ASCO Guidelines

Dr. Douglas Peterson presents the latest evidence-based guideline from ISOO, MASCC, and ASCO on the prevention and management of osteoradionecrosis (ORN) in patients with head and neck cancer treated with radiation therapy. He covers topics such as recommended initial workup, best practices for prevention of ORN of the head and neck before and after radiation therapy, nonsurgical and surgical management of ORN, and management of adverse events associated with ORN. Dr. Peterson also comments on the importance of this guideline and what researchers should address moving forward. Read the full guideline, "Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: ISOO-MASCC-ASCO Guideline" at www.asco.org/head-neck-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/head-neck-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02750. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, bringing you timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all our shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today, I'm interviewing Dr. Douglas Peterson from UConn Health, lead author on "Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: International Society of Oral Oncology, Multinational Association for Supportive Care in Cancer, American Society of Clinical Oncology Guideline." Thank you for being here, Dr. Peterson. Dr. Douglas Peterson: Thank you, Brittany. My pleasure to be here. Brittany Harvey: Before we discuss the guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Peterson, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the topic we're here to discuss, Dr. Peterson, could you first provide an overview of the scope and purpose of this joint ISOO-MASCC-ASCO guideline? Dr. Douglas Peterson: I'll be pleased to do so, Brittany. Again, thank you for the opportunity to represent the panel in this guideline. The panel has strived to present a guideline that brings consistency in clinical practice regarding prevention and management of osteoradionecrosis of the jaw (ORN) based on the highest quality contemporary science. Given the mechanistic and clinical complexity of ORN, we also stress the importance of interprofessional oncology care of these patients. The team includes, but is not limited to, clinicians representing radiation oncology, head and neck surgery, medical oncology, otolaryngology, dental medicine, oral medicine, oral oncology, oral and maxillofacial surgery, and patient advocacy organizations. So it really is a collective enterprise that we bring to bear in the guideline. In some cases, the panel has been fortunate to be able to utilize a high quality evidence base in the literature upon which we could build strong recommendations. In selected other cases, however, we utilized informal consensus given the low evidence quality in the field. The recommendations presented have been carefully framed in this context, with the goal of providing state-of-the-science guidelines in clinical decision making and management of ORN. I'd also like to point out that the guideline brings linkage to other guidelines published by ASCO and other major oncology organizations, regarding management of symptoms and other supportive care needs associated with ORN. These companion guidelines include addressing pain, dysphagia, oral care, trismus, and psychosocial impact and survivorship, to name a few. I'd also like to say that combining the expertise of ISOO, MASCC, and ASCO has provided an important opportunity to produce this guideline. This has been a comprehensive effort by many experts. In addition to the outstanding input from the panel, I am also personally so very grateful for the expert input from ASCO's Evidence-Based Medicine Committee, as well as endorsements from other key organizations, including the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine as endorsees of the guideline. Finally in addition, Dr. Nofisat Ismaila's leadership as ASCO staff has been absolutely invaluable as well. Brittany Harvey: Excellent. I appreciate you providing that background on the development of this evidence-based guideline, which was developed by a multi-organizational and multidisciplinary panel. So to dive into the key recommendations of this guideline, this guideline addresses six clinical questions. So, starting with question one, what key points would you like to highlight regarding how ORN is characterized, graded, and reported, and what is the recommended initial workup for patients? Dr. Douglas Peterson: Osteoradionecrosis of the jaw of the mandible and maxilla should be characterized in the view of the panel as a radiographic, lytic, or mixed sclerotic lesion of bone, and/or visibly exposed bone, and/or, importantly, bone probed through a periodontal pocket or fistula. In the latter case, the clinical appearance of exposed bone may be extremely subtle. ORN is occurring within an anatomical site previously exposed to a therapeutic dose of head and neck radiation therapy. So we have a combined radiographic/clinical approach characterizing the lesion in the context of the patient having received previously a therapeutic dose of head/neck radiation therapy. We do recommend that clinicians evaluate ORN based on the most contemporary staging system, the ClinRad system, which is cited in the publication itself. We also advocate for the use of the ClinRad staging system not only in clinical assessment of patients, but also in clinical trials moving forward. We'll touch a little bit later on future research opportunities as well. Finally, the initial evaluation of ORN should include a clinical intraoral examination, and again, the appearance of exposed bone may be extremely subtle, and/or a formal radiographic examination. The guideline delineates the various types of radiographic examinations that we recommend. Brittany Harvey: Understood. Thank you for reviewing those recommendations regarding reporting and characterization of ORN, as well as the workup. The next section of the guideline, it focuses on best practices to prevent ORN of the head and neck prior to radiation therapy. What are the key recommendations of that section? Dr. Douglas Peterson: As with other adverse events in oncology patients, prevention is key. Prevention of ORN does require interprofessional management. The guideline lists several key recommendations along these lines. Now, an important caveat in what the guideline presents is that the target coverage of the tumor should not be compromised in order to avoid radiation dose to bone. So that's a very important caveat. Now having said that, focused effort should be made to reduce the mean dose to the jaw and the volume of bone receiving above 50 Gy whenever possible. So it's really a balance between maximizing target coverage of the tumor while limiting exposure to normal bone. In addition, a dental assessment by a dentist and dental specialist, if possible, is strongly advised prior to therapeutic-intent radiation therapy. The purpose of this assessment by the dental team is to identify and remove teeth which will place the patient at risk of developing ORN during the patient's lifetime, and to comprehensively educate the patient about the lifelong risk of ORN. Dental extraction in advance of radiation is often a consideration to these patients, and if clinically indicated, should occur at least two weeks prior to the commencement of radiation therapy. Now having said that, in the setting of a rapidly progressive tumor, extraction should be deferred and not cause delay in the initiation of radiation therapy. Brittany Harvey: So you just touched on key points of prevention prior to radiation therapy. Following those recommendations, what does the expert panel recommend regarding best practices to prevent ORN after radiation therapy? Dr. Douglas Peterson: This can be a challenging clinical issue. So the panel recommends that before finalizing dental treatment plans that may include extractions in patients with a history of head and neck radiation therapy, a review of the radiation therapy plan should be performed with particular attention focused on dose to the mandible and maxilla. For teeth in areas of high-risk for ORN, alternatives to dental extraction may be possible, for example, root canal or endodontic procedures, crowns, or dental restorations, or dental filling should be offered unless the patient has recurrent infections, intractable pain, or other symptoms that cannot be alleviated without extraction. So it really becomes a combined clinical decision making effort between the dental team and oncology team. One controversial area has been hyperbaric oxygen being administered prior to dental extractions in patients who have received head and neck radiation therapy previously. The panel does not recommend routine use of prophylactic HBO prior to dental extractions in these patients who have received prior head and neck radiation therapy. However, the evidence base here is limited with low quality and we offer a weak strength of recommendation. It is a controversial area, so we did also include a qualifying statement that prophylactic HBO may be offered to patients undergoing invasive dental procedures at oral sites where a substantial volume of the mandible and/or maxilla receive at least 50 Gy. This is an area of controversy. We can talk about this in the future research directions, but clearly, new high quality research related to the role of HBO in the management of these patients is needed. Brittany Harvey: Definitely. Thank you for touching on those points and that area of controversy. We can definitely touch on that a bit later as we talk about future research in this field. As you mentioned, Dr. Peterson, this guideline addresses both prevention and management. So, in moving into the management of ORN, how should ORN be managed nonsurgically? Dr. Douglas Peterson: The guideline relative to nonsurgical management of ORN is focused on the use of pentoxifylline. Now this maybe used in, and this is important, in cancer-free patients with mild, moderate, and severe cases of ORN. But pentoxifylline, the guideline also notes, is most likely to have a beneficial effect if the treatment is combined with tocopherol, antibiotics, and prednisolone as well. So there's clinical judgment involved in the nonsurgical management of ORN, centered with pentoxifylline in combination with tocopherol, antibiotics, and prednisolone. Brittany Harvey: Understood. And then expanding on the management of ORN, what are the key points for surgical management of ORN? Dr. Douglas Peterson: The panel offered several recommendations for which the strength of the recommendations was strong. Just to cite a few, in partial thickness ORN as defined by the ClinRad stage one and two that we talked about earlier, surgical management can start with transoral minor interventions which can lead to resolution over time. It may take