In this episode, we review the high-yield topic of ⁠⁠Pancreatic Cancer⁠⁠⁠⁠⁠⁠⁠⁠ ⁠⁠from the Oncology section.

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In this episode, we review the high-yield topic of Pancreatic Cancer from the Oncology section.

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In this podcast, Dr. Wiliams speaks with pancreatic cancer experts Dr. Ursina Teitelbaum and Dr. Nuzhat Ahmad about pancreatic cancer diagnosis and management, and then Dr. Bryon Katona joins to discuss pancreatic cancer prevention and GI oncology genetic workups in general.

Pancreatic cancer is the third most common cause of cancer death in the United States. Timothy Donohue, MD, chief of surgical oncology at the University of California, Los Angeles, provides an overview of the disease.

Read the articles:

Screening for Pancreatic Cancer

Pancreatic Cancer

Interview with Chyke A Doubeni, MD, MPH, USPSTF member and coauthor of Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement

Is cancer screening worth it, and how can GPs have that conversation?

This episode of Deep Breath In explores the intricacies of assessing risks and benefits of cancer screening, featuring Michael Bretthauer's insights from a JAMA Internal Medicine study.

That meta-analysis combined efficacy of various cancer screening studies - and found most screenings showed minimal gains in extending overall life expectancy, though some slightly reduced cancer-specific mortality.

That leaves GPs with the challenge of communicating these nuanced findings to patients. Michael explains how he tries to convey complex concepts to patients, despite the societal inclination toward extensive testing despite low risks.

Reading list;

Jama paper - Estimated Lifetime Gained With Cancer Screening Tests
A Meta-Analysis of Randomized Clinical Trials

The BMJ analysis  - Current policies on early detection of prostate cancer create overdiagnosis and inequity with minimal benefit

Interview with Brent S. Rose, MD, author of Association of Prostate-Specific Antigen Screening Rates With Subsequent Metastatic Prostate Cancer Incidence at US Veterans Health Administration Facilities. Hosted by Jack West, MD. Related Content:

• Association of Prostate-Specific Antigen Screening Rates With Subsequent Metastatic Prostate Cancer Incidence at US Veterans Health Administration Facilities

The utility of prostate-specific antigen (PSA) screening for prostate cancer detection is impacted by detection of cancers with low risk of mortality. Editorialist Jeffrey J. Tosoian, MD, MPH, discusses a pragmatic approach to prostate cancer screening with JAMA Deputy Editor Mary L. (Nora) Disis, MD. Related Content:

• A Pragmatic Approach to Prostate Cancer Screening
• Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI
• Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality

Interview with Katrina E. Donahue, MD, MPH, USPSTF member and coauthor of Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. Hosted by JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS. Related Content:

• Skin Cancer Screening
• Screening and Prevention of Skin Cancer
• Screening for Skin Cancer
• What Is Mohs Surgery?
• Skin Cancer Screening

Colorectal cancer is one of the most common cancers diagnosed each year worldwide. This highly anticipated series will take an in-depth look at this disease. In this first episode, we discuss the basics, including staging, tumor markers, and microsatellite instability testing, before tackling the management of colorectal cancer in upcoming episodes.

Content:

- What is the incidence of colorectal cancer (CRC) in the US?

- How are CRC patients staged?

- What is the role of CEA?

- What are microsatellites and mismatch repair proteins, and how do they come into play for treatment purposes?

- Who needs germline testing?

- What is the TNM staging for CRC?

- What are some high risk factors we need to pay attention to on the pathology report?

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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Listen in on: Apple Podcast, Spotify, and Google Podcast

In this episode, we review the high-yield topic of Colorectal Cancer (CRC) from the Oncology section.

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Interview with Michael J. Barry, MD, author of USPSTF Recommendation—Screening for Lung Cancer

CHEST March 2022, Volume 161, Issue 3

Nichole T. Tanner, MD, MSCR, FCCP joins CHEST Podcast Moderator, Dominique Pepper, MD, to discuss adherence in lung cancer screening in centralized and decentralized approaches.

Guest: Sebastian Fernandez-Bussy, M.D.

Host: Darryl S. Chutka, M.D. (@ChutkaMD)

Lung cancer is the second most common malignancy in both men and women.  Survival rates depend on how early the cancer is discovered, with a survival rate much higher in localized disease than for patients with distant metastases. Therefore, an early diagnosis becomes extremely important. One of the problems with early diagnosis is that until recently, we’ve not had an effective screening test for lung cancer. In this podcast, we’ll be speaking with Sebastian Fernandez-Bussy, M.D., an Interventional Pulmonologist from the Division of Pulmonary and Critical Care at the Mayo Clinic in Jacksonville, Florida, and we’ll discuss proven techniques for lung cancer screening.

Specific topics:

• Benefits in survival in finding lung cancer at an early stage
• Candidates for screening patients at an increased risk for lung cancer
• Evidence showing the benefits of lung cancer screening
• Differences in radiation for chest CT scans used for screening vs. a typical diagnostic chest CT scan
• Frequency of indeterminate pulmonary nodules found on chest CT
• Insurance and Medicare coverage for lung cancer screening

Connect with the Mayo Clinic’s School of Continuous Professional Development online at https://ce.mayo.edu/ or on Twitter @MayoMedEd.

Interview with John D. Cramer, MD, author of Incidence of Second Primary Lung Cancer After Low-Dose Computed Tomography vs Chest Radiography Screening in Survivors of Head and Neck Cancer: A Secondary Analysis of a Randomized Clinical Trial

CHEST August 2023, Volume 164, Issue 2

Anthony J. Gerbino, MD, and Anton Manyak, MD, join CHEST Podcast Moderator, Dominique Pepper MD, to discuss the harm associated with imaging abnormalities related to lung cancer screening (LCS).

DOI: https://doi.org/10.1016/j.chest.2023.02.010

Disclaimer: The purpose of this activity is to expand the reach of CHEST content through awareness, critique, and discussion. All articles have undergone peer review for methodologic rigor and audience relevance. Any views asserted are those of the speakers and are not endorsed by CHEST. Listeners should be aware that speakers’ opinions may vary and are advised to read the full corresponding journal article(s) for complete context. This content should not be used as a basis for medical advice or treatment, nor should it substitute the judgment used by clinicians in the practice of evidence-based medicine.

Dr. Kate Diomede, social media editor at Thorax, is joined by Dr. Sam Janes (1) to discuss the history of lung cancer screening, and its use in early detection. They also examine the process and results of his recent paper, "Growing small solid nodules in lung cancer screening: safety and efficacy of a 200 mm3 minimum size threshold for multidisciplinary team referral". The paper is available online: https://thorax.bmj.com/content/78/2/202

(1) Lungs for Living Research Centre, UCL Respiratory, University College London, UK.

Please engage in the conversation through the social media channels (Twitter - @ThoraxBMJ; Facebook - @Thorax.BMJ · Pulmonologist) and subscribe on your preferred platform, to get the latest episodes directly on your device each month.

CHEST November 2023, Volume 164, Issue 5

Polina V. Kukhareva, PhD, MPH joins CHEST Podcast Moderator, Dominique Pepper MD, to discuss improving lung cancer screening in the primary care setting.

DOI: https://doi.org/10.1016/j.chest.2023.04.040

Disclaimer: The purpose of this activity is to expand the reach of CHEST content through awareness, critique, and discussion. All articles have undergone peer review for methodologic rigor and audience relevance. Any views asserted are those of the speakers and are not endorsed by CHEST. Listeners should be aware that speakers’ opinions may vary and are advised to read the full corresponding journal article(s) for complete context. This content should not be used as a basis for medical advice or treatment, nor should it substitute the judgment used by clinicians in the practice of evidence-based medicine.

CHEST March  2023, Volume 165, Issue 3

Allison C. Welch, MPH, and Jed A. Gorden, MD join CHEST Podcast Moderator, Alice Gallo de Moraes, MD, FCCP, to discuss how American Indian and Alaska Native adults perceive and use lung cancer screening.

DOI: https://doi.org/10.1016/j.chest.2023.10.025

Disclaimer: The purpose of this activity is to expand the reach of CHEST content through awareness, critique, and discussion. All articles have undergone peer review for methodologic rigor and audience relevance. Any views asserted are those of the speakers and are not endorsed by CHEST. Listeners should be aware that speakers’ opinions may vary and are advised to read the full corresponding journal article(s) for complete context. This content should not be used as a basis for medical advice or treatment, nor should it substitute the judgment used by clinicians in the practice of evidence-based medicine.

Lung cancer is the second most common cancer in the United States. An estimated 238,340 people in the U.S. will be diagnosed with lung cancer in 2023, and 64% of lung cancers are diagnosed at stage III or IV. With all of these facts, it’s surprising that lung cancer screening, a tool that could save lives, is rarely used. Why is that? Who does that impact the most? And what changes can be made? We spoke with Jeff Yang, MD, a thoracic surgeon at Massachusetts General Hospital and founder of the American Lung Cancer Screening Initiative, about symptoms, recommended lung cancer screenings, and available treatment options. We then spoke with Narjust Florez, MD, associate director of the Cancer Care Equity Program and a thoracic medical oncologist at Dana-Farber Cancer Institute, about the stigma and lung cancer patients experience and how patients can better advocate for themselves.

Read WebMD Centerpiece: Catching A Killer

See omnystudio.com/listener for privacy information.

Interview with Michael Barry, MD, USPSTF vice chairperson and author of Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement

Related Article(s):

Screening for Colorectal Cancer

Guest: John B. Kisiel, M.D. (@DrJohnKisiel)

Host: Darryl S. Chutka, M.D. (@ChutkaMD)

Colorectal cancer is the third most commonly occurring cancer for both men and women and ranks second to lung cancer as a cause of cancer mortality. Yet it’s estimated that up to one quarter of eligible adults in the United States have never been screened for colorectal cancer and nearly one third are not up to date with their screening. We now have a variety of accepted screening tests for colorectal cancer and each carries its own risks and benefits. This podcast will review colorectal cancer screening, including when we should start screening, the various available screening tests, as well as their advantages and limitations. Our guest for this episode is gastroenterologist, Dr. John Kisiel from the Mayo Clinic.

Connect with the Mayo Clinic’s School of Continuous Professional Development online at https://ce.mayo.edu/ or on Twitter @MayoMedEd.

Mandip Aujla talks to Olusegun Alatise about colorectal cancer screening in Nigeria.

Read the full article:
Colorectal cancer screening with fecal immunochemical testing: a community-based, cross-sectional study in average-risk individuals in Nigeria

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The Lancet global Health in conversation with...  is part of the Lancet Group podcast offering. 

Editorial team: Editor-in-Chief Zoë Mullan, acting deputy editor Pingyue Jin, senior editors Shangrong Han, and Gavin Cleaver.

Podcast editing: Matteo Simonetti

Visit https://www.thelancet.com/multimedia to learn more. 

Find the best science for better lives at thelancet.com

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Emilie Breekveldt (Erasmus Medical Center, Netherlands) discusses a new analysis of the faecal immunochemical testing-based colorectal screening programme in the Netherlands. 

Read the full article:
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(21)00368-X/fulltext

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March is colorectal cancer awareness month. According to the American Cancer Society, nearly double the number of young adults under 55 are being diagnosed with colorectal cancer. And while it’s a highly treatable cancer, many people will not have symptoms in the early stages of colorectal cancer. So, when should regular screening begin? And what measures can we take to lower our risk for colon cancer? What do we need to know about the latest research on a blood test for colon cacner screening? We spoke to Jaydeep Bhat, MD, MPH, gastroenterologist, and physician lead for resource stewardship at The Southeast Permanente Medical Group, Kaiser Permanente Georgia, about what puts someone at a higher risk for colorectal cancer, the various screening tests available, questions we should ask our primary care doctors, and small and actionable lifestyle changes we can make to reduce our risk.

See omnystudio.com/listener for privacy information.

Harrison's PodClass provides engaging, high-yield discussions of key topics commonly found on rotational and board exams in internal and family medicine. 

Harrison's Principles of Internal Medicine, 22nd Edition

Each year in the United States, about 240,000 women and 2,100 men are diagnosed with breast cancer. The average risk of a woman in the United States developing breast cancer sometime in her life is about 13%. This means there is a 1 in 8 chance she will develop breast cancer, which is why breast cancer awareness and screening are so important. In May 2023, the United States Preventive Services Task Force (USPSTF) lowered the breast cancer screening age from 50 to 40 – but do these age screenings apply to everyone? What factors contribute to a high-risk classification for breast cancer, and how do we identify if we are at genetic risk? We spoke with Lauren Nye, MD, board-certified oncologist at the University of Kansas Cancer Center and Clinical Medical Director of Breast Cancer Prevention, about the importance of assessing your cancer risk, learning your genetic history, and prioritizing your overall health.

See omnystudio.com/listener for privacy information.

An interview with Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, MA on "Management of Hereditary Breast Cancer: ASCO, ASTRO, and SSO Guideline." This guideline covers recommendations for the management of patients with breast cancer with germline mutations in breast cancer susceptibility genes. Read the full guideline at www.asco.org/breast-cancer-guidelines

An interview with Dr. Neelima Denduluri from Virginia Cancer Specialists, U.S. Oncology in Arlington, VA and Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update." This update addresses the use of adjuvant trastuzumab emtansine and the use of biosimilar forms of trastuzumab. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Neelima Denduluri from Virginia Cancer Specialists, US Oncology in Arlington, Virginia, and Dr. Sharon Giordano from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, co-chairs on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update."

