious side effects that are related to inflammatory signs and symptoms. And so I do think that it's important to have a discussion about what I just group as "itises" that patients can really have. Any "itis" can occur. But the seriousness is, really, anywhere between 3% and 10% of that. And the other thing that I'm very vigilant about with the patients is that-- I remind them that these side effects can occur at any point in time while you are on the drug, and then through several months after you've stopped the drug. So I think that that's really important to be very vigilant. It's a very different approach than chemotherapy, where we really have a great understanding of exactly when those nadirs are. So I spend time making sure-- and every time I see the patient, going over that whole list again to make sure-- that they are doing well. So that's really how I approach a patient. And of course, make sure that they have a good understanding of those side effects. RAMI MANOCHAKIAN: Thank you, Dr. Kelly. Dr. West, do you agree that this patient is the ideal candidate for atezolizumab and you would offer that? JACK WEST: I would. And I would say that it's a slightly different situation from why ADAURA is compelling to me. And I would say that ADAURA is most compelling despite the limitations in DFS being assessed in the middle of ongoing EGFR-inhibitor therapy. Here, we don't have a hazard ratio of 0.12 or 0.17 or something like we did in ADAURA. But it is certainly impressive, certainly for the high-PD-L1 subgroup. And this is in patients who have completed their therapy in the past, and the benefit is sustained. We also know from the mechanism of action over years of treating patients with advanced disease with targeted therapies and immunotherapy that immunotherapy can have remarkably sustained benefit, even after patients stop it. And so it's not hard to envision that patients will have a time-limited course of immunotherapy and still have very sustained, potentially permanent benefit from it. So I am impressed by the improvement in disease-free survival, even if it isn't of the same magnitude as what we saw with ADAURA, because it is being measured after patients have completed that therapy, and in particular for the patients with high PD-L1. I do think that we need to be very thoughtful about whether patients in the 1% to 49% group are likely to benefit, in terms of overall survival, because we don't yet have overall survival data. The hazard ratio for disease-free survival is 0.87 here. And we've talked about the risks with immunotherapy are not generally catastrophic, but a lot of patients will have somewhat modest but sustained issues with thyroid problems, et cetera. And this is the adjuvant setting. Patients may already be cured, and you're talking about an additional year of coming into the clinic for therapy. That is very costly and can have toxicities that I wouldn't want to minimize. So for me, personally, I would say it is quite compelling for those with high PD-L1. It's something to discuss for somebody with low PD-L1 in the 1% to 49% range, but not something that I would consider nearly as striking a benefit. It does seem to me, from the subset analysis, that much more of the benefit of immunotherapy is limited to those with high PD-L1. RAMI MANOCHAKIAN: Thank you. So in conclusion, if I ask each one of you, please, to give a word of advice for oncology providers regarding the implementation of adjuvant atezolizumab into routine care today-- and also, of course, we know this field is evolving in a very great and promising way. What are you envisioning in the near future will bring for patients with early-stage lung cancer and, of course, could change what we're talking about today? Dr. Kelly? KAREN KELLY: So first of all, I think adjuvant atezolizumab is a significant advance in the field of adjuvant therapy for lung cancer. Remember, we have not had an advance in many, many, many years. And in the subset of patients, particularly those with high PD-L1, I think the data is impressive. To Dr. West's point about the 1 to 49, I do agree that we have to be careful, but we need more data. And I think that is where having the results of the other trials will be very, very helpful. Now, we all know that PD-L1 is really a gradient. And so I do want to say that we can't just focus on one parameter from these trials. We do that, particularly, I think-- the PD-L1s greater than 50% with a hazard ratio of 0.43, a solid number there-- that works. But when you're at 45 or 40 or 30, you really need to take into consideration other patient characteristics and other factors in making those decisions. And of course, that's a shared decision with the patient as well. So I think it's important to remember there are other factors that we all synthesize when we're talking to a patient and trying to make the best recommendation. So that's the art of medicine, is taking the science and putting it together to really help that patient that is sitting in front of you. So nonetheless, this is an advance. And remember, this is how we started with stage IV disease. So I really do think, to Dr. West's point about the fact that these patients, after a year, are having this really impressive disease-free survival, we're very optimistic that that will translate into cures. Now, I want to be clear here that overall survival doesn't mean cure. But again, if we look at cure fraction, I think we will see that with immunotherapy, because we are seeing that. And I know Dr. West and you also probably have cases where you're pretty confident that you've probably cured those patients with stage IV disease. We see that in a very silent way. [LAUGHTER] JACK WEST: I really agree. I have been commenting recently, reflecting that we have been pretty reluctant to say the C word, say "cure" for patients who have phenomenal unprecedented results with immunotherapy for stage IV disease, I think, based on our tenets that it's categorically not curable. But I think that immunotherapy has changed everything, and the rules are different. I would say that the IMpowere010 trial is very important, does change practice, should change practice, and is just the beginning for introducing immunotherapy into the early-stage setting. There are many other trials coming, looking at immunotherapy. In the adjuvant setting, we have seen very provocative data for neoadjuvant, which I think is also quite compelling and has the advantage of giving you more feedback about how your treatment actually worked. You're not treating blind. I think that in the next three to five years, we will have multiple different strategies, options to choose and that it's going to be a real quantum leap in how we translate some of the benefits that we have enjoyed in stage IV disease into earlier-stage disease to translate to better overall survival. I think that we will begin to see that for some of these earlier trials, and so we will be able to talk not just about disease-free survival, but overall survival. We will be talking about this for immunotherapy and targeted therapies. And so just like it's been about 15 years since everything changed in the adjuvant setting with chemotherapy, this is the next iteration of that, where we are working on how best to refine our strategies in a more individualized way than chemo for everybody, but to personalize the optimal perioperative treatment strategy for the patient's individual cancer characteristics. RAMI MANOCHAKIAN: Thank you. Thank you very much to both of you. I don't think we could have ended on a better note. It's definitely a hopeful era for patients with lung cancer. With all the recent advancements and research, I think our patients are living longer, living better. We still have a long way to go and, hopefully, more to happen in this field where we're able to offer our patients some personalized treatment depending on so many different factors. This is all we have for today. I'd like to thank very deeply Drs. Kelly and West for a great conversation and for sharing their insight and expertise. Thank you to all our listeners. Thank you to our wonderful ASCO staff, and hopefully, for more ASCO Education Podcast to keep covering this topic of lung cancer. [MUSIC PLAYING] Thank you all. JACK WEST: Thanks for the opportunity. RAMI MANOCHAKIAN: Thank you. SPEAKER 1: Thank you for listening to this week's episode. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

In this episode, oncologist Bryan Schneider and infectious disease expert Adrian Gardner from Indiana University, share what it has been like to get knocked down with COVID-19 twice, care for patients during the pandemic, lead the University's COVID response, and even a supreme court case on vaccination. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 12/7/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. PAT LOEHRER: Hi. I'm Pat Loehrer. I'm a director of the Centers for Global Health and Health Equity at Indiana University Simon Cancer Center. DAVE JOHNSON: And I'm Dave Johnson. I'm a medical oncologist at UT Southwestern in Dallas, Texas. PAT LOEHRER: Well, welcome back to ASCO's education new podcast series entitled Oncology, Etc. Today, we'll be joined by two outstanding guests, Dr. Bryan Schneider and Dr. Adrian Gardner. We're going to do a deep dive about COVID-19. And Dave, I was thinking-- I was reflecting on my life. The thing in medicine is when new diseases come out. So in our earlier lives, when we started there, was no such thing as Lyme disease, HIV/AIDS-- tumors didn't exist. And then just in the last couple of years now, we have COVID-19, the SARS CoV 2. And I think as physicians, it's kind of exciting. What's your experience been with the COVID-19 in the wards at Parkland? DAVE JOHNSON: Well, it's been really, very challenging. You know, I don't know that the public yet has fully grasped the magnitude of this disease. I mean, 700,000-plus Americans have died of this disease. That's an astonishing number when you think about it. And I was just on the general medical wards just a couple of weeks ago with a wonderful team of residents and students. Patients with this disease are very sick. We often downplay it, but I'm telling you, these people are really quite ill and can get ill and symptomatic rapidly, within hours. So this is a serious illness. But I agree with you. One of the things I told the residents a year ago was to keep a journal, that there are a few times during the course of your training and career where a new disease emerges, and you can be part and parcel of that. And keeping a diary of what happened is something that I wish I had done when AIDS emerged back in the '80s, or other disease processes, like Lyme, as you mentioned. PAT LOEHRER: And syphilis for you, wasn't it? DAVE JOHNSON: Well, that was sort of the [LAUGHS] Hippocratic oath days, but yeah, no. I think that was-- I think-- I can't remember. We were hanging out together at the time, so I don't remember exactly. Yeah, no, it's been really remarkable. The thing that's been interesting to me is the response of individuals and their families to the disease, particularly once the vaccines came available. So maybe we can delve into that a little bit today, because I know one of our guests has actually experienced that himself, so we'll know more about that later. PAT LOEHRER: I don't think, to be honest, that we could have a better collective wisdom than we have today with Dr. Schneider and Dr. Gardner, who will talk about their personal and professional and I think the global impact of COVID. I don't think there's any two people better than that. The only thing we could do better is if Anthony Fauci was here by himself. But these guys are tremendous people. Dr. Gardner went to medical school at Brown, did his fellowship and infectious disease at Beth Israel, and then did his MPH at Harvard, and joined the faculty in Indiana University in 2012. When he was a student, he spent time in Kenya, with Joe Mamlin from Indiana University as part of the AMPATH program. And he came back to become the field director there. And he is just an outstanding person. He's now the director of the Center of Global Health for Indiana University and the Associate Dean for Global Health and has led the contact tracing for Indiana University. And he's going to give us some input from this. Bryan, again, I've known forever. He's just an outstanding medical oncologist. He is now a Professor of Medicine and Medical and Molecular Genetics here at IU. He's a Vera Bradley chair of oncology. He is the founding chair of our precision genomics program and just a superstar in breast cancer as well as pharmacogenomics and was one of the first to describe the unique neuropathy associated with the taxanes in breast cancer. So it's just a pleasure to have both of you here. DAVE JOHNSON: You know, Pat, it's great to have that talent there. It balances out the negativity of other faculty members. But that's great. Welcome, both of you. PAT LOEHRER: I loved you a minute ago. I've turned mute on from a distance here. Adrian, tell me a little bit about yourself, growing up and how you got to where you were. ADRIAN GARDNER: Sure, thanks. And thanks so much for the invitation and for being part of this and for the generous introduction. So as you said, Pat, I'm a product of an international environment. That's an important part of my upbringing, actually. I was born in Scotland to two parents that-- born and bred in Scotland and grew up in Scotland. I spent the first six years of my life really living in France and then moved to Lawrence, Kansas, which was quite a cultural shift, but spent four years there. And it was great, actually, time in my life to be there, before moving to the East Coast, where I went to school and did all my medical training. So I'd had international experiences before, and I think that was an important part of my upbringing and something I sought for my kids, in the sense that it just immediately resets your sense of the world and makes you feel like a global citizen as opposed to just sort of more limited-- the community you're surrounded by. But it really wasn't until my experience as a fourth-year medical student at Brown that I had the opportunity to see health care in a low-resource setting and see that. And that was a very powerful experience professionally and personally. And as you said, it was the time when Joe Mamlin was really just dreaming up what the HIV response was going to look like, this nice institutional partnership that we'd set up in Western Kenya. But we set it up in the middle of the global pandemic. And true to our mission of responding and leading with care, felt a need to respond to the HIV pandemic. And that started really by-- was motivated by personal interactions that Joe had with some individuals who he saw firsthand come back to life, the Lazarus effect that has been reported. And that really spawned this whole response, changed my career and certainly my life, and had profound effects on my life. So that's a bit of who I am as an individual and how I got to where I am today. PAT LOEHRER: And we're going to touch on some of the work that you're doing now. But before I do, Bryan, tell us a little bit about and your background, where you grew up and how you got to where you are today. BRYAN SCHNEIDER: Thanks to you, and Dave as well, for having me on. And this will be an interesting perspective, because I think I'm coming on here as the patient this time, so it'll be a different view. But in contradistinction to Adrian, I am a pure Hoosier. I was born in the southern part of the state and raised there and then drove three hours north to Indianapolis, where I've set up for the last 25 years, and just been really lucky to be here at Indiana University. And Pat, you may not even remember this-- about 25 years ago, you were my formal mentor for med school, and so one of the influences and sticking around here along with some other real greats along the way. So have done, as you mentioned, breast medical oncology here in genomics and have had an absolute blast. So thanks for having me on. PAT LOEHRER: Oh, we love having you. And just as an aside, Bryan-- one is I think the world of you, and so proud of what you've accomplished. But Bryan's backyard actually was the home of Henry Lynch, and where he first described Lynch syndrome down in southern Indiana. And I think no greater tribute in his legacy than what you have done with precision genomics. It's really terrific. DAVE JOHNSON: Yeah. Maybe we'll have some time to delve into that. But actually, I'm curious, Bryan-- you mentioned that you've come on as the patient. My understanding is you've had firsthand experience with COVID, not just as a physician, but as the recipient of that wonderful new virus. Maybe you could tell us a little about that? BRYAN SCHNEIDER: Yeah, an interesting experience to be sure. So about 2 and 1/2 months ago, I tested positive for COVID and got really sick. Yeah, my three-year-old son had brought it home from his preschool and infected his older brother, who's almost 12, and then my wife and myself. And so was a really fascinating experience, I guess, and brought about some aspects to the virus that I had never really thought about. PAT LOEHRER: Now, Bryan, you also had COVID before, too. BRYAN SCHNEIDER: Yes. And the first time-- I was probably one of the very, very early cases and got really sick with it and lost my sense of taste and smell. I actually got one of the purple fingers, which I went to the ER for. I thought I was having a or something. And at the time, those weren't well-recognized symptoms. And that loss of taste and smell went months for me. So, yeah, I think I have frankly had the infection twice. The second time, though, was documented and certainly got really sick with the second one. DAVE JOHNSON: Can you elaborate on your second case? When you say you got really sick, was it a respiratory illness or were there other symptoms? BRYAN SCHNEIDER: Yeah, there were two aspects to it that were interesting. I think the first was physical. I got a sense of fatigue that I don't know that I have ever experienced before. It was one that I literally just could not get out of bed. And you know, I lost about 10 to 15 pounds from just being anorectic. And I'm not an overly thick human to begin with. But the big one was shortness of breath. And we had a pulse ox at home. My wife's a pediatrician, and I was sating in the high 80s. And I work out five or six times a week, so keep in pretty good shape, and I was stopping midway up the stairs to sit down, because I felt really tachycardic and just lightheaded. And so that degree of physical punishment is something like I have never expected or felt before. But the psychological part of it was really something I did not expect. And one part of that was an odd sense of guilt. I was getting texts and calls from a lot of friends checking on me, and many were baffled and asking, hey, did you not get vaccinated? Or what was going on with that? And so that-- it was a very odd sensation to me, because I, of course, had been vaccinated and I mask and all those sort of things. The other was one of real fear. I worried-- you know, luckily, I guess, our family all got infected around the same time, so we didn't have to think about quarantine. But I started wondering, could I have infected a patient? I take care of immunosuppressed breast cancer patients, before I was symptomatic. And then even after I came back to work, I had quarantined for quite some time, but I was really fearful. I would find myself double masking, washing my hands incessantly, and even holding my breath when I was trying to listen to heart and lungs during examination. So that sort of psychology was something I don't think I really expected with this infection. DAVE JOHNSON: How long did it take you to get beyond that, or are you beyond that part? BRYAN SCHNEIDER: Yeah. You know, I feel back to my baseline now. And I certainly don't worry about it on a