time. It may take weeks or even a few months. Now this minimally invasive surgery may include debridement, sequestrectomy, alveolectomy, and/or soft tissue flap closure. Furthermore, small defects, clinically, for example, less than 2.5 cm in length, may heal spontaneously with local topical measures such as we described. It is recommended that larger defects, larger than 2.5 cm, in general be covered with vascularized tissue. Brittany Harvey: Appreciate you reviewing those recommendations regarding surgical management of ORN. So to wrap up our discussion of the recommendations with the final clinical question, what is recommended for assessment and management of adverse events associated with ORN? Dr. Douglas Peterson: This is a really important area as well in addition to prevention and management of ORN per se. The panel recommends that patients should be assessed by their healthcare providers for the presence of adverse events at the time of ORN diagnosis and periodically thereafter until the adverse event resolves based on patient status including any interventions or the adverse events that are clinically indicated. The panel and its literature evaluation learned that there is a relative lack of data specifically directed to the management of adverse events associated with ORN. However, this is such an important area that we wanted to address it head on. And so the management we recommend should be informed by pertinent available other guidelines that had been developed for analogous symptoms and/or disease states. The guideline provides links to these companion guidelines developed by ASCO as well as by MASCC and ISOO, the European Society of Medical Oncology, and NCCN. And so in the guideline we provide links on management of adverse events as produced by these other organizations. Table 3 presents a summary of the guidelines that address symptoms and supportive care needs associated with ORN. Brittany Harvey: Thank you for reviewing all of these recommendations. It's clear that the panel put a lot of work and thought into these recommendations and provided needed guidance in areas with limited evidence. We'll have links available in the show notes for listeners to be able to go and read these recommendations for themselves and refer to the tables that you mentioned. So in your view, Dr. Peterson, what is the importance of this guideline and how will it impact clinicians and patients with head and neck cancer? Dr. Douglas Peterson: As we talked about throughout this podcast, the guideline is designed to synthesize the contemporary science regarding ORN and translate that into recommendations for clinical practice in both prevention and management. As noted in the guideline, oncologists plus other interprofessional healthcare providers have been directly involved in the creation of the guideline, that interprofessional theme, which we believe is so essential given the mechanistic and clinical complexity of ORN. Now, in addition to the expertise of the panel, the pending widespread distribution of the guideline represents an additional important opportunity for extending the impact across clinical oncology. So in addition to the publication in the Journal of Clinical Oncology, dissemination by MASCC and ISOO as well as our endorsees, the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine will also be key in broadening the impact and hopefully the utilization of the guideline. And members of these organizations may very well be involved in the management of these patients as well. And then finally, the guideline is also designed to stimulate future research based on current gaps of the knowledge and we touched on some of those gaps, for example, with HBO for which new high quality research is needed. Brittany Harvey: Absolutely. It's great to have so many partners in this guideline and we hope that this guideline will have a large impact for patients with head and neck cancer to improve their quality of life. So then your final comment leads nicely into my last question and that we've already talked a little bit about some of the future research opportunities that this guideline highlights. So, to wrap us up, Dr. Peterson, what are the outstanding questions regarding osteoradionecrosis of the jaw secondary to head and neck radiation therapy in patients with cancer? Dr. Douglas Peterson: There are several key areas that the panel identified as we went through a rigorous review of the highest quality literature. Some of the key areas to address moving forward include: prospective studies are needed to evaluate the clinical presentation, trajectory, and response to treatment of ORN-related symptoms and function impairment, in other words, the adverse event side of the story. In addition, social determinants of health, quality of life, and psychosocial impact of ORN warrant further investigation in head and neck cancer survivors as well. In addition, new research including randomized controlled trials and prospective multicenter trials regarding the systemic and surgical treatment of ORN is also warranted, and we touched on, for example, hyperbaric oxygen. Hyperbaric oxygen has been a long standing management strategy of ORN. However, the trials to date are of limited quality in relation to supporting its use. So high quality new research related to the role of HBO in these patients is needed. And the expert panel also encourages creation of predictive tools, a priori tools, directed to development, grading, and staging of ORN. These could include, for example, bone turnover markers and genetic markers to name two. And finally, the research opportunities that are presented in the guidelines such as what I briefly summarized today should ideally be addressed in large prospective multicenter observational studies of risk, outcomes, and financial cost of ORN or the various treatment strategies that are highlighted in the guideline. Brittany Harvey: Excellent. Well, we'll look forward to research that addresses those outstanding questions and I want to thank you so much for your all your work on this guideline and for taking the time to share the highlights of this guideline with me today, Dr. Peterson. Dr. Douglas Peterson: Thank you. My privilege to do so, Brittany. Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.

Dr. Raymond Chan and Dr. Larissa Nekhlyudov share the newest standards and practice recommendations from MASCC and ASCO on survivorship care for people with advanced or metastatic cancer. They discuss highlights of the standards across seven domains: person-centered care, coordinated and integrated care, evidence-based and comprehensive care, evaluated and communicated care, accessible and equitable care, sustainable and resourced care, and research and data-driven care. Drs. Nekhlyudov and Chan also comment on the impact of these standards for clinicians and for patients with advanced and metastatic cancer and the goal of providing high-quality evidence-base survivorship care for all patients. Read the standards, "Survivorship Care for People Affected by Advanced or Metastatic Cancer: MASCC-ASCO Standards and Practice Recommendations" at www.asco.org/standards. TRANSCRIPT These standards, recommendations, and resources are available at https://asco.org/standards. Read the full text of the standards and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP.23.00716. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Larissa Nekhlyudov from Brigham and Women's Hospital and Harvard Medical School, and Dr. Raymond Chan from Flinders University, authors on, "Survivorship Care for People Affected by Advanced or Metastatic Cancer: Multinational Association for Supportive Care in Cancer (MASCC) and American Society of Clinical Oncology (ASCO) Standards and Practice Recommendations". Thank you for being here, Dr. Nekhlyudov and Dr. Chan. Dr. Raymond Chan: Thank you for having us. Dr. Larissa Nekhlyudov: Great to be here. Brittany Harvey: Then, before we discuss these standards, I'd like to note that ASCO takes great care in the development of its guidance products and ensuring that the ASCO conflict of interest policy is followed through each panel. The disclosures of potential conflicts of interest for the expert panel, including the guests on this episode today, are available online with the publication of the standards in the JCO Oncology Practice, which is linked in the show notes. So then, to dive into the content of the standards and recommendations. First, Dr. Chan, could you provide both an overview of the scope and purpose of these joint MASCC-ASCO standards and practice recommendations? Dr. Raymond Chan: Thank you, Brittany. First of all, as outlined and introduced by yourself, I would like to acknowledge that this is a great collaboration between the Multinational Association for Supportive Care in Cancer and ASCO. And if you may indulge me for a minute, I would like to give you a little bit of background of how this all started. It was in 2019 when I came across an article written by Ms. Terry Langbaum and Dr. Thomas Smith, who wrote a piece in the New England Journal of Medicine outlining the insufficient work and research done to advance care for people with incurable, long-term, metastatic cancer survivorship. And both Terry and Tom were living with metastatic cancer, and with their lived experience, they provided a new level of meaning to our work. And subsequently, in honor of Terry Langbaum, who is a renowned and esteemed hospital administrator who worked in cancer care, Dr. Thomas Smith and myself created the Terry Langbaum Cancer Survivorship Fellowship and appointed Dr. Nicholas Hart to complete this work. Within this work, we aim to develop international standards and practice recommendations to guide care for people living with treatable but incurable, metastatic, and advanced cancer. In this work, we conducted an extensive systematic review involving 81 studies, 17 guidelines, and framework documents, gathering the wisdom and consensus from 77 experts from 33 countries around the globe. Together, we reached consensus on 45 recommendations that we hope will be helpful for the clinical care community in improving care, experiences, and outcomes for people living with metastatic cancer. Brittany Harvey: Excellent. Thank you for providing this essential background information and describing the impetus for this project. Then, as you discussed, Dr. Chan, these standards and recommendations have over 45 recommendations within them. So I'd like to review each of those key points from each section. This document provides these standards and practice recommendations across seven domains. So to start with that first domain, Dr. Chan, what are the key points you'd like to highlight regarding person-centered care? Dr. Raymond Chan: Sure, Brittany. Now, without repeating what is in the document because I hope that this podcast can lead