Thank you for being here, Dr. Denduluri and Dr. Giordano.

Dr. Neelima Denduluri: Thanks for having us.

Dr. Sharon Giordano: Yeah, we're delighted to be here. Thank you.

Brittany Harvey: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Denduluri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Neelima Denduluri: Our institution has received research funding from companies including Genentech.

Brittany Harvey: Thank you. And Dr. Giordano, do you have any relevant disclosures that are related to this guideline topic?

Dr. Sharon Giordano: No, I don't have any relevant disclosures. Thank you.

Brittany Harvey: Thank you. Then let's get into the guideline content. Dr. Denduluri, what prompted this focused update of the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer guideline?

Dr. Neelima Denduluri: There was an FDA meta analysis and several other studies that showed that patients that did not receive a pathologic complete response after preoperative therapy in the HER2-positive setting had a worse prognosis. In the past, we didn't have actionable findings to improve their outcome.

But there was a trial, the KATHERINE trial, that randomized patients that received chemotherapy and trastuzumab, plus or minus pertuzumab, that did not achieve a pathologic complete response to receive standard of care trastuzumab or 14 cycles of trastuzumab emtansine. And the patients that received trastuzumab emtansine had a significantly improved outcome over those that received standard of care trastuzumab. These were very impactful findings that changed care for women with early breast cancer. Therefore, we wanted to update the guideline.

Brittany Harvey: So Dr. Giordano, there are two new recommendations in this guideline update. First, what does the guideline say regarding the use of adjuvant trastuzumab emtansine following standard preoperative chemotherapy and HER2-targeted therapy for patients with HER2-positive breast cancer with residual invasive cancer in the breast or lymph nodes at surgery?

Dr. Sharon Giordano: So the first recommendation was based on the data from the KATHERINE trial that Dr. Denduluri just mentioned. And so their recommendation is that patients with HER2-positive breast cancer who have pathologic invasive residual disease at surgery to either in the breast or the lymph node after standard pre-op chemo with HER2-targeted therapy should be offered 14 cycles of adjuvant trastuzumab emtansine unless there's a recurrence or unworkable toxicity. So basically stating, based on the data from KATHERINE, that if patients have residual disease after their chemotherapy for HER2-positive breast cancer, they should get adjuvant trastuzumab emtansine. And the panel overall felt that the evidence behind this-- the quality of the evidence was very high, and it had a strong recommendation for this treatment.

Brittany Harvey: And then second, Dr. Denduluri, how does this guideline address the use of biosimilar forms of trastuzumab?

Dr. Neelima Denduluri: So biosimilars are increasingly being incorporated into clinical practice, and the guidance that we have from the FDA is that the efficacy of biosimilars compares well with standard trastuzumab. So, we said that patients that would receive trastuzumab are allowed to receive trastuzumab biosimilar without what we think will negatively impact their outcome.

Dr. Sharon Giordano: For that recommendation, we also had input from the Breast Cancer Guideline Advisory Group that helped us decide to expand the update to include the biosimilars. We think that at least five biosimilars have been approved by the FDA, and based on similar efficacy and similar safety data felt that it was appropriate to use them or trastuzumab in a setting where previously we had just used trastuzumab.

Brittany Harvey: Great. And then how will this guideline update impact clinical practice?

Dr. Sharon Giordano: I think that many practitioners have already adapted clinical practice to start to use adjuvant trastuzumab emtansine based on the KATHERINE data, but we certainly hope that this guideline update will reinforce the practice of providing adjuvant trastuzumab emtansine for patients with HER2-positive breast cancer with residual disease after preoperative treatment. The improvement in outcomes was really clinically meaningful for patients, so this does seem to be a significant step forward in the treatment of HER2-positive breast cancer.

Dr. Neelima Denduluri: Additionally, I think that it's important to remember, as clinicians, that we should think about preoperative therapy in those patients with higher-risk HER2-positive disease, because we know that we can impact their outcomes if they don't achieve a pathologic complete response. And hopefully this guideline will heighten the awareness that we need to do that. The other question that we commonly are asked is, even if there is a small amount of residual invasive carcinoma, should we switch to trastuzumab emtansine instead of trastuzumab plus or minus pertuzumab. And what the KATHERINE data did show is that patients that-- even if they had a small amount of residual cancer burden, they still derived benefit.

Obviously, we have to think about the safety, and we also wanted to outline that in this guideline that trastuzumab emtansine is associated with a higher risk of neuropathy and thrombocytopenia and liver function abnormalities. So we certainly need to worry about that. And those patients that do have poor tolerance, we can go back to their HER2-targeted backbone they received in the preoperative setting.

Dr. Sharon Giordano: Yeah, those are great additional points.

Brittany Harvey: Definitely. And you've both already touched on a bit of how adjuvant therapy impacts patients, but how will these guideline recommendations affect patients?

Dr. Neelima Denduluri: I think that really, as Dr. Giordano stated, this is an overwhelming benefit that we don't normally see in terms of impacting outcomes. So the addition of trastuzumab emtansine potentially has good efficacy for them and improves their outcomes.

Dr. Sharon Giordano: Yeah, I agree. I think this trial was associated with a really meaningful reduction in risk of recurrence and better outcomes. So this really is a step forward for treating HER2-positive breast cancer.

Dr. Neelima Denduluri: The other interesting thing about this trial is that it did not delay their local therapy. They allowed concurrent trastuzumab emtansine with radiation therapy. And they also, in terms of systemic therapy, allowed endocrine therapy with trastuzumab emtansine, similar to what we do with trastuzumab plus or minus pertuzumab in the adjuvant setting. So as Dr. Giordano stated, really impactful in terms of efficacy, well-tolerated in most situations, and pragmatic in terms of not holding up the local therapy and the systemic therapy that they may need additionally.

Brittany Harvey: Great, thank you so much for sharing that information about how it impacts patients. I appreciate you both coming on the podcast today and for all your work that you put into updating these guidelines. And thank you for your time today Dr. Giordano and Dr. Denduluri.

Dr. Sharon Giordano: Thank you so much. It was a pleasure.

Dr. Neelima Denduluri: Thank you both, and thank you Brittany for always working so hard to make sure that these guidelines help our patients.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. 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 iTunes 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.

An interview with Dr. Beverly Moy from Massachusetts General Hospital, co-chair on "Chemotherapy and Targeted Therapy for Patients With HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update." Updated guidance addresses optimal sequence of therapy & indications for treatment regimens. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

[MUSIC PLAYING]

SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey. And today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, co-chair and lead author on chemotherapy and targeted therapy for patients with HER2 negative metastatic breast cancer that is either endocrine pre-treated or hormone receptor negative ASCO guideline update. Thank you for being here, Dr. Moy.

BEVERLY MOY: Thanks for having me, Brittany.

BRITTANY HARVEY: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

BEVERLY MOY: I do not have any relevant disclosures related to this guideline topic.

BRITTANY HARVEY: Great. Thanks so much. Then let's get into what this update covers. So first, what prompted the update of this ASCO guideline and what does the scope of this guideline update?

BEVERLY MOY: So this guideline update was developed to address both chemotherapy and targeted therapy for women with advanced HER2 negative breast cancer that is either endocrine pre-treated or hormone receptor negative. So it really focuses on chemo and targeted therapy.

The original ASCO clinical treatment guideline was published in 2014 and really focused on chemotherapy, since that was generally the standard of care at that time. Since 2014, however, there have been several important new therapies that have become available based on robust evidence from numerous clinical trials.

These include, but are not limited to, BOLERO-6 and PEARL trials for hormone receptor positive HER2 negative metastatic breast cancer, the ASCENT and EMBRACE trials for triple negative metastatic breast cancer, and the EMBRACA trial for metastatic breast cancer associated with germline BRCA1 or 2 mutations. So it really was important to update the guideline in a fairly urgent matter.

BRITTANY HARVEY: Great. Well, then this guideline addresses four overarching clinical questions. For each of these, I'd like to review the key recommendations for our listeners. So starting with question one, is there an optimal sequence of chemotherapy and/or targeted therapy for patients with triple negative metastatic breast cancer either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So clinical question one really focused on patients with metastatic triple negative breast cancer. So for patients with metastatic triple negative disease, the first key question is, what is the Programmed cell Death Ligand 1, or what we call PD-L1 status? If the disease is PD-L1 positive, then patients may be offered first line therapy with an immune checkpoint inhibitor plus chemotherapy. And that's a very important development.

If the disease, however, is PD-L1 negative, patients should be offered single agent chemotherapy rather than combination chemotherapy, unless they have symptomatic or immediately life-threatening disease, and you really need to get a response more quickly. In those cases, combination chemotherapy can be used.

After the first line, if patients with metastatic triple negative breast cancer have received at least two prior therapies, then they should be offered treatment with the new antibody drug conjugate called sacituzumab govitecan, which is a very exciting development in the treatment of metastatic triple negative breast cancer.

If the patient has a germline BRCA1 or 2 mutation and has metastatic triple negative disease and have been previously treated with chemotherapy, then they may be offered treatment with an oral PARP inhibitor rather than chemotherapy, also a very exciting development that this guideline update addresses.

BRITTANY HARVEY: Great. Thank you for reviewing those recommendations for triple negative metastatic breast cancer. So then next for clinical question two, what are the indications for chemotherapy versus endocrine therapy in endocrine pre-treated estrogen receptor positive metastatic breast cancer?

BEVERLY MOY: So clinical question two focuses on women or patients with metastatic hormone receptor positive breast cancer who have developed progressive disease on a prior endocrine therapy with or without targeted therapy. So really is focusing on patients with metastatic hormone receptor positive breast cancer that have become fairly resistant to endocrine therapy alone. These patients may be offered treatment with either endocrine therapy with or without a targeted therapy or single agent chemotherapy.

Brittany, I think it's important for listeners to realize that there is another important clinical practice guideline update that's being released simultaneously with this guideline. And that one is called endocrine therapy and targeted therapy for hormone receptor positive metastatic breast cancer. This other guideline update will describe in detail recommendations for the various targeted therapies that can be used with endocrine therapy, such as CDK4/6 inhibitors, PI 3-kinase inhibitors, and others.

So I encourage everyone to read this guideline as well. Importantly, both guidelines state that treatment choice should be based on individualized patient and provider assessment of preferences, risks, and benefits.

BRITTANY HARVEY: Great. And thank you for pointing out that companion guideline. Listeners can also listen to a podcast episode with Dr. Burstein on that particular guideline, which will be available in our podcast feed.

So then next, what are the key recommendations for the third question in the guideline, which is, is there an optimal sequence of non-endocrine agents for patients with hormone receptor positive but HER2 negative metastatic breast cancer who are no longer benefiting from endocrine therapy, either with or without BRCA1 or BRCA2 germline mutations?

BEVERLY MOY: So this third question really focuses on patients with hormone receptor positive HER2 negative disease and the optimal sequence. Essentially what we recommend is that germline BRCA1 or 2 patients with metastatic hormone receptor positive HER2 negative breast cancer who are no longer benefiting from endocrine therapy, those patients may be offered an oral PARP inhibitor in the first through third line setting rather than chemotherapy. And that is evidence that is evolving and important, and that's what the guideline recommends at this time.

BRITTANY HARVEY: Great. And then clinical question four was the last question addressed in this guideline update. And what did the panel say regarding at what point should a patient be transitioned to hospice or best supportive care only?

BEVERLY MOY: So this obviously is an incredibly important question for clinicians and oncologists to consider. The current literature and evidence does not allow us, at this time, to make a firm recommendation regarding at which point a patient's care should be transitioned to hospice or best supportive care only.

When to transition is a decision that really needs to be shared between the patient and clinician in the context of an ongoing conversation regarding goals of care. The conversation of that integration of supportive care and eventual consideration of hospice care really should start early in the management of metastatic breast cancer. And these conversations have to occur throughout.

I would also refer listeners to other important clinical treatment guidelines on the ASCO website about incorporation of palliative and supportive care for patients with metastatic cancer. I think those are incredibly valuable guidelines.

BRITTANY HARVEY: And then you've touched on this a bit as you've talked about the recommendations, but in your view, what is the importance of this guideline update? And how will these updated recommendations impact both clinicians and patients?

BEVERLY MOY: I think that this is an extremely important guideline update. It provides really important clinical guidance about the new use of immune checkpoint inhibitors, which really is the first time immune checkpoint inhibitors are clearly recommended for the treatment of breast cancer. It also provides important clinical guidance about this new antibody drug conjugate, sacituzumab govitecan, and PARP inhibitors for the treatment of metastatic breast cancer.

These are all important and effective new treatments for breast cancer. And every clinician should be aware of their optimal uses. I will point out that many unanswered questions remain. And that was really an exciting part of doing this guideline update to look at these unanswered questions, such as what we described earlier, the optimal time to transition to best supportive care only and the widespread use of molecular tumor profiling. As treatments get more complicated and the entire oncology community are increasingly tasked to absorb new data, ASCO guidelines are enormously helpful in giving people an easy to access tool that takes into account the latest data.

BRITTANY HARVEY: Great. Thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Moy.

BEVERLY MOY: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at surveymonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss episode.

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An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on "Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

[MUSIC PLAYING]

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org.

My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein.

HAROLD BURSTEIN: Glad to be with you.

BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Burstein, do you have any relevant disclosures that are related to this guideline topic?

HAROLD BURSTEIN: I do not.

BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update?

HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers.

And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have.

In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines.

BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer?

HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer.

And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib.

So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy.

In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy.

BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations.

So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases.

The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors.

So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy.

So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant.

And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease.

BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer?

HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself.

So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer.

We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs.

It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully.

The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time.

But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease.

So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant.

And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline.

Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease.

And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation.

One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive.

And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations.

So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy.

BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline.

HAROLD BURSTEIN: Work in progress.

BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients?

HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations.

And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at.

The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach.

Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them.

Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines.

BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein.

HAROLD BURSTEIN: Happy to join you and thanks very much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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An interview from Dr. Larissa A. Korde from the National Cancer Institute and Dr. Dawn L. Hershman from Columbia University on "Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline." This guideline covers the optimal use of neoadjuvant therapy for women with invasive, non-metastatic breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one podcast.asco.org.

My name is Brittany Harvey, and today I am joined by Dr. Larissa Korde from the clinical investigations Branch of the Cancer Therapy Evaluation Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute in Bethesda, Maryland, and Dr. Dawn Hershman from the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, New York, co-chairs on Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Thank you for being here Dr. Korde and Dr. Hershman.

DR. LARISSA KORDE: Thank you for having us.

DR. DAWN HERSHMAN: Yes, thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available on-line with the publication of the guideline in the Journal of Clinical Oncology. Dr. Korde, do you have any relevant disclosures that are related to this guideline topic?

DR. LARISSA KORDE: I do not.

BRITTANY HARVEY: And Dr. Hershman, do you have any relevant disclosures that are related to this guideline topic?

DR. DAWN HERSHMAN: No, I do not.

BRITTANY HARVEY: Great, thank you both. Then, Dr. Hershman, to kick off the content of the guideline, first, can you give us a general overview of the scope and the purpose of this guideline?

DR. DAWN HERSHMAN: Yeah, sure. In breast cancer, we have seen a plethora of studies looking at neoadjuvant therapy for breast cancer. And as we've learned over time, that neoadjuvant therapy has focused on the role of, really, response as a predictive marker and whether or not the improvement in a pathologic complete response rate translates into benefit in terms of long-term outcome. And the fact that several studies have shown that has really increased our interest in looking at pathologic complete response rate and its predictive value.

So part of the guideline is really to help us really elucidate as the understanding of biology of breast cancer has evolved over time, what scenarios where neoadjuvant therapy is the best choice for patients, and what the real purpose of neoadjuvant therapy is. So the guidelines' purpose is really to help us develop recommendations concerning the optimal use of neoadjuvant therapy, whether it be chemotherapy, endocrine therapy, or targeted therapy for a variety of different biologic subtypes. And I think the overarching principle is that the expert panel strongly advocated for a multidisciplinary team in the management of these patients. Specific guidelines really go into details about each of the scenarios where we would use this therapy.

BRITTANY HARVEY: Great. Then I'd like to review some of those key recommendations that you just mentioned for our listeners. So Dr. Korde, which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

DR. LARISSA KORDE: So when we sat down to write this guideline, we thought through this question in many different ways. But we basically ended up sort of dividing patients by breast cancer subtype and then coming up with recommendations separately for each subtype. So broadly speaking for triple negative breast cancer patients and for HER2-positive breast cancer patients, we felt that the kind of most important triage point is that in both those diseases, there are effective treatments that can be used in the adjuvant setting in patients who do not have a pathologic complete response to neoadjuvant therapy. And so broadly speaking, it's those patients where there would be an adjuvant therapy decision point, or recommendation in whom the neoadjuvant response is important. Those would be the patients in whom we would most strongly recommend neoadjuvant chemotherapy.

In ER-positive disease, we looked at both chemotherapy and endocrine therapy in the neoadjuvant setting. And we know that both of these can improve response. Pathologic complete response is less common in patients with ER-positive disease. But there are also benefits to neoadjuvant treatment in those patients in terms of being able to reduce the size of the surgery, reduce potentially morbidity from surgery, and then also in terms of being able to convert patients who were not lumpectomy candidates from mastectomy to lumpectomy. And so in the guideline we outline the scenarios for ER-positive patients in which neoadjuvant therapy would be recommended as well.

BRITTANY HARVEY: Great, got it. Then Dr. Hershman, what do the guidelines say about how clinicians should measure response in patients receiving neoadjuvant chemotherapy?

DR. DAWN HERSHMAN: Yes, so patients undergoing neoadjuvant therapy should really be monitored by their provider at each visit with a clinical examination at regular intervals. And we really felt that the role of breast imaging was really for patients where there was some clinical suspicion of progression during that therapy to ensure that patients were not progressing during treatment. And ultimately, the best modality for imaging was the modality that was most effective at the point of diagnosis, whether it be mammogram, ultrasound, or MRI, that should be the imaging modality used at follow up.

We did not feel that there were any specific blood markers or tissue based markers at this time that should be used for monitoring patients undergoing neoadjuvant therapy. Much of that is done for clinical trial purposes, but not so much in the clinic. And that when patients had completed their treatment, pathologic complete response rate is the most important outcome and would be really assessed at the time of surgery as the absence of any invasive disease in either the breast or the lymph nodes.

But in order for that to be good for clinical decision making, it's really imperative that the clinician and the surgeons make sure that the tissue is removed that is suspect to begin with, so to make sure that the clips that defined where the tumor was evaluated and that the tumor bed is clear of any evidence of disease.

BRITTANY HARVEY: Great, that's helpful information. So then, Dr. Korde, you mentioned that the recommendations are divided up by biologic subtypes. So what are those neoadjuvant systemic therapy regimens recommended for the following patient population-- so first, those with triple negative breast cancer, second, those with HER2-negative hormone receptor positive breast cancer, and then finally, for those with HER2-positive disease?

DR. LARISSA KORDE: So maybe we can divide this up a little. Let's start with the triple negatives. For triple negative breast cancer patients who are embarking on neoadjuvant chemotherapy, and that would be patients with clinically node positive disease, and/or at least T1C disease, and again, with the thought that the goal is really to think about whether adjuvant therapy recommendations would be altered based on PAP CR. But in that setting, we recommended that patients be offered an anthracyclines and taxane containing regimen.

We also found data supporting the use of carboplatin with neoadjuvant therapy for the purpose of increasing the likelihood of PCR. So we noted that while there is good data showing that PCRs increase with carboplatin, there is more conflicting data regarding the effect of carboplatin on long-term outcomes. Although, hopefully, new clinical trials that are ongoing now or that are in follow up may clarify this question a little bit more.

We felt at the time that we wrote the guideline, and certainly, this is potentially an evolving topic. But at this point, we felt that there was insufficient evidence to recommend routinely adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early stage breast cancer. And again, there may be more data on this upcoming in the next few years. So maybe Dawn can take the next category, the HER2-negative hormone receptor positive patients.

BRITTANY HARVEY: Yeah, that would be great.

DR. DAWN HERSHMAN: Absolutely. So we felt for this population of patients that neoadjuvant chemotherapy could be used instead of adjuvant chemotherapy in any patient where the chemotherapy decision could be made without the benefit of having the results from the surgical pathology data, or any results from the specific genomic testing. So if the decision was made that the patient was going to need chemotherapy regardless, that would be a patient that could get it neoadjuvantly.

We felt that for postmenopausal patients with hormone receptor positive HER2 negative breast cancer that neoadjuvant endocrine therapy with an aromatase inhibitor could be offered to either increase local regional treatment options, if there was no intent for surgery, endocrine therapy could be used for Disease Control. So in a patient where they really were not a good surgical candidate, we could offer this therapy to try to control their disease. For premenopausal patients with hormone receptor positive HER2-negative disease, we did really not feel that neoadjuvant endocrine therapy should be routinely offered outside of a clinical trial. Because in this scenario, there really wasn't enough evidence to offer this approach.

BRITTANY HARVEY: And then Dr. Korde, do want to finally address those patients with HER2-positive disease?

DR. LARISSA KORDE: Absolutely. So in patients with HER2-positive disease that is either node positive or high risk node negative, we felt it would be appropriate to offer neoadjuvant therapy with either an anthracycline and taxane containing regimen, or a non-anthracycline-based regimen in combination with targeted therapy. And we did feel that targeted therapy should include trastuzumab and may also include pertuzumab. For patients with smaller tumors, really those in whom it's unclear whether the more aggressive for on-chemotherapy regimens or even any chemotherapy at all is needed, for example, those with very small tumors, T1A and T1B, we did not feel that neoadjuvant should be routinely offered. And we did note that in those patients with smaller tumors, an alternative regimen, the APT regimen of paclitaxel and Trastuzumab is something that has been studied in the adjuvant setting. But again those patients with these very small node negative tumors, in general, would not be routinely offered neoadjuvant chemotherapy.

BRITTANY HARVEY: Great, thank you both for reviewing those neoadjuvant systemic therapy approaches for those specific patient populations. So Dr. Hershman, in your view, what is the importance of this guideline? And how will it impact clinical practice?

DR. DAWN HERSHMAN: Yeah, that's an excellent question. I think as our data has shown more and more studies where there's a benefit to giving adjuvant treatment based on the response of patients in the neoadjuvant setting to get additional benefit long-term amongst patients with residual disease, I think that these guidelines really can help clinicians to understand those scenarios where we know we can maximize treatment.

I think ultimately the goal of neoadjuvant therapy is that it gives us opportunities to both escalate treatment in patients that are at high risk that don't have great responses, and de-escalate therapy in patients that have outstanding responses. And so I think this will help clinicians understand what those benefits are.

BRITTANY HARVEY: Definitely. It seems like it will provide some clarity for those scenarios. So finally, Dr. Korde, how do you envision that these guideline recommendations will affect patients with non-metastatic breast cancer?

DR. LARISSA KORDE: Well, I think building on Dr. Hershman's answer to the previous question, really, the key here is to be able to personalize or tailor the therapy for individual patients. So in those patients whose disease is very high risk, or did not respond to initial therapy, patients can be given appropriate escalation of treatment. And for patients who have an excellent response to treatment in the neoadjuvant setting can potentially be spared other treatments. And so I think that the main use of neoadjuvant treatment and the use of this guideline in terms of how it affects patients is being able to offer the most appropriate therapy for each patient.

BRITTANY HARVEY: Great, well, thank you both for your work on this guideline on neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer. Appreciate your leadership on this guideline. And I want to thank you also for taking the time to speak with me today, Dr. Korde and Dr. Hershman.

DR. DAWN HERSHMAN: Thank you.

DR. LARISSA KORDE: Happy to be here. Thanks so much.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. 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 iTunes 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.

An interview with Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, NC, panel member on "Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Carey discusses the updated recommendation on the use of pembrolizumab for patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage triple negative breast cancer. For more information, visit, www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast Series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, expert panel member on Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk Early-stage Triple-negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Carey.

Dr. Lisa Carey: It's a pleasure to be here, Brittany. Thank you!

Brittany Harvey: Great! First, I 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Carey, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Lisa Carey: I do not.

Brittany Harvey: Thank you. Then what prompted this rapid update to the Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline, which was last published in 2021?

Dr. Lisa Carey: You know, what prompted it where there were a number of changes that had come out, particularly things like the use of immune checkpoint inhibitors, and the adoption of the neoadjuvant strategy that really made us feel that these were overdue for practice guidelines. And in particular, there were some very important changes that came out early this year, particularly with the pembrolizumab use.

Dr. Brittany Harvey: Great, so, based on these changes in the pembrolizumab use, what is the updated recommendation from the guideline panel?

Dr. Lisa Carey: The recommendation actually is for patients who fulfilled the KEYNOTE-522 trial criteria. KEYNOTE-522 was a seminal trial in early triple-negative breast cancer, meaning, treatment-naive of the use of pembrolizumab incorporated into a chemotherapy-based regimen given neoadjuvantly, and then with the continuation of the immune checkpoint inhibitor pembrolizumab adjuvantly.

This was important because we had been using, for a couple of years now, immune checkpoint inhibitors in PD-L1 positive or immune-activated triple-negative breast cancers in the metastatic setting. But we had not had evidence of improved survival or outcomes in early triple-negative breast cancer, so that's where KEYNOTE-522 comes in. This was a trial in which patients with early untreated triple-negative breast cancer, who fulfilled at least greater than T1N0, - and I want to make that pretty clear, this is a pretty broad net for early triple-negative breast cancer; the vast majority of triple negatives will be eligible for this treatment based on the population that was studied - and they receive four chemotherapy drugs, so, a taxane plus platinum, followed by an anthracycline-based regimen, either with or without pembrolizumab throughout the entire neoadjuvant course. They then went to surgery, and then they went on to receive adjuvant for another nine cycles, adjuvant pembrolizumab.

The trial had already reported an improvement in pathologic complete response with the addition of the immune checkpoint inhibitor, which has also been seen with other immune checkpoint inhibitors. But what was reported a few months ago, and then published early this year, was the impact on event-free survival. So, there was a statistically significant improvement in event-free survival with the addition of pembrolizumab, which, at that point, it's a highly clinically meaningful endpoint, there are now two highly clinically meaningful endpoints. Both of these were the primary endpoints of this study. And so, it has rapidly been adopted on that basis for use and we felt because of that it needed to be addressed in a rapid update for helping clinicians interpret the data and use them effectively.