day-to-day basis now. But my first clinic or two back was really hard for me, psychologically and emotionally. And part of me even wondered, should I profess to all my patients that I've had COVID? Or what things can I do to help protect them? And again, it was that mental aspect that I just didn't really anticipate prior to heading back to my clinic. DAVE JOHNSON: You know, this is eerily reminiscent of the physician who's had cancer who experiences extreme fatigue for the first time, chemotherapy-induced fatigue, after having described it many, many times before-- BRYAN SCHNEIDER: Right. DAVE JOHNSON: --and who has a guilt sensation in many respects as well. So quite the experience, for sure. PAT LOEHRER: Dave was talking about himself, by the way. BRYAN SCHNEIDER: No, I can only imagine. And you're right. We do try to paint a picture to patients about how things are going to feel, and it's amazing. When it's internalized or when you're feeling, it's-- it can often bring about a sense of, wow, I don't know that I-- I may have underplayed this to some of my patients in the past. And it really does provide some degree of empathy that's hard to capture if you haven't felt it. DAVE JOHNSON: So when I was on the wards, Bryan, I must confess, there were times when we walked into a patient's room with COVID who, of course, had not been vaccinated long after the vaccines were approved. Our professionalism prevents us from doing anything other than taking care of those people, but I'm wondering how you feel about caring for patients who have not been vaccinated or refuse to be vaccinated. BRYAN SCHNEIDER: Yeah. I mean, I think probably similar to a lot of people listening here today, it's a bit frustrating. And I think we all take care of patients who have a really tough diagnosis. And we're in the interesting field of giving patients medications that really immunosuppresses them, so we spend time counseling on the fact that you may get really sick or hospitalized or even die from neutropenic sepsis. And I think that is something that rests really hard with patients who are already dealing with a life-threatening diagnosis. And so now, trying to do that counseling in the face of a global pandemic like we haven't seen for a hundred years has really brought around a sense of duress and distress in my patients like I've never seen before. You know, I even had a patient who moved away from her family to be quarantined during adjuvant therapy, which I, of course, recommended against. But it really impressed upon me how big a deal this was. And so to see their frustration, and then in contradistinction, understanding that some people didn't want to pitch in to help-- it was very frustrating and honestly just made me very sad for people who I know were really struggling with this. DAVE JOHNSON: Actually, I had one more question to ask you. You mentioned coming back-- did you, in fact, share your diagnosis with your patients? I mean, I-- when I had cancer and came back, I made a pact with myself that I wasn't going to do that. But then I learned that the nurses were telling patients that I had cancer, and I found that it actually was helpful to share that diagnosis with many of my patients so that they could ask questions and feel that they had someone who really had experienced what they were either going through or about to go through. So I'm wondering how you've shared your diagnosis of COVID with patients, if at all. BRYAN SCHNEIDER: No, that's a great question. And I may have followed a similar pattern. At first I didn't. I didn't know what to do, to be frank. I didn't know if my saying that would make that patient, in that moment, more stressed out or worried, and I certainly didn't want to add to that. So I took it upon myself to try to make myself as safe to them as possible. But now that I've had a little chance to reflect on it, I have shared it. And I think for some of my patients, it's been good for them to hear what that experience was like. I think it's also-- Dave, as you probably know, I think it also reminds them we're human, too, and we experience some difficulty with physical health and I think in some ways it allows us to bond in a little bit deeper way. DAVE JOHNSON: I agree. PAT LOEHRER: I want to turn the attention over to Adrian now. Adrian, you're in a unique position, obviously one because of your experience in Kenya, and we want to hear about that, but also your responsibility for Indiana University. What some of the listeners may recall is that there was a decision made that you were part of that actually mandated that students in Indiana University be required to have vaccination before they came to school. We were in Kenya at the time when we heard that there was some consideration about that from the state legislature in terms of how-- mandating that. And eventually, this was a case that in which eight students took this case to cohort that eventually reached to Amy Coney Barrett, who decided to find in favor of Indiana University. It was a landmark decision here. But tell us a little bit about your experience on the leadership role of COVID and the impact that you see in terms of yourself personally and from the field of the university. ADRIAN GARDNER: Yeah. Thanks, Pat. I think it's really two different worlds in my mind, in some ways, although clearly linked by this global pandemic. You know, I was just finishing my eight-year stint, essentially, in Kenya in March of 2020 when we got the news that the entire world was about to be declared a level 4 by the State Department. And well, that-- I remember actually talking to Joe Scodro on the phone. And he's like, what the heck does that mean? That's not in our playbook of what we do when things happen and we need to bring trainees home and sort of-- PAT LOEHRER: Scodro being the lead counsel for Indiana University here. ADRIAN GARDNER: Thank you. Yeah, yeah. So for me-- I mean, obviously I was making a transition back to a US-based career in this position as the Director for the Center for Global Health. But you know, I had a dramatic change in my position, right? I mean, who is going to do global health operations in the middle of a pandemic? Well, nobody, because nobody was traveling. So we had really shifted all of our Kenya operations to a virtual support. We pulled all our trainees and long-term faculty back, initially. And my own position here is-- got pulled into a leadership role in Indiana University's response to the pandemic, along with three other physician leaders. And we all took on a different component of the response. So I was involved in the contact tracing, in part because we had some experience with contact tracing and global settings and tuberculosis and HIV. And while the transmission dynamics are obviously quite dramatically different and has different implications, but some of the principles around contact tracing were similar in the sense that contact tracing is not about really a stick, but it's more about extending a carrot and extending the support that allows you then to create an enabling environment-- and a quick phone call, in this case-- to allow people to identify what it is to quarantine and isolate effectively. To get to the Supreme Court issues and around mandates-- I think it was fairly obvious-- we were part of a restart committee that had been put together by the Dean of the School of Medicine, Jay Hess, and it was fairly noncontroversial among that group that we were going to need vaccine as we marched through this. And we immediately set up a lot of testing infrastructure and what we called mitigation testing at that point of asymptomatic individuals in addition to creating systems that enabled people to-- with symptoms, to enable testing very quickly and to get results back and to get that whole infrastructure in place. But it was pretty obvious to us-- it was a group of medical, public health, and ethics and legal folks-- that we were going to need a high level of immunity to get back to anything normal, right? And as we began planning for the summer and the fall of 2021, it was like-- it's a no-brainer. I mean, the only way you're going to get high levels of immunity, if you want to bring people back into the same classroom, if you want to have people living in dormitories, if you want to have them engage in the normal activities that college kids want to engage in, then you've got to have a very high level of immunity. And the only way to really achieve that is going to be through vaccine mandates. And again, it wasn't-- it didn't feel unprecedented, because you have to get a whole bunch of vaccines when you go off to college or when you go to elementary school. And that's really the only way to achieve that high level of coverage that allows us to not have a bunch of measles in our environment. And we still have mumps, despite high levels of coverage. But yeah, it felt weirdly noncontroversial. But of course, the whole politicization, I think, of the whole response to the pandemic made this more controversial. And clearly, there are people that feel very strongly about it. But I think this-- framing it in a context of personal freedom versus public good has not been particularly healthy for us as a country. I guess I'm not terribly surprised that the Supreme Court ultimately ruled against the preliminary injunction. I think the formal case is still pending, but it's maybe been overtaken by events, because now there are government mandates that are requiring vaccine or regular testing of just about-- lots of different industries and government employees and things. So I think it was important that we took a stand on this. And I think it has set a precedent, I think, for other universities. There were initially some hospital systems doing the same. But I think it's made it a lot easier to keep moving through industries and health systems with this kind of decision. PAT LOEHRER: Parenthetically, there's-- this week, they announced the-- we've reached over a million cases of COVID in Indiana. But the lowest county for infectious rate is actually Monroe County, which is where Bloomington is, where Indiana University is. And it's less than half of the rate of the state. And so I think kudos to you and the staff that have done this. Just maybe briefly, could you reflect on your experiences in Kenya, here in the United States-- lessons learned by you or by the university or by public officials about the contrast? I am reflecting now about a patient I saw today, that-- we were talking about the booster vaccine. And unfortunately, in Kenya, most people haven't gotten their first vaccine, either. So reflect a little bit about the global impact as you've seen personally. ADRIAN GARDNER: Yeah. So again, I think it's felt like two different worlds, but obviously struggling with the same thing, right? So I think on a global perspective-- so Kenya has-- Kenya got off to a pretty good start because they were kind of late to the game when it came to COVID, and they were able to jump on and learn from some of the lessons about physical distancing and shutting things down that actually enabled them to escape in the beginning. Of course, there was probably transmission going on behind the scenes that we weren't detecting, and even till now, the numbers that are officially reported are really just the tip of the iceberg. I think know that. Kenya has only reported 250,000 cases and just over 5,000 fatalities nationwide since the beginning of the pandemic. But there are serology studies that suggest that 50%, 60% of the population may have actually been infected-- at least, right? And that's based on blood donor studies and things. So I mean, I think some of the initial challenges, obviously, around access to PPE-- as we think about health care settings there, which are-- our partnership is based in, as you know. It's just the lack of infection control and the ability to even think about infection control because you're lacking space. As you know, Pat, in many of these wards in low-resource settings, there are two patients in every bed. And one might have active pulmonary TB and one might be getting chemotherapy for breast cancer. And it's less than ideal. But as you think about how to respond to that, it's pretty hard when you don't have any space, right? I mean, we did a lot here in terms of retooling space and utilizing space that was not being used and putting in negative pressure rooms where they were needed and this kind of thing that just weren't options in Kenya. One good news was that I think in Kenya, in particular, the testing capacity was able to get an early jump because the HIV infrastructure, PEPFAR, the President's Emergency Plan for AIDS Relief, had established seven regional laboratories that were obviously running HIV viral loads and so had PCR platforms. And they were able to rapidly retool those and convert them into COVID testing laboratories for PCR. So that was good, but then never really got to the same point where we need to get to, which is that it's readily accessible to everyone in rural regions and rapid testing in order to inform triage protocols [INAUDIBLE] patients and try to figure out how to develop that. So there's been testing available, but just not in the quantities that were sufficient. You know, I think we've been able to work across virtual platforms to share knowledge about management and clinical protocol development. That's been another success story. Certainly our partnership is longstanding and so has allowed those relationships that have withstood the test of nonpersonal interaction. And of course, the biggest elephant in the room now is this issue of vaccine equity, as you pointed out. So about 5% of the population in Kenya has been vaccinated. Part of that is vaccine access. Part of it is probability distribution infrastructure. Think about low resource settings-- many of them do quite well with vaccine delivery, but they're early childhood vaccines, right? So they have whole infrastructure around maternal child health that's set up to do this. There's not a lot of infrastructure for rapidly mobilizing 50 million adults to try and get them in for a two-shot series. So how do you do that? I mean, yes there are some community assets in terms of community health workers and things, but so far, at least, the vaccine quantities available have not been sufficient to allow that kind of infrastructure to really take over, at least in Kenya. But it holds promise, I think. But then they also are up against the same, I think-- some of the same challenges that we face here in terms of vaccine misinformation and lack of trust. This is an area where I think trust is really key ingredient in health systems, and I think we've seen it in our own inequalities that have been made very, very obvious in our own country and really, the issue globally. And it's not a new lesson. We knew it from Ebola and other very obvious infectious diseases that have resulted in high degrees of death because of lack of trust. When I have taken care of patients here and I've had those same experiences that Dave was talking about earlier, where you want to just ask the patient, so why didn't you get vaccinated? As an infectious disease provider, we've been called in to a lot of these cases, and I've taken the opportunity to ask a couple of times-- not in a judgmental way, but trying to set the stage and just-- what is it about the system? And a lot of-- some of it is misinformation. Some of it is this politicization and political bias. But some of it is just a very subtle mistrust and this notion that you don't feel completely welcomed or resected within the health care setting. And that's enough to just turn it off to this point where, eh, I'm just not ready to do that. And I think that's sometimes more subtle than we appreciate, but it has a huge impact. DAVE JOHNSON: We're getting close to the end of our time. I want to pivot back, if I may, just for a quick moment to Bryan. This may be an out of-- from left field type of question, but we learned a lot about early chemotherapy from the infectious disease world. We took some of the infectious disease principles and applied them in the early years of chemotherapy. Do you think there's much to be learned from a precision medicine standpoint from the COVID pandemic? What are you taking away from not just your personal experience but the larger experience, if anything? Or is that just-- is it just too early to say? BRYAN SCHNEIDER: No, I mean-- I think I've always admired the speed and efficiency with which breakthroughs have happened in infectious disease. And I mean, the idea of a brand new virus coming on board a couple of years ago and coming to the point where we are today shows, I think, real innovation, but the ability to get behind a question and, as a community, answer it well. And I think from that standpoint, that's something that all disciplines, including oncology, can learn. I certainly think we're seeing more and more intersection, too, with the way we think about treating cancer and its impact on immunity. And so certainly in that way I think there's real connections. But I do think some of the innovations that were brought about from the NCI with the vaccines are going to really also herald in things that will be game-changers in the world of oncology and therapeutics as well. DAVE JOHNSON: That's great. PAT LOEHRER: If I can throw in something, too-- I think, Dave, particularly as we talk about global health, many of the cancers that we see in the low-to-middle income countries are caused by viruses. One of the number one causes of cancer in sub-Saharan Africa is cervical cancer. We could eradicate that by getting vaccines out there. In terms of the lessons learned, I think the lessons learned in oncology is that we need to deal more with population health and with prevention than we do with the treatment towards the end of the life. And hopefully that will be a lesson that we can take home with us around the world. ADRIAN GARDNER: Yeah, and Pat, I think we do need to do better as a global community in terms of sharing vaccine and getting manufacturing up, and not just for vaccines but PPE and therapeutics. It's just not fair, the world we live in now. And at least we all know that and we take it for granted in some ways. But it shouldn't be this unfair, right? And that's been part of the problem globally, and it's part of the problem in the United States. DAVE JOHNSON: Yeah. PAT LOEHRER: But the tail end also is access to drugs for chemotherapy, too, and to have radiation available for all these patients. So it is-- this access is an important part of health equity globally. And I think it behooves all of us to be involved with this mission. DAVE JOHNSON: Well, again, we've come to the end of our time. And we want to thank all of our listeners, but most of all, we really want to thank Bryan and Adrian for a wonderful interview. We really appreciate your time and you sharing your experiences with us. Thanks again to the listeners for tuning in to Oncology Etc. This is an ASCO educational podcast. We want to talk really about anything and everything, so if you have an idea for a topic or a guest, we invite you to share that with us and email us at education@ASCO.org. So thanks again. And remember, Pat, I before E except after C. PAT LOEHRER: [LAUGHS] Well, I'll see you later, then. DAVE JOHNSON: No, wait a minute. Wait a minute. Eight, leisure, sovereign, weight, weird, foreign, vein, neighbor-- apparently it doesn't work. [LAUGHTER] My second-grade teacher taught me that rule, and it's just wrong. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In the second part of this Oncology, Etc. episode Drs. Patrick Loehrer (Indiana University) and David Johnson (University of Texas) continue their conversation with Dr. Susan Desmond-Hellmann, exploring the prominent leadership roles she held, from first female Chancellor at UCSF to CEO of the Bill and Melinda Gates Foundation and member of Facebook's Board of Directors. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 11/18/21 TRANSCRIPT SPEAKER 1: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. PAT LOEHRER: Hi, Everybody. I'm Pat Loehrer. I'm director of the Centers of Global Health at Indiana University, Melvin and Bren Simon Comprehensive Cancer Center. DAVE JOHNSON: And I'm Dave Johnson. I'm Professor of Medicine here at UT Southwestern Medical School in Dallas, Texas. So Pat, we're back for another episode of the award winning "Oncology Et Cetera." PAT LOEHRER: Just seems like last month we were here time, you know? Time just flies. DAVE JOHNSON: Exactly. Before we get started, you were telling me about an interesting book you were reading-- something about friends or something. Can you elaborate? PAT LOEHRER: Sure, sure, yeah. This book I picked up-- actually, my wife picked it up. It's called First Friends. It's written by Gary Ginsburg. It's a really interesting book. It was-- basically talks about-- it probably has about eight or nine presidents but the importance of having a friend that guides him. And these were people that were, in many ways, unelected people that were close to the presidents that helped change the face of what we see today, and some of them are stories of really good friends and some of them are, I think, opportunistic friends. But it gives you a background of people like Madison and Lincoln and Roosevelt and Woodrow Wilson. It's actually a fun read. DAVE JOHNSON: I'll definitely put it on my reading list. It sounds like a pretty exciting one. Well, speaking of influential people, we're really excited to jump back into our interview with Dr. Helman. In our last episode, we covered her early life and career, her work in Uganda, her views on global oncology, and her experiences in private practice and industry. In the next half of our interview, we'll learn more about her incredible career and her multiple leadership roles. Let's start by hearing about her time as chancellor of UCSF. PAT LOEHRER: Let me transition a little bit. What I'd like to do is talk a little bit about your leadership. One Of the next big roles you had, you became chancellor at UCSF, correct? SPEAKER 2: Mm-hm. PAT LOEHRER: And so as Dave said, I think you were the first woman in that role. SPEAKER 2: I was. PAT LOEHRER: You were a groundbreaker from that capacity. So now instead of working for people-- obviously, I understand that there's people you work for when you're chancellor too, but tell a little bit about that transition from industry back into academics and how that felt in the role of being a leader and then maybe the responsibility of being the first female chancellor. SPEAKER 2: There were parts of being the chancellor at UCSF, I would say most parts of it, that I just thought were fantastic. I loved being back at a hospital and clinics. Just the way the hospital and clinical enterprise at UCSF works, the chancellor is the board. And so once a month, you'd have neurology or cardiology come and tell you about what had happened, quality control, things that had gone on and I would have done that all day long. I mean, it was just so interesting. It was so important to run a great clinical enterprise that getting back closer to patients and medicine I thought was fantastic. The other thing was the educational enterprise, and UCSF, as you know, has medicine, pharmacy, dentistry, nursing. I always tell people, no undergraduates, no English majors, no marching band. And the other chancellors reminded me, no athletic director, which apparently is a very good thing. So UCSF is a very special and unusual place. And I loved the science. I would show up at research seminars and things like that as often as I could. So there were so many parts of being at UCSF that I thought were just off the charts great. The hardest thing about being at UCSF-- being the first female chancellor, I think, was challenging but not in ways that you might expect. I was used to being a woman leader in medicine and biotech, which was unusual. So being the only woman in the room, being the first, wasn't new to me. But the thing that was hard on our family was there are roles for the spouse of the chancellor that fit more neatly into more of a classic female role, hosting things. There was a tea party for the wives of the faculty that the wife of the chancellor typically had. And for some reason, Nick didn't think that that suited him. We sort of laughed about that. DAVE JOHNSON: He can't make tea? SPEAKER 2: He can't make tea to save his life. And he's a strong introvert, which made it worse. I will tell you, some of the under-recognized, underreported people in life are spouses of chancellors and presidents of universities. And talk about unpaid labor-- my goodness! And so we sort of struggled with how did Nick show up, what did that look like. Because we didn't have any role models for what that looked like. I still laugh that Bill Clinton said he would be First Laddie. So when you have a pattern recognition, life is easier. And then being one of 10 chancellors at the UC system, I struggled a little bit with the UC Regents just because it felt-- I became chancellor in 2009, and we had some fiscal realities that we were dealing with. And the pace of the UC Regents and the format of the UC Regents, I actually made a proposal for UCSF to kind of break off from the other 9. And that was not well-received, got me in the newspaper. And I did not do that again. People saw it as disloyal and not very smart. But all in all, I thought then and think now that our public universities are absolutely-- they're treasures in America. And I was really proud to be a part of it and hope that I had made a contribution. DAVE JOHNSON: Speaking of leadership, what was it like to be CEO of the Bill and Melinda Gates Foundation? What caused you to step away from chancellor to philanthropy? PAT LOEHRER: It's not a step down. It's not a step down, basically. DAVE JOHNSON: It is not a step down. SPEAKER 2: So I would say a couple of things. First of all, Bill and Melinda pushed me hard to take the job. I was not looking to change. My husband worked at the Gates Foundation for a couple of years on HIV. So they knew us, and they knew Nick better than me. But they knew both of us. We awarded Melinda the University medal at UCSF. And to my great surprise and happiness, she accepted and came. I later think that she was using that as a reason to talk to me about the CEO job, but she got a twofer. And I was really compelled by the mission. Who wouldn't be? I was really compelled by the mission and the chance to get back into global health after the experience I had had in Uganda. But I'll tell you, it is the ambition of the Gate Foundation, the scope of the Gates Foundation, the resources, and the need to get something done. I tell you, it is hard work. It is really hard work-- from China to India to all of the continent of Africa and then US education. Throw that in on top of things. So I was thrilled to be a part of driving the agenda and the mission. Some really talented people who are working very hard at the Gates Foundation-- I was surprised, especially on US education, with the amount of pushback. And I worked really hard to be successful at working with Bill, who's known as a tough character and lived up to that mutation. DAVE JOHNSON: Good to know, just in case he calls Pat or me. PAT LOEHRER: Yeah, yeah, I'm not going to get a medal at UCSF either. So that's a-- DAVE JOHNSON: You never know, Pat. PAT LOEHRER: It's a non-starter. And this may not apply to you, but there's a lot of maybe disproportionate number of women who feel they suffer from this imposter syndrome. To be honest, Dave and I have talked about that. We both feel in that syndrome too. But along the way, I mean, if you think about growing up in Reno, Nevada, and suddenly now being a chancellor and head of the Gates Foundation, the National Academy of Science, was there ever this sense of the, wait a minute, you know, what's going on? Is this real? SPEAKER 2: For me, there has always been that sense. There has always been that sense, and I look at it as I hope there always will be that sense-- that the kind of need to demonstrate your value. And there's a part of the imposter syndrome that is humility and not overestimating what you can do. And so on my best days, I think that leads me to say I've got to work with really terrific people. My job is to bring out the best in others. If I lead, it's because there's a great thing we're going to accomplish, and I can help people see where we're going together. And so I definitely have had imposter syndrome. But the one thing that I probably overused and kind of grew to like too much was the thing of people underestimating me and then proving them wrong. That gets a little wearying after a while. It's like, OK, we're going to waste some time while you decide whether I'm worthy or whether I can do this. And let's not waste that time. Why don't you assign to me-- give me some confidence, and I'll live up to that. And I mentioned Art Levinson was my boss for most of the time I was at Genentech. And he had no time for imposter syndrome. He was like, look, how many promotions do you have to get before you think, OK, I can get this done? He thought that was sort of-- he just didn't have time for it. We have things to do, and he had jobs to get done. And one of the things I loved about him is he would constantly push me to say, you're capable of more than you think you are, which I think is the sign of a fantastic manager, which he was and is. And so I've tried to push myself to do that. And the thing is, like, you can do this. Come to me for help. We'll make sure you succeed, but don't underestimate yourself. And I think that's a consequence of imposter syndrome is both wasting time proving yourself and not taking on something that you think, actually, let me give that a try and stack the deck in favor of succeeding. And so I think that's the thing that-- there's a certain fierceness that I've always had that I like about myself that, like, of course we will succeed. Failure is not an option. Of course we will succeed. And I think that comes from working on things that I value a lot and care about a lot. PAT LOEHRER: You have been on a number of different boards, including Pfizer as well as Facebook. And in that capacity, you've seen a lot of leaders. Can you talk a little bit about the strengths and the weakness of various leaders as well as serving on the boards and the capacities of the different companies? SPEAKER 2: Yeah, well, first, let me say I know ASCO is actually a really good about being careful about conflicts of interest and things like that, and I am too. So when I became chancellor at UCSF and then CEO at the Gates Foundation, I avoided being on life sciences boards. And so I got asked a lot by Biotech and pharma boards to be on their boards. Initially, I joined Procter Gamble's board, where I served for, I think, about six years. And then I joined Facebook's board. And those were both fantastic experiences. And I actually joined the boards for two very different reasons. One, P&G's board, I wanted to learn about branding and consumers. And I felt like in medicine, I didn't really learn about consumers or branding as much as I needed to or might. And then Facebook's board I joined because as Dave mentioned, I was with Charles Sawyers. We wrote the precision medicine report for the National Academy. And I really love-- to this day, I love the concept of using the social network to connect people. There was sort of an infamous story or famous story-- it's actually a good story-- of patients with a certain form of myeloma who found each other on Facebook and went to Genentech and said, make a new medicine for those of us with this genetic abnormality. And we'll all enroll in a trial. And so these connections to me felt really powerful on precision medicine. And so getting to work with CEOs at Procter and Gamble, the CEO Mark Zuckerberg at Facebook, I do see the really different attributes of leaders. But when you're a board member, you see those attributes of leaders with a very different lens. What's the return to shareholders? How does the community think about them? What's the impact-- and increasingly for Facebook, what's the impact on the world? What's the impact on our social discourse and our ability to have a free and fair election? A lot of those things became much more operative on the Facebook board while I was on the board and really tough social issues that continue to this day. DAVE JOHNSON: Yeah, so we could go on for another hour, hour and a half, but I have one question to ask you which may seem a little bit silly in retrospect. But if you could look back on your youthful self at 21 or 22 knowing what you know now, with all the things that you've done during the course of your career, what advice would you give yourself? And perhaps I'll addend that by saying what advice would you give particularly to young women in the medical profession who are trying to balance that work-life balance that everyone talks about and worries about and struggles with, quite frankly. SPEAKER 2: I'll give you one thing I should have done better and one thing that I think I did well. So the advice on the one thing I should have done better, I think slow down a little bit and take a bit more time for fun and enjoyment. I was extremely worried about money when I was in college, and being number two of seven-- every summer, I worked. I remember at one point in medical school, I had three weeks off, and I got a job for those three weeks at a deli making sandwiches. And I went to college for three years, crammed it into three years so I wouldn't have to pay for the fourth year. So I just think that I could have taken on more loans. I could have done some things to just dial it down a bit because you don't get those years back. And that's such a great time of your life when you're 21, 22, something like that. So I wish I'd have just slowed down a bit and not been so driven for those seven years of university and medical school that I really just either worked or studied all the time. The thing that I feel like I did well, and I would say this to anybody who's going into medicine, is there's so many opportunities. There's so many wonderful things to do. But whoever your spouse is, whoever your partner in life is, take the time and energy to make sure that's the right person for you. I feel so blessed. Actually, my husband, who I've mentioned several times in this discussion, Nick, was my roommate in San Francisco when I was an intern, like real roommate. And we've been roommates ever since. And we're very compatible. He's one of seven kids too. It's another Catholic school kid. And we just have fun together and support each other. And there's no way I could have taken these crazy jobs or done the kinds of things I've done without Nick. So having a wonderful, supportive partner makes everything better. DAVE JOHNSON: That definitely resonates with Pat and me. We're both very blessed to have wives and spouses of, for me, it's 52 years. I can't remember, Pat. Yours is close. PAT LOEHRER: I had my first date with my wife 50 years ago, yeah. DAVE JOHNSON: Yeah. SPEAKER 2: OK, so you guys know what I'm talking about. PAT LOEHRER: Absolutely. DAVE JOHNSON: Yeah. PAT LOEHRER: Yeah. DAVE JOHNSON: Go ahead, Pat. PAT LOEHRER: I was going to ask a question that you probably may have already answered there, but Bob Woodward just came out of an interview with Colin Powell. One of the last questions he asked him was if he could reflect on that one person that was a moral compass for him. And so for you, that one person, alive or dead, that has been not the most powerful person you've met but the one that's really influenced you the most in terms of giving you direction, who would that be for you? SPEAKER 2: Probably, if I look at through line the entire time I've been alive, it would be my dad. He had the ability to look at a room and find the person who was struggling and go over to them. And I really loved that about my dad. PAT LOEHRER: I love it. DAVE JOHNSON: One last question. So we're at the top of the hour, and I know you're a very busy person. Pat and I love to read, but we're also documentary fiends and whatnot. We're interested. What have you read recently that really resonated with you? Do you have a recommendation for us? SPEAKER 2: I will say during the pandemic, I've gotten back into reading biographies, which I love. DAVE JOHNSON: Yeah. SPEAKER 2: So I did the Caro, Lyndon Baines Johnson, which, Master of the Senate is really good. But my favorite book of the last two years is The Code Breaker, Walter Isaacson's book about Jennifer Doudna. DAVE JOHNSON: Yeah. SPEAKER 2: One of the things I love about Walter Isaacson is he teaches you science through his biographies. Like, I think I understand relativity based on his Einstein biography, which is great. But The Code Breaker is really super good. DAVE JOHNSON: Yeah, we both read it. We couldn't agree with you more. PAT LOEHRER: Love it. Love it. DAVE JOHNSON: So Sue, again, it's been a real honor to have you as our guest, and we really appreciate the time you've taken. Thank you so much, and we hope you enjoy the beautiful weather in Alamo California, and I hope it does turn green and the rain continues for you. SPEAKER 2: Thank you so much. It's been my pleasure. Thank you both. DAVE JOHNSON: Take care. SPEAKER 2: Bye. DAVE JOHNSON: I want to take the moment to thank our listeners for tuning in to "Oncology Et Cetera," an ASCO educational podcast where Pat and I really will talk about anything and everything. So if you have an idea or a topic you'd like to share with us and like for us to pursue, please email us at education@asco.org. Thanks again, and keep in mind that Pat is a giant in oncology, but he's a short instructor. Thanks, everybody. SPEAKER 1: Thank you for listening to this week's-- to make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In the second part of this ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of new therapies for mantle cell lymphoma and follicular lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 11/15/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to part 2 of ASCO Education Podcast on New Therapies for Lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical trials for lymphoma. I am also the Elwood V. Jensen professor and chief of the Hematology and Oncology section at the University of Chicago. PAOLO STRATI: Hello to everybody. I'm Dr. Paolo Strati. I'm a hematologist, and medical oncologist, and assistant professor in the Department of Lymphoma and Myeloma and in the Department of Translational and Molecular Pathology at the University of Texas MD Anderson Cancer Center in Houston, Texas. In part one of this podcast episode, we discuss recently approved therapies for diffuse large B-cell lymphoma. And today, we will be exploring instead new therapies for follicular lymphoma and new therapies for mantle cell lymphoma. SONALI SMITH: Wonderful. So we are going to start off today with a discussion about a patient case. The individual is a 55-year-old woman with previously untreated follicular lymphoma, low-grade advanced stage, and low tumor burden, and low FLIPI. She was diagnosed three years ago and had observation but more recently developed a 7-centimeter retroperitoneal mass with impending ureteral compression and no PET/C concern for transformation, specifically with an SUVmax of 5.3. Despite this radiological finding, the patient had a performance status of 0, no symptoms, no significant comorbid health conditions, and was given R-CHOP time six cycles, followed by achievement of a CR. She was then observed, but, unfortunately, 18 months later, the PET/C showed diffuse low FDG-uptake adenopathy, and a lymph-node biopsy was repeated. This showed a follicular-lymphoma relapse. So Dr. Strati, tell us a little bit about your approach to follicular lymphoma in the initial setting. Do you consider GELF criteria? And how do you select second-line therapy in this patient? Does the early progression of disease within 18 months-- she falls into the category of POD24, or the Progression Of Disease 24 months-- how does this affect your treatment choice going forward? PAOLO STRATI: Thank you, Dr. Smith. Those are all very good questions. So going to your first question-- we typically use GELF criteria, as you know, developed in France now many years ago, most of the time of initial diagnosis. And that's to determine whether a follicular-lymphoma patient does, indeed, have an indication for treatment. And this criteria, as you know, are based on lymph node size and number, oragnomegaly, cytopenia. However, it's still debated whether this should also be applied at time of relapse. And in this particular case, the patient, as you said, had what we call a POD24, or progression of disease within 24 months from initiation of chemoimmunotherapy. Given the suboptimal outcome of these patients, I think that it will not be unreasonable to treat these patients even if they don't formally meet GELF criteria-- so even if they don't have formal indication for treatment at time of relapse. Once the decision is made, standard second-line options for patients with follicular lymphoma currently include chemoimmunotherapy So if the patient received R-CHOP in frontline, it would be BR. But if they receive BR in frontline, of course, R-CHOP, but also, immunotherapy with R-squared-- so Rituximab, Revlimid-- or lenalidomide, a single-agent anti-CD20 monoclonal antibody, obinutuzumab, which is specifically approved by the FDA in the United States for rituximab-refractory follicular-lymphoma patients, and in very selected cases-- and this is still open for debate-- a high-dose chemo with a platinum-based agent followed by autologous stem-cell transplant. We don't know at this time what's the ideal second-line strategy for patients like the one that you described in your case-- so a follicular-lymphoma patient with POD24. And to this regard, all are very eagerly awaiting the results of an ongoing SWOG trial, 1608, which is a randomized phase II study comparing in second-line chemoimmunotherapy, immunotherapy, and also, [INAUDIBLE] kinase inhibitor for this patient with POD24. Finally, one thing which I think is important to consider is that even if R-squared is not currently approved by the FDA in the frontline setting in the United States and, actually, is not approved at all in Canada, in Europe as a frontline treatment, in the United States, it's possible to use it in frontline thanks to existing guidelines. And over the last few years, its frontline use in our country has actually meaningfully increased. This is creating a new clinical scenario that we never met before. And there are no standard second-line options currently established for these patients, patients who receive frontline R-squared, emphasizing the need of translational research to understand more of the biology of patients who relapse after frontline R-squared but also, emphasizing the need to mostly look into clinical trials when these patients, unfortunately, experience a relapse. SONALI SMITH: Yes, thank you, Dr. Strati. I agree. I think that it is the way that frontline follicular lymphoma and in the relapsed setting exists is that we have a toolbox and no real clear data on how to personalize the therapy. So your comment about needing some better translational work to fine-tune the clinical trials is really important. So for this patient, though, she did receive R-squared for 12 cycles and achieved a complete remission after six cycles. 12 months later, a PET/CT showed diffuse, low-level adenopathy, "low level" meaning low uptake on a PET scan. And she had another lymph-node biopsy. This showed persistent follicular lymphoma. So now how do you select your third-line option knowing that we have biologic therapy, as well as cellular therapy, available to this patient? PAOLO STRATI: So going back to the metaphor that I used before, we have a very nice toolbox, often third-line. But also, in third-line, there's really no strong, robust translational data to drive us when it comes to treatment selection. Agents currently approved by the FDA in the United States as a third-line standard option for patients with relapsed/refractory follicular lymphoma include, as you alluded, [INAUDIBLE] kinase inhibitors, currently three-- copanlisib, duvelisib, and idelalisib, and an EZH2 inhibitor called tazemetostat. The three [INAUDIBLE] kinase inhibitors currently approved in third line have very similar efficacy with a response rate of 50% and a median progression-free survival of about 10 months. And the selection among the three is typically based on toxicity profile, which is more on the autoimmune side for duvelisib and idelalisib and more on the metabolic side with hyperglycemia and hypertension for copanlisib. Also, one element that, in my experience, is typically used to select one of these three is the route and the frequency of administration because we have to remember that idelalisib and duvelisib are both given orally twice a day, whereas copanlisib is given intravenously three times a month. And so, of course, different patients may have different preferences. As a matter of fact, though, the use of [INAUDIBLE] kinase inhibitors for relapsed follicular lymphoma in the United States and I would say, also, in other countries, is quite limited, mostly due to toxicity and relatively limited efficacy. Tazemetostat, the EZH2 H2 inhibitor that I mentioned previously, has a response rate that can vary between 30% and up to 70%, significantly higher in patients who do have a documented EZH2 mutation. But the median progression-free survival is about a year, no matter whether the mutation is present-- so not that different from [INAUDIBLE] kinase inhibitors in the same setting. Of interest, given the short duration of response, we may consider these agents as a bridging therapy for follicular-lymphoma patients. We [INAUDIBLE] proceed with CAR T-cell therapy because, as you mentioned in your question, CAR T-cell therapy, and specifically, Axi-cel, has been recently approved by the FDA as a third-line option for patients with relapsed/refractory follicular lymphoma based on results from the ZUMA-5 study. It's important, however, to emphasize that Axi-cel has shown better efficacy and safety data in follicular-lymphoma patients as compared to large B-cell lymphoma patients than we discussed in the previous episode of this podcast. And, as such, Axi-cel may potentially represent a curative option for patients with follicular lymphoma, a condition that, historically, has been considered incurable. Tisa-cel and other CAR T-cell products targeting CD19 currently approved by the FDA for large B-cell lymphoma but not yet for follicular lymphoma, may also be soon approved by the FDA for patients with follicular lymphoma based on the ELARA study. And we're all eagerly awaiting the results of this study and, potentially, its approval in the next few months. SONALI SMITH: That's great to hear. And, hopefully, we will continue to have more options, including more cellular-therapy options for patients. So this particular patient proceeded with the standard of care Axi-cel. That went quite well. There was only grade 1 cytokine release syndrome, no neurotoxicity. And the patient achieved a complete remission on both the day-30 and the day-90 PET/CT. Unfortunately, there was relapsed six months later. So what standard options are there at this time? And would you consider an allogeneic stem-cell transplant at this point? PAOLO STRATI: So I have to say that, based on some of my data, I'm not surprised this patient did quite well in terms of safety, and I'm very sorry to hear that was one of those few patients who relapsed after an initial complete remission after Axi-cel. In fourth line, our options are a little bit more limited. The FDA has recently approved in fourth line, for patients with relapsed/refractory follicular lymphoma, a new [INAUDIBLE] kinase inhibitor called umbralisib. [INAUDIBLE] umbralisib response rate is quite similar to other [INAUDIBLE] kinase inhibitors, about 50%. However, the median progression-free survival that, as I mentioned before, is about 10 months for the [INAUDIBLE] kinase inhibitors currently improving third line instead has not be reached yet two years for umbralisib. And also, the toxicity profile seems to be more limited, similarly to idelalisib and duvelisib, more on the autoimmune side. Therefore, definitely umbralisib would be an interesting option for the patient case that you described. As for your second question, the possibility to use allogeneic stem-cell transplant for patients with relapsed/refractory follicular lymphoma, retrospective studies have shown the allogeneic transplant is effective in follicular-lymphoma patients, particularly those with POD24, like the patient you described in the scenario. But the transfer-related mortality is significant and needs to be taken into consideration. But most important of all, as CAR T-cell therapy has been approved for follicular lymphoma very recently, we really have no data regarding the use of allogeneic stem-cell transplant in follicular-lymphoma patients who relapse or progress after Axi-cel and CAR T-cell therapy in general. This last statement really applies to any approach as, again, Axi-cel has been approved for follicular lymphoma only within the last 12 months. And this, once again, emphasizes the importance of translational research and clinical trials for these patients. And as such, I think that, along with umbralisib, there is a standard option. Clinical trial's definitely the best option for patients with follicular lymphoma whose disease is either refractory or relapses after CAR T-cell therapy. SONALI SMITH: Yes. Thank you for these insights, Dr. Strati. I agree. The post cellular therapy, or the post CAR-T space is a very challenging situation, and I appreciate your perspectives. So as an update, this patient received umbralisib for six months and had an initial response with a partial remission but eventually progressed and then proceeded to a clinical trial, now on a novel oral-immunomodulatory agent and has been in a complete remission for four months. PAOLO STRATI: That's great to hear. And I hope that this remission will be durable, emphasizing, again, the importance of clinical trials for patients with lymphoma in general, and particularly, those who relapse or are refractory to standard treatments. It was very interesting to listen to this case. Thank you for asking your question, Dr. Smith. I'm going to ask your opinion now about a second case. This is a 67-year-old man with diabetes that has a long-lasting history of rectal bleeding, for which he underwent a colonoscopy in 2016 that revealed hemorrhoids and scattered polyps that were not malignant on biopsy. However, as part of routine follow-up, a colonoscopy was repeated five years later, and this, unfortunately, showed diffuse nodularity of the colon with several areas of ulceration. Biopsy of the nodules showed a mature B-cell lymphoma, CD20 positive, CD5 positive, BCL2 positive, SOX11 positive, but negative for CD10. FISH testing confirmed a translocation 11;14. There was no evidence of TP53 mutation, and Ki-67 was 40%. So Dr. Smith, what do you think about the overall potential histological diagnosis? And how do you approach this patient in terms of staging and prognosis discussion? SONALI SMITH: Yes, so this poor patient, with long-standing rectal bleeding-- I mean, this can happen. It's not a very common presentation for mantle cell lymphoma, but we know that mantle cell lymphoma is very likely to involve the GI tract and can often be extranodal. In terms of the histology itself, this is very classic. The co-expression of CD20 along with CD5 is only seen in CLL and mantle cell lymphoma. And in this case, the mantle cell lymphoma's confirmed by SOX11 positivity, CD10 negativity, and then, also, of course, the FISH [INAUDIBLE] translocation of 11;14 with a cyclin-D1 overexpression. When it comes to prognosis in mantle cell lymphoma, there's a number of different prognostic indices, but the two biologic features that I think are most important are P53 status, as well as the proliferation rate. Patients who have a TP53 mutation typically have chemo-resistant disease. And we have no really good approach in terms of how to treat these patients the best. PAOLO STRATI: Thank you, Dr. Smith, for outlining the diagnostic and prognostic approach to patients with mantle cell lymphoma. You alluded in your answer about the regenerative treatments, so I wanted to ask you, how do you, in general, treat patients with mantle cell lymphoma and, more specifically, this case. And also, we keep dividing patients with mantle cell lymphoma in transplant-eligible and ineligible, but the big question is, do all patients who are transplant-eligible need transplant? And what's year overall approach to this major dilemma? SONALI SMITH: Yes. That's a really good question. The general approach to treatment for mantle cell lymphoma is based on the concept of fitness and age. So we end up dichotomozing patients into one of two groups. They are either young and fit, or they are older and unfit. And, of course, this is somewhat controversial because age itself is just a number, and there is significant variability based on function and other medical conditions. Complicating that further is that many clinical trials have used 65 as the arbitrary cutoff between young and old, whereas some transplant studies have actually gone all the way up to age 70. So if I focus on the fact that this is a 67-year-old man who has no real significant history and clearly has a disease that needs treatment, my general approach has been to follow the younger-and-fit approach. And as you mentioned, the historical approach to this has been to think of treatment in three phases. There is induction, there's consolidation with a high-dose chemotherapy and autologous stem-cell transplant, and then there is maintenance rituximab for three years, which has been shown to have a survival advantage. But your question-- I think there are many unanswered areas when it comes to approaching a patient who is going to be treated with an aggressive multimodality approach. So first, in terms of the induction itself, there is data that cytarabine-based regimens likely achieve a deeper minimal residual disease state than aklylator-based therapy. And so cytarabine-containing regimens have really become the standard of care against which other regimens are compared. That being said, there was at least a SWOG study that randomized patients between BR and hyper-CVAD and found that BR was a sufficient type of induction. And some of this controversy led to an ongoing Intergroup trial, which is EA4181, that takes patients with newly diagnosed mantle cell lymphoma, previously untreated, like our patient, and randomizes them to bendamustine, rituximab with or without cytarabine and with or without a BTK inhibitor, in this case, acalabrutinib. So outside of a clinical trial, I would use a h based induction regimen, but I have preferred to put most patients onto that. But your second question, which is, do all patients need high-dose chemotherapy and autologous stem-cell transplant, is really important. This is associated with a need for inpatient admission, high-dose chemotherapy with subsequent late toxicity. And remembering that mantle cell lymphoma remains an incurable disease, the question is whether or not all patients should get this. So to address this, there is the EA4151 trial, which is also being done through the United States Intergroup. And this is using a very unique minimal residual-disease assay to randomize patients to either transplant plus maintenance or maintenance alone. And so this is a next-generation sequencing test. And if patients have a negative MRD status at a very deep level, then patients will get randomized to one of those two arms, whereas if they have minimal residual disease that is detectable, then they will go ahead and get the standard of care. So for this patient, he opted to be on the clinical trial and was randomized to BR, plus cytarabine, plus acalabrutinib. But outside of a trial, I really would have considered intensive induction, including the Nordic regimen that includes high-dose cytarabine, followed by transplant and maintenance rituximab. Now some may argue with me that this person is 67 years old, and the Nordic regimen is quite intense. And I think this is where some of the art of medicine may come in. And, hopefully, we can have some type of assessment tools to better predict who can tolerate intensive induction. But I'm quite impressed by some of the transplant data that do lead to seven- and 10-year remissions in some cases. Of course, this new trial will tell us whether or not we're overtreating many of the patients, particularly based on their MRD status. PAOLO STRATI: Thank you, Dr. Smith. It was very helpful. I think you outlined really well how challenging it can be to treat patients with mantle cell lymphoma and how important it is to tailor treatment based on biological but also, patient-related data. This is all that we have for today. Thank you, Dr. Smith, for a very delightful conversation. It's been very helpful to review together today the treatment of patients with follicular lymphoma, and mantle-cell lymphoma, and safety and efficacy of novel therapies for these patients. Thanks, everybody. And, particularly, thank you to all the listeners who tune in to this episode of the ASCO Education Podcast. And thank you, Dr. Smith, for your time. SONALI SMITH: Thank you. It was such a pleasure to have this conversation today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

Part one of this two-part Oncology, Etc. episode features an inside look at the amazing career of Dr. Susan Desmond-Hellmann (spanning from early AIDS research in Kenya and drug development at Genentech, to serving as UCSF Chancellor and CEO of the Bill and Melinda Gates Foundation). Hosted by Drs. Patrick Loehrer (Indiana University) and David Johnson (University of Texas). Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 11/04/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. DAVE JOHNSON: I'm Dave Johnson. I'm a Professor of Medicine here at UT Southwestern Medical School in Dallas, Texas. PAT LOEHRER: I'm Pat Loehrer. I'm Director of the Centers of Global Health at Indiana University Melvin and Bren Simon Comprehensive Cancer Center. DAVE JOHNSON: We have a remarkable guest today, Dr. Susan Desmond-Hellmann. She's like the Wonder Woman of oncology who's done many amazing things during the course of her career. It would take us more than an hour or more just to read off her CV. But very briefly, Dr. Hellmann is a graduate of the University of Nevada, Reno where she got both her Bachelor and her medical degrees. She received her medical training at the University of California, San Francisco. And then after that, did something really interesting. She went to Uganda for a couple of years and worked at the Ugandan Cancer Institute where-- maybe we can delve into that a little bit later during the course of this discussion to find out what she did while she was there. After which, she also did a couple of years of private practice and then joined industry, first at Bristol Myers, where she was instrumental in the development of a very important drug for a lot of different diseases-- paclitaxel And then in the mid-90s, she joined this little biotech company called Genentech, first, I think, as a clinical scientist. But over the course of a few years, she rose to the level of president of product development and really was instrumental in developing many drugs, including trastuzumab and bevacizumab. In fact, I think it was Forbes magazine that named her as one of the world's seven most powerful innovators, which we have to ask her more about that later, about being a powerful innovator. After really a stellar career in the industry, she then went back into academics. She became the chancellor of the University of California, San Francisco, and I believe the first woman to hold that position, if I'm not mistaken. During her tenure, many remarkable things happened at UCSF, including growth of their campus in the Mission Bay. She was responsible, with a committee put together by the National Academy of Sciences, of producing the report entitled Toward Precision Medicine, Building the Knowledge Network for Biomedical Research and a New Taxonomy of Disease. In March of 2014, I believe it was, she took yet another position, this time in the world of philanthropy, where she became the chief executive officer of the Bill and Melinda Gates Foundation, a position she held until December of 2019. And that's certainly something we want to ask her about. Dr. Hellmann has many, many accolades. I can't list them all, but she's a member of the Biotech Hall of Fame, the American Academy of Arts and Sciences, the National Academy of Medicine, and she's even received an honorary science degree from Princeton University. They won't even invite us to the campus, Pats. I'm not sure what it takes to get an honorary degree, but Sue, welcome to Oncology, Etc. And thank you so much for agreeing to this interview. SUSAN DESMOND-HELLMANN: Well, thank you for having me. I'm really glad to be here and look forward to our conversation. DAVE JOHNSON: Pat, why don't you ask the first question. PAT LOEHRER: So Sue, if you could tell us a little bit about yourself from birth until your early career and what shaped your early directions. SUSAN DESMOND-HELLMANN: Well, I'm actually a California native and grew up in Reno, Nevada, thus the University of Nevada connection. I'm one of seven children. I'm number two. And my affinity for science and medicine and all things regarding patients came from my dad, who was a retail pharmacist. And that's how we moved from California to Nevada. My dad and his partner Jim opened up one of those Rexall Owl drugstores-- if you ever remember those with the owl picture-- and were partners for many years, ran a pharmacy in Reno, Nevada which, when we got there, was a really small town. And I often chuckle when people say, oh, there's something sort of funny about growing up in Reno, Nevada. Did you go to casinos all the time? The fact of the matter is that my parents were very strict disciplinarians. We weren't allowed to work in the casinos as summer jobs, much less go to the casinos. I went to Catholic school for 12 years. Going to college was the first time I didn't wear a uniform to school, which was funny. But both my values and my passions came from worshiping my dad and the contributions he made to people feeling better. PAT LOEHRER: Love it. Love it. DAVE JOHNSON: It's fantastic. May I ask-- I presume you chose to go to UCSF for your medicine training because of your California connection. Is that right? Or was there other reasons? SUSAN DESMOND-HELLMANN: There were two main reasons. One is UCSF was far and beyond my number one choice because of its reputation. And when I interviewed there, I just was so astounded that I recognized the names of my medical textbooks among the faculty. That was a big deal for me. Holly Smith was a chair of medicine. I mean, it was the dream to go to UCSF. My dad was born and raised down the street from UCSF. And my grandma still lived there. And so, for me, it was also-- being the first time I had been away from home-- it was close enough to Reno that it wasn't crazy to drive back for the weekend. So a little bit more close to home and much more importantly, for me, the mecca where I would just get to be around so many talented people. PAT LOEHRER: When you were there, it was really at the early times of the AIDS pandemic. And there is some wonderful people there that I'm sure you interacted with, included Paul Volberding and the other group. So tell me a little bit about that influence. And that probably led, in part, to the transition to Uganda. But tell us a little bit about that part of your story. SUSAN DESMOND-HELLMANN: So my time at UCSF, first of all, I think it's, especially being in the midst of COVID-19, it made so many of us recall what it was like to be in San Francisco in 1982. It was really exhausting and terrifying to be a health care provider when so many of your patients-- first of all, they died quickly before antiretrovirals. But there was such a lack of understanding of what was going on initially. And so the medical program at UCSF, like a lot of programs of its nature, in New York, LA, led to Paul Volberding, Don Abrams, Laurie Kaplan, a lot of colleagues-- the oncologists became AIDS doctors and oncologists, because of Kaposi sarcoma and lymphoma and other maladies. And I remember I did an additional year as chief resident. And one of our concerns was whether or not the medical residents were overweight HIV and underweight kidney disease and hypertension. And there was a concern that people might not come for the residency because they were worried about catching AIDS. I mean, we were part of a study to test us. And happily, unless you had a needle stick, you really weren't at great risk. But the residency was very much influenced by that. I was very much influenced by that I had a lot of passion for caring for the patients. I think I had a lot of empathy for what they were going through. And think about this, go home and tell your parents you have HIV. And by the way, they didn't know you were gay, because a lot more people were closeted in those days. That's a really tough set of circumstances. So by the time I was an oncology fellow and then a faculty member, I saw, really, all the patients at UCSF at the University Hospital who had AIDS-related cancers. That became my specialty. And I was funded by the California State Task Force on AIDS to study Kaposi sarcoma. But when the Rockefeller Foundation came to UCSF to ask them to study heterosexual transmission of HIV, the late Merle Sande and Dick Root asked my husband, who's an infectious disease doc, and I to move to Uganda and accept this Rockefeller grant and study heterosexual transmission of HIV and Kaposi sarcoma. And I actually think it's a bit of a funny story. But it was less funny then, because I was so uncertain. I had never been east of Chicago at that point in my life. But we flew and moved to Uganda. So I became a global citizen quite quickly. And it was both the most important experience that my husband and I had had in medicine and life. And to say it was challenging would be an understatement. I mean, we did not have consistent electricity or running water. And we had this multi-page grant where we were supposed to do ELISAs and Western blots. It was a little crazy, but we got some things done and that was the important thing. DAVE JOHNSON: So Pat's never been further between Indianapolis and Chicago. So he resonates with him. [LAUGHTER] DAVE JOHNSON: So you were there how many years? You were there two years, I think. SUSAN DESMOND-HELLMANN: Two years. DAVE JOHNSON: And did you accomplish the things that you set out to do while you were there? Or how did that go? SUSAN DESMOND-HELLMANN: We worked with our Ugandan colleagues and really transformed what you could do at Uganda Cancer Institute at the TB clinic in collaboration with folks from Case Western Reserve and for the AIDS program. So by the time we left, things just were dramatically better and different. We also did a lot of teaching, a lot of patient care. And so there was a service element to what we did, which was really essential that that be part of it. I had the opportunity, when I was at Gates Foundation in 2019, to return to Uganda. And the one thing you got at Cancer Institute, which was founded by NCI-- our National Cancer Institute, they are excellent at record keeping, all paper. And they dutifully pulled out some of the notes I wrote on my patients with Kaposi sarcoma with the references and citations. So this sort of nerdiness that we had at UCSF did transport to Kampala Uganda. DAVE JOHNSON: I hope they gave you some copies of those, with the name struck out of course, for your private collection. That's cool. SUSAN DESMOND-HELLMANN: It was actually pretty astounding to return. And now Fred Hutch has a collaboration with Uganda Cancer Institute and has done a lot of renovations and new science on the virology of Kaposi sarcoma. PAT LOEHRER: So before we skip from this and move to something else, if you could reflect a little bit about what you currently think the importance of global oncology is. It obviously had an influence on you. And how do you think it should fit in or does fit in now? UCSF has got its fingerprints around the globe now. I'm on their EAB. SUSAN DESMOND-HELLMANN: Well, let me just say from-- I'll speak to this sort of personally and then in a more big-picture way. Personally, I felt that the slogan of the Gates Foundation and every place can be too "slogan-y," so you always have to be careful about this. But the slogan that I just so had an affinity for is "all lives have equal value." All lives have equal value, for me, says that someone struggling or suffering, no matter where they are in the world, is worthy of our care and attention. And global oncology, I think, reflects that. So one of the things that I learned when I was there-- and I felt really good about this. I was glad that I learned from colleagues in Uganda and they learned from me. And so there was a real collaboration on figuring out-- I'll give you a real example. As you know, Kaposi sarcoma causes a lot of edema and lymphedema in the lower extremities. Well, if you've got lymphedema in your lower extremities, you can't farm, you can't dig, you can't feed your family. And we had bleomycin and vincristine. And with a combination of those two, in relatively small amounts to avoid toxicity, I could get someone back on their feet literally. And well, that's a great thing. And so the practical nature of symptom improvement, the avoidance of side effects, the attention to quality of life was amplified by my experience there. So I think those kinds of things-- I always like, in life, you give and you get. I gave. I contributed. I worked hard. And I got a lot of new knowledge and understanding. In addition, the deep understanding of pathophysiology that came from thinking about African Kaposi sarcoma, Mediterranean Kaposi sarcoma, age-related Kaposi sarcoma. There's just a lot of science, just a lot to learn if you were paying attention and probing what was going on. So I think global oncology is extremely important. And it's important that it be sustainable and appropriate and with, always, service and training as a component, not only research. PAT LOEHRER: Agreed. I agree. DAVE JOHNSON: We have so much to cover, I don't want to spoil everything. But I'm really curious when you left Uganda, you went into private practice, right? SUSAN DESMOND-HELLMANN: Mm-hmm. DAVE JOHNSON: How did that happen? SUSAN DESMOND-HELLMANN: We had to pay the rent. DAVE JOHNSON: There you go. SUSAN DESMOND-HELLMANN: Yeah. Yeah, when we came back, there was no global health. There was no place for us at UCSF. So we had one of those surreal academic experiences of sitting down with the new chief of medicine and him saying, there's no money for you. So you'll need to do a lot more clinical care and earn your salary. And Nick, you're going to-- my husband-- you'll need to write at least two R01 grants. And so you better get moving. And we were disappointed that there really wasn't a place or mentorship or anything for us at UCSF. But we didn't have time to lick our wounds. So Nick is from Kentucky. And we moved back to Lexington, Kentucky and went into private practice. DAVE JOHNSON: Yeah, economic necessity has changed. SUSAN DESMOND-HELLMANN: I mean, I can make it a little more romantic and interesting, but it was economic necessity. And honestly, I love patients, I love oncology, and I thought that was fine. One of the learnings from that was how deeply I missed research and R&D. And I'm very academically oriented. And so both Nick and I realized, when we were there, that we did very well. People liked seeing us as clinicians. And we were well-trained and could take good care of people. But it wasn't the right fit. DAVE JOHNSON: So from there, if I remember correctly, you transition to industry. SUSAN DESMOND-HELLMANN: Yeah, actually it's a good story. So Nick got called up about from Bristol Myers Squibb, did he want to come and join their infectious disease group up in Connecticut at Wallingford. And he said, of course, I would love that. But I won't come unless you take my wife too. And they said, no, we have a nepotism rule. We won't take your wife. And he said, well, you haven't met her yet. They said, why do we want a private practice oncologist at Bristol Myers Squibb. We need serious clinical trials people. And so Nick was somewhat persistent. And he just said, I won't come. He's a good husband. That's it. PAT LOEHRER: Sounds like it. SUSAN DESMOND-HELLMANN: He still is. And so they hired me as a consultant. And they were really busy on Taxol. It had gotten approved for ovarian cancer but not yet for breast cancer. And so I like to say they stuck me doing drug safety. And saying, she's like an LMD, she's a clinician. We'll have her do drug safety. She can't cause too much harm over there. And I tell you, the opposite of going into private practice, which was just, like I said, not a great fit. I felt like I had died and gone to heaven. First of all, it is probably embarrassing and says something about me, I loved drug safety-- loved, loved, loved drugs-- it's like thinking like an epidemiologist, a clinician, a good physician. You know, I love statistics and epi. I had gotten an MPH at Berkeley while I was an oncology fellow. And I just love analytics and inference and all of that stuff. And so after a couple of months they had changed me-- they got a dispensation from the CEO so I could be a real employee. And I became the project team leader for Taxol, which was fantastic. It was such a great experience. I loved the colleagues at BMS. And we were making one of the first new oncology drugs in a while. DAVE JOHNSON: Yeah, I think, if memory serves me correctly, that's about the time we first met. SUSAN DESMOND-HELLMANN: Yes. DAVE JOHNSON: And paclitaxel was being investigated in lung cancer. And that really is our connection. But those were heady times. We thought we were on top of the world. SUSAN DESMOND-HELLMANN: Well, you know, it had been a while since there had been new active chemotherapies in oncology. And they were heady times. It was also just so interesting and hard to remember now how much the toxicity of paclitaxel had put it on the shelf, this hypersensitivity reactions and the collaboration with the National Cancer Institute. There was a lot about the product development of paclitaxel that I remember and learn from. And I was just really grateful to be with Renzo Canetta and people like that, who it felt like going to UCSF where I thought, OK, Floyd Rector in nephrology. Now I get all these folks who I was using bleomycin and platinums. And they had written those package inserts. DAVE JOHNSON: Yeah. PAT LOEHRER: Yeah Bristol Myers basically owned oncology. I mean, all the products were going on there. And at that time, as you guys know, there's only one or two drugs a year that got approved for oncology. And today it is vastly different where each week there's a new drug or a new indication for oncology. The world has just changed tremendously. SUSAN DESMOND-HELLMANN: Yes. PAT LOEHRER: Yeah, it's been incredible. So Dave, where do you want to go next on this one? DAVE JOHNSON: Well, I think one of the things that I think our listeners might want to learn about is Sue's transition to Genentech. I mean, it wasn't like the powerhouse organization it is today when you went there. I mean, not that it was a hole in the wall, but it wasn't the biomedical powerhouse that it is. What attracted you? I'd love to hear from you, what brought you to Genentech? SUSAN DESMOND-HELLMANN: So I would say three things. The first thing was Art and his ambition. And so Art-- DAVE JOHNSON: You might want to tell people who Art is. SUSAN DESMOND-HELLMANN: So Art Levinson, who then was the head of R&D and later became the CEO of Genentech, so Art Levinson worked in Mike Bishop's lab at UCSF. And so he, in many ways, showed up as a molecular oncologist as the head of R&D at Genentech. And his ambition was that Genentech would be an oncology company. When I talked to Genentech, they had precisely zero oncology drugs. The furthest along was gamma interferon in their pipeline. So it didn't actually look very promising at the time. But Art was very compelling to talk to, and his dream. The second thing was research. Bristol Myers Squibb was fantastic. But especially being in Connecticut, where you were sort of removed from the research enterprise, I saw BMS as fantastic clinical development organization and sales organization. They did a lot of licensing deals. That was their claim to fame was they were really good at licensing. And I respected that a lot. But the ability to sit down with the research folks and think about what you would do with an anti-HER2 or an anti-VEGF-- and I just really respected Genetech's research capabilities and organization. And the third thing was we made the decision-- which wasn't an easy decision to make. We had built a house in Connecticut. We were happy there. I don't know if you remember the winter of '94 was huge blizzards in Connecticut. Before we moved to Connecticut, I didn't even own a winter coat. So it was rough to experience winter in the Northeast. And my family was in Reno and San Francisco. And so moving back here was compelling. PAT LOEHRER: Not the romance that you had in Christmas in Connecticut with Bing Crosby. It just wasn't the same, was it? SUSAN DESMOND-HELLMANN: Well, I did love fall. I'll tell you, nothing like autumn in Connecticut. There's a lot to like about Connecticut. So it wasn't an easy move. But coming back West was a good thing. DAVE JOHNSON: Well, what was the first really successful product that you worked on with Genentech? I should know, but I don't remember. SUSAN DESMOND-HELLMANN: Oh, the first successful product that I worked on with Genentech was a collaboration with IDEC on Rituxan. And rituximab was really interesting because there's some real heroes at Genentech, including a business development guy, David Ebersman, who heard that maybe an antibody could work, even a chimeric antibody could work for lymphoma. And so with Antonio Grillo-Lopez and the rest of the folks at IDEC, we got the first antibody approved in 1997. And that made a massive difference. I don't think people recognize how important rituximab was for trastuzumab, which was really only a year later-- less than a year later-- approved for HER2 positive breast cancer. But for me, that opened the era of antibodies and made people believe you could repetitively give a patient with cancer an antibody and they would tolerate it. DAVE JOHNSON: How confident are you that would work? SUSAN DESMOND-HELLMANN: I was very confident that rituximab would work. There was a lot of information. I wasn't sure we could make it. That required a lot of biotech manufacturing expertise that Genentech had, which was great. But I felt good about that. But there was a myth, at the time, that you could treat a liquid tumor, you could do heme, lymphoma or leukemia with an antibody. But there was this big worry you couldn't get into the tumor with a solid tumor. So I was not at all confident about Herceptin. Trastuzumab was not a give-me. But rituximab I was confident about. PAT LOEHRER: This concludes part one 2-part interview with Dr. Susan Desmond-Hellmann. It was a wonderful discussion. In part 2, we'll talk a little bit more about Dr. Desmond-Hellmann's incredible leadership roles, including her time as chancellor at UCSF and the CEO of the Bill and Melinda Gates Foundation. Thank you to all our listeners for tuning into Oncology, Etc. an ASCO Education Podcast where we'll talk about anything and everything. If you have an idea for a topic or a guest you'd like to see on the show, please email us at education@asco.org. Thanks again. And just remember anything, because Dave doesn't. SPEAKER: Thank you for listening to this week's episode. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In the second edition of this two-part Oncology, Etc. episode, hosts Dr. Patrick Loehrer (Indiana University) and Dr. David Johnson (University of Texas) continue their conversation with Dr. Otis Brawley, a distinguished professor of Oncology at Johns Hopkins and former Executive Vice President of the American Cancer Society. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us Air Date: 10/5/2021 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] DAVID JOHNSON: Welcome back to Oncology, Etc, and our second segment of our conversation with Otis Brawley, professor of Medicine at Johns Hopkins Medical School and the Bloomberg School of Public Health. Pat, I don't know about you, but Otis is a very impressive man, and he had a lot of really interesting things to say about his career development, family, et cetera in the first segment. This second segment, we're going to get to hear more about his time at the ACS. What were your thoughts about segment one? PATRICK LOEHRER: Well, I loved talking to Otis, and you too, Dave. Parenthetically, Otis once told me in a dinner conversation we had that he felt like Forrest Gump, and I can identify with that. Where over the field, our field of oncology over the last several decades, we've met some incredibly wonderful people, and we've been lucky to be part of the history. The three of us, I think, do have a deep sense of the historical context of oncology. This is a young field, and there's just some extraordinary people, many of them real true heroes, and Otis has his figure on the pulse of that. DAVID JOHNSON: Yeah, that's why he's been in some of the right places at the right time, and we'll hear more about that in this segment coming up now. PATRICK LOEHRER: Now Otis has had a career in many different areas, including ODAC, the NCI, the ACS, now at Hopkins. So let's hear a little bit more about Dr. Brawley's experience at the American Cancer Society and particularly with his experience with the former CEO, John Seffrin. DAVID JOHNSON: Sounds great. [MUSIC PLAYING] OTIS BRAWLEY: John and I had a wonderful run at the American Cancer Society. Got to do a lot of things. Got to testify for the Affordable Care Act. Got to do some of the science to actually argue that the Affordable Care Act would help. And I was fortunate enough to be there long enough to do some of the science to show that the Affordable Care Act is helping. DAVID JOHNSON: Yeah, I mean actually all of the things you accomplished at the ACS are truly amazing. Let me ask you, just on a personal level, what did you like most about that job, and then what did you like least about that job? [LAUGHTER] OTIS BRAWLEY: I like the fact-- there were a lot of things I liked about that job. There were a couple hundred scientists and scientific support people that you got to work with. And I used to always say, I do politics so you can do science. And what I used to like the most, every Wednesday afternoon that I was in town, I would walk around just to watch those people think. I used to joke around and say, I'm just walking around to see who came to work today. But I really enjoyed watching them work and watching them think, and that was fun. Another fun aspect of the job was people used to call and ask a little bit about the disease that they are a family member would have. And sitting down with them on the phone in those days-- we didn't have Zoom-- and talking to them through their disease. Not necessarily giving them advice on what to do in terms of treatment, but helping them understand the biology of the disease or connecting them with someone who was good in their disease. And I happen to, by the way, have sent some patients to both of you guys. That was a lot of fun. Then the other thing, of course, was the fact that you could actually influence policy and fix things. I'll never forget sitting across from Terry Branstad, then the governor of Iowa, and convincing him that the right thing to do is to raise the excise tax on tobacco in Iowa. Being able to see that you're effective and to see that you're positively influencing things. The bad side, some of the politics. I didn't necessarily like how some of the money was being raised or where they were raising money from. I think that you have to have a certain standard in terms of where you accept money. And we always had that tension with the fundraisers. But it's also true-- and I will give them a nod-- you can't do the fun things unless you raise money. So I really truly enjoyed my time at the American Cancer Society. And by the way, a shout out to Karen Knudsen, who is the CEO running the American Cancer Society now. And I'm fully committed to helping the ACS and helping Karen be successful. DAVID JOHNSON: One of the things I read-- I think I read this that you had said that one of your proudest accomplishments was revising the ACS screening guidelines. Tell us just a little bit about that. OTIS BRAWLEY: Yeah, going all the way back to the early 1990s, I started realizing that a lot of these guidelines for screening, or back then, this is before the NCCN guidelines for treatment even, that were published by various organizations, including the American Cancer Society. We're almost the equivalent of-- get the impression that in the 1960s, it would have been a smoke-filled room. But you gather a bunch of people into a room, and they come up with, this is what we should be doing. Indeed, the American Cancer Society in 1991 endorsed annual PSA screening for prostate cancer based purely on getting a group of primarily urologists into a room, and that's what they came up with. There was very little review of the science. There really was no science at that time except the science to show that PSA screening found cancer. There were no studies to show that led to men benefiting in that they didn't die. Indeed, in 1991, there was no study to show that treatment of early prostate cancer saved lives. The study to show treatment of prostate cancer saves lives was first published in 2003, and the radiation saves lives in 1997, 1998. Surgery saves lives in 2003 and screening has a small effect published in 2009. But they started recommending it in 1991 in this almost smoke-filled room kind of atmosphere. When I got to the American Cancer Society, I started an effort, and we involved people from the National Academy of Medicine, we involved people from the NCCN, from the American Urological Association, the American Academy of Family Physicians, the American College of Physicians. And we got together in that almost smoke-filled room again, but the idea was, how do you make responsible guidelines? And we wrote that up into a paper guide widely accepted by all of the organizations, and it involves a review of the literature that is commissioned by someone. And they spend a long time reviewing the literature and writing a literature review. And then you have a group of experts from various fields to include epidemiology and screening, social work, someone who's had the disease. Not just the surgeons and medical oncologists who treat the disease but some population scientists as well. They sit down and they reveal all of the scientific data, and then they start coming up with, we recommend this. And then they rank how strong that recommendation is based on the data. We published this in 2013 in The Journal of the American Medical Association. I do think that was important, you're right. That's Otis trying to bring his policy and his belief in orthodox approach to science and bring it all together. PATRICK LOEHRER: So let me reflect a little bit more on something. There is a book that I also just recently read by Dax-Devlon Ross, and it's a book entitled, Letters to my White Male Friends, and it was a fascinating read to me. You have this public persona and professional persona of being an outstanding physician, clinician, public speaker. But what we the three of us have never really had the conversation today is we have much more interest now in DEI. One of our other speakers talked about the fact that there's a tax that is placed upon underrepresented minorities and academics. They are all expected to be on committees. They have to be doing different things. And so the things that they love to do, they can't do it because they have to represent their race or their gender or their ethnicity. OTIS BRAWLEY: I have been blessed and fortunate. There are problems, and there are huge burdens that Black doctors, and women doctors by the way, have to carry. I have been fortunate that I have skated through without a lot of that burden. Maybe it has to do with oncology, but I will tell you that I have been helped by so many doctors, men and women, predominantly white, but some Asian, Muslim, Jewish, Christian. I don't know if it's oncology is selective of people who want to give folks a fair shake and really believe in mentoring and finding a protege and promoting their career. I have been incredibly, incredibly fortunate. Now that I say that, there are doctors, minority doctors and women, who don't have the benefits and don't have the fortunes that I have had, and we all have to be careful for that. As I said early on, John Altman told me that I will thank him by getting more Blacks and women into the old boys club. And so that was his realizing that there is a-- or there was a problem. I think there still is a problem in terms of diversity. Now I have seen personally some of the problem more outside of oncology in some of the other specialties. More in internal medicine and surgery, for example. By the way, there are also some benefit. I did well in medical school in third and fourth year in medical school at the University of Chicago because there were a group of Black nurses who were held that I wasn't going to fail. The nurses took me under their wing and taught me how to draw blood, how to pass a swan. The first code I ever called, there was a nurse standing behind me with the check off list. And so there are some advantages to being Black as well. But there are some disadvantages. I've been very fortunate. My advice to Black physicians is to keep an open mind and seek out the folks in medicine who truly do want to help you and truly do want to mentor you. And for the folks who are not minority or not women in medicine, I say, try to keep an open mind and try to help everybody equally. PATRICK LOEHRER: Thank you. DAVID JOHNSON: I want to go back to your book for a moment. And again, for those who've not read it, I would encourage them to do. So it's a really honest book, I think, well-written. You made a comment in there-- I want to make sure I quote it near correctly. You said that improvement in our health care system must be a bottom up process. What do you mean by "bottom up?" OTIS BRAWLEY: Well, much of it is driven by demand from patients and other folks. The name of the book was, How We Do Harm. And the synopsis is there are bunch of people who are harmed because they don't get the care that they need. And there's a bunch of people who are harmed because they get too much medicine and too much care. And they rob those resources away from the folks who don't get care at the same time that they're harmed by being overtreated, getting treatments that they don't need. The other thing, if I can add, in American health care, we don't stress risk reduction enough. I used to call it "prevention." Some of the survivors convince me to stress "activities to reduce risk of disease." We don't do a lot in this country in terms of diet and exercise. We try to do some work somewhat successfully on tobacco avoidance. We need to teach people how to be healthy. And if I were czar of medicine in the United States, I would try to make sure that everybody had a health coach. Many of us go to the gym and we have a trainer. We need trainers to teach us how to be healthy and how to do the right things to stay healthy. That's part of the bottom up. And in terms of costs you know my last paper that I published from the American Cancer Society, I published purposefully, this is my last paper. Ahmedin Jemal who's a wonderful epidemiologist who I happen to have worked with when I was at the National Cancer Institute and again later in my career at the American Cancer Society, I pushed Ahmedin-- he publishes these papers, and we estimate x number of people are going to be diagnosed with breast cancer and y number are going to die. He and I had talked for a long time about how college education reduces risk of cancer death dramatically. If you give a college education to a Black man, his risk of death from cancer goes down to less than the average risk for a white American. There's something about giving people college education that prevents cancer death. I simply challenged Ahmedin, calculate for me how many people in the United States would die if everybody had the risk of death of college-educated Americans. And he came back with of the 600,000 people who die in any given year, 132,000 would not die if they had all the things from prevention through screening, diagnosis, and treatment that college-educated people. Just think about that-- 132,000. Then I started trying to figure out what drug prevents 132,000 deaths per year? And I couldn't think of one until recently, and it happens to be the coronavirus vaccine. Which ironically has shown itself to be the greatest drug ever created in all of medicine. But in cancer, there's no breakthrough drug that is more effective than just simply getting every human being the care from risk reduction and prevention all the way through treatment that every human being ought to be getting. The solution to some of that starts with fixing third grade and teaching kids about exercise, about proper diet. PATRICK LOEHRER: We're going to have to wind things up here. But real quickly, a book you would recommend? OTIS BRAWLEY: Skip Trump, who's someone that we all know, wonderful guy used to run Roswell Park Cancer Center, just published a book actually it's coming out in September called, Centers of the Cancer Universe, A Half Century of Progress Against Cancer. I got a preprint of that, and it is a great book. It talks about what we've learned in oncology over the last 50 years since Richard Nixon signed the National Cancer Act. Keep in mind, he declared war on cancer on December 23, 1971. So we have an anniversary coming up in December. PATRICK LOEHRER: I want to close. Another book, I read the autobiography of Frederick Douglass. It's a wonderful read. It really is good. There were some endorsements at the end of this book, and one of them was written by a Benjamin Brawley, who wrote this review in a book called, The Negro in Literature and Art in 1921. And Benjamin Brawley was writing this about Frederick Douglass, but I would like to have you just reflect a moment. I think he was writing it about you, and I'm just going to read this. He basically said, at the time of his death in 1895, Douglass had won for himself a place of unique distinction. Large of heart and of mind, he was interested in every forward movement for his people, but his charity embraced all men in all races. His mutation was international, and today, many of his speeches are found to be the standard works of oratory. I think if your great, great grandfather were here today, he would be so incredibly proud of his protege, Otis. And it's such a privilege and pleasure to have you join us today on Oncology, Etc. Thank you so much. OTIS BRAWLEY: Thank you. And thank both of you for all the help you've given me over the years DAVID JOHNSON: Great pleasure having you today, Otis. I want to also thank all of our listeners for tuning in to Oncology, Etc. This is an ASCO educational podcast. We really are here to talk about anything and everything. So we're looking for ideas. Please, if you have any suggestions, feel free to email us at education@ASCO.org. Thanks again, and remember, Pat has a face for podcasts. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcasts. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

Oncology, Etc. is a monthly ASCO Education podcast exploring topics in oncology through interviews with emerging thought leaders, physicians, and innovators. In this episode, hosts Dr. Patrick Loehrer (Indiana University), Dr. Jamie Von Roenn (ASCO), and Dr. David Johnson (University of Texas) discuss the importance and impact that friendship has made on their careers. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us Air Date: 8/3/2021 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. PATRICK LOEHRER: Hi, I'm Pat Loehrer. I was born in Chicago, moved to Indianapolis when I was in high school, went to Purdue University, went to Rush Medical College, came here to Indiana University. And I've been on faculty ever since. I'm now a distinguished professor and the former head of our Cancer Center and Director of our Centers for Global Oncology. JAMIE VON ROENN: So hi, I'm Jamie Von Roenn. I'm a medical oncologist and trained at Rush with Pat and subsequently stayed in Chicago at Northwestern and came here to ASCO as the VP of Education about eight years ago. DAVID JOHNSON: Hi, I'm Dave Johnson. And I'm in Dallas, Texas. I'm a medical oncologist originally from Georgia, spent a large part of my career on the East Coast and in Tennessee before relocating to Dallas to become Chairman of Medicine in 2010. I stepped down from that position last year and now serve as an elder statesman [INAUDIBLE]. So we are excited to be here today for a new endeavor sponsored by ASCO, a podcast entitled Oncology, et cetera and with a heavy emphasis on the et cetera. We are here to talk with thought leaders, physicians, authors, innovators in oncology and beyond. To be honest with you, we have a lot of interests. And so I'm going to turn to Jamie and ask Jamie, why are we doing this? Jamie is the instigator behind this. So Jamie, why are we doing this podcast? JAMIE VON ROENN: So I think the primary reason we did this is to remind people why they chose oncology, that all three of us are people who are super excited about this profession, about what we've learned and what we've given and how we've shared it with each other and with the profession in general, that it's the science. It's the relationships. It's change. And it's incredibly fulfilling on all of those levels. DAVID JOHNSON: Yeah, Pat, what are your thoughts? PATRICK LOEHRER: When Jamie asked us to do this, this was something that we jump at. I love Jamie dearly. Dave and I both share this mutual admiration society. I deeply admire Jamie. And, to do something with Dave who is one of my closest professional friends, this was just a great opportunity. We thought in our conversations, though, as we talked with other people, that it would be good just to talk among ourselves and particularly about the notion of friendship and what it means to each of us personally with the idea that maybe those listening might reflect on that in their own lives. DAVID JOHNSON: Yeah, so you mentioned-- you made a distinction there, Pat. I'd like to know what that distinction represents. You said you had your personal friendships and your professional friendships. How do those differ? PATRICK LOEHRER: Well, you know, I'm not sure how it is for you, but my wife is outside of medicine. I've known her. I had my first date with her 50 years ago. And I have friends that I really don't like to talk about business with. I just talk about other things, our kids, family, whatever. Our friends in medicine are a little different. We have deeper conversations about our work. And there are certain aspects of our work that I think touch us personally. We have patients that we've become close to that are rough. And, many times, I don't share those interactions with my friends at home because it's just not important to them. So I treasure especially you guys, I treasure deeply. We've shared a lot over the years. JAMIE VON ROENN: So it seems to me that friendships in general are built on shared experiences and that the experiences in medicine are so different from anything else. And, if you don't have friends in your profession, you may not actually have the opportunity to share and sort of have a sounding board for how difficult things are sometimes in spite of how inspiring it is. DAVID JOHNSON: Yeah, I think I like your distinction. Both of you pointed out the shared experience. The world of an oncologist, viewed from the outside, may appear to be a rather morbid specialty, but, in fact, it's one that I personally find incredibly rewarding. But there are those moments that are challenging and difficult-- patient encounters, professional setbacks, et cetera. And it's nice to have someone within the profession itself that can relate to those experiences, especially failure. I know, Pat, you've had lots of failures. [LAUGHTER] JAMIE VON ROENN: I think we all have. PATRICK LOEHRER: Thank you. Just as a background, there have been, in this group, five runs for ASCO presidency. And only one of them has been successful. So yeah, we know failure, Dave. JAMIE VON ROENN: But I think it's important because no one is successful all the time. And it's your friends who actually get you through that and let you see, OK, yeah, I'm still OK. And I think it's the other side of that too. Everyone who's honest has suffered from the imposter syndrome. And it's your friends you can openly share that with. And it helps you go the next step when you're struggling. DAVID JOHNSON: So you mentioned that the two of you met during your residency training. What prompted that friendship then? And how has it been sustained over the last many years? I won't say the number of years, but a lot of years. JAMIE VON ROENN: So we actually met when I was a medical student, and Pat was my intern who I worked with. And then, when I was an intern, Pat was the resident. DAVID JOHNSON: So that accounts for all your problems in the medical field? JAMIE VON ROENN: It accounts for how well trained I am. DAVID JOHNSON: I see. JAMIE VON ROENN: But I think it was the sense of joy in the profession that probably connected us and a love of people. I don't know. Pat, what would you say? PATRICK LOEHRER: Well, it was a special time back then in medicine. Our particular hospital was a resident-run hospital. I think we acted first and then asked permission from the attendings later on. And it was really very special. There's a lot of people from Rush who have gone into oncology in many different areas. And so it was very special. Jamie I knew. We really did not keep in touch until she gave a plenary paper at ASCO. And I remember writing her a note. And I was so proud to see her up there. And I wrote that in a note. And we started, basically, communicating and getting together regularly. And so, each year at ASCO, as you know, we get together, the three of us, collectively or individually, and have a dinner. It's really the highlight of the meetings for me. DAVID JOHNSON: Yeah, I mean, I had the good fortune of Pat and I coming together, I think, shortly after I completed my fellowship. And Pat and I were both starting our academic careers, he at IU and I at Vanderbilt at the time. And we interacted through one of the major NCI cooperative groups that, unfortunately, no longer exists. It may have been due to our work, Pat, that caused the Southeast group to divide. But it was through Pat that I met Jamie. And so that's been really one of the most rewarding relationships that I've had professionally over the last, now more than 40 years. I mean, it's been a long time really. PATRICK LOEHRER: And we were on the ABIM together, the three of us, which was a riot. It's another one that seems like a thankless position, but we realized how hard it is to write very good questions. And we would spend a lot of time together doing this. I learned tremendously from the two of you and the others around the ABIM. JAMIE VON ROENN: Yeah, that was a remarkable experience for us because it's a small group of people putting their ego outside the door and working together. DAVID JOHNSON: And the challenge of maintaining one's knowledge base, I mean, honestly, I hadn't thought that much about it until I was invited to join the ABIM. And thank you, Pat, for making that possible. I consider it one of the highlights of my professional career is being a part of that. And I realize how controversial the work that ABIM is doing today, but, still, I think it was a wonderful experience. JAMIE VON ROENN: We've been pretty lucky to share multiple professional activities. I mean, when you were president, Dave, I was on the board. We shared ABIM. We shared some ECOG work way back. It's been a lovely crossing of paths beyond friendship . DAVID JOHNSON: Yeah, I mean, I think one piece of advice that I give to residents, and especially those who are interested in heme-onc fellowship, is find a friend. It's really important that you do so. I was fortunate to have the two of you and some other friends during the course of my career. And I must say, turning to a friend for advice, for assistance, for mentorship-- I can't remember who said it first. Having a friendtor is really, really important in the course of one's professional development. JAMIE VON ROENN: It's an important message because it takes time. When people are in training, they often think they don't have time, but this is a value on every level. It's more than worth the time. PATRICK LOEHRER: I just want to jump on that friendtor. We all have had people that we work closely with. In Indiana, it's been Larry Einhorn who was a role model for me when I was a medical student and then became a mentor when I was a fellow at a junior faculty. And he is, again, one of my closest friends. And he is one that gives me advice, but also just listens. And, similarly, he'll come in and ask me advice, which was mind boggling that someone of his stature would lean on us. But I was trying-- I was just going to put a caveat or a corollary to your statement about finding a friend. Dave, what I tell people, I think it's more important to be a friend than to have them. I think, if you get into the habit of helping other people and being a friend, you'll collect people close to you down the road, but, boy, it's not a one-way street. It really has to be the best friendships in which you give and you also happen to receive, but it's really a nurturing process. It just doesn't happen by chance. It happens because the people make an effort in it. JAMIE VON ROENN: Absolutely. DAVID JOHNSON: So what do you look for in establishing those friendships, Pat? What attracts you to an individual to even consider establishing a friendship? PATRICK LOEHRER: Well, I like to have friends who are dumber and uglier than I am. And that's why I really migrated to you. I mean, I think, when I looked around the room, I said, this guy could be my friend. DAVID JOHNSON: It's amazing. I saw myself in the mirror when I saw you. JAMIE VON ROENN: So I'm going to take that more seriously and say I think what we have done with each other is looked for people with values that connect and that, in the end, whatever those values are, that's what makes the friendship last. PATRICK LOEHRER: Well, it's interesting. As we talk about, in academics, one might think that you become friends with people in your own disciplines, but Jamie was a age researcher in palliative care. Dave, you were a thoracic oncologist. And I was a GI. And the loneliest friendship would be with thymoma people. But none of us really merged together because of our own professional disciplines. It really was something else. I think there was a higher power that pulled us together. DAVID JOHNSON: Oh, I think Jamie touched on it. I mean, it's the values that we share, I think. And I'll go back to something we talked about earlier, which is our shared love of the profession itself. I think I was 10 years old when I first seriously thought about being a physician. You may argue that a 10-year-old can't think seriously about anything, but, throughout my youth, all the way through college and, ultimately, medical school, medicine was my goal. And I've never regretted making that decision. I know there's a lot of unhappiness in the medical profession in this day and age and a lot of talk about burnout. One recent study actually even suggested that over half of all physicians would not recommend medicine to their children as a profession. I find that disheartening. I'd be delighted if my child were to choose such a profession. She didn't, but I would have been delighted had she done so. And I know, Pat, you have children who have pursued medicine as a career. PATRICK LOEHRER: Yeah, I was-- actually, at my son's graduation, I was up in the balcony away from everyone else taking photos, but I did find myself with a tear coming down my eye watching him just because it was an affirmation that my life was something that didn't steer him away from medicine. I think he did find, in my life, the joy that you can find in this profession. I want to change this a little bit to you guys, Dave, because you talked about the profession. And, several years ago, well, you both have had some really tough episodes in your life, but, Dave, you came down with lymphoma many years ago. And I do remember an ASCO presentation that I think Jamie helped put together in which there were several of you. I think Nick Vogelzang and Sandra Horning were up there. And you shared your experience of having cancer and shared some of the stories, I think, of friendship. But I do remember the phrase that you used at the end of the talk about how you had a deeper appreciation about the majesty of our profession. That's always touched me, but can you reflect a little bit about your illness and having lymphoma as a cancer doctor and what you learned in terms of this topic of friendship? DAVID JOHNSON: Well, we, as oncologists, think we know what it's like to have a serious illness. And I certainly was no different than most oncologists. But, when I myself was diagnosed with a malignancy, I must say, I had many of the emotions that I've witnessed in my patients. And, also, suddenly, my brain went completely blank. I couldn't think about what it was that needed to be done. And I, like most patients, began searching for the perfect answer. How would I deal with this? But I was also curious because, a few years prior to my own diagnosis, another faculty member at the institution where I was at the time had been diagnosed with ALS. And he wrote a very personal and moving piece that was published in The New England Journal about his experiences at that institution and how he was treated by his fellow physicians. And, actually, what he had to say was not all that complimentary in some instances. And I wondered myself how I would be dealt with by my fellow physicians. And I must say, my experience was virtually the polar opposite. I was surprised, honestly, at how heartfelt the good wishes were, the way that my colleagues went out of their way to try to make sure that I was successfully treated, was dealt with appropriately, even colleagues at my institution that I had not known that well finding excuses and reasons to drop by the office that seemed manufactured, quite frankly, but were clearly, again, intended to lift my spirits and make me feel positive about my future. It really made me realize just what a special profession we're in and then, to have friends that I could turn to, such as you and others, who really did a lot to lift my spirits. So, when you see that, you can't help but be really moved by the men and women who come into this profession and particularly those who choose oncologist as a specialty. PATRICK LOEHRER: I had a colleague who succumbed to glioblastoma. And he was-- when he was first diagnosed, he told me there were three kinds of friends, he realized. There were the long-lasting friends that he's always had. There were people who he thought were friends who kind of just faded away, mainly because they didn't know what to say. And then the third group were these unexpected friends, people that he didn't really know that very well, but came into his life and really made a difference. It was very insightful. DAVID JOHNSON: Yeah, I mean, that's exactly the experience I had as well. And the group that unexpected was perhaps the most surprising to me, but really I came to appreciate greatly. PATRICK LOEHRER: Many years ago, when we were doing the board questions, Jamie was not able to come because her husband Kelvin had been diagnosed and then, shortly thereafter, passed away from cancer. I knew him when I was a resident. He was a feared neurosurgeon. He made Ben Casey look like Dr. [INAUDIBLE] He was an incredibly intense, wonderful man, but I've not talked much deeply about that. And, with some reluctance, Jamie, I don't know if you want to share a little bit about how you felt as a palliative care doctor, and then here's your husband who's dying of cancer. JAMIE VON ROENN: Sure. And it kind of echoes what both of you have said. Here I was, a palliative care doc. And I thought I understood what death and dying was about. And, after Kelvin died, I was blown away. And I recognized, I said the right things, but I never really understood them. And it changed the way I talked to patients forever. And I too had the same experience of friends who are new, old, and otherwise, those that disappeared because they were too uncomfortable. And I was shocked that there were partners, oncologists, who could never ever say anything to me because they were too uncomfortable talking about death. And here it was something they were supposed to be trained to deal with. And, in fact, I remember, many times, Pat, you calling and checking in on me. And I remember in particular one day when I was down, and you said, wow, you are in a dark hole. And I was. And it took a long time, but it's friends that get you through and the ability to talk about what nobody wants to hear that helps you recover ultimately and move on. And those are life friends, but there's something different about people like the two of you who understand these experiences from a different perspective. DAVID JOHNSON: Yeah, I mean, I think these shared experiences, they're not shared in the sense that we experienced it personally, but the fact that we were able to relate to one another and share those very personal moments only fortifies and solidifies an existing friendship. And there are a lot of people I would not have that discussion with, but there are a few. And you are certainly among those two that I would. PATRICK LOEHRER: Well, I mean, you guys mean a lot. And I know-- I'm trying to think of the time. Back when I was thinking about becoming a heme-onc division chief. I gave Dave a call. Dave was head of heme-onc at Vanderbilt, I think, for 68 years or something. I can't remember. You were there for a long time. And I called him up. And I thought for sure there would be this, yeah, Pat, you'd be great. You'd be a wonderful division chief, but there was just this silence. It was like, I don't know, about 90 seconds of just pure silence. And then you said, yeah, it's mostly a good job. Then you reflected a little bit about this. And, in terms of this rejection, I think the other thing you taught me is it's OK not to be the first choice. But I can't remember. What choice were you for the division chief? DAVID JOHNSON: 11. PATRICK LOEHRER: 11. Yeah, I love that. I love that. DAVID JOHNSON: That's true. I mean, they interviewed 10 people before I was offered the job. So I knew I was in the top of all candidates. PATRICK LOEHRER: Top hundred, huh? This is like Rock and Roll Hall of Fame [INAUDIBLE]. DAVID JOHNSON: They ran out of candidates. PATRICK LOEHRER: Well, you know, that part, I've got to be honest with you. The stories with you guys have helped me out quite a bit because junior people would look up and say, oh, look at these guys. Aren't they successful? But they don't realize that we have stumbled and failed over the years in many things. And the best thing you can do is just laugh about it when you try. But, going back to the notion of friendship, there is no greater joy than I have is to see you guys, who are my friends, succeed. And a definition, I think, of a friend, at least a minor definition, is, when someone gets an award, that you find greater joy in them getting the award than you would if you got it yourself. If you find yourself kind of jealous and wondering, well, I wish I had that, probably, it wasn't your friend then. But I've gotten so much joy in watching you guys succeed. JAMIE VON ROENN: So I think there's a corollary to being a good mentor, which is, when your mentees surpass you, then you were successful. And it's the same with friendship. PATRICK LOEHRER: I'm one of the most successful people in the world then. DAVID JOHNSON: I was getting ready to say, I think we've all succeeded wildly then. [LAUGHTER] JAMIE VON ROENN: But that is the goal. I mean, what's the point of being able to help people if you don't make them the next set of stars? DAVID JOHNSON: We've been lucky to have a lot of really terrific men and women who we've been able to work with over the years and call them mentees, but, in reality, we've been their mentees. They've been the ones that have taught us so much. I'm very proud of all of them. JAMIE VON ROENN: Yeah, I think that is something to be proud of. And, when I look back, it's those things that make me most excited about what I've accomplished. PATRICK LOEHRER: Well, I think, every good relationship, you really get more out of it than you get into it. Even as we have our heart to hearts with our patients and having end of life discussions, I usually get so much out of that in a reflection of their own personal love for each other and their family and what they treasure in life. But, again, with you guys, unabashedly, I'll say this in public. I love you deeply. And I appreciate your friends. CS Lewis had a book called The Four Loves in which the most unnatural of the four loves was friendship, but it's what he actually thought was probably the most important one because it's so unique. And it's not expected, but you guys, I think, are an important part of my life. And I thank you for that. JAMIE VON ROENN: I love you both and feel the same. It's the luckiest thing there is. DAVID JOHNSON: Yeah, absolutely, absolutely. Thank you so much for that. Well, I think our time is about up for today. I want to thank all the listeners. I'm sure there's tens of thousands listening to this. Well, I just called Pat's friends and told them listen. So we plan to do this monthly. We already have a scheduled guest for our next podcast. It'll be Dr. Otis Brawley who I think many of you know by reputation, one of the leading luminaries in oncology in the United States. He's now at Johns Hopkins. I think it'll be a really enlightening and fun conversation to hear what Otis has to say about the current state of oncology in this country. So, with that, we'll sign off until next month. Thanks, everybody. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

The incidence of colorectal cancer among people under 50 is rising. In this ASCO Education podcast episode, medical oncologist Nilofer Azad (Johns Hopkins Medicine) and epidemiologist Caitlin Murphy (UT Southwestern Medical Center) discuss risk factors, screening, and treatment. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us Air Date: 7/28/2021 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. NILO AZAD: Welcome to the ASCO learning podcast episode focusing on early-onset colorectal cancer. My name is Dr. Nilo Azad, and I'm a medical oncologist and Associate Professor of Oncology at Johns Hopkins Medicine. I'm joined today by Caitlin Murphy, an Assistant Professor of Epidemiology at the University of Texas Southwestern Medical Center. We wanted to start today with a patient case, just to give a little bit of context about the kinds of patients that we are dealing with. A year ago, a patient presented to my clinic who was 32 years old. She was having significant symptoms of rectal obstruction. She was having trouble going to the bathroom. Her bowel movements were difficult. She was having bloody stools, and she had gone to see a gastroenterologist who had done a colonoscopy, biopsied her tumor, and found that she had adenocarcinoma of the rectum. Now, luckily, at that time, she didn't have any metastatic disease. But her tumor was quite large, 15 centimeters in size, and so we decided to move forward with doing chemotherapy in the neoadjuvant setting. She got aggressive chemotherapy with FOLFOX for three months. And when we did a scan, unfortunately, we found that the tumor had grown. Now, she still didn't have any disease outside of the rectum but, during that time, we had gotten some molecular testing back which showed that the patient had mismatch repair deficiency or microsatellite insufficiency. So we decided to try something a little outside of the box at that time, where we started treatment with immunotherapy. She had a dramatic response to immunotherapy. Her tumor shrank. And, six months later, she went to surgery and, though on scan it still looked like she had a large tumor, it turned out that that tumor was only scar and that she'd had a complete response. She came back to see me, last week, in clinic. She looks fantastic, and she's moving forward with planning for a family with her husband. So, Dr. Murphy, can you tell us a little bit about the trends in early-onset colorectal cancer incidence in the US and globally? CAITLIN MURPHY: Of course. I'll start, first, by talking about trends in early-onset colorectal cancer in the United States. Incidence rates began increasing here in the early 1990s and have nearly doubled over time, from about eight cases per 100,000 persons in the early 1990s to 16 per 100,000 persons in today. The largest increases have occurred in 40 to 49-year-olds. They account for about 80% of all cases. And we've also noticed that incidence rates of rectal cancer versus rates of proximal colon or distal colon cancers have been the largest increases in incidence. We've also seen a similar increase in local and distant stage disease. And, to me, one of the most compelling observations that we've made is that incidence rates have increased successively across generations, or about the year that you were born. There's a very clear and marked increase in incidence rates starting with persons born in and around 1960, or who we sometimes call Generation X. Epidemiologist like to call this a birth cohort effect because essentially we see incidence rates increasing across birth cohorts. More recently, we've observed that incidence rates have started actually increasing in people in the early 50s, the 50 to 54 age group, and this really does not appear to be driven by early stage disease as we might expect with more screening in that age group. But perhaps the increase in this early 50s age group is driven by the same things happening in people under the age of 50. Globally, we've seen a similar increase occurring in countries that have colorectal cancer screening and even in countries that don't have colorectal cancer screening. There was a recent analysis of 36 countries, and it found that incidence rates have increased in 19 of those 36 countries. Nine of those countries had stable or declining trends in incidence in older adults. There really wasn't a clear pattern among those countries in terms of the degree of Westernization or income level that might explain those trends. And, importantly, that birth cohort effect that I mentioned as occurring in the United States, where we see increasing incidence rates starting with Generation X, has also been reported in many other countries, including Canada, Australia, and some East Asian countries. NILO AZAD: And, Dr. Murphy, what is the current thinking regarding causes of this increased incidence of colorectal cancer that we're seeing in young people? CAITLIN MURPHY: Generally, there are two schools of thought about what's going on here. The first thought is that this is the same disease that's happening in older adults, but it's just now occurring at a younger age. For example, we've seen a steady rise in factors that we know increase the risk of colorectal cancer in older adults, like obesity and diabetes. And, these factors, we also know are now increasingly occurring at a younger age. But many of my clinical colleagues like you, Dr. Azad, tell me that most of the patients they diagnosed with early-onset colorectal cancer are otherwise fit and healthy and have no obvious risk factors like those. And so this second school of thought about what might be going on here is that this is really a different disease than what's happening in older adults, driven by as of yet unknown risk factors that have also increased in the population. NILO AZAD: Yes, I definitely feel like that the cohort of patients that I see in my clinic-- and, of course, at a place like Johns Hopkins, we see a little bit more of a skewed cohort in terms of seeing more younger patients-- that most of them aren't people that I would traditionally look at and say that they've got a risk factor that explains the situation. What are the main risk factors for early-onset colorectal cancer? CAITLIN MURPHY: There's still a lot of research to be done in understanding what the risk factors for this disease are. And I like to think of the risk factors that we know about as affecting early-onset colorectal cancer as falling into one of four sort of categories. The first category is having a genetic predisposition, so either having a family history of colorectal cancer or even a family history of an advanced adenoma or having a hereditary syndrome like Lynch syndrome or polyposis. Together, these account for about 40% of all new cases and many of the cases that don't have a traditional phenotype or mutations associated with colorectal cancer. So, for example, many of the patients we see with Lynch syndrome don't necessarily have the typical phenotype that we've expected to be associated with Lynch syndrome over the past however many years. The second category is what I like to call established risk factors. Or maybe another way to think about this is usual suspects, so already known causes of colorectal cancer in older adults. I mentioned these earlier, obesity, diabetes, but then there's also smoking, physical activity, and sedentary behavior. Then the third category is what I call early life factors, and the importance of understanding early life factors is really driven by the fact that incidence rates have increased by generations. Remember that first cohort effect I was describing to you earlier. This birth cohort effect tells us that risk factors in very early periods of life or vulnerable periods of growth and development are important. It also tells us that we should rethink some of those usual suspects or established risk factors as occurring very early in life. For example, instead of just thinking about obesity, thinking instead about birth weight or childhood obesity as well as growth trajectories in infancy. And then, finally, the fourth category is unknown risk factors. So the trends in incidence point to some clues, whether things in the population have increased over time or by generation, that might help us understand what's going on here. Some examples of those unknown risk factors might include environmental chemicals like flame retardants or endocrine disruptors, antimicrobials, or other infectious agents. And there really has been no research on these unknown risk factors but, again, people think that these might be related to early-onset colorectal cancer just because the trends in their prevalence have mirrored the trends in incidence. NILO AZAD: So, Dr. Murphy, you've really laid out wonderfully both the risk factors that we're seeing in some of these younger patients and then just the changes in incidence and occurrence as well. So how has that affected screening guidelines, going forward, as well? CAITLIN MURPHY: In 2018, the American Cancer Society recommended lowering the age to initiate average risk colorectal cancer screening from starting at age 50 to age 45. At the time, when this was done, all of the GI societies and the United States Preventive Services Task Force recommended still continuing at age 50. This recommendation from the American Cancer Society was a qualified recommendation, meaning that it's based on simulation modeling and not necessarily empirical evidence driven from randomized trials or other clinical studies. More recently, just last fall, in 2020, the United States Preventive Services Task Force released a draft recommendation to do the exact same thing, so lowering the screening age for average risk people from 50 to 45. The idea of a draft recommendation simply means that they put the recommendation out there for public comment and then consider some of those comments before either revising that recommendation or making the recommendation official. Like the qualified recommendation, initiating average risk screening at age 45 has a grade B recommendation from the task force, meaning that they have fair compared to strong evidence to support that recommendation. And I expect that we'll be seeing a final one coming this spring or summer. NILO AZAD: Is there anything unique about colorectal cancer in young patients biologically? CAITLIN MURPHY: That's a good question and something we still don't know a lot about. I'll just give one example of that. We know from certain studies that early-onset colorectal cancer seems to be enriched for certain molecular subtypes like an immune subtype, although the research in this area is really limited by a small number of studies. And most of the studies have been conducted just as a single center and not at the population level. NILO AZAD: And how do our patients that are younger do in terms of survival, compared to their older cohorts? CAITLIN MURPHY: Most studies that have looked at this report no difference in survival between younger and older patients with colorectal cancer. We do know, however, that younger patients are more likely to be treated aggressively with surgery, multimodality chemotherapy, and/or radiation therapy. This really raises an important question. If younger patients have no survival advantage despite more aggressive treatment, this could mean that younger patients have tumors that are more aggressive or that they respond differently to treatment regimens that have been developed for older patients with colorectal cancer or risk disease are over treated. With that in mind, I want to revisit our patient case, the 32-year-old woman with rectal cancer. Dr. Azad, what should be discussed with a young patient before starting therapy? What kind of testing needs to be done? NILO AZAD: So when we have young-onset colorectal cancer, just as you mentioned, there are a subset of these patients that have a genetic predisposition to developing colorectal cancer and other tumors as well. And so these patients absolutely need to be assessed for these genetic syndromes. So for my patient, in particular, I mentioned that she had mismatch repair deficiency or microsatellite instability. That suggests that she had what was called Lynch syndrome. And Lynch syndrome is something that, now, luckily, we actually have therapies for in terms of having immunotherapy. But knowing about that kind of a syndrome is important for this patient for her future planning, for the other tumors that she might develop, and of course for counseling for the rest of her family as well. And what was actually interesting about this case was that she had traditional mismatch repair testing with immunohistochemistry of her tumor, and that testing came back that she had microsatellite stable disease. So initially we actually didn't think that she had microsatellite instability. But because her family history was such that I was still suspicious that this was true, we sent second testing using a different kind of assay, and that's where it became clear that she had mismatch repair deficiency. So it's really important to maintain a high index of suspicion and recognize that even some of the tests that we send are not perfect and, if you still have a high index of suspicion for reasons like the family history or a patient having a second cancer previously, that you should follow that instinct and make sure that you're doing as deep testing as necessary. The other issue, of course, with younger-onset colorectal cancer, especially for people as young as my patient was, is the question of fertility. And so because she had rectal cancer and, as part of the paradigm for rectal cancer, these patients will have radiation, she was not going to be able to carry a fetus or embryo to term after completing therapy. So that's something that we need to understand early, have those conversations early, and get a multidisciplinary team involved that usually involves fertility experts as well as gynecologists. And so, for her, what we ended up doing was doing an egg harvest. And then she had in vitro fertilization performed, and then they were able to store embryos for her and her husband. And now they're actually looking forward to moving forward with surrogacy. CAITLIN MURPHY: So it sounds like your patient had to navigate a lot at the beginning of her diagnosis, considering fertility options, grappling with a new diagnosis at the age of 32, and then going through all of the workup and diagnostic testing. After that, what kind of treatment options would be appropriate for her? NILO AZAD: So, at this point, we actually aren't treating early-onset colorectal cancer any differently, in terms of how we actually treat the cancer, compared to people who develop colorectal cancer at a more average age. That said, our patients do have specific needs that we need to incorporate and discuss, both when they're diagnosed and as they start treatment and then later as they complete treatment and for their survivorship. So, clearly, we talked about the fertility issues. But when you've got a patient who's in their 30s or 40s and they're undergoing chemotherapy that's going to leave them with potentially lifelong neuropathy as one of the long-term side effects, that's really something that we need to discuss with patients, both so that they know about it, but what impact could that have on their professional function. For example, this week, I saw a 40-year-old woman who is newly diagnosed, and she is actually a concert musician. And so the idea that this may actually result in meaningful disability for her for what her chosen profession is, it's something that we need to discuss with these patients because they likely have 20 or 30 more years of professional life that is ahead of them and makes a huge difference for them, and financially as well. And, on that front, when you are treating people who are kind of in the prime of their life when it comes to their earning potential, that's also a really big issue that needs to be discussed. Sometimes people, in fact, lose their jobs because of the amount of time that they have to take off for treatment during that time. And so working with social work and making sure that we are addressing these issues and not just focusing on the things that are physical is really important. I'm a believer that impact on sexuality and body impact is not something that is only for the young. But, clearly, that's something that we need to discuss for all ages of patients when it comes to the kind of therapies that we have, especially with rectal cancer where, a lot of times, patients are left with a temporary or permanent colostomy. And I also think that there is some real issues around feeling isolated from your peers. It's still very rare to develop colorectal cancer, or any cancer, below the age of 50. And so because of that, even though we are seeing an increase in incidence, a lot of times, this is an area where patients can really have significant mental anguish because they feel so isolated from their peers that aren't having to deal with these issues. So I think all of these are really important features of dealing with early-onset colorectal cancer. CAITLIN MURPHY: I think you said it exactly right, that these patients are in the prime of their life and not necessarily just navigating cancer treatment-related factors, but also having to deal with family and care-giving responsibilities, their job, their economic situation, and their social situation. If all other disease factors and patient characteristics were similar, though, but the patient that you talked about was older, let's say, aged 55, would you do anything different in terms of her care? NILO AZAD: So, you know, with that particular patient, we were trying very hard to see if we could find a way that she might not have to have radiation because we knew that radiation was going to take away her fertility. And so when she had that initial progression on chemotherapy, what we did was a little bit out of the box, at that point, using data that existed in the metastatic setting showing that immune checkpoint therapy was very effective in patients with mismatch repair deficiency and treating a patient that didn't have metastatic disease, hoping for an excellent response, which is what we got. Now, fortunately or unfortunately, while she had a fantastic response, because the tumor didn't regressed completely and left her with that scar tissue, she did end up getting radiation because we couldn't be confident that we had gotten a complete response with just the immunotherapy. But I do think that, with younger onset colorectal cancer, what often happens is that we dance a little outside of the box in terms of trying to do things that would help preserve patients' fertility or preserve some of their overall function that might be a little bit different than what we might do for people 20 or 30 years older. I think that, in the right circumstance, that can be the right thing for our patient. But it is something that you have to do very carefully because, as you mentioned, it may well be that sometimes our younger patients are being treated more aggressively than they need to be just because they come in, and they have less comorbid conditions. And people feel comfortable being more aggressive when they might not need it. CAITLIN MURPHY: This is a really great conversation. And, as an epidemiologist, I often get lost in the numbers and forget about the real impact that this disease has on patients. And so I really appreciated learning about the patient case. NILO AZAD: Thank you, Dr. Murphy, for joining us as well. I think that this is such a great way for us to put some of those really objective data together in terms of what we're seeing with more patients that are developing young-onset colorectal cancer; what groups that we're seeing that in, both in terms of ethnic groups and risk factors; and then combine it with some of the key features that are important in terms of patient care, which I would say means that all patients should be getting genetic testing, all patients should be treated aggressively, and that there are many both physical and psychosocial factors that we need to be taking into account when we're treating our young-onset colorectal cancer patient. So thank you so much for your time. I've really enjoyed talking about this with you. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning Center at elearning.asco.org.