you to that document and for you to read it in detail, it is really around a comprehensive set of principles that experts felt were important to ensure that patients themselves participate in the care as much as possible. It is around respecting their agency and making sure that their clinical and psychosocial care needs associated with their metastatic cancer diagnosis are considered and addressed. Brittany Harvey: Absolutely. Thank you for providing those key points regarding person-centered care. So, moving into that next section, coordinated and integrative care, what points would you like to highlight there? Dr. Raymond Chan: Thank you, Brittany, for the question. The standards and recommendations within this section are really around articulating the coordination, navigation, and the multidisciplinary care team approach requirements for this population. In particular for people living with metastatic or advanced cancer, it is not a given that they will be able to access survivorship care services or palliative care services. And a lot of the time, we know that care access is around the resource setting. And a lot of the time, palliative care services may not necessarily be able to cover people living with relatively longer prognosis, such as this population, the longer term metastatic and advanced cancer population. Another point is around transition and the shared care arrangement between the oncology team, survivorship care clinicians where available, and the palliative care team. Once again, these recommendations really articulate the importance of a well-coordinated, integrated approach for these patients. Brittany Harvey: Absolutely. Those points that you just highlighted are important for care for the whole patient. So then, next, Dr. Nekhlyudov, I'd like to turn to you for the next couple of sections. Could you review what the highlights are for the next section: evidence-based and comprehensive care? Dr. Larissa Nekhlyudov: Yes. Thank you, Brittany. This standard emphasizes that people affected by advanced or metastatic cancer receive the most up-to-date, evidence-based, comprehensive, multidisciplinary, and interprofessional survivorship care and receive it in programs that continuously evolve their approach as guided by evidence. So as such, it is important that these survivorship programs are informed by ongoing professional development, including educational programs for healthcare professionals, that also includes active contributions by those affected by advanced or metastatic cancer. The other piece is that people affected by advanced and metastatic cancer should receive comprehensive care that encourages and supports informed decision-making in order to promote health, manage disease, and reduce stress. Brittany Harvey: Definitely, those are very important points regarding care of the patient. So then, moving into the fourth domain, Dr. Nekhlyudov, what are the key points for evaluated and communicated care? Dr. Larissa Nekhlyudov: So the famous line is, "What can't be measured can't be improved." And so it is important that clinicians routinely and systematically evaluate and monitor supportive care needs and provide appropriate referrals to relevant survivorship care services and healthcare professionals. In order to do that, we need to establish multidirectional communication systems that take into account communication with patients and communication across healthcare professionals involved in their care. Effective communication, of course, needs to be timely, it needs to be clear, effective, respectful, and appropriate. We all know that communication is challenging across cancer care, but it may be particularly so in this specific patient population. For example, in communicating with patients, cancer care clinicians may be comfortable communicating with those with early-stage cancers or patients with early- stage cancers. And may also have had training to communicate with those patients nearing the end of life. But as we already mentioned, those affected by advanced or metastatic cancer may have different needs and as such, it is important that there is additional training for clinicians to address survivorship care needs among these individuals and their caregivers. And then, in addition to patient-clinician communication, to enable timely communication and collaboration between multiple healthcare providers who may be involved in caring for these patients, enhanced and secure communication strategies are needed. And as with everything else, it's important that healthcare settings engage in service evaluations and quality improvement activities to continue to examine what works, what does not, and make changes that are needed. Brittany Harvey: It is important that these patients with metastatic or advanced cancer have their unique needs met by providing care and appropriate communication to them. So then, into the next section. Dr. Nekhlyudov, I believe Dr. Chan mentioned this briefly already in talking about being able to access care as part of integrative care. But what is recommended regarding accessible and equitable care? Dr. Larissa Nekhlyudov: Right. Absolutely. I mean, as with any healthcare or cancer care, the standard emphasizes that cancer survivorship care for all people affected by advanced or metastatic cancer is not only comprehensive but also accessible. So affordable, acceptable, available, appropriate, and equitable. And the key is that it does not vary based on someone's personal, cultural, or religious factors. It is important that health workforce diversity and cultural awareness training with the development and provision of culturally and linguistically appropriate resources, that these can help healthcare professionals better understand and cater to the unique needs of the cancer survivor and the caregiver populations. We also need to develop metrics to assess the evaluation and improvement and make sure that supportive care options are innovative, inclusive, and targeted towards eliminating disparities. Some of the work that Dr. Chan has otherwise led is looking at provision of telehealth and virtual care for cancer survivors. So particularly for this patient population, it is important to examine the potential benefits of virtual healthcare so that these patients who may have a lot of different needs, physical challenges, mental health challenges, caregivers, that we don't necessarily bring them to the healthcare setting and can potentially provide them the care that they need. And the last thing that I would like to point out with respect to this is that people affected by advanced or metastatic cancer may face additional challenges particularly returning to work in some capacity and should be supported by advocacy groups, or consumer groups as they are often called internationally, that advocate for accessible and equitable care and then work with specific personnel to access employment, financial and legal assistance that they may need. Brittany Harvey: Those are important for providing both inclusive and individualized care to every patient who a clinician may see. So then following those points, what is recommended and what are the key points you'd like to highlight regarding sustainable and resourced care? Dr. Larissa Nekhlyudov: Thanks, Brittany. This is a really important point, and not to take away from any of the other standards, but in order for us to provide ongoing high quality cancer survivorship care for people affected by advanced and metastatic cancer, we need to have a sustainable and adequately resourced approach to do so. So, these standards acknowledge that not all countries or healthcare systems have access to sufficient resources. As such, supportive care may need to utilize a step-care or resource stratified approach that offers the least resource-intensive care that aligns with the needs of the patient, but then also takes into account resources that are available, but really the care should not stop there. Survivorship care interventions and models of care should be cost-effective yet clinically relevant and meaningful and need to have the adequate financial investment by the healthcare systems. So healthcare settings providing survivorship care for those affected by advanced and metastatic cancer have to be properly resourced in order to provide high quality ongoing care. And this includes intentional planning for support services, and where healthcare settings provide these programs with adequate level of human resources, equipment, facilities, and leadership who value support, facilitate, and appropriately invest in such care. And as we mentioned before, it's always important to continue to evaluate what is being provided, what is being offered, sort of what are the return on investment metrics in order to continue to evolve the programs to serve the needs of the population. Brittany Harvey: Understood. I appreciate you providing highlights across these past couple of domains. So then to turn to the last domain, Dr. Chan, what is recommended regarding research and data-driven care? Dr. Raymond Chan: So the panel actively advocated for cancer registries to enable population-wide surveillance of the incidence and prevalence of people with advanced or metastatic cancer. Knowing the number of people with advanced or metastatic cancer is extremely important for care planning. We also advocated for the active involvement of people affected by advanced or metastatic cancer to participate in the co-design of research so that we can make sure that our research better meets the needs or end-users and enhance the rigor, relevance, reach, and impact of survivorship research. The last point I would like to highlight is that a number of survivorship trials out there only limit the population or the focus of the trial being on early stage disease, people treated with curative intent. And within this standards and principles, we advocated for research trials to explicitly include people affected by advanced or metastatic cancer in the clinical trials and trying to address also the barriers that impede people from enrolling or participating at all levels. Brittany Harvey: Thank you both for reviewing these key points, standards, and practice recommendations across these seven domains. These standards and recommendations cut really across all aspects of care for people impacted by advanced and metastatic cancer. Dr. Nekhlyudov, in your view, what is the importance of these standards and how they will impact clinicians? Dr. Larissa Nekhlyudov: Thank you for that question, Brittany. The MASCC-ASCO standards were developed, as we already mentioned, to promote the provision of high-quality, evidence-based survivorship care for people with advanced or metastatic cancer emphasizing the need for care that is person-centered, coordinated and integrated, evidence-based and comprehensive, evaluated, and