Brittany Harvey: Understood, and I appreciate your work and the panel's work to rapidly interpret this data. So then, what should clinicians know as they implement this recommendation for the use of pembrolizumab?

Dr. Lisa Carey: I think the key elements are unlike the metastatic setting, there's really no role for PD-L1 testing in the early triple-negative setting because the pembrolizumab seemed to improve outcomes regardless of PD-L1 status, which is a big difference from what's true in the metastatic setting where all of these immune checkpoint inhibitors seem to only benefit patients that are PD-L1 positive. So, it's kind of regardless of PD-L1 status.

It's also true that in the KEYNOTE-522 study when they did do PD-L1 testing, most early triple negatives are PD-L1 positive. There really wasn't a subset of patients in the trial. And again, this is T2 or greater in tumor size or node-positive, who didn't seem to benefit from it.

So, it's a pretty broad recommendation. The 'however' is that, as we all know at this point, when you add immune-directed therapies, you have a different set of toxicities you have to be aware of, specifically what they call immune-related adverse events or irAEs, which are, of course, essentially autoimmune.

The thing that you have to remember is these can be permanent. These are frequently glandular disorders. Typically things like thyroid disease, which can be handled with replacement, but you can sometimes have colitis, myositis of different kinds, pneumonitis, and things like that. And some of these can be permanent.

So, they have to be monitored very carefully. And ASCO has a guideline for managing irAEs and patients treated with immune checkpoint inhibitors - because again, we use these in lots of tumor types - that gives a lot of detailed practice recommendations, that clinicians should really consult frequently, not just in triple-negative, but in other disease types that we use these drugs.

Brittany Harvey: Great. Thanks for explaining that aspect of the guideline. So then, you just mentioned that this recommendation is broadly applicable to many patients with early-stage triple-negative breast cancer. So, how will these guideline recommendations impact patients with early-stage triple-negative breast cancer?

Dr. Lisa Carey: Well, it means that it's a totally new game. So, as you are evaluating a patient, first off, virtually all of these are treated neoadjuvantly now, except for the T1N0s, and pembrolizumab and the addition of pembrolizumab should be considered in all of them.

Again, if they have, particularly organ-threatening autoimmune disorders themselves, they are a poor choice for these drugs, but otherwise, it should at least be considered. It's also true that there's been for many years a debate about the optimal chemotherapy to give in triple-negative breast cancer in the backbone that was used to which pembro was added had four drugs in it. And I think for that reason, that is considered the standard of care now.

I do think one of the challenges for us moving forward is to decide if we need all of those drugs or not. I think a challenge for us also is to figure out who actually benefits from, again, these are five drugs, you know, a lot of therapy, a fair amount of toxicity. And so, I think that's a challenge going forward.

Brittany Harvey: Thank you. And then finally, you just mentioned a couple of upcoming challenges, including the debate about the optimal chemotherapy regimen. But what are the outstanding questions regarding neoadjuvant therapy for patients with breast cancer?

Dr. Lisa Carey: I think the outstanding questions regarding neoadjuvant therapy are one thing. I think neoadjuvant therapy, there isn't a lot of outstanding questions that are medically related other than what's the right backbone and things like that, because I think the neoadjuvant paradigm, if you're just purely talking about whether you're giving drugs before or after surgery, the drugs themselves tend to be the same because the key endpoint for the medical oncologist and for the patient, of course, is their outcome from a relapse standpoint.

But it's also true that the neoadjuvant approach allows tailoring of the medical therapy. Like, in the past before we had immune checkpoint inhibitors, patients who received chemotherapy and had residual disease would get additional chemotherapy.

That wasn't allowed in the KEYNOTE study. So, I think many people, because patients with residual disease in KEYNOTE, still had pretty poor outcomes are incorporating additional chemotherapy, specifically adjuvant capecitabine with the pembrolizumab, but there's no data for that.

So, I think that's a challenge that we do have to address. I think the other challenge is simply surgical management: whether we can use these improved pathologic response and clinical response outcomes to minimize some of the local therapies, in addition to tailoring the medical therapies.

Brittany Harvey: Great! Well, we look forward to maybe tackling some of these challenges when we have more data in upcoming guidelines. I want to thank you so much for your time to rapidly update these guideline recommendations and for your time speaking with me today, Dr. Carey.

Dr. Lisa Carey: It's my pleasure. Thank you so much, Brittany.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. 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 on iTunes 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.

An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on "Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update." They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

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ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik.

DR. ZAKALIK: Thank you for having us.

DR. TUNG: Thank you so much. Pleasure to be here.

BRITTANY HARVEY: First, 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 full conflict of interest information for this guideline panel is available online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic?

DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer.

BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures?

DR. ZAKALIK: I do not.

BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline?

DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting.

And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same.

And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers.

BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel?

DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify.

For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence.

BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice?

DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common.

And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting.

But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better.

BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer?

DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation.

But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benefit of molecular genetic testing for hereditary risk to therapy for patients with early nonmetastatic breast cancer. So as clinicians who see patients with breast cancer, it is further made more important to recognize what the guidelines are for genetic testing. To think of whether a patient meets criteria that are currently outlined for genetic testing, as this will have a significant potentially major impact on patients' outcome. And already in the clinic, we have been focused on recognizing who may have a BRCA mutation. Obviously, this data will make that even more important, because this therapy is so beneficial for patients. And I think going forward, it will fuel a discussion of possibly reevaluating who gets genetic testing, now that it's particularly important not to miss patients who have BRCA mutations when they develop breast cancer.

So I think that physicians who are in the clinic will not only have a therapeutic option, but also will be hopefully recognizing more patients who have a BRCA mutation in that the therapy is so markedly better now with this new data. And in the future, we may possibly expand our guidelines for testing. And I think that remains to be determined, based on a number of factors that go into this decision.

BRITTANY HARVEY: Well then, you've both touched on this a bit, regarding outstanding questions for both genetic testing and the use of capecitabine. But finally, Dr. Tung, given this recent study and guideline update, what are the outstanding questions regarding the use of PARP inhibitors in the adjuvant setting?

DR. TUNG: Right. We have already listed a couple. The capecitabine question is one that I won't repeat. And I think who gets tested would be another one that Dana just mentioned. I think a big one, as of yesterday, is immune therapy. Yesterday, the FDA approved pembrolizumab, based on the KEYNOTE-522 study for patients with triple-negative breast cancer. And that population in KEYNOTE was very similar to the one in OlympiA for BRCA carriers, namely patients with T2 tumors, or involved axillary lymph nodes. So for BRCA carriers, we're going to have to make some decisions here, namely, should they receive pembrolizumab and olaparib together, for those who have residual disease after neoadjuvant chemotherapy. I think everyone right now is digesting KEYNOTE-522 and this FDA approval. And so that's something that will have to be worked out.

I know in other diseases there is safety data for the combination of pembrolizumab and olaparib. But again, I think that's something that we're all going to have to sort out. I don't think there's going to be any data forthcoming immediately about the use of pembro, olaparib, and the combination, et cetera for our patients. So that's a big one I think another question that comes up is, how long after a BRCA carrier finishes their chemotherapy and local therapy are they eligible to take olaparib? What about patients that finished six months ago, or a year ago, or longer? And again, I don't think there are any data for that, and we're going to have to use some clinical judgment. There was precedent for this kind of question when adjuvant trastuzumab was approved and in 2005, when the adjuvant trials demonstrating such an impressive benefit for trastuzumab were announced and published.

I remember that we were administering trastuzumab to patients who'd completed their chemotherapy within the last year. So I think for many, that may be a timeline that makes sense. But again, there are no data. So still questions, and we're going to as always have to use some clinical judgment. And others, Dana, that you can think of?

DR. ZAKALIK: No. I think this is tremendously exciting new data. It really provides hope for patients who are young, often, when they're diagnosed. Because hereditary breast cancer tends to manifest itself at a young age. And so for our women in the prime of their life, when they have high risk and develop breast cancer, I think this just really gives us tremendous hope and opportunity for improving the lives and saving lives in the future of patients who have high-risk disease. Very exciting data.

DR. TUNG: Yeah, I agree completely. I think the investigators are really to be congratulated. This was a very large study. 1,800 BRCA carriers, international study. Very hard to do with a situation, a disease that's relatively uncommon. Only 3% to 5% of all breast cancer. So really a terrific effort with a significant, major impact for our BRCA carriers with breast cancer.

BRITTANY HARVEY: Definitely. This is an exciting update for patients with breast cancer. And we'll look forward to hearing more research about those outstanding questions that you mentioned. So I want to thank you both for your efforts to update this guideline recommendation so quickly, and provide evidence-based recommendations for both clinicians and patients. And thank you for taking the time to speak with me today, Dr. Zakalik and Dr. Tung.

DR. ZAKALIK: Thank you.

DR. TUNG: My pleasure.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. For more information, visit www.ASCO.org/breast-cancer-guidelines. 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.

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An interview with Dr. Beverly Moy from Massachusetts General Hospital in Boston, MA, lead author on "Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update." Dr. Moy reviews data from the recently published DESTINY-Breast04 study, and the ASCO Expert Panel's updated recommendation on the use of trastuzumab deruxtecan. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guideline podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy.

Dr. Beverly Moy: It's my pleasure. Thank you for having me.

Brittany Harvey: Great. First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Beverly Moy: I do not have any relevant disclosures that are directly relevant to this guideline topic.

Brittany Harvey: Thank you. Then let's talk about this rapid update. So first, what prompted a rapid update to this guideline on chemotherapy and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, which was last updated in 2021?

Dr. Beverly Moy: First, I would state that ASCO issues rapid guideline recommendation updates when really important advances in the treatment and management of cancer have been presented. This mechanism really allows clinicians to keep up with the rapid advances in cancer management. The fact that a rapid update had to be issued just one year after the full updated guideline that was published in 2021, as you just mentioned, is really a testament to the advances in cancer research and clinical trials that have been made recently.

But I will state that the reason why this rapid update was done was because the result of the DESTINY-Breast04 study were so strong and compelling and showed such a large degree of benefit to a large group of metastatic breast cancer patients that we felt as the guideline panel that this rapid update had to be out there. We really wanted to make sure that the oncology community was aware of these results. That's based on the strength of the trial. The DESTINY-Breast04 trial was a very large randomized study that showed that trastuzumab deruxtecan significantly improved progression-free survival and overall survival compared to treatment of physician's choice in patients with metastatic, "HER2-low" breast cancer.

Brittany Harvey: So then based off this new data from the DESTINY-Breast04 trial that you just mentioned, what is the updated recommendation from the guideline expert panel?

Dr. Beverly Moy: So the updated recommendation is that patients with HER2-low, or to be specific, HER2 IHC1+ or 2+ and ISH negative metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease, if they're hormone receptor-positive, are refractory to endocrine therapy, those patients should be offered treatment with trastuzumab deruxtecan.

Brittany Harvey: And then what should clinicians know as they implement this new recommendation for trastuzumab deruxtecan?

Dr. Beverly Moy: I think that there are a few things that clinicians really need to be aware of. One is that it significantly improved progression-free survival and overall survival, and that's pretty important. The paper was published in the New England Journal of Medicine, and folks can refer to that study specifically. But to be specific, it improved progression-free survival at a median follow-up of about 18 months from 9.9 months with trastuzumab deruxtecan compared to 5.1 months with treatment of physician choice in the entire study population. Median overall survival was 23.4 months with trastuzumab deruxtecan and 16.8 months with treatment of physician's choice. So that's really a marked improvement in both of those outcomes.

It is also important to note that trastuzumab deruxtecan has a very important side effect, and that's the potential of developing drug-related interstitial lung disease or pneumonitis. And that could be very serious. This side effect was confirmed in about 12% of the patients who received trastuzumab deruxtecan, and about 1.3% of patients actually had severe symptoms requiring oxygen, and three patients in the study, so less than 1% actually died of this side effect. So that's something that needs to be monitored for very carefully, and clinicians need to be very cognizant of this potential side effect when using this drug.

Brittany Harvey: Thank you for reviewing both the impact on survival and then the adverse event of interstitial lung disease. So how does this guideline update impact patients with breast cancer?

Dr. Beverly Moy: So metastatic breast cancer is incredibly common. And this HER2-low, and I say, "HER2-low" because this is a definition that has never been made before. The patients with HER2 IHC1+ or 2+ and ISH negative disease, that's a very large group of patients. That's a lot of patients. So it's really important that this guideline is going to impact a very large group of patients. Again, it's those who've had at least one prior line of chemotherapy in the metastatic setting. And if they had hormone receptor-positive disease, it has to be refractory to endocrine therapy. But that's a lot of patients. And the results of this randomized study do show that trastuzumab deruxtecan is superior to other treatment of physician's choices that were available before this study came out in terms of its efficacy. So this guideline is very significant for clinicians and metastatic breast cancer patients across the world.

Brittany Harvey: Definitely. It's great to have a new option and one that has such a great clinical impact for patients.

So then finally, Dr. Moy, what are the outstanding questions regarding chemotherapy and targeted therapy for HER2-negative metastatic breast cancer?

Dr. Beverly Moy: I think like any good study, this raises a lot of other important questions. Again, this HER2-low definition that I described is an interesting one. It's a very large bucket of patients. One obvious question is, would this drug be as effective in patients who are truly HER2-negative, so HER2 IHC of 0? Kind of, overnight, the results of this study has changed the paradigm for many oncologists because we used to just say HER2-positive or HER2-negative. And now we're looking back at patients' charts to see what their immunohistochemistry results were. Does it really matter if it's IHC 0 or 1+ or 2+? So that would be very interesting.

