Conversations with the Pioneers of Oncology: Dr. Trevor Powles

Dr. Hayes interviews Dr. Trevor Powles his involvement with translational medicine in the UK and early bisphosphonate.

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.

Conflict of Interest: Dr. Powles has not reported any conflicts of interest to ASCO.

TRANSCRIPT

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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Welcome to JCO's Cancer Stories-- The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all the shows, including this one, at podcast.asco.org. Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist, and I'm a translational researcher at the University of Michigan Rogel Cancer Center in Ann Arbor. And I'm also the past president of the American Society of Clinical Oncology.

Today I am privileged to be your host for a series of podcast interviews with the founders of our field-- today in particular Dr. Trevor Powles. Over the last 40 years, I've been fortunate to have been trained, mentored, and inspired by many of these pioneers. It's my hope that through these conversations all of us can be equally inspired by gaining an appreciation of the courage, the vision, and frankly the scientific understanding that these men and women who established the field of clinical cancer care over the last seven decades. By understanding how we got to the present and what we now consider, quote, "normal," end of quote. I hate using quotes, but in oncology I think we can also imagine our work together towards a better future for our patients and their families during and after cancer treatment.

As I've noted today, I'm really honored to have as my guest on this podcast Professor Trevor Powles. He's really generally considered one of the true pioneers in breast oncology. Dr. Powles was raised in London, where he went to medical school. He trained in medicine and surgery at St. Bartholomew's Hospital and associated affiliates, graduating from medical school in 1964. He went on to obtain a PhD at the Institute of Cancer Research. He directed his thesis towards hypoglycemia and bone metastasis.

Following his PhD, he then completed specialist training in medical oncology at the Royal Marsden and further pursued training in endocrinology with Professor Philip Bundy, [? who was ?] then Chief of endocrinology at Yale before moving to the UK. Dr. Powles remained at the Royal Marsden hospital during the bulk of his distinguished medical career, first as head of the Marsden breast cancer unit, and ultimately is the founding chairman of the Committee for Clinical Research for the entire Royal Marsden. After he retired-- which again requires [INAUDIBLE]-- at the age of 65, Doctor Powles has served on staff at the Cancer Center at London Parkside.

Dr. Powles has authored hundreds of peer reviewed papers. He's mentor of many of the leaders in breast college around the world, which we will discuss in a second. And he's really won too many awards and honors from me to list here, but they include the coveted William McGuire Award presented annually at the San Antonio Breast Cancer Symposium-- and by the way, so have two of his mentees, Professors Mitch Dowsett and Ian Smith. And he's also won the Nancy Brinker Award. Many of you know Miss Brinker founded the Komen for the Cure Foundation. And perhaps what is perplexing to those of us in the colonies, in 2002 he and his twin brother Ray were named Commanders of the Most Excellent Order of the British Empire, or CBE for short-- which of course is one of the highest honors one can obtain in the UK-- for their work in breast in Trevor's case, and haematologic cancers in Ray's case.

Trevor, I know that a lot of your work also was done with a variety of other contributors, including Dr. John Kanis, Dr. Eugene McCloskey, and of course Sandy Patterson [? period. ?] You've always been quite generous in pointing out that they had a lot to do with your own contributions, and we appreciate that as well. Dr. Powles, welcome to our program.

Thank you very much, and thank you for those kind words.

Yeah. Actually, I interviewed someone a few weeks ago, and he said, "Geez, that sounded like my mother wrote that."

[LAUGHTER]

I have a number of questions for you, and I want to start out-- your research and your background was really in endocrinology of the 1960s. And that was a particularly exciting time for endocrinology with the discovery of the hormones not more than 20 years before that, and then the increasing knowledge of understanding of [? the ?] peptides steroid hormone receptors. What made you veer off from that field into oncology in general and breast cancer specifically?

When I was working at the Hammersmith Hospital doing my endocrinology [INAUDIBLE] endocrinology there. And one of the conditions we would be looking at would be hypercalcemia with hyperparathyroidism. And hypercalcemia was occurring very commonly in the breast cancer patients in the oncology and the radiotherapy department. [? And ?] to begin with, we thought this would just be another paraendocrine-type syndrome, and that was the thing that really fired my interest. From there, I then wanted to do my PhD to look more into what was causing the hypercalcemia with breast cancer, and that started the whole path of finding out about bone metastases, what they were doing, how they were causing the hypercalcemia, and the path just continued and continued.

Most of your work-- I'm going to get to some of the other things you've done-- has been endocrine therapy, endocrine processes, and the bone metastasis, which is really endocrinology. In the United States about that time, most of the excitement in the 60s was around chemotherapy. Was it difficult for you to stick with the endocrine approach?

No, it wasn't really. When I first started, all of in the endocrine treatment was ablative treatment. And I knew that from when I was doing my endocrinology is that the hypophysectomy, adrenalectomy, oophorectomy, those were the early days for chemotherapy at using combination chemotherapy and metastatic disease. [INAUDIBLE] and endocrine therapies were far better treatments from the chemotherapy. And although I was doing chemotherapy because we started with single agents then combination treatments-- and there was a lot of chemotherapy going on at that time at the milestone for haematological cancers, lymphoma, teratomas, et cetera-- I was able to do that, but I really focused on the endocrine side.

And coming back to the hypercalcemia, the one thing that really impressed me was when I was originally doing my endocrinology was that rapid response you could get to the hypercalcemia by ablative endocrine therapy for oophorectomy, or adrenalectomy, or hypophysectomy. And that was really the thing that started all of the research I did in bone. It started on my PhD with in vitro work. We set up bone assays, I went to Cambridge to [INAUDIBLE] very famous scientist Cambridge to teach us how to do the bone assays for in vitro bone assays. We also set up the animal model with breast cancer. We were able to show that breast cancers could cause bone breakdown and osteolysis in vitro.

We could find that we could block that by using drugs like aspirin, and that got us very interested in cross [? demandings. ?] We could then go into the animal experiments. And when we had a rat model using breast cancer that we knew from our assays caused bone breakdown in vitro, and when we did that in the animals by injecting into the aorta we could get bone metastases [? and ?] soft tissue tumor. When we gave aspirin, we could completely prevent the bone metastases-- quite dramatic experiments. And that was what really fired me into getting into the oncology, getting into the endocrine treatment in oncology because of my background in endocrinology. And that has stayed ever since.

So what was the timing there? This is the late 60s?

My PhD was 1970 to '73. I was at the Hammersmith from '67 to '69, and then I went to [? Barts ?] to endocrinology, and then I came back and then with Bondy in the Marsden, and then I got on the staff of the Marsden as a senior lecturer in 1975.

So what you just described to me sounds like translational science. That word wasn't coined until probably 20 years later. Was it unique where you were to be taking things from the lab straight out to the clinic? And where there obstacles to doing that?

No, there weren't. The thing that was good about that was we were doing the laboratory work based on what we'd seen, what I'd seen in the endocrinology with the hypercalcemia and the bone metastases, and responding to endocrine therapy. I then was in the PhD, doing the PhD, and then I was able to translate that into the clinic once I then became a consultant.

So the main work I was doing when I was first a consultant, the research work, was actually looking at hypercalcemia bone metastases in patients. We had a surprise because when we took the aspirin into patients, we could see no effect at all even though we'd had very dramatic effects in vitro and in vivo. And it was only when the bisphosphonates came through that we were able to then use those, because at this stage we knew it was working on osteoclasts. And it was only when we started to get the bisphosphonates that we really got into the dimension of first of all, being able to treat the hypercalcemia, then being able to switch off the bone metastases, bone pain, and bone fractures with bisphosphonates. And then take it into the adjuvant, I was then able to take it into the adjuvant scene and set up the first adjuvant bisphosphonate trial.

So I'd gone right from in vitro, I continued the path right the way through to clinical work. And then what happened was that if we did the bisphosphonate trial and we got the result of just like that had happened in the rats-- it stopped the development of bone metastases and it stopped the hypercalcemia in the rats, but didn't affect the soft tissue. So in the humans, we had exactly the same result where we were able to reduce bone metastases, not have an impact on soft tissue or other disease, and improve mortality. And so we've gone right the way through. It's a story that's extraordinary from my point of view, because I was able to follow the whole path all the way through. And you're absolutely right. That is a really good example of translational research where you hang in there until you get the answer.

What's the history behind transferring the bisphosphonates from prevention of osteoporosis in cancer? Now they're widely used as well as denosumab. In fact, it's malpractice not to use them in a patient with bone metastasis. How did you make that leap where you're standing next to somebody who was treating osteoporosis, and you said, "I wonder if that should work?" And how did you get hold of the drug? There's got to be a history behind it.

Well, we were looking. We were looking for [? anti-osteodiscitis ?] agents [INAUDIBLE] the aspirin didn't work but [INAUDIBLE] worked so we knew for no reasons at all that it would prevent, stop hypercalcemia. And so we were going down that path, and two really important people in the way the path was going. One was Herbie Fleisch, and Herbie Fleisch [? had ?] suddenly produced bisphosphonates. It was a terrific story if anybody was interested in bone, because it was an agent that clearly was working on osteoclasts, and that was the target we were after. We knew at that stage that the cancer cells had to activate osteoclasts in order to cause the bone breakdown and develop in bone.

And the second person who was key was Craig Mundie, who again I met. And I went over to the Boston Dental Hospital several times, and I met Craig and the others there, and that was linking up with being able to see the story that they were developing where tumor cells were activating osteoclasts that were then causing bone breakdown that was then producing growth factors to activate the cancer. So it became a really preferential site for bone metastases to develop because of the interaction between the cancer cells and the osteoclasts. So then there's Herbie Fleisch in Switzerland. I had a few skis with him. He was a very good skiier.

But the spin off was that bisphosphonates were going to be the thing that we really [INAUDIBLE] to be looking at. And then we tried four different bisphosphonates. Five foot was a guy in Amsterdam who had APD that was actually the forerunner for [INAUDIBLE]. And the one that worked best for us was clodronate, which we got originally from Finland.

And we set up the bone trials. We had to go through three stages. We had to-- first of all, before we could use adjuvant, we had to show that it worked in metastatic bone disease. And it did. It reduced what's called skeletal related events-- that's fracture, hypercalcemia, pain-- requirements of radiotherapy.

We then did a trial for phase 3 trial of using clodronate for patients who had metastatic disease but who didn't have bone metastases. And we could reduce the risk of them getting bone metastases. And then we had the justification for doing the--

So let me interrupt you for a minute. Now you're about 1983 or '4 I think when that was probably? Is that right?

It was-- yes, it would be. With the adjuvant trial, we would have started in '86. I think. That's the window of time.

And then in that trial, we didn't get the results from that until I think it was 1997 when we did the first analysis, and that we were able to then show in that randomized-- it was placebo controlled as well-- we were able to show a reduction in bone metastases and improved survival. And then we did a subsequent analysis in 2006. So we've got longer term data. Back then where other bisphosphonate trials were going on, adjuvant bisphosphonate trails going on, and then we had the meta analysis in 2015, Oxford meta analysis, which I was involved with Rob Coleman. And we did the analysis there, which confirmed that we could reduce bone metastases and improve survival with adjuvant bisphosphonates. So the story that starts from a test tube, so to speak.

Oh, there's one other very interesting experiment we [INAUDIBLE] that's never been repeated. Right at the beginning, we were able to show that doing co-cultures-- you're reminding me of things now-- doing co-cultures of the bone assay with human breast tumors I'd get from the Marsden while I was at the institute. We'd have fresh human tumors, and we would do a co-culture and some of them could cause the complete breakdown of the bone assay, and others would not have osteoporosis. And we did a follow up of those patients-- it was only about 30 patients, I think-- and we did a follow up of those patients, and those who had the most bone breakdown in vitro [? with ?] [? those ?] patients who were then going to get the bone metastases. That was a real incentive to show that link that we were getting. So we knew something was going on there.

And that experiment was going on in 1971. And in 2015 with the meta analysis of bone mets and mortality. So that's a long story. That's the story.

Let me say that this entire story reiterates the phrase that, "On the shoulders of giants we all stand." You look at the number of people you've laid out who led to this story, which is still ongoing. It's actually fascinating. I want to return just a minute to your work with endocrine therapy of breast cancer and your work with tamoxifen.

But first of all, a lot of young people listen to this. 'Cause I came in the field just as surgical ablation of many of the origins of estrogen was going away. Can you talk about what it was like to take care of the patients who were having hypophysectomies and adrenalectomies and oopherectomies? I recall thinking, "I'm an endocrinologist here. I'm not a medical oncologist," as a first year fellow taking care of Addison's disease and other things.

There are two things about ablative endocrine therapy. The first was that the responses could be very dramatic, and it was quite a high response rate. There was something [INAUDIBLE]-- don't forget we weren't basing it on ER. ER came later, and then [INAUDIBLE]. Even not based on ER, we were getting 30% to 40% response rates, particularly in bone.

The second thing is the management of the patients. The hypophysectomies were relatively easy, because I'd already got experience of patients who got pituitary failure from my endocrinology, and that's much it easier to manage. But the adrenalectomies are much more difficult because you can get very acute glucocorticoid symptoms if you're not getting cortisol, whereas in hypophysectomies it's a relatively slow process. And they were much more difficult to look after.

But the thing that was important about it was the fact that although we were doing it, these patients were getting hypercalcemia [INAUDIBLE]. You could have a patient who was hypercalcemia, you do ablative surgery, within 48 hours the calcium is back to normal. In fact, it will go hypoglycemic sometimes on bone hungry [INAUDIBLE] thing.

And from a clinical point of view, it was some of the best responses we ever saw even up to this time. Now one of the things that came out of that was that we had one patient-- I can say a name because he's long since dead and [INAUDIBLE] anyway-- her name was Mrs. Pottinger. It's engraved in my mind forever. And she had bone metastases, and she was not particularly well and also had some heart problem. And she was due to have adrenalectomy, and she wasn't well enough for adrenalectomy.

And so what I did is I'd used [INAUDIBLE] when I was at the Hammersmith as part of treating Cushing's disease. And so I'd already knew about medical treatment for-- so I then decided that we would do-- and I think it must have been the first patient. I had to get permission from [INAUDIBLE], and I still got the letter I wrote to the medical director of [INAUDIBLE] then saying could we use [INAUDIBLE].

So what we do is the basis was in order to get her well enough to have her adrenalectomy, and she did exactly the same as she would have done if we'd done adrenalectomy. Within 24 to 48 hours, she's getting better, the pain's going, the calcium's down. So she then refused to have an adrenalectomy. There's no way she is going to have it. She said, "No I'll continue with the [INAUDIBLE]." And she continued on [INAUDIBLE] for over a year before she died.

And that started a whole new thing. [? Ian ?] [? Smith ?] was my registrar at the time. And so we decided we'd do a phase 2 trial. We did a Phase 2 trial of [INAUDIBLE] on the understanding we were doing a medical adrenalectomy.

And that started the whole story that we were doing using [INAUDIBLE], because a [INAUDIBLE] came over, I had various other people come, and what we found was the story was. It wasn't the medical adrenalectomy by blocking postmenopausal estrogen. And then we went down the pathway of doing various, about three or four different aromatase inhibitors with Mitch doing all of endocrinology. It's a wonderful time. We had Adrian Harris, Charlie [INAUDIBLE]-- [COUGHING]. [INAUDIBLE].

[INTERPOSING VOICES]

That's a parade of stars. Were you talking across the Atlantic a lot during that time with Dick [? Stanton, ?] and Angela Brody, and the other two who were also--

Yes. Angela Brody was the one who got us a source for [INAUDIBLE]. That was the phase 2. Charlie led on that on the phase 2. That was Angela getting us to do that and linked him with Mitch. And Dick Stanton, yes it was a lot of collaborative work with Donald MacDonald. And a lot of the endocrinologists I knew. So that was how that whole story rolled.

That's an amazing library. Let me take you back now to your childhood. I know you and your identical twin, Ray-- by the way for the listeners, if you Google either Trevor or Ray Powles, you'll see pictures of the two of them standing together. And I challenge you to tell who's who.

[LAUGHTER]

Anyway--

Well I could. I could tell the difference.

Yeah I know you can tell the difference. I know that you were both young boys in London during World War II. Tell me about the experience then, and how your mother moved you.

Obviously, we were very young. My father was in the Navy abroad, so my mother was alone and was looking after my older brother David, who was four or five years older than us. And I can remember the bombing. I can remember quite a lot about it, surprisingly.

We were evacuated up into the north of England 1943, 1944, something like that. And we were there for I think something like six months. And it was an incredible story. I went back to see-- I hadn't been back-- I went back to see-- I was up in the north of England, and I suddenly thought I'll go over. We were at a place called Stockton. And so I was five when we left-- four, four years old when we left.

And I had no idea. I knew it was Stockton, and I knew the name of the house was the Priory, and I had a faint recollection of the door. And then I went up to Stockton, and I found the house we were in. And I knocked on the door, and it was a major-- a colonel-- Colonel Brown and his sister who lived there. And the sister was still alive, and she must have been about 90.

[INAUDIBLE].

And she looked at me and she said, "You're one of the twins."

[LAUGHTER]

So we had a chat.

[INTERPOSING VOICES]

At the time, did you think of this as being frightening, or was it just a great adventure for a young boy?

Yeah, I wasn't unaware of danger. My house was bombed down the road flattened and presumably a lot of people died, but I was unaware of danger as such. We had a shelter-- it's something called a [INAUDIBLE] shelter, I think it was called-- that was half buried with corrugated iron as the top thing. And if the siren went, I can remember that we would have to go out and get into the shelter. And we could hear the V-1s very, very-- I can still remember. You can hear the V-1s coming over. It made a hum-- [HUMMING] --like that.

And it's gradually getting louder and louder, and then it would stop, and then it would just fall out of the sky at an angle. It would go down at about 45 degrees. So if you could hear the [? stop ?] overhead, you weren't going to be hit. But if you could hear the [? stop ?] coming towards you, there was a chance you were going to get hit. I can remember that. Everybody was sitting listening to where these bombs were cutting out their engine.

So that's one of the things I can remember. And I can remember the V-2. It was a huge bang if one went off.

I know that you and Ray both also developed tuberculosis as young boys. What was the background behind that, and how were you treated?

Yeah, Ray-- we'd just finished school. And we weren't sure what we were going to do, and Ray had developed [INAUDIBLE], which again didn't mean anything to me. He coughed up a couple of times or [INAUDIBLE] of blood. And the next thing he's carted off and he's got tuberculosis, and he's been taken down to a sanatorium down near the Thames out along the marshes sort of thing. And he's there for six months. And during that six months, I can't see him and everything, and I thought, "Well, you know I'd like to do medicine. I think this is rather a good thing."

So what I did, I then applied for medical school and got a place. And then Ray gets better, and he then applies to medical school, and he gets a place as well. The dean said to Ray when he saw it, he said, "Haven't we seen you here before?" And Ray said, "No, it's my twin brother." And he then says, "Did we accept him?" And Ray said, "Yes." And then he said, "Pity."

[LAUGHTER]

And it was the end of the interview. The next thing, he's in as well.

[LAUGHTER]

And then I get TB, because it's about an 80% chance you get it if an identical twin's had it. And I was in the hospital for three months. So we were both back a year. I would have been a year ahead of Ray, but in fact then suddenly we're both back a year. And it was quite an interesting year for me, because I only had one subject to do. So I was able to do some reading, things like Darwin and that sort of stuff. And then we just carried on.

And you were treated with streptomycin in those days?

[INAUDIBLE]. You had 50 grams of strep.

Yeah, yeah. Sounds like you used that as a springboard to change the practice of medicine. So in every cloud there's a silver lining. The one thing I want to bring up-- I remember several years ago at one of the San Antonio meetings, and you and Dr. [? Bernie ?] Fisher were the bait. And he did all but call for you to be arrested and locked up because your study was negative, and of course the [? PL1 ?] one was positive. And you very graciously responded to that, "You know, Dr. Fisher, I didn't start this trial up to be negative."

[LAUGHTER]

That was a great response.

My goodness did I not admire him. The reason I did the trial is-- again, this is a funny story. I did a lot of horse riding, as you know. And what I did is after the 1985 first meta analysis, Oxford meta analysis, that was the first one to show that chemotherapy worked for the [INAUDIBLE] and other trials that chemotherapies show the reduction. And it showed that tamoxifen worked. That was the first meeting where I was really convinced that both those were positive effects.

Up till then, it was one trial and you couldn't be sure if it was going to be reproduced all the like. And that was the 1985 meta analysis meeting in Oxford. And then I came back home, and I got on my horse, and I rode for a week. I took the horse down to the South Downs. The South Downs is a long, expansive country, and it took me five days, I think it was, of riding to get across from one side to the other where I'd stop in a pub. I had to go down the week before and plan out exactly what I was going to do.

So I've got five days on a horseback thinking, and that was where I thought, "Well, where do we go from here?" You might say, well, let's do bigger and better chemo or the like, right? And you might say endocrine therapy, let's do more tamoxifen, or different doses, or [INAUDIBLE] down those paths. So I said, "But if you really want to do something different, the two things you could do would be for chemotherapy is why not give it before surgery?"

That was the time when I really thought neoadjuvant chemotherapy was where we ought to be going, because then we could see that they're responding or not et cetera. But tamoxifen, if it weren't for adjuvant therapy, then it should work for prevention. We had a clinic at the Marsden that I took over because somebody was leaving-- which was a family history clinic, and they all had very strong family histories three or four relatives, et cetera, et cetera. And I took over this clinic, and I thought to myself we could do a prevention trial here with tamoxifen. We'll do a pilot.

What happened at the Marsden they just had a ethics committee set up, one of the first in the world. This is in 1985. And it had never met, it had only passed the trials to be done. And so the first meeting of the ethics committee at the Marsden was to discuss the prevention, because it was such a awful thing to do. Do you know what I mean?

And but after two or three goes, I got it through the ethics committee mainly because a colleague of mine who was the head of medicine then was Tim McIlwain. He pushed it through because he said "Look, it makes so much sense." And we did a [INAUDIBLE] and we had an agreement that we could do 250 patients randomized, then go to 500. And then we had a national meeting to discuss setting up the national program. And so it was a feasibility trial actually looking to see what the toxicity was or whether it was acceptable to do it. And we had such a spin off from that, because tamoxifen at that stage was supposed to be a pure anti estrogen.

And we were screening all the tissues, we were doing bones that [INAUDIBLE] from the clotting factors. Everything. Cholesterol. We were doing, measuring everything in pre and post menopausal women. And everywhere we looked, tamoxifen wasn't acting as an anti estrogen. It was acting as an estrogen effect, so much so that at the Think Tank-- I presented it at the Think Tank, and I said, "Look these aren't [INAUDIBLE] tamoxifen and anti estrogen at all."

And I thought Mark, dear old Mark Lippert, was going to have an epilepsy, which 'cause it's correct because it is an anti estrogen breast cancer effect. But that was the first time. So then in the paper I wrote, I called it a selective anti estrogen. But I didn't coin [INAUDIBLE], but I did coin the expression, the first published thing of a selective anti estrogen.

I remember that paper.

[INAUDIBLE].

I remember that. So I want to finish up with just--

Let me just finish up one thing. Can I just finish up one thing?

[INTERPOSING VOICES]

Because it links into [INAUDIBLE]. So after Think Tank presented it possibly as an estrogen. And what was happening is we've got a bell shaped curve that was very narrow. So we were on the estrogen side as opposed to the anti estrogen side, right? And that was what was happening in the normal tissues. So I had a slides that said, "Tamoxifen is not an anti estrogen."

You probably remember if you were there. You were there. We go out on the boat, and we get stranded out of the boat in the mist-- the one you've mentioned about where you and I and Mark, et cetera-- when we're approaching the time after about four hours when we're thinking about meeting our maker, Mark says to me, "I've really got to have a word with you about this anti estrogen."

Well one other thing-- and this is going to be more my talking than yours. I really just touched on the surface of your contributions to the field, but I think probably the greatest is your mentoring history. And you've already hit on a few of these, but I travel extensively and I'm struck by the number of times I've been in some remote area-- or at least remote to me-- and corner of the world, and somebody-- it's usually my host-- volunteers that he or she trained at the Royal Marsden with Trevor Powles. And I think it's one of the things you should be most proud of all the many things you've done. And I want to know that you set up a system that was opening and inviting and also somehow funded to support people to come from all over the world.

What made you do that? How did you do that in the first place? It's hard to do.

Certain people came to me, which was very nice. We did have funds. I would be able to get funding even at that stage. There are many more hurdles for getting funding now than there were then. And the other thing about it was the fact that I find that people-- many times we've [INAUDIBLE] [? mentioning ?] things-- but one of the things I really did [? let ?] is let people have the run of doing things as opposed to me doing it maybe with the assistant. And that was very rewarding for me in terms of results and [INAUDIBLE], 'cause people were very motivated to do it, people like you, and Charlie, and the others.

So in some senses, I think it was the fact I was looking for the results we wanted to get rather than anything else. That's probably the basis of it, and therefore people came who ere good. And I'm very lucky I had very, very good people come.

So just to go through the list briefly-- Ian Smith, Mitch Dowsett, Troy [? Kohns, ?] Adrian Harris, Paul Goss, who am I leaving out? Anyway, it's a who's who of breast cancer, especially endocrinology and breast cancer. And they all came out of your brilliance. So we owe you not just for what you've done, but who you've trained to do even more.

Very kind of you to say that, but in fact they get the credit because if you look through my publication lists you can see.

Actually, I left out Steven Johnston, of course, who is--

Steve. Yeah, Steve.

Yeah. OK, we've run out of time. I very much appreciate the fact that you've taken time to come on and do that for us. I'm sure our listeners will be thrilled by the stories you've told-- at least I always am-- and it's great to hear most of them again. And I hope sometime we can even do this again. So thank you for all you've done, thank you for all the people you've trained, and thank you for taking time to do this today.

Well, thank you so much for asking me.

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