communicated, accessible and equitable, sustainable and resourced, as well as research and data-driven. For clinicians, these standards and practice recommendations provide a critical resource in order to facilitate tailored and effective care for people living with advanced or metastatic cancer across disciplines and settings. As we know, and much of it is due to the efforts of ASCO, cancer care is always changing resulting in changing prognoses. As such, people diagnosed with cancer in the past that had poor prognosis are now living and are living longer. And so diagnoses that fall into this specific category of patients that we're discussing here today will continue to evolve. And likewise, advanced cancer is less clearly defined for other cancer such as hematologic or CNS malignancies, but these survivors may face similar issues and challenges. So overall, applying these standards will help provide survivorship care to these patients. And the important piece is that what we hoped to achieve with these standards is that when we consider survivorship care, we are not only applying it to those who have early stage disease. We're not applying it only to those whose disease has been "cured." We're not applying it to those who have been deemed disease-free or those who have completed treatments. We really need to make sure that clinicians understand the challenges experienced by often disregarded or forgotten population of cancer survivors and yet acknowledge the ever changing landscape of cancer survivors and appropriately apply these survivorship standards for people affected by advanced or metastatic cancer. And I think as Ray would probably say as well, we should focus on including rather than excluding people with cancer, all cancers, from survivorship services and programs. Brittany Harvey: Definitely. This is an important population with often unrecognized or unmet needs, and the goal of these standards, as you've mentioned, is to provide a better quality survivorship care for patients with advanced and metastatic cancer. So that leads nicely into my final question for you, Dr. Chan. In your view, how do these standards and recommendations impact people affected by advanced or metastatic cancer? Dr. Raymond Chan: As we continue to promulgate these standards of recommendations, I believe that patients will benefit from these standards in three ways. First, as clinicians, researchers, and service planners continue to improve care as per outlining the standards, patients are going to indirectly benefit from it. It is meant to lead to better care, better experiences, and better outcomes. Secondly, it is around the expectations of care. Many of us here would know that if we don't expect that care, it is unlikely that we would go and try to access it. And so it is extremely important that patients know what to expect. So now that I have been diagnosed with advanced or metastatic cancer, what does good care look like? So in the past, there are a number of pallaiative care standards whereby people are thinking, "Do I need palliative care? What does good palliative care look like?" Their set of standards. And now, these standards would enable patients to develop that expectation around what good care looks like. Thirdly is around the patients, the family units, and their navigators or their care networks to advocate for themselves, to advocate for the patient, to be able to access that care from the care team. So we hope that as we continue to promulgate these standards, that benefit would be translated into the real world for people affected by advanced or metastatic cancer. Brittany Harvey: Excellent. We definitely hope that this improves care for all patients impacted by advanced and metastatic cancer. So, I want to thank you both so much for this important work to develop these recommendations and standards. And thank you for taking the time to speak with me today, Dr. Nekhlyudov and Dr. Chan. Dr. Larissa Nekhlyudov: Thank you. Great to be here. Dr. Raymond Chan: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full standards and practice recommendations, go to www.asco.org/standards. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and 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, experiences, 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.

Dr. John Gordan, a leading expert from UCSF, shares insights on the latest ASCO guidelines for systemic therapy in advanced hepatocellular carcinoma. He details updated recommendations for first-, second-, and third-line treatments, emphasizing personalized care and team communication. The discussion also addresses treatment options for patients with liver function impairment and highlights the impact of clinical trial evidence on future therapies. Gordan explores the potential of combining local and systemic approaches to enhance patient outcomes.

Dr. Lisa Law and Dr. Randy Taplitz share the latest evidence-based recommendations from ASCO on vaccines in adults with cancer. They discuss recommended routine preventative vaccinations, additional vaccinations and revaccinations for adults undergoing HSCT, CD19 CAR-T treatment, or B cell-depleting therapy, guidance for adults with cancer traveling outside the U.S., and recommendations for vaccination of household and close contacts of adults with cancer. Dr. Law and Dr. Taplitz also share their insights on the guideline, including the importance of this guideline for adults with cancer and their clinicians, future advances in research, and current unmet needs. Read the full guideline, "Vaccination of Adults with Cancer: ASCO Guideline" at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00032 The ASCO Specialty Societies Advancing Adult Immunization (SSAAI) Project is supported by the Centers for Disease Control and Prevention (CDC) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award to the Council of Medical Specialty Societies (CMSS) (with 100 percent funded by CDC/HHS). The contents are those of the authors and do not necessarily represent the official views of nor endorsement, by CDC/HHS or the U.S. Government. Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I am interviewing Dr. Lisa Law from Kaiser Permanente and Dr. Randy Taplitz from City of Hope Comprehensive Cancer Center, authors on "Vaccination of Adults with Cancer: ASCO Guideline." Thank you for being here, Dr. Law and Dr. Taplitz. Dr. Lisa Law: Thank you. Dr. Taplitz: Thank you, Brittany. Brittany Harvey: Before we discuss this guideline, I'd like to take note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Taplitz and Dr. Law, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content, here first, Dr. Taplitz, can you provide a general overview of both the scope and purpose of this guideline on vaccination of adults with cancer? Dr. Randy Taplitz: Yes, so people with cancer often experience a compromised immune system due to a variety of factors. This includes chronic inflammation, impaired or decreased function of the hematopoietic system, and treatments that compromise their immune function. Because of this, people with cancer are at a higher risk for infection, including with vaccine-preventable diseases. Also, response to vaccines in patients with cancer may well be affected by this underlying immune status, and their anticancer therapy, as well as the severity of the underlying malignancy. The purpose of vaccination in this group of patients is to prevent infection or to attenuate the severity of the disease when infection cannot be fully prevented. This ASCO review builds on a 2013 guideline by the Infectious Diseases Society of America, or IDSA, and uses what's called a systematic literature review of 102 publications between 2013 and 2023. This includes 24 systematic reviews, 14 randomized clinical trials, and 64 non-randomized studies. The largest body of evidence in these studies, not surprisingly, addresses COVID vaccines on the efficacy and safety of vaccines used by adults with cancer or their household contacts. ASCO convened an expert panel to review this evidence and formulate recommendations for vaccinations in this population. Brittany Harvey: Understood. I appreciate that context, Dr. Taplitz. So then, next, Dr. Law, I'd like to review the key recommendations of this guideline. The guideline addresses four overarching clinical questions. So starting with the first question, what are the recommended routine preventative vaccinations for adults with cancer? Dr. Lisa Law: Thank you, Brittany. Before I start, I just want to wholeheartedly thank the first author of this paper, Dr. Mini Kamboj, Dr. Elise Kohn from the NCI, as well as the ASCO staff in putting this publication and guideline together. It is a very, very important guideline, and I echo everything Dr. Taplitz just said. So going back to your question, what are the recommended routine preventative vaccines for adults with cancer? As per this guideline, there are about 7 to 8 based on patient age and risk. Namely, they are: seasonal flu, RSV for those aged 60 or above, COVID-19, Tdap, Hepatitis B, Shingrix, Pneumococcal vaccine, and the HPV vaccine. These vaccines should ideally be given two to four weeks before therapy. However, non-live vaccines can be given anytime during or after chemo, immunotherapy, hormonal treatment, radiation, or surgery. Brittany Harvey: Excellent. Thank you for reviewing those vaccinations and the timing of them as well. So then, following those recommendations, Dr. Taplitz, what additional vaccinations and revaccinations are recommended for adults undergoing hematopoietic stem cell transplantation, CD19 CAR-T treatment, or B-cell depleting therapy? Dr. Randy Taplitz: Many studies have shown that stem cell transplant recipients essentially lose immunity from childhood immunizations, and we know that these individuals are very vulnerable to infection, particularly in the first year after transplant. Revaccination is critical to help restore their immunity. The optimal timing of vaccination is based on our understanding of adequate immune reconstitution with B and T-cell recovery so that the individual can mount a response to the vaccine. We know that a lot of factors influence this immune reconstitution, including the age of the stem cell transplant recipient, the source of the donor, the time from transplant, graft-versus-host disease prophylaxis, the treatment and severity of graft-versus-host disease, and the vaccine type and antigens used. There are a number of bodies throughout the world, IDSA as I mentioned, CDC, American Society for Transplant and Cellular Therapy, European Society for Blood and Marrow Transplant, and European Conference for Infections and Leukemia. All of these bodies have guidelines that approach vaccination in stem cell transplants. However, variation does exist in the use of a variety of things including whether to use immune predictors to help guide vaccination, and there is really not consensus on whether this immune predictor guided vaccination is more likely to produce a protective immune response versus a standardized schedule. In addition, the duration of protection is incompletely understood. The bottom line in these guidelines is that they recommend complete revaccination starting for most vaccines at 6 to 12 months after stem cell transplant, in order to restore vaccine-induced immunity. And I just want to go through a few of the particulars. For COVID-19, which is a three-dose series in the primary series, influenza - generally high-dose influenza - and pneumococcal vaccine, PCV20 in general, ultimately four doses, can be administered, starting as early as three months after transplant. Although there is really not much data to guide the use of the recombinant zoster vaccine in allogeneic stem cell transplant, the vaccine can be administered after the end of antiviral prophylaxis, which in general is 12 to 18 months after allogeneic and 3 to 12 months after autologous stem cell transplant. Some of the other vaccines, such as hepatitis B, Tdap, meningococcal vaccines, and HPV revaccination in those less than 45 are also recommended. I want to also spend the moment talking about the two recently licensed RSV vaccines, which were essentially studied in less compromised hosts and really without any immunogenicity data in stem cell transplant, and thus, there is no recommendation in this guideline for the use of these vaccines after transplant. Live vaccines, such as MMR and varicella – varicella would be in varicella-seronegative patients without a prior history of varicella – should be delayed for at least two years and only given in the absence of active graft-versus-host disease or immunosuppression. Moving briefly to CAR T, which is an immunotherapy that involves adoptive cell therapy, given the available data and after a review by the group, it was recommended that adults with hematopoietic malignancies receiving CAR T therapy directed against B-cell antigens should receive influenza and COVID-19 vaccines either two weeks before lymphodepletion or no sooner than three months after the completion of therapy. Administration of non-live vaccines preferably should occur before CAR T treatment or at least 6 to 12 months after, following the same timing as what we recommend for stem cell transplant. There is really little data to guide the safety and timing of administration of live vaccines after CAR T therapy. In terms of adults receiving B-cell depleting therapy, they are generally unable for time to mount an effective humoral response but may have at least partially intact cellular immune responses. They are encouraged to be revaccinated for COVID-19 no sooner than six months after completion of B-cell depleting therapy, and they should receive influenza vaccine approximately four weeks from the most recent treatment dose for patients on chronic therapy. For other non-seasonal immunizations, vaccines ideally should be given two to four weeks before commencing anti-CD20 therapy or delayed until 6 to 12 months after completion, except for the recombinant zoster vaccine, which can be given one month after the most recent dose of B-cell depleting therapy. Brittany Harvey: I appreciate you reviewing each of those vaccinations and when they should be given, and reviewing the available data – albeit, limited data – in these situations. So beyond these routine preventative vaccinations and revaccinations that you've both just described, Dr. Law, what additional vaccinations does the expert panel recommend for adults with cancer traveling outside the United States? Dr. Lisa Law: Good question. As per these ASCO guidelines, adults with solid or blood cancer traveling outside of the United States should follow the CDC standard recommendations for their destination. For the 2024 CDC Yellow Book, travel vaccines, in general, should be delayed until three months from the last chemotherapy or, and for those with solid tumors, ideally when the disease is in remission. Of note, hepatitis A, typhoid, inactivated polio, Hep B, rabies, meningococcal vaccine, and Japanese encephalitis vaccines are considered to be safe. In all cases of travel, patients should be counseled by their healthcare provider about the travel timing, with the additional attention to the regional seasonality of infections, for instance, influenza is more common in late summer in Australia, and also with attention to any outbreaks that may be occurring globally at the time of travel. Brittany Harvey: Absolutely. Those are key points for clinicians to discuss with their patients as they consider upcoming travel. So then, the final clinical question that the panel addressed, Dr. Taplitz, what vaccinations does the panel recommend for household and close contacts of adults with cancer? Dr. Randy Taplitz: Thank you. Yes, it is recommended that all household members and close contacts, when possible, be up to date on their vaccinations. And the only further thing I would say is that there are some special considerations for the use of live vaccines in household contacts, particularly in stem cell transplant recipients. Contacts of people who receive stem cell transplants should preferably receive inactivated influenza vaccines. As was mentioned, MMR and varicella vaccines are both safe to administer to close contacts. Vaccine strain transmission to immunocompromised hosts has not been associated with MMR use in family members. Eleven cases of the varicella vaccine strain transmission are described in the published literature, but none occurred in compromised hosts. Because the vaccine strain can cause severe and fatal varicella in profoundly immunocompromised people, precautions are advised to avoid close contact with a person with a vaccine-induced rash. For household contact travelers, MMR and yellow fever vaccines are considered safe. Oral cholera should be avoided. For smallpox vaccines, the second-generation ACAM2000 has rarely been associated with vaccinia transmission and should be avoided because of this. But the live replication-deficient MVA-based JYNNEOS vaccine is felt to be safe for household contacts of immunocompromised individuals. Brittany Harvey: I appreciate you reviewing the importance of vaccination for household and close contacts, and some of those precautions that individuals should take. I appreciate you both for reviewing all of these recommendations. So then in your view, Dr. Law, what is the importance of this guideline, and how will it impact both clinicians and adults with cancer? Dr. Lisa Law: In my opinion, this is a very important guideline that is long overdue in the oncology community and will have a huge impact on both clinicians and adults with cancer. Over the years, I have often been asked by my colleagues and patients, "Can I have the flu vaccine, and if so, when?" So this guideline really is going to be helpful. More importantly, our cancer patients are living much longer. They may have years of quality of life even with third or fourth line of treatment, especially, for instance, like CAR T for myeloma and lymphoma. However, we know that with additional treatment, that carries a substantial risk of infection complication among these immunocompromised patients. So it is of paramount importance to inform our patients and colleagues to be proactive in advocating preventive therapy ahead of time, meaning trying to get the patients appropriately vaccinated as early as possible to generate immunity. Another case in point is the Shingrix vaccine. I used to see lots of shingles, but ever since we have the recombinant Shingrix, I have fewer encounters. And this is huge because post-herpetic neuralgia robs a patient's quality of life. So, again, it is very important to recommend appropriate vaccines for our cancer patients. Brittany Harvey: Absolutely. It is key to ensure patients receive these preventative vaccines, and we hope that this guideline puts an emphasis on that for clinicians and patients. So finally, to wrap us up, Dr. Taplitz, what are the current gaps in knowledge regarding the vaccination of people with cancer? Dr. Randy Taplitz: There are a number of really important gaps in knowledge and really critical unmet needs that require research and other dedicated efforts. Among these are, and I think paramount, are really the participation of people with cancer with varied types of immunocompromise in vaccine trials. Where vaccine trials are only for cancer patients, obviously is ideal, testing vaccines in the appropriate population. But when that's not feasible, pre-existing cancer should not preclude eligibility, and inclusion of cohorts of people receiving anticancer treatment should be incorporated prospectively. So that's really critical because the quality of our guidelines is based upon the data. We use the data for developing guidelines and gathering more data in the particular patient population is really, really critical. Secondly, work for creating more immunogenic vaccines and research to understand the immune response to vaccines after immuno-depleting therapies, particularly with newer therapies such as CAR T and newer B cell therapies, bispecific antibodies, etc. is really critical. We need to really understand the immune response and have the most potent vaccines available to these people who may have impaired immune responses. Switching gears a little bit, we really need mechanisms to promote institutional commitment to integrate and sustain immunization best practices for people with cancer. This will largely be through multidisciplinary, team-based approaches, protocol-based vaccination standing orders, and leveraging data sharing so that we can all be on the same page with giving vaccines to these individuals. We also need education and evidence-based decision-making tools, emphasizing preventive care through immunization, the availability of educational resources to clinicians and patients to address commonly asked questions and also misconceptions about vaccination, that's absolutely critical. And finally, I think we need to develop strategies for addressing unique challenges and factors contributing to vaccine hesitancy during cancer therapy. We need to focus on patient and clinician communication, and very importantly, we need to consider health equity considerations in the development and approach to vaccines in these compromised patients. Brittany Harvey: Definitely, we'll look forward to research and advances in these areas that you've just described to support these guidelines and increase vaccine uptake. So I want to thank you both so much for your work on this important guideline, and thank you for your time today, Dr. Law and Dr. Taplitz. Dr. Lisa Law: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. 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.

Dr. Ilana Braun and Dr. Eric Roeland join us on the ASCO Guidelines podcast to discuss the latest evidence-based recommendations on cannabis and cannabinoids in adults with cancer. They discuss nonjudgmental patient-clinician communication, the relatively narrow cancer-related indications for which there is actionable clinical evidence for cannabis and/or cannabinoids, and key information for adults with cancer and their clinicians. Dr. Braun and Dr. Roeland also review the limited evidence regarding cannabis and cannabinoid use in adults with cancer and the outstanding questions and importance of research in this area. Read the full guideline, "Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline" at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcast hosts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Ilana Braun from Dana-Farber Cancer Institute, and Dr. Eric Roeland from Oregon Health & Science University, co-chairs on "Cannabis and Cannabinoids in Adults with Cancer: ASCO Guideline." Thank you both for being here Dr. Braun and Dr. Roeland. Dr. Ilana Braun: Thanks so much for having us, Brittany. Dr. Eric Roeland: Thanks, Brittany. Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Braun and Dr. Roeland, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then to jump into the content of this guideline, first, Dr. Roeland, could you give us an overview of both the scope and purpose of this guideline? Dr. Eric Roeland: Sure, Brittany. I think it's important for everyone to recognize just how common the issue of cannabis or cannabinoid use is amongst people living with cancer. And I think clinicians in academia as well as through community sites, we are asked about the use of cannabis on a daily basis. And so our target audience is really to focus on clinicians providing care to adults with cancer, but also the health systems in which we work because this is a very complex issue, as well as the people living with cancer and their caregivers, as well as researchers dedicated to this field. Brittany Harvey: So as you mentioned, this is a complex issue, and I'd like to review the key recommendations of this guideline. This guideline provides recommendations across three clinical questions that the expert panel targeted. So, starting with the first question, what is recommended for patient-clinician communication regarding cannabis or cannabinoids? Dr. Ilana Braun: Given the high prevalence of medicating with cannabis or cannabinoids that Eric references, somewhere in the neighborhood of 20% to over 40% of adults with cancer consume cannabis products, ASCO's guideline offers the following common-sense, good practice statement: In the clinic, providers should routinely and non-judgmentally inquire about cannabis consumption or consideration of cannabis, and either guide care or direct adults with cancer to appropriate resources. In other words, the guideline works to fully destigmatize this conversation. The guideline goes on to offer suggestions for taking a cannabinoid and cannabis history. This includes the goals of use, how the products are sourced, what formulations are being used (including the ratios of active ingredients like THC and CBD), the inactive ingredients (for instance coconut oil), whether it is herbal or synthetic, and whether the product is pharmaceutical grade or non-pharmaceutical grade. And then other questions like routes of administration, dosing schedules, perceived benefits and risks, and whether the products are being used adjunctively or as a replacement for standard treatments. It is also probably important to query potential contraindications, such as a history of cannabis use disorder or psychosis. Brittany Harvey: Thank you for reviewing those good practice statements. Those are key for non-judgmental communication and taking an accurate and complete history. So following those statements, the expert panel next addressed the question: Does use of cannabis and/or cannabinoids by adults improve cancer-directed treatment? What recommendations did the expert panel provide for this section? Dr. Eric Roeland: When we think about the use of cannabis or cannabinoids in treating the underlying cancer, it's incredibly important to recognize the excitement that patients and clinicians have around the potential promise. Much of this data is generated from preclinical models. However, when we're engaging patients consuming cannabis or cannabinoids to augment their cancer-directed treatment, we could find no evidence to support its use. And so we do not recommend that patients be using it to augment treatment, nor do we recommend that patients should be using it instead of their cancer-directed therapy. And I think this is a major challenge for multiple oncologists, where their patients may be using these with a goal of treating their cancer, and then present with very advanced cancer and/or multiple poorly controlled symptoms. Dr. Ilana Braun: And I think that there are some areas of particular concern. For instance, there were two oncologic cohort studies that suggest that cannabis, which we know is an immune modulator, may actually worsen immunotherapy outcomes. These outcomes included median time to progression and overall survival. There are obvious limitations of preliminary observational data, and we now need to gather prospective, gold-standard data. But for the time being, the guideline recommends that clinicians should advise against adults receiving immunotherapy from medicating or considering medicating with cannabis and cannabinoids. And then I think there are some additional reasons for concern. First of all, this type of therapy tends to be very expensive and not covered by insurance and there are some risks for drug-drug interactions, in terms of pharmacodynamic ones, Cannabis may exacerbate neuropsychiatric side effects of opioids and even benzodiazepines. In terms of pharmacokinetic drug-drug interactions, it's not a particularly risky substance, but there are three to be wary of in particular: warfarin, buprenorphine, and tacrolimus all have high-risk interactions with cannabinoid products. Brittany Harvey: I appreciate you both for reviewing these recommendations and evidence regarding the use of cannabis and/or cannabinoids regarding cancer-directed treatment. So then the last clinical question, Dr. Braun, what is recommended regarding use of cannabis and/or cannabinoids in managing cancer treatment-related toxicities and/or symptoms? Dr. Ilana Braun: The first thing to make clear is that high-quality clinical evidence evaluating the utility of cannabis and cannabinoids for adults with cancer is limited as Eric has said. The evidence that does exist weakly supports a practice of using cannabis and cannabinoids to address refractory chemotherapy-induced nausea and vomiting when standard treatments have failed. For other potential oncologic indications, like management of cancer-related pain, there is weak, negative, conflicting, or no evidence. But that being said, a 2017 monograph published by the National Academies of Science, Engineering, and Medicine concluded that there is substantial evidence that cannabis is an effective treatment for chronic non-cancer pain, and I'm sad to say, that chronic non-cancer pain happens too in adults with cancer. Brittany Harvey: Thank you for reviewing those recommendations as well. So you've both touched on this a little bit in that patients are often asking clinicians for recommendations regarding cannabis and/or cannabinoids, but in your view, what is the importance of this guideline, and what should clinicians know as they discuss these recommendations with their patients? Dr. Eric Roeland: Probably one of the most important points is for clinicians to ask and to be open and to create a space where our patients are telling us about what they're using. I think we've all had patients that we've been surprised that have been using cannabis or cannabinoids in conjunction with other medications that may increase the risk of unwanted side effects or risks, including sedation or falls. I also find it challenging that many patients are receiving recommendations for the use of cannabis or cannabinoids directly from friends or family instead of through their medical providers. Therefore, I think one of the very first things is to just make sure that you're asking about it and then inquiring what the goal of their use is. When we talk about the use of cannabis, we also need to recognize the difference between the available data that can guide us in evidence-based recommendations, as well as the enthusiasm and available access that patients have to cannabis that has really outpaced our ability to research it. So it's important to recognize these tensions that we're living with in clinic day-to-day. Brittany Harvey: Absolutely. Those points are key for clinicians as they discuss this complex issue with their patients. Following that, how will these guideline recommendations affect adults with cancer? Dr. Ilana Braun: One really important takeaway from these guidelines is that they clearly state that cannabis and cannabinoids are medicinal, and for a medical community to clearly articulate this point is notable. I suspect they will provide encouragement, legitimacy, confidence, and even a script to oncology clinicians who were previously reticent to inquire, document, and provide clinical recommendations around non-pharmaceutical cannabis and cannabinoids. It may have a similar effect even at the institutional level in terms of supporting these practices. At the same time, I suspect they will encourage those who are recommending oncologic use of cannabinoids and cannabis for myriad cancer-related indications to adopt a more circumscribed approach. The reason I say this is that the cancer-related indications for which there is actionable clinical evidence at this time are quite narrow. So all this to say, I believe these guidelines will lead to greater transparency around cannabis decision-making in the clinic, as Eric mentions, but also lead to a possible narrowing of indications for which cannabis is clinically recommended. Dr. Eric Roeland: Another major role of the use of these guidelines in clinical care is informing clinicians and patients about cannabis. Cannabis has been used by humans as a plant for thousands of years, and although it's a very complex plant with hundreds of parts, the two parts that researchers have studied most are delta nine-tetrahydrocannabinol, or THC, and cannabidiol, or CBD. In rough terms, THC can cause a high feeling, while CBD typically does not. And there are multiple types of products that have different ratios of THC and CBD. So it's critical for people to understand what those ratios are, how many milligrams of those things there are, as well as what are the programs within your region to measure or quantify what's actually in the products you're consuming. If a person with cancer medicates with cannabis, most oncologists would prefer that they use it by mouth, such as an edible, rather than inhaling or smoking cannabis given concerns about potential impact on lung function. One challenge when consuming cannabis by mouth is that it can take up to two hours to have its full effect. So patients should be very careful not to take too much or to stack their doses, which can cause sedation, confusion, and even increase the risk of falls. Whereas when patients are consuming cannabis by breathing in a smoke or vapor, they typically feel the effects almost right away, which is why patients sometimes prefer smoking or vaping as their preferred route of administration. Brittany Harvey: Understood. Definitely. We hope these guidelines provide key information and clarity for both adults with cancer and their clinicians. So then, finally, you've both mentioned that there is limited evidence regarding cannabis and cannabinoid use in adults with cancer. So what are some of the outstanding questions regarding cannabis and cannabinoids in cancer care? Dr. Eric Roeland: Thanks, Brittany. I think the questions also align with priorities for future research, and we need to recognize that the lack of evidence aligns with some of the challenges of funding research in this space. However, ongoing future research priorities include what is the nature of healthcare disparities pertaining to medical cannabis use by adults with cancer, and what are effective means to address these disparities? We also wonder, what are the optimal strategies to maximize communication in the oncology clinic regarding medical cannabis and/or cannabinoid use? And when we're thinking about cannabis and/or cannabinoids for cancer treatment specifically, we still need to know do cannabis and/or cannabinoids possess clinically meaningful anticancer activity in humans. We also need to understand what are the drug-drug interactions with our standard-of-care cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, radiation, and combinations of all the above. We also are wondering what the effect of cannabis and/or cannabinoids on outcomes in adults with cancer receiving some of our newer therapies, including antibody-drug conjugates and some of our newer vaccine therapies. Dr. Ilana Braun: I might add that collating the existing research as the guideline did is a very good first step and should serve to highlight where the gaps in knowledge lie. This guideline discusses some of the unique challenges to conducting cannabis and cannabinoid research, including limitations in funding source and study drug, red tape procedures, and issues around legalization. I believe it will take a group of highly determined and creative researchers to move the needle forward in this area, but we must. Brittany Harvey: Definitely. Thank you both so much for all of your work developing this guideline and creating these evidence-based recommendations. And thank you for taking the time to come on the podcast today and teach us all a little bit more about cannabis and cannabinoids in cancer care. And thank you for your time, Dr. Braun and Dr. Roeland. Dr. Ilana Braun: Thanks so much, Brittany. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and 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.

Dr. Angela DeMichele, Dr. Lynn Henry, and Dr. Harold Burstein present the latest breast cancer rapid recommendation update impacting two ASCO guidelines. This update focuses on the new option, capivasertib plus fulvestrant, for patients with hormone receptor-positive, HER2-negative metastatic breast cancer with activating PIK3CA or AKT1 mutations or inactivating alterations in PTEN based on data from the recent CAPItello-291 trial. They discuss the updated recommendations on lines of endocrine treatment and selecting between the options for patients with activating PIK3CA mutations. Additionally, we discuss implications for clinicians and patients, and what ongoing research is occurring in the field. Read the latest update, "Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer – Capivasertib-Fulvestrant: ASCO Rapid Guideline Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00248 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute, Dr. Angela DeMichele from the University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, co-chairs on "Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Capivasertib–Fulvestrant: ASCO Rapid Guideline Update." Thank you for being here, Dr. Burstein, Dr. DeMichele, and Dr. Henry. Dr. Harold Burstein: We're happy to be here. Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes. So then, to kick us off, Dr. Burstein, could you first describe what prompted this rapid update, which provides updated recommendations for two ASCO guidelines: the biomarkers for systemic therapy in metastatic breast cancer guideline, and the endocrine treatment and targeted therapy for hormone receptor-positive, HER2-negative metastatic breast cancer guideline? Dr. Harold Burstein: Thanks, Brittany. Well, this team has been working, as you mentioned, actually, on two guidelines, which are clearly evolving in parallel and kind of converging, actually, when you look at data, as we'll be talking about in the next few minutes. The particular catalyst here was a large randomized clinical trial which looked at a new targeted therapy in the space of estrogen receptor-positive, HER2-negative breast cancer. That drug is capivasertib. And the trial was the so-called CAPItello study. In that trial, patients who were receiving second-line therapy with fulvestrant were randomized to that treatment alone, or that plus capivasertib. So the data from that study were the first strong signal that we needed to update the guideline because they were important clinical data. The other strong signal was that the drug was tested in a cohort of patients who had a specific set of mutations in their cancers. And that included PIK3CA mutations, a class of mutations for which we already had a targeted drug. But it also included some new potential targets, including mutations in the AKT gene itself, capivasertib is an AKT inhibitor, as well as loss of PTEN protein functionality, which potentially sensitizes tumors to the targeted action of this drug as well. So while we had a couple of guidelines catching up on the endocrine therapy space, which is increasingly looking like a targeted therapy space, it was clear that this major study, which had clinical and diagnostic implications, would sort of push them together and served as the impetus for updating both guidelines at the same time. Brittany Harvey: Understood. I appreciate that background information. So then, Dr. DeMichele, based on this updated data that Dr. Burstein just described, what is the updated recommendation from the guideline panel regarding lines of endocrine treatment? Dr. Angela DeMichele: Well, I think this is where the biomarker evolution that Dr. Burstein just referred to really comes in because now we have the opportunity to perform genomic testing in patients who have ER-positive, HER2-negative metastatic breast cancer, on either the tumor or commonly from the blood. And we can now start to tailor treatment to the specific genomic abnormalities that that patient's tumor contains. So now our guideline really marries both the genomic abnormality with the therapeutic option. First-line treatment remains endocrine therapy plus a CDK 4/6 inhibitor. But things then really start to diverge once we enter second and third-line therapy because at that point, we now have the option to test for several genomic markers: ESR1 mutations, PIK3CA mutations, AKT1 mutations, and PTEN inactivation. And based on whether the tumor has one or any of those mutations, we can then select the therapy based on that. So in the case of capivasertib, as you just heard, that is a therapy for patients whose tumors have PIK3CA mutations or activating mutations in AKT1 or loss of PTEN. But other patients who don't have one of those mutations may, in the second line, go on to another drug. For example, if they have an ESR1 mutation, they then may be eligible to take elacestrant. Patients who have no targetable mutations still have a targeted option in that they can use everolimus. And in all of these settings, the endocrine therapy partner for this line of therapy is typically fulvestrant. So now we're really starting to tailor therapy in the second- and third-line based on genomic changes. Brittany Harvey: Excellent. That information is helpful for choosing optimal therapy tailored to the individual patients, as you just described. So then, Dr. Henry, what guidance does the expert panel provide regarding choosing a PIK3CA targeted option? Dr. Lynn Henry: Thank you. So for patients whose tumors are found to have an activating mutation in PIK3CA, we now have two drug options: either alpelisib or capivasertib in combination with fulvestrant. And the problem is, these drugs have not been compared head-to-head. We can't say that one is clearly better than the other, either in terms of efficacy or in terms of side effect profile. What we do have is information from two separate trials in which they were each tested against placebo. The efficacy appears to be fairly similar based on the data that we have. It does appear that the side effect profiles may be slightly different. And so, when you have a patient sitting in front of you and you're trying to decide how best to treat her, you really have to think about, what symptoms does my patient already have? What is she more or less likely to tolerate? So what we do know is that it appears that the rates of grade 3 diarrhea and rash were slightly higher with capivasertib. It looks like hyperglycemia was higher with alpelisib, as was treatment discontinuation. So really you have to make an individualized decision when you have a patient sitting in front of you about which drug you'd like to try. Of course, if someone doesn't tolerate one drug, you can always switch to the other one. Brittany Harvey: I appreciate that analysis and to provide guidance without a head-to-head trial and to specifically provide options based on an individual patient's profile. So then, Dr. DeMichele, what should clinicians know as they implement these new recommendations? Dr. Angela DeMichele: Well, first of all, I think most clinicians now are becoming more familiar with the procedures required for doing genomic testing. But this is something that now has become the standard of care. And so, it is incumbent upon all of us who treat these patients to understand what the options for genomic testing are for that patient, which companies offer this testing, how to send a sample, and how to interpret the report that comes back. So, I think this has really added a level of complexity to the therapy for patients. I also think that one can't simply apply an algorithm to a patient. We have to really treat the whole patient and we have to take into consideration, as Dr. Henry said, the toxicities of these agents and the cost which is also a major issue. So I think that while it is more complex, really that doctor-patient relationship is so important in communicating what these genomic tests mean for a patient and for their options, and also important for the clinician to really understand what the different therapeutic agents might mean for a patient, and really try to pick the agent that's best for that patient. Using genomic testing is just one of several different features that they'll consider. Brittany Harvey: Absolutely. It's key to obtain the data needed to select appropriate patients and to recognize the complexity. So then, Dr. Henry, in your view, how will this update impact patients with metastatic breast cancer? Dr. Lynn Henry: Yes, so as we've discussed, I think this is really exciting. Over the last few years, we have had quite a number of new medications that have become available for patients and have been FDA-approved. And so this is yet the latest in a series. For those patients whose tumors have a PIK3CA mutation, as we discussed, there are now two options. So you have a choice depending on which one is better covered by insurance, by which one you may tolerate better. But I think the other thing is now, although it's a smaller subset of patients, there are patients out there whose tumors have mutations in AKT1 or alterations in PTEN, and so there's an entirely new endocrine therapy-based option available for them that wasn't available before. So I think that thinking about the new data that are out there, the new drugs that are out there, really is exciting because there are new options available and hopefully there are more to come as well. Brittany Harvey: Absolutely. It's great to have these new options. So, finally, Dr. Burstein, Dr. Henry just mentioned what's to come. Could you touch on what some of the outstanding questions are regarding endocrine therapy for patients with metastatic breast cancer? Dr. Harold Burstein: A couple of things to say. First, ER-positive metastatic breast cancer is the most common kind of metastatic breast cancer, roughly three quarters of metastatic cases of breast cancer will be hormone receptor-positive cancers. So this is a very big public health issue around the world, actually, breast cancer being the number one most commonly diagnosed cancer of women around the world. So minor or major improvements in treatment for advanced ER-positive breast cancer really have a tremendous impact. The second thing is it's been remarkable to see the progress in the past decade. We've gone from simply targeting the hormonal access itself with medicines like tamoxifen or aromatase inhibitors or an injectable selective estrogen receptor degrader like fulvestrant to incorporating targeted therapies at the same time. And this whole class of drugs called CDK4/6 inhibitors has emerged which we use in either first- or in second-line therapy. Those drugs have transformed our standard of care, improved survival for patients with advanced ER-positive disease, now with median survival nearly 50% longer than what we had seen in the past. And if you've heard, we have a wealth of opportunities. We can target PIK3CA, we can target ESR1 mutations. Other drugs emerging in the space include PROTACs which is another way of degrading the estrogen receptor. And so there's going to be more progress in the years to come. So one of the biggest challenges has been to try and understand, is there really an optimal way to use these drugs, or can we be smarter about the particular sequence of all these particular things that are happening. So one example of this was a recent study that is on a drug, not as yet FDA-approved, called inavolisib, which is a PIK3CA targeted drug used in first line in combination with a CDK4/6 inhibitor and endocrine therapy. And that study, for a high-risk group of women with ER-positive metastatic disease, actually showed a dramatic improvement in overall survival, asking the question if combining some of these targeted therapies together might yet further improve outcomes. And as you've heard from the diagnostic space, one of the other interesting things is that tumors evolve over time. And so acquisition of the estrogen receptor mutations, ESR1 mutations, which are typically not found early in the course of advanced breast cancer but otherwise later, now have targeted treatments. So there's a whole bunch of stuff going on all at the same time, including multiple ways of targeting things, serial testing to look for acquisition of ESR1 mutations and new pathways to explore. It's an embarrassment of riches in some respects because it has meant it's actually really hard to write a guideline as you've heard, which says, "Do this first, do this second, and do this third." I suppose that's a good problem to have under the circumstances, but it's going to require really thoughtful clinical trials and careful analysis to help guide specific lines of treatment recommendations like that. Brittany Harvey: Excellent. We'll look forward to these exciting, continuing developments for patients with metastatic breast cancer. And I want to thank you all so much for your work to develop this rapid recommendation update for these two guidelines. And thank you for taking the time on this podcast today. Dr. Harold Burstein: Thanks. Dr. Lynn Henry: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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, experiences, 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.

Dr. Natash Leighl and Dr. Jyoti Patel discuss the updated living guideline for stage IV NSCLC with driver alterations, covering therapies for EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They emphasize key changes, recent trials, importance of biomarker testing, and impact on clinicians and patients. Stay tuned for future updates.

Dr. Patel and Dr. Leighl discuss updated guidelines for treating stage IV NSCLC without driver alterations, focusing on biomarker testing and treatment options. They explore the impact of immunotherapy over chemotherapy in first-line treatment and emphasize the importance of patient-clinician communication to improve outcomes.

Drs. Banu Arun and Sana Al Sukhun discuss the ASCO resource-stratified guideline on systematic treatment for metastatic breast cancer. They highlight the four-tier resource setting approach, key recommendations for different breast cancer subtypes, and implementation considerations. This guideline is crucial for optimizing cancer care in regions with limited resources.

Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on "Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline." Thank you for being here, Dr. Bedrosian and Dr. Robson. Dr. Mark Robson: My pleasure. Dr. Isabelle Bedrosian: Thank you, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline? Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management. Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space. So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing? Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation. Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to. Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing. So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing? Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation. Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will. Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing. Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled? Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling. Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate. Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families? Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk. And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations. Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do. Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well. So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer? Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier. And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do. Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is "I'm at risk and I would like to reduce my risk." And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with. Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps. So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian. Dr. Isabelle Bedrosian: Thank you, Brittany. Dr. Mark Robson: Thank you for having us. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.