Another outstanding question is: what about the use of trastuzumab deruxtecan earlier in the treatment? I said that it should be offered for patients who've received at least one prior line of chemotherapy? What about first line chemotherapy in the metastatic setting? And there are multiple studies studying this drug in actually early stage breast cancer as well. So lots of unanswered questions about this compound that's pretty remarkable.

Brittany Harvey: Great. Well, I want to thank you so much for your time today, Dr. Moy, for discussing the results of the DESTINY-Breast04 trial with me, and for your work to rapidly update this guideline.

Thank you so much.

Dr. Beverly Moy: Thank you, Brittany. It was a pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. 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 iTunes 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.

An interview with Dr. Fabrice André from Institute Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on "Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update." This updated guideline provides precise guidelines on previously endorsed genomic assays and recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in patients with ER-positive HER2-negative tumors, and for those with HER2-positive or triple-negative breast cancer. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Fabrice André from Institut Gustave Roussy in Paris, France, and Dr. Komal Jhaveri from Memorial Sloan Kettering Cancer Center in New York, NY, authors on "Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update." Thank you for being here Dr. André and Dr. Jhaveri.

Dr. Fabrice André and Dr. Komal Jhaveri: Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of guidelines and ensuring that the ASCO conflict of interest policies follow each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. André, do you have any relevant disclosures that are directly related to this guideline.

Dr. Fabrice André: No.

Brittany Harvey: Thank you. And Dr. Jhaveri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Komal Jhaveri: No.

Brittany Harvey: Great, then let's talk about the content of this guideline update. So, Dr. Jhaveri, what prompted the update to the biomarkers for adjuvant endocrine therapy and chemotherapy in early-stage breast cancer, and what is the scope of this guideline update?

Dr. Komal Jhaveri: So, since the biomarker guideline published in 2016, there were several new publications that came out between January 2016 and October 2021 that provided perspectives on the use of some of the genomic assays broadly, or specifically in women based on menopausal status, age or number of lymph nodes.

Additionally, new biomarkers such as programmed cell death receptor ligand 1 or PD-L1, stromal TILs, circulating tumor DNA, or circulating tumor cells, or new applications, like extended endocrine therapy have also been developed.

So, this updated guideline provides precise guidelines on previously endorsed genomic assays and also provides recommendations on the use of new biomarkers to guide endocrine therapy and chemotherapy in ER-positive HER2-negative, HER2-positive, and triple negative breast cancer.

Brittany Harvey: Great. Thank you for setting the stage for this guideline. So, then Dr. André, I'd like to review the key recommendations of the guideline for our listeners. So, starting with, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for patients with newly diagnosed ER-positive HER2-negative breast cancer?

Dr. Fabrice André: Thank you. So, when we are focusing on a newly diagnosed patient with ER-positivity HER-2 negative in the context of the question about deciding on chemotherapy. First, the 21 gene recurrence score should be used in patients with node-negative and in patients with 1-3 node positive who are postmenopausal.

In premenopausal, this test will be used only in patients with node-negative. The second test that is recommended is the MammaPrint 70-gene signature. And here the recommendation is to use this test if the patient is older than 50 and is node-negative or 1-3 node-positive.

If the patient is 50 years or younger, the clinician should not use this test. Then also a recommendation is that the clinician could use the 12 gene risk score EndoPredict if the patient is postmenopausal and has breast cancer node negative or 1-3 positive-node.

And finally, for the genomic test for the patient, the doctor could use PAM50. If the patient is postmenopausal and has breast cancer that is node-negative. Something new in this recommendation is the recommendation that the clinician could use Ki67. If the patient is postmenopausal and has stage I-II breast cancer with very specific recommendations on the cut off for positivity.

Brittany Harvey: Great. Thank you for reviewing those recommendations, Dr. André, and highlighting the new Ki67. So, then, in your introduction, Dr. Jhaveri, you discuss the application of assays for extended endocrine therapy. So, which biomarkers should be used to guide decisions regarding extended endocrine therapy for patients with ER-positive HER2-negative breast cancer?

Dr. Komal Jhaveri: Thank you. So, a quick word about extended endocrine therapy. I think extended adjuvant endocrine therapy, which is beyond five years of primary endocrine therapy, has certainly demonstrated improved outcomes, however, with modest absolute benefit and added toxicity and tolerability issues. Furthermore, while extended endocrine therapy is endorsed by clinical practice guidelines, clear guidance on individualized approaches to optimize patient selection for prolonged endocrine regimens, also remains limited. And this really underscores the need for prognostic and predictive information from genomic assays that can help guide this important clinical question we face.

One such example that has now borne out has been the breast cancer index and really collected evidence from now five studies supports the prognostic and predictive utility of this assay, such that if a patient has node-negative or one to three positive nodes, and has been treated with five years of primary endocrine therapy, to guide decisions about extended endocrine therapy, the clinician may offer Breast Cancer Index with either tamoxifen or aromatase inhibitors or tamoxifen, followed by an aromatase inhibitor.

Brittany Harvey: Great, thank you, Dr. Jhaveri. So, then, Dr. André, which biomarkers should be used to guide decisions on adjuvant therapy for early-stage HER2-positive breast cancer or triple-negative breast cancer?

Dr. Fabrice André: Well, first, we have to be sure that we are good at defining HER2-positive breast cancer and triple-negative breast cancer. So, it's always good to remind colleagues to have quality control assessment in place for HER2, estrogen receptor, and progesterone receptor stainings.

So far, when it's about predicting the benefit of adjuvant chemo or trastuzumab, there is no genomic test that is recommended in patients with HER2-positive or triple-negative breast cancer.

Brittany Harvey: Great, thank you. So, then, Dr. Jhaveri, what recommendations did the expert panel make regarding emerging biomarkers?

Dr. Komal Jhaveri: When we're talking about emerging biomarkers, we're referring to stromal TILs, we're referring to PD-L1, circulating tumor cells, and circulating tumor DNA. And while there is a lot of emerging data, currently, clinicians should not be utilizing these new biomarkers to guide decisions about adjuvant endocrine therapy or chemotherapy, as we do not have sufficient evidence to support their use.

Brittany Harvey: Great and that's important for clinicians to know. So, then finally, Dr. André, in your view, how will these updated guideline recommendations impact both clinicians and patients?

Dr. Fabrice André: So, we know Komal mentioned this at the beginning that now there is a very large amount of new publications, new data coming every day in the field of cancer. So, the only way for clinicians to deliver the best treatments for patients is to have the right guidelines with the right methodology, and ASCO is really putting in place a very rigorous methodology to deliver guidelines.

And this is the best way to be sure that all patients will have access to the best decision by the doctor. So guidelines are also here to decrease the disparities in terms of the expert decision, and any patient in the world can have access to the best decision, thanks to guidelines delivered by ASCO and all the colleagues of the panel that worked very hard to deliver these guidelines.

Brittany Harvey: Excellent! Well, thank you both so much, and the entire expert panel for your work to update these guidelines, and for taking the time to speak with me today, Dr. André and Dr. Jhaveri.

Dr. Komal Jhaveri: Thank you.

Dr. Fabrice André: Thank you, Brittany.

Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines in interactive resources in the free ASCO guidelines app available in iTunes or Google Play Store. If you've 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 or service organization activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, FL, and Dr. Carey Anders from Duke University in Durham, NC, co-chairs on "Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update." This guideline reviews evidence in both the local therapy management and systemic therapy management for patients with HER2-positive breast cancer and brain metastasis, and provides updated recommendations for these patients. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, Florida. And Dr. Carey Anders from Duke University in Durham, North Carolina, co-chairs on 'Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update'. Thank you for being here. Dr. Ramakrishna and Dr. Anders.

Dr. Carey Anders: Thank you.

Dr. Naren Ramakrishna: Thank you.

Brittany Harvey: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Ramakrishna, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Naren Ramakrishna: No.

Brittany Harvey: And Dr. Anders, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Carey Anders: I do. I would just like to disclose that I receive research funding, compensated consulting roles, and royalties from several of our industry partners who are developing brain permeable compounds.

Brittany Harvey: Thank you. Let's talk about the content of this guideline. So, Dr. Anders, what prompted an update to this guideline? And what is the scope of this guideline update?

Dr. Carey Anders: Thank you for that question, Brittany. Our previous guideline in the management of HER2-positive breast cancer brain metastasis was published in 2018. And since that time, we've seen significant progress in both the local therapy management and systemic therapy management for our patients with HER2-positive breast cancer and brain metastasis.

I think collectively, this body of work really prompted the panel to think through the changes that we could make to improve the care of our patients taking these updates into account. I'd love to hear Dr. Ramakrishna's take on the rationale for the update as he was also involved in the 2018 guideline.

Dr. Naren Ramakrishna: Thank you, Carey. Well, it's really an exciting time right now for breast cancer brain metastasis treatment. And the recent data that Dr. Anders referred to has really opened up a whole new era in terms of therapeutic possibilities for breast cancer brain metastasis patients.

In the past, we've relied on traditional methods of treatment like whole-brain radiotherapy, surgery, and stereotactic radiosurgery as mainstays of treatment. But this exciting data that Dr. Anders referred to, has resulted in the possibility of avoiding certain of the local therapy options in select patients, which has the potential to increase patient survival and quality of life, and is a major advancement.

Brittany Harvey: Excellent. It's great to hear about those advancements. So, then next, I'd like to start by reviewing the guideline recommendations for our listeners. Dr. Ramakrishna, what are the key recommendations for local therapy for patients with HER2-positive breast cancer and brain metastases?

Dr. Naren Ramakrishna: Since the 2018 updated guidelines, we've continued with our stratification of patients by prognosis by the number of metastases, size of metastases, and also whether they are symptomatic or asymptomatic.

Overall, the changes include the offering of systemic therapy for patients after multidisciplinary review for asymptomatic metastases, particularly those less than two centimeters in size. In select cases, one might also offer it for patients with metastases larger than that.

The other major change that we see in this update is an increasing reliance on stereotactic radiosurgery rather than whole-brain treatment as a local therapy option, both in the post-operative setting and for single or multiple metastases, for which surgery is not recommended.

Finally, we see a significant change in the application of whole brain radiation, where whole-brain radiation is recommended typically for extensive disease, either with multiple, very large metastases, or many, many small metastases. We recommend whole brain treatment to always be administered with a neuroprotectant, and where possible, with what's called hippocampal sparing, which is thought to reduce the neurocognitive negative effects of whole-brain radiation treatment.

Brittany Harvey: Understood, I appreciate those recommendations for local therapy and that overview that you provided. So then Dr. Anders, in addition to those recommendations, what are the key recommendations for systemic therapy for these patients?

Dr. Carey Andres: Sure, Brittany, happy to review. I think some of the general principles from the 2018 guidelines remain in place. So, for instance, our patients who have progressive disease in the brain, are eligible for local therapy and have controlled extracranial disease, we still recommend continuing the current HER2-directed therapy along with the same algorithm for the treatment of patients with HER2-positive metastatic breast cancer.

There are some interesting and exciting changes to the guidelines with the advent of several of the promising systemic therapies that Dr. Ramakrishna outlines such that we do have the option of leading with systemic therapy for our patients with small asymptomatic lesions in the brain predominantly based on the HER2CLIMB clinical trial which established tucatinib, capecitabine and trastuzumab in this setting.

So, in concert with our local therapist, we have the consideration for moving to the HER2CLIMB regimen in the setting of active asymptomatic brain metastasis in concert with our local therapist. So, that's one key change from the 2018 guidelines.

Another is the introduction of the compound trastuzumab deruxtecan, an antibody-drug conjugate, which has been shown in second line in the setting of metastatic HER2-positive breast cancer to be superior to our traditional T-DM1 therapy in this setting.

In the study, the Destiny-Breast03 study that illustrated the superiority of trastuzumab deruxtecan patients with stable brain metastasis were included and illustrated in this compound, illustrated significant benefit for patients with stable brain metastasis.

So, in addition to the HER2CLIMB regimen in the setting of stable brain metastasis, we also have the option of trastuzumab deruxtecan in this setting. And that was an update in our 2022 guidelines.

So, we essentially have more systemic therapy tools in our toolkit to consider in concert with local therapy. And I just want to emphasize the importance of communication between the systemic therapy team and the local therapy teams, particularly when we're making the decision to move forward with the systemic therapy in the setting of progressive or stable brain metastasis.

Brittany Harvey: Thank you. Yes, that multidisciplinary care is key, and I appreciate your reviewing those updates. So then, in addition to those what is recommended regarding screening for the development of brain metastases for patients with HER2-positive breast cancer?

Dr. Carey Andres: So, this is a very active conversation. And in fact, I had this very conversation with two patients in the clinic just yesterday. So, should we be screening our patients with advanced HER2-positive breast cancer with brain MRIs in the absence of symptoms? I think the bottom line is we just don't have the data yet. I think we will have the data and in fact, there are ongoing prospective studies trying to determine whether or not screening brain MRIs in the absence of symptoms in this setting will improve our patient survival, and also improve our patients' quality of life.

Until we have that data because we do have these new tools in the toolkit for systemic therapy treatment, the panel loosens the guidelines a bit to say that it's not that we no longer recommend screening in the asymptomatic state, but there's not enough data for or against. And I think this really will help the physician and patients as they're making decisions about their screening and restaging studies in a personalized manner.

In addition to the lack of data, we also strongly recommend that clinicians and patients have a very low threshold to obtain a brain MRI in the presence of symptoms and this is really important with regards to communication about symptoms as subtle as they may be. I'd love to hear Dr. Ramakrishna's take on this challenging space where we clearly need more data.

Dr. Naren Ramakrishna: Yes, Carey, I completely agree that it's quite challenging and the practice patterns are quite diverse throughout the country. It's also a source of a great deal of apprehension and anxiety for patients who automatically typically would assume that more frequent screening is better, especially when they do develop brain metastasis if that's to occur.

So, we do look forward to better data for guidance. And it certainly is an area that should undergo multidisciplinary reviewing recommendations for any particular patient.

Brittany Harvey: Understood, thank you both for reviewing the evidence as it states now and we'll look forward to that emerging data for perhaps a future guideline update. So then, Dr. Ramakrishna, what in your view is the importance of this guideline update and what does it mean for clinicians?

Dr. Naren Ramakrishna: Well, this is a practice-changing update. I mean, I don't think that's an overstatement. Because for the first time, upfront therapy is going to include the possibility of systemic therapy. And this also means that there has to be multidisciplinary and multimodality discussions regarding local versus systemic therapy for a large proportion of HER2-positive breast cancer brain metastasis patients. So, practice patterns are going to shift as a result of the incorporation of systemic therapy into the treatment paradigm.

And finally, the other very important, practice-changing local therapy change is that the use of whole-brain treatment will be reduced relative to stereotactic radiosurgery, but in some cases, also as a result of the use of systemic therapy, and when it is employed, it must be utilized with a neuroprotectant and/or hippocampal sparing.

Brittany Harvey: Great and then finally, how will these guideline recommendations affect patients with HER2-positive metastatic breast cancer and brain metastases?

Dr. Carey Andres: So, I would just echo Dr. Ramakrishna's comments about the advances that we've seen and the importance of multidisciplinary care. I think from a systemic therapy perspective, we have the wonderful problem of having multiple agents to consider in this space. And as we've seen, really an explosion of HER2-directed therapies that are now approved and available to patients. One of our challenges has been how to sequence these therapies.

And so, we were hopeful that these guidelines will help clinicians and patients determine when to pick individual regimens that best fit the patient's scenario, whether or not their brain metastases are stable at that decision tree, or whether or not they're progressive at that decision tree.

I would also point the listeners to the updated guidelines in the management of patients with HER2-positive metastatic breast cancer, as these guidelines will certainly complement the decision-making and systemic therapy, incorporating the presence or absence of brain metastasis.

Brittany Harvey: Great, and yes, thank you for highlighting that companion guideline. Both are available at asco.org/breast-cancer-guidelines and in the Journal of Clinical Oncology.

So, I want to thank you both so much for your work on these guidelines and for taking the time to speak with me today, Dr. Anders and Dr. Ramakrishna.

Dr. Naren Ramakrishna: Thank you very much, Brittany.

Dr. Carey Andres: Thank you! Thanks for the opportunity.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. 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 iTunes 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. Beverly Moy is back on the ASCO Guidelines Podcast to discuss the latest guideline rapid recommendation update regarding sacituzumab govitecan for patients with hormone receptor-positive HER2-negative metastatic breast cancer based on recent evidence published in TROPiCS-02. Dr. Moy reviews how this update intersects with the previous rapid recommendation update on trastuzumab deruxtecan and future areas of research that may impact further updates to this evidence-based guideline.

Read the latest update, "Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

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. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update'.

Thank you for being here, Dr. Moy.

Dr. Beverly Moy: Thank you for having me, Brittany. I'm glad to be here.

Brittany Harvey: Then first, 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 full conflict of interest information for this guideline panel is available in line with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Beverly Moy: I do not have any relevant disclosures.

Brittany Harvey: It's great to have you back on the podcast. Last we spoke, we were discussing the July 2022 rapid update of this guideline regarding the use of trastuzumab deruxtecan. What prompted the second rapid update to the guideline?

Dr. Beverly Moy: Thank you very much for that question, Brittany. The guidelines committee decided to issue another rapid guideline update because of the second interim analysis results of the TROPiCS-02 trial. This trial showed that sacituzumab govitecan had a significant improvement of over three months in overall survival compared to chemotherapy of physician's choice in patients with pretreated metastatic hormone receptor positive and HER2/neu-negative breast cancer. So we felt that the strength of this data compelled the ASCO guideline ommittee to issue yet another update.

Brittany Harvey: Understood. So then, based off this strong data that you just mentioned from TROPiCS-02, what is the updated recommendation from the guideline expert panel?

Dr. Beverly Moy: So the guidelines expert panel really wanted to get this information out because we felt compelled that clinicians should be aware that sacituzumab govitecan is another treatment option for patients with endocrine-resistant metastatic hormone receptor- positive and HER2-negative breast cancer. So we felt that clinicians may use this drug in patients who have received at least two prior treatments in a metastatic setting.

Brittany Harvey: Okay, you just mentioned this is one of several treatment options. So as this new recommendation is implemented, what should clinicians know?

Dr. Beverly Moy: So, I think that clinicians really need to be aware that sacituzumab govitecan, which is a newer drug, as an antibody drug conjugate, it really does have a role in patients with metastatic hormone receptor positive, HER2/neu-negative endocrine-refractory breast cancer. I think clinicians have been used to this drug in the setting of metastatic triple-negative breast cancer, but the results of theTROPiCS-02 trial would show us that it actually has a lot of efficacy and even an overall survival benefit in patients with metastatic hormone receptor-positive breast cancer. So clinicians should be made aware that this is a treatment option that does give an overall survival benefit.

Brittany Harvey: Great. It's great to hear that there's an overall survival benefit with this drug.

So, in addition to that, how does this rapid update impact patients with hormone receptor-positive HER2-negative metastatic breast cancer?

Dr. Beverly Moy: So I think that it's important for clinicians to remember that patients with metastatic hormone receptor-positive HER2/neu-negative breast cancer, the first-line therapies are endocrine therapy and targeted therapies. But when their disease becomes endocrine refractory, we have several treatment options, and usually the standard is sequential single-agent chemotherapy. What this guideline update is telling us is that sacituzumab govitecan, when compared to other treatments of physician's choice, really does improve overall survival and progression-free survival. So it really should be considered.

Brittany Harvey: Excellent. And then finally, are there ongoing research developments that the panel is keeping an eye on for any future updates to this guideline? I know this guideline was last published in 2021 and there's already been two rapid updates to it.

Dr. Beverly Moy: Yes, that's a really great question, Brittany, because this is a very active field, and I think that it's important actually to take this guideline update with sacituzumab govitecan in the context of our last guideline update, which, as you said earlier, was with the other antibody drug conjugate trastuzumab deruxtecan. That was our last guideline update in patients who had what we call metastatic HER2 low disease, where trastuzumab deruxtecan had a significant overall survival advantage as well.

So what these two guideline updates are really pointing out is that there's this new class of drugs, these antibody drug conjugates, that have so much promise and so much activity in metastatic breast cancer, whether it's hormone receptor-positive or hormone receptor-negative. So future research really has to help us clarify how do we sequence these drugs most appropriately now that we have these two very active treatment options that have a significant overall survival advantage. And then research also has to really guide us into the resistance mechanisms that may be in common or not in common with these two antibody drug conjugates. So I think that we're really looking at results of future trials to see how best to sequence them, if they should be used earlier in treatment in the metastatic setting, and we await the results of those trials.

Brittany Harvey: Absolutely. We'll look forward to those future research developments and work with you and the panel to continuously update these guidelines.

So I want to thank you so much for your work leading these guideline rapid recommendation updates, and thank you for your time today, Dr. Moy.

Dr. Beverly Moy: Thank you, Brittany, for having me.

Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast series. 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.

An interview with Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, WA, co-chairs on "Systemic Therapy for Advanced HER2-Positive Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on systemic therapies for advanced HER2-positive breast cancer, focusing on second-line, third-line, and greater treatment. Read the full guideline.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, co-chairs on 'Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: ASCO Guideline Update'. Thank you for being here. Dr. Giordano and Dr. Davidson.

Dr. Sharon Giordano: Thank you.

Dr. Nancy Davidson: Thank you for having us.

Brittany Harvey: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Giordano, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Sharon Giordano: No, I do not.

Brittany Harvey: Thank you. And Dr. Davidson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Nancy Davidson: No, I do not.

Brittany Harvey: Thank you. Let's talk about the content of this guideline update. So first, Dr. Giordano, what prompted an update to this guideline on the systemic therapy for advanced HER2-positive breast cancer, and what is the focus of this update?

Dr. Sharon Giordano: So, we were prompted to update the guidelines for HER2-positive metastatic breast cancer because several new studies have been presented and published, which are really changing our standard of care approaches.

We have new therapies and new combinations that have resulted in improvements in progression-free survival and in overall survival for this patient population. Given the clinical importance of these new studies, we felt that an update of the treatment guidelines was clearly needed. Overall, the focus of our update is really in the title, so, it's systemic therapies for advanced HER2-positive breast cancer. And specifically, what we're focusing on is updating the recommendation for second-line therapy, and then adding multiple new options for systemic therapies for third-line and greater treatment.

Brittany Harvey: Great. Thank you for that overview. So, then I'd like to review the updated recommendations of this guideline for our listeners. Starting with, Dr. Davidson, what is recommended for first-line therapy for patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: So, that was the part of this guideline that really did not change. In the previous iteration and in the current iteration, we felt that the evidence suggested that a combination of trastuzumab and a taxane should be the first-line treatment for individuals with metastatic HER2-positive breast cancer unless they have some sort of contraindication to the taxanes.

Now, the evidence supporting that is very strong. The trial that supported this continues to be updated and continues to show benefit. So, that's a very high level of evidence and our recommendation on this was extremely strong.

Brittany Harvey: Great. And then following those first-line recommendations, Dr. Giordano, what is recommended for second-line treatment for these patients?

Dr. Sharon Giordano: So, we did change our recommendation for second-line treatment for HER2-positive patients. The current new recommendation is, and I quote from our guideline, "If a patient's HER2-positive, advanced breast cancer has progressed during or after first-line HER2 targeted therapy, and the patient has not received trastuzumab deruxtecan, clinicians should recommend trastuzumab deruxtecan as a second-line treatment."

So, as I said before, this recommendation is a change from our prior second-line recommendation. Previously, we had recommended T-DM1. So, this change was really, I think, one of the most important changes to the guidelines with this update.

We made the recommendation based on the initial presentation of the results of the Destiny-Breast03 trial, really given the magnitude of the benefit that was seen in the study. And the manuscript I would note was published this month in the New England Journal of Medicine.

Overall, the study showed statistically significant and highly clinically meaningful reduction in progression-free survival. So, just to give you some of these numbers, to kind of give you a sense of how big the impact was, so 76% of patients who were treated with trastuzumab deruxtecan versus 34% of patients treated with trastuzumab emtansine were alive and without disease progression at a year, with a hazard ratio of 0.28.

The response rates are also quite impressive with 80% versus 34% response rates. And the overall survival data are still immature but do favor treatment with trastuzumab deruxtecan and that hazard was 0.55.

So, I will note though, that toxicity was a bit higher with the new drug, with trastuzumab deruxtecan. So, any grade adverse events were 98% versus 87%. And then if you look at grade three and four drug-related adverse events, it was 45% versus 40%.

I think of note, rather than just kind of the overall numbers, though, one thing that clinicians need to be aware of is the risk of interstitial lung disease with this new drug. And this occurred in about 10% of treated patients in this study, although only 1%, or I think it was two patients, who had grade three or higher pulmonary toxicity. So, this is a toxicity that is specific to this drug that clinicians do need to be aware of.

Dr. Nancy Davidson: I think the other thing on that, Sharon, is that the incidence was lower in the Destiny Breast03 trial than it had been in some of the really early studies of this agent, so, that should be reassuring to us. Although, of course, it doesn't mean that the side effect doesn't happen, you have to take note of it.

Dr. Sharon Giordano: That's a great point. It definitely was lower than we'd seen before. So, a little bit of a relief, but still there.

Brittany Harvey: Great, thank you both for reviewing that data. I appreciate the overview. So then, following those recommendations for second-line treatment, Dr. Davidson, what are the recommended options for third-line therapy for patients with HER2-positive advanced breast cancer that has progressed on second-line or greater HER2 targeted therapy?

Dr. Nancy Davidson: Well, of course, this is the area where there has been considerable change as well. And that's because of the wealth of new anti-HER2 agents that Dr. Giordano talked about earlier.

So, we had a variety of recommendations for clinicians and patients to make decisions about how to proceed. I think certainly one of them, is that if the patient did not receive trastuzumab emtansine (T-DM1) in the second line, as we just talked about, our new recommendation would be that they would not, that they would receive trastuzumab deruxtecan, so you put off for T-DM1 in that [third-line] setting. And that's a new recommendation for us. And the strength of the recommendation is quite high.

Another agent that's come along that's very exciting is tucatinib, one of the small molecule inhibitors. And we think that that is also an alternative, that tucatinib in combination with trastuzumab and capecitabine, again, nice activity and pretty strong recommendation based on analyzed critical trials. And then finally, if for some reason the patient didn't receive the trastuzumab deruxtecan in a second-line setting and you're now in the third-line setting, that would be a very reasonable agent for them as well.

Those are all pretty strong recommendations. And I think the choice of which to proceed will depend a little bit on the decision making between the patient and the doctor about the mode of administration, your side effect profile, what seems the most appropriate, and it might be more one of the order of the recommendation. As opposed to saying, 'This one, but not that one', it might be, 'Pick this one next and know that you will be able to return to some of these in the future.'

Now, there are a lot of other possibilities here. We already had available to us neratinib and capecitabine, that continues to be part of the portfolio. And we also had lapatinib and capecitabine, also part of the portfolio. Other combinations of chemotherapy, trastuzumab could be considered, a new agent called margetuximab with chemotherapy, which has also come on to the market.

And of course, there's the possibility of thinking about the anti-HER2 agents in the context of endocrine therapy for those patients who have estrogen receptor-positive breast cancer as well. And new information suggesting that you might, in some cases, even think about one with CDK 4/6 inhibitors in the context of trastuzumab and fulvestrant.

So, lots of possibilities here that patients and doctors can weigh, and again think about order of administration as opposed to selecting for or against the other. I do think that the leading contenders at the beginning are going to be T-DM1 or trastuzumab deruxtecan, if that hasn't been used, or tucatinib in combination, those would be my personal preferences.

Brittany Harvey: Great. Thank you for reviewing those options and describing where a patient might receive these during their treatment.

Dr. Nancy Davidson: I'd like to hear Dr. Giordano's thoughts on that, how would you stack those up?

Dr. Sharon Giordano: Yeah, well, as you said, I think it does depend on what the patient's been treated with previously. I mean, certainly, T-DM1 or trastuzumab deruxtecan, if they haven't had those agents. Otherwise, I think the data from the tucatinib trastuzumab capecitabine regimen is pretty impressive as it did show an overall survival benefit. And as you know, I think that regimen is also really interesting, because it does seem to have some efficacy for patients with brain metastases. That actually has a very nice advantage.

Then the other ones, I think it just sort of depends on what they've seen previously, what side effects they may be experiencing, and kind of other quality of life issues. I don't see that there's a clear way to sequence the other ones since most of them haven't really been directly compared head-to-head against each other.

Brittany Harvey: It seems like it may be an individual discussion between clinicians and patients at that level. So, then, Dr. Giordano following that, how will this guideline impact clinicians and what should they know as they implement these updated recommendations?

Dr. Sharon Giordano: I think the bottom line is really the clinicians are now going to have more options for the treatment of HER2-positive advanced breast cancer which is fantastic news to have all these different choices and options for our patients.

To me, I think probably the most important changes and recommendations, again, are the addition of trastuzumab deruxtecan in the second-line setting just given the very impressive clinical benefit that's seen with that drug, or, as Nancy mentioned in the third-line setting if patients, for some reason haven't received it previously.

And then I also think, as we talked about, the tucatinib combination is really an exciting new combination that does seem to have significant clinical benefit. I think the clinicians will need to be aware that that might be an option for patients with CNS metastases that are progressing. And also, just to be aware, as we mentioned before, about the risk of the interstitial lung disease with trastuzumab deruxtecan but it's really encouraging to me to have such a long list of drugs and combinations that we can use to treat our patients.

Brittany Harvey: Excellent. Those are great points. So, then finally, to wrap us up, Dr. Davidson, in your view, how will these guideline recommendations impact patients with advanced HER2-positive breast cancer?

Dr. Nancy Davidson: Well, Brittany, I think one thing we hope, of course, is that those patients will cumulatively have a longer survival, and a better survival as a consequence of all of these new insights that we've been able to make.

I can imagine it would be maybe a little confusing to patients that there are so many things that they might potentially be able to choose from, but this is one where I think that the larger the panel of agents that you have available to you, the happier it is.

So, I hope that patients are going to look at this as an opportunity for partnership with their oncologists to try to figure out of all these possibilities, what's the best one for me now, and they're going to have the comfort of knowing that there'll be other things that they can fall back on in the future, and that, hopefully, these things will improve outcomes. And again, without excessive toxicity.

This last thing I'm going to hope that clinicians and physicians will remember is that we've made a lot of headway here, but that our results are not perfect. And so, right now, we're able to change guidelines, these guidelines today because of clinical trials that have been put together in the last several years and successfully implemented. And I hope that we're going to continue to do that because until we get to a point where survival from HER2-positive breast cancer is 100%, we've got work to do. So, they're going to be other new clinical research strategies, and I hope that doctors and patients will take advantage of those whenever possible.

Brittany Harvey: Absolutely, both hoping for longer survival and better quality of life and looking forward to more clinical trials to give clearer answers. I want to thank you both so much for your time today and for all of your work on updating these guideline recommendations, Dr. Davidson and Dr. Giordano.

Dr. Nancy Davidson: Thanks, Brittany.

Dr. Sharon Giordano: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guideline Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines.

There's a companion guideline update on the management of advanced HER2-positive breast cancer and brain metastases also just published in the Journal of Clinical Oncology and on asco.org. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes 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 expressed 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.

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'.

Thank you for being here, Dr. Henry.

Dr. Lynn Henry: Thank you very much for inviting me to participate.

Brittany Harvey: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Henry, do you have any relevant disclosures that are related to this guideline topic?

Dr. Lynn Henry: No, I do not.

Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update?

Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time.

When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included.

The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well.

Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing?

Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone.

This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations.

Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma.

Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor.

Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor.

Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations?

Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation.

Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline.

Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations?

Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor.

This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums.

In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor.

The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants.

Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency?

Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time.

Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer?

Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test.

At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy.

The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater.

Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use.

Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high?

Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab.

In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs.

In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used.

Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden?

Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions.

However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically.

Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables.

So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment.

Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase?

Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions.

So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer.

Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA?

Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression.

Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question.

Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells?

Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer.

To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer.

Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations?

Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer.

Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers.

Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future.

Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer?

Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients.

Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers.

Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry.

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 series. 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 on iTunes 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.

Picture this: it's day 1 of fellowship and your attending needs you to "get consent for treatment." Huh? How do you educate your patient? We share our tips!

In this episode, we discuss important considerations, including “does my patient need a port?”, “what if drugs extravasate?”, “how do I keep side effects of drug classes straight?!”

*The resources we share are our OWN opinions. Naming of resources are not endorsements. We are not sponsored by any of these entities.

Pharmacology 101:

* Irritant vs. Vesicant:

** Each drug is deemed one of these based on the degree of tissue damage that can result if drug extravasates under skin. 


** Vesicant: needs central access


** Irritant: can be given peripherally 


* Does my patient need a port/picc?

** If vesicant; for continuous infusions over several days (e.g. 5-FU); some patients with difficult access may request. 


*Advantages of ports:

** Easy access for labs


** Easy access for chemotherapy/fluids


* Disadvantages:

** Risk of infection


** Risk of thrombosis 


* General overview of chemotherapy side effects:

** Going to target the fastest growing cells in the body, which includes cells that line the GI tract, skin, hair/nails, and blood cells


** Therefore side effects are related:

*** GI: nausea/vomiting, diarrhea (sometimes constipation), decreased appetite, taste changes


*** Low blood counts

**** WBC nadir ~10-14 days (generally), and recover 21-28 days after chemo


* What about unique side effects of chemotherapy classes? How do we keep them straight?

** We love keeping “Chemoman” from the USMLE study days in mind!


* Anthracycline

*** MOA: Topoisomerase inhibitors


*** Ends in “rubicin”


*** You might hear people call doxorubicin the “red devil”


*** Used in lots of cancers


*** Hair loss occurs with this one


*** Known to cause cytopenias and associated with higher nausea potential 


*** Unique side effects:

**** Heart failure (always get baseline echo!)


**** Development of MDS and leukemia 


* Alkylating agents

** MOA: Drugs add alkyl group to the guanine base of the DNA molecule, preventing linking of strands


** End in “fosfamide”


** fosfamide or cyclophosphamide (AKA cytoxan)


** Used in lots of cancers


** Known to cause cytopenias and hair loss


** Unique side effects:

*** Secondary MDS or leukemia possible 


*** Ifosfamide = neurotoxicity = methylene blue antidote


*** Cyclophosphamide = hemorrhagic cystitis due to acrolein byproduct accumulation = prevent by giving mesna to protect bladder


* Antimetabolites

** MOA: Purine analog, pyrimidine analog, folate antagonists; therefore prevent production of base pairs or binds instead of normal base pairs


** End in “abine” - capecitabine, cytarabine, gemcitabine, cladribine, fludarabine


** Also 5-FU and 6-MP in this category so “number followed by dash”


** Unique side effects:

*** Think bone marrow suppression in this category  


* Platinum agents

** MOA: Believed to cause cross-linking of DNA


** End in “platin”


** Associated with high risk of neuropathy 


** Unique side effects:

*** Cisplatin:

**** Nephrotoxicity 


**** Ototoxicity 


**** High risk of nausea; need special prophylaxis 


*** Carboplatin: cytopenias


*** Oxaliplatin: higher rates GI side effects 


* Microtubule agents

** MOA: Impair microtubule function, therefore impacting cell division


** End in “taxel” or vincristine/vinblastine (“V-stine”)


** Unique side effects: Neuropathy


Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

Instagram: @TheFellowOnCall

Listen in on: Apple Podcast, Spotify, and Google Podcast

Picture this: it's day 1 of fellowship and your attending needs you to "get consent for treatment." Huh? How do you educate your patient? We share our tips!

In this episode, we discuss the fundamentals and some of our favorite resources.

*********The resources we share are our OWN opinions. Naming of resources are not endorsements. We are not sponsored by any of these entities. *********

1) How do you know what regimen to use for a disease?

* www.NCCN.org :

** National Comprehensive Cancer Network

** Free resource, but need to make an account!

** Provides stepwise approach to workup, choosing a regimen, and surveillance information, treatment for refractory disease

* www.HemOnc.org :

**Organized by disease type with long lists of treatment options

** Provides a breakdown of regimen, but also provides the primary literature that lead to the regimen’s approval for use!

**We cannot highlight how important it is to remember to check out the primary literature!

2) Patient education: Use these to drive discussion; you still want to walk your patients through these

* www.Oncolink.org : Ronak’s favorite resource

* www.Chemocare.com : Vivek and Dan’s favorite resource

3) Basic Terminology:

* Cycle: The number of days between one round of treatment until the start of the next; abbreviated with “C”

* Days: Counts the actual days within a cycle; abbreviated with “D”

* Example: C1D1: Cycle 1 of a regimen, day 1 of this cycle

4) Dosing:

* Always have updated height and weight for patients

** Many drugs are dosed based on body surface area (BSA)

** Other drugs use area under the curve (AUC)

* Always get a CMP and CBC prior to giving treatment

5) General categories of cancer therapies:

* Cytotoxic: Kills cells in the body

** Analogous to antibiotics killing bacteria

** Relatively non-specific in terms of what cells they target; but they’re often specific for parts of the cell replication cycle

* Immune therapy: Harness the immune system to attack cancer

** More specific than cytotoxic agents

* Targeted therapy: Drugs made specifically for known mutations

** A cancer with a distinct mutation in a protein is then a target for this drug

** In general:

***“Mab”- antibody targeted for phenotypic expression

***“ib”- small molecule for driver mutation

** Targeted cytotoxic chemotherapy: a monoclonal antibody specific for a mutation linked to very potent chemotherapy

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

Instagram: @TheFellowOnCall

Listen in on: Apple Podcast, Spotify, and Google Podcast

We have now covered the fundamentals of pharmacology. This week, we sit down with Renee McAlister, PharmD, BCOP to learn more about the nuances of pharmacology from an expert that does this day in and day out.

*The products/resources we share are our OWN opinions. Naming of resources are not endorsements. We are not sponsored by any of these entities.

Pharmacology Capstone:

* Irritant vs. Vesicant:

** For extravasation, what to do?

*** Not a great general source; would recommend checking institutional guidelines.

*** Different drugs may require a cold vs. warm compress.

*** Some drugs have antidotes - it is best to just look this up when it happens

* Why is there a “cut off time” to get in chemotherapy orders?

** Many hospital pharmacies are not 24 hours, therefore need prep time.

** Many drugs take a long time to prepare!

** A lot verification goes into ensuring that the drugs are correctly ordered, prepared, and handled. Therefore this requires adequate staff to do this safely.

* What does "ideal body weight” mean?

** Calculated by the patient’s sex, height, and the calculated body weight based on this information

** Helps with drug-dosing to ensure that drugs are not over/under-dosed

* What does “AUC” mean?

** Incorporates renal function and the amount of exposure you want the patient to have to the drug. Based on the Calvert equation.

** It is important to re-calculate each time with a new Cr to ensure that this is updated.

** Example: https://reference.medscape.com/calculator/169/carboplatin-auc-dosing-calvert

* What is the role of granulocyte colony-stimulating factor (GCSF)?

** Helps to prevent the risk of infection, especially from endogenous bacteria.

** GCSF helps to minimize the window of neutropenia related to treatment with chemotherapy

** NCCN guidelines (www.nccn.org) provides guidelines about febrile neutropenia risk. A risk >20% means that we build in GCSF administration into the treatments.

*** If risk 10-20% with certain risk factors, we may consider adding GCSF

*** Always look at the paper that was what the approval of the regimen was based off of - they will comment on if/how GCSF was used during the study.

*** If patient develops neutropenic fever during a cycle, if even the drug is not traditionally one that we consider GCSF for, it would be appropriate to consider GCSF for future cycles to decrease the risk of febrile neutropenia.

* What are the different “types” of GCSF?

** Examples:

*** Filgrastim (“Neupogen”) - daily dosing, short-acting GCSF

*** Pegylated-filgrastim (“Neulasta”) - don’t have to give daily dosing; one time shot because it lasts for longer

*** On-body injector (OBI) - a device put on the arm that delivers pegylated- filgastrim at approximately 26 hours after chemotherapy

** Dosing: Very different dosing for all of these medications; pay attention to the dosing!

* Supportive care:

** How do you decide what anti-emetics to include?

*** NCCN supportive care guidelines is a great place to start

*** Regimens with >90% emetic potential should get at least three agents (for example: ddACT, cisplatin based regimens)

**** Example: 5-HT3 receptor antagonists, dexamethasone, olanzapine, and aprepetant

*** Moderate emetic potential (30-90%), add at least 2 drugs

**** Example: 5-HT3 receptor antagonists and dexamethasone

*** Lower risk (30%): usually one one drug

**** Example:5-HT3 receptor antagonists

** If patients have refractory nausea in a cycle, add another agent. When adding drugs, always ensure you are incorporating the patient’s other medical history AND drug-drug interactions

* Pharmacists are an amazing source of information! Please reach out with questions!

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

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Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis.

This week, we sit down with guest pulmonologist Dr. Greta Dahlberg to discuss how she thinks about and works up lung nodules concerning for malignancy.

Lung nodules:

* For discussions about incidental lung nodules and lung cancer screening, check out Episode 197 from our friends, The Curbsiders (link: https://thecurbsiders.com/podcast/197)

* Nodule vs. mass:

** “Micronodule” is <3mm

** “Nodule” is <3 cm

** “Mass” is anything bigger

*Characteristics of “benign” vs. “malignant” nodule

** Most important thing is change over time; therefore always good to have old imaging if possible.

** If growing overtime, even if slowly, that should raise red flags for malignancy

** Volume doubling time (link: https://radcalculators.org/volume-doubling-time-vdt-calculator-for-pulmonary-nodules-volume-based/)

*** If doubling time <20 days, it’s often infectious

*** Average lung cancer doubling times is 100 days

* Benign:

** Smooth

** Calcifications (diffusely or popcorn calcifications)

** Internal fat appearance

* What about a spiculated nodule?

** This is when there are nodules with “little hairs” coming off, often thought to be malignant

** Dr. Dahlberg reports that odds ratio of it being malignant is 2.5, so it is high, but not that high. So spiculated does NOT necessarily mean malignant.

* Workup before referring to Pulmonary:

** Dedicated CT scan of the chest

** Obtain old imaging

** PET CT

*** Expert tip: If growing, whether it’s hot or not, it warrants a biopsy

*** PET can help identify spread and/or nodal involvement

* Biopsy approaches (we don’t know approach which one is better … There are studies ongoing!):

** Transthoracic biopsy (CT guided):

*** Performed by IR

*** Major risk: pneumothorax (20-25% have one after procedure!)

*** Benefit: Does not need general anesthesia

**Transbronchial biopsy:

*** Performed by Pulmonary

*** Requires general anesthesia and paralyzing

*** Options while doing biopsy:

**** EBUS

**** Fluoroscopy

*** Major risks: Pneumothorax (1.5% have one, less than half need chest tube)

*** Benefit: You can also do EBUS to stage mediastinum. Remember- we always look to upstage a cancer and by looking at the mediastinum, this helps to accomplish that

* What if someone has two lung nodules on contralateral sides?

** Likely both will be sampled

** If PET has one nodule that is more FDG-avid than the other, they will go after that first. But they can sample both if safe.

* Does PET help with bronchoscopy?

** It can help, but appearance during bronchoscopy is more important

* When is something NOT amenable to bronchoscopy?

** The middle third of the lung is hardest and most technically challenging

** Lower lobes of lungs, made difficult by atelectasis

** Contrary to common belief, peripheral lesions are easier due to anatomy of the lungs

About our guest: Dr. Greta Dahlberg (link: https://medicine.vumc.org/person/greta-dahlberg-md) is a pulmonary/critical care fellow at Vanderbilt University Medical Center in Nashville, TN. Thank you so much for joining us!

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Lung Cancer Histology and Staging

*Workup for a nodule that is concerning:

**Ensure there is a dedicated CT scan of the chest to evaluate

**Try to obtain old imaging; the rate of change is important

**Can get PET, but even if a lesion if not FDG-avid, but growing quickly we should consider biopsy anyway

**Referral to pulmonary medicine, who can assist with biopsy and also regional lymph node evaluation (important – more below)

**PFTs are often ordered because it provides information about lung function in anticipation of possible surgery for treatment

Lung Cancer Histology:

*Non-small cell lung cancer (NSCLC)

**Umbrella term for a variety of cancers

**Increased risk in smokers

**More common types:

***Adenocarcinoma (~50% of all lung cancers)

****Most common overall; cancer of the mucus producing cells

****IHC: TTF-1, NapsinA, CK7 positive

***Squamous Cell Carcinoma (22.7%)

****More often seen in patients with a smoking history

****IHC: p63 positive and cytokeratin pearls

***Remaining ~15% are the other types of lung cancer / mixed histologies

**Small cell lung cancer (SCLC)

***Neuroendocrine tumor with very different pathology

***Much more aggressive than NSCLC

***Oncologic emergency

***IHC: Chromogranin and synaptophysin positive

IHC pearls: TTF-1 usually means lung cancer (but can be negative in squamous cell lung cancer). This will be important in the future (we promise :])

*Staging for NSCLC:

**Nodal evaluation: lymph node evaluation is part of the workup for NSCLC

**Single digit = central/mediastinal nodes (higher risk)

**Double digit = peripheral/hilar/intrapulmonary lymph nodes (lower risk)

**“R” vs. “L” is direction

*Pearl: Why is this important? If there is nodal involvement, systemic therapy is going to be necessary

*Putting it all together:

**T: Tumor size: T1-4

**N: Nodal involvement

***N0: no nodal involvement

***N1: Nodes closest to the primary tumor (double digits)

****Ipsilateral peribronchial, hilar, intrapulmonary

***N2: Further away (single digit)

****Ipsilateral mediastinal and/or subcarinal LN

***N3: Contralateral any node or supraclavicular LN

**M: Metastasis – in lung cancer, patients with certain patterns of metastatic disease are still curable!

***M0: no mets

***M1a: Contralateral lobe, pleural effusion or pericardial effusion à these are generally still curable!

***M1b: single site of metastatic disease à these are generally still curable!

***M1c: multiple sites of metastatic disease à these are generally not curable

*Staging for SCLC:

**Limited stage - meaning it can fit in “one radiation field”

**Extensive stage - does not fit in “one radiation field”

*Once lung cancer is diagnosed:

**Go to NCCN to learn the flow of ongoing management

**Complete staging (if not already done):

***CT C/A/P (don’t necessarily need if a PET scan is done)

***PET Scan

***MRI brain à in general this is needed, but there are some exception to this (see NCCN)

**Referral to pulmonary for nodal evaluation

References:

NCCN.org

https://doi-org.proxy.library.vanderbilt.edu/10.1016/j.semcancer.2017.11.019-Article about IHC markers for lung cancer

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This week, we complete our breast cancer series, focusing on triple-negative breast cancer (TNBC). The last few months have been quite the journey! Please continue to refer to our shownotes to help navigate this complex disease treatment paradigm.

Content:

- What is the data about recurrence of disease of TNBC?

- The history of how we got to our current standards of care

- Important trials to support our current treatment paradigm

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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This week, we continue our discussion about metastatic breast cancer, focusing on HER2+ disease.

Content:

- What is the data about recurrence of disease of different breast cancer subtypes?

- The history of how we got to our current standards of care

- Important trials to support our current treatment paradigm

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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After several weeks of covering localized disease, this week, we shift our discussion to metastatic breast cancer, focusing first on ER+ disease.

Content:

- Importance of taking a biopsy at time of disease progression

- What endocrine therapy backbone do we choose in metastatic ER+ disease?

- What agents can we add to endocrine therapy for metastatic ER+ disease?

- What is "visceral crisis"?

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This week, we round out our discussion on the early stage breast cancer, turning our attention to the triple negative subtype. Once again, there are a lot of trials and data, but be sure to check out the show notes for the highlights!

Content:

- What is TNBC?

-What is the data to support the use of neoadjuvant therapy in this disease?

- What is "pathologic CR" and how is different than "residual cancer burden"?

- Can we ever omit neoadjuvant therapy?

- What are our options for chemotherapy regimens in neoadjuvant and adjuvant setting?

** This episode has been sponsored by HemOnc.org

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We continue on our journey through early stage breast cancer, this time turning our attention to HER2+ disease. There is a lot of data in this episode, as you will both hear and see. To make this easier, we highlight key takeaways to make understanding this even easier.

Content:

- What is HER2?

- Discovery of trastuzumab

- Data for use of trastuzumab in adjuvant and neoadjuvant setting

- Data for use of pertuzumab in adjuvant and neoadjuvant setting

- Data and use of trastuzumab emtansine (TDM-1) in the adjuvant setting

- Management of HER2+ stage I breast cancer

- Highlights of key trials that shape the paradigm of management

- Our approach to management

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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This week, we continue discussing the management of early stage ER+/HER2- breast cancer. If you have not done so already, be sure to check out Episode 057 for the first part of this discussion.

Content:

- Who warrants chemotherapy?

- Who benefits from gene expression assays?

- What are important gene expression assays used clinically?

- Post-treatment surveillance and survivorship

- Targeted agents in the adjuvant setting

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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After several weeks of incredible discussions with our special guests, it’s time that we dive into the medical oncology regarding breast cancer. We start our discussion with the first of our two-part discussion on early stage (AKA non-metastatic) ER+/HER2- breast cancer.

Content:

- What information do we need to consider in patients with HR+ breast cancer?

-What is the role of chemotherapy?

-If chemotherapy is indicated, what are the treatment options? Why?

-Anti-estrogen therapy selection and duration

-Is there a role in ovarian suppression in HR+ disease?

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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So much incredible progress has been made in the management and treatment of breast cancer, largely thanks to advances in available therapies and drugs. A good understanding of pharmacology is key to selecting the correct regimen and providing counseling to your patients. This week, are so fortunate to be joined by special guest Dr. Danielle Roman, PharmD, who is an Oncology Clinical Pharmacy Specialist at West Penn Allegheny Oncology Network in Pennsylvania, as she helps us navigate breast cancer pharmacology.

Content:

- A discussion about different anti-estrogen therapies

- Counseling about anti-estrogen therapy side effects

- An overview of regimens used in ER+, HER2+, triple negative disease

- Highlighting key trials related to the approval of these agents

- Supportive care for breast cancer patients

** This episode is sponsored by HemOnc.org!

**Thank you to our guest, Dr. Danielle Roman

** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodes

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The language of breast cancer can be confusing and very technical. In this episode, we help you learn and understand so many important words and phrases that have important implications on diagnosis and management. Understanding these will not only help you learn more about breast cancer, but it will also ensure you are better able to communicate the lingo to your patients!

Content:

- Definitions of important terms and phrases pathologists include on their reports

- Important terminology to understand

- Fundamentals of TNM staging for breast cancer

- Important buzzwords to know when reading clinical trials in breast cancer

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The Fellow on Call is thrilled to partner with so many of our podcasting friends be a part of #NephMadness 2023 this year. In today’s episode, we welcome three incredible guests to our show, Dr. Matthew Abramson, Dr. Timothy Yau, and Dr. Scott Stockholm, to talk about the two very critical topics in hematology/oncology. The first is a discussion about immune checkpoint inhibitor-related AKIs. The second is a discussion about hypomagnesia in our patients. To learn more about NephMadness and to cast your votes, be sure to check out: https://ajkdblog.org/tag/nephmadness2023/. We’d love to see Onconephrology snag that #1 spot :)

Content:

- What is the mechanism of immune checkpoint inhibitor-associated AKIs?

- What is the etiology of ICI-related AKIs?

- How do we work these up?

- How do we treat? Steroids? Do we biopsy?

- Can we re-trial ICI in someone who had ICI-related AKI?

- How do we use ICI in patients with kidney transplants?

- What are symptoms of hypomagnesemia?

- A refresher on magnesium homeostasis

- How do we manage hypomagnesemia?

- What drugs are associated with hypomagnesemia?

**A huge thank you to Dr. Joel Topf and the team at NephMadness for the invitation to be a part of this podcrawl, helping to collect resources, and create a show outline

** A huge thank you to our guests!

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Molecular Testing Pearls

In Part 4 of our Heme Path series, we thoroughly examine the details of molecular testing and how it relates to hematologic and oncologic malignancies

I. Molecular Testing Basics

A. Provides a means of assessing patient’s genotypes, specifically at smaller changes in the genetic information

B. How is it performed?

1. Polymerase chain reaction (PCR)-based testing, which involves using a specific primer that is complementary to the area of interest on the patient’s DNA

2. PCR can allow for both amplification and quantification of gene of interest

C. Can look for either single gene mutations (faster) or a panel of mutations (slower but more information) also known as NGS

II. Clinical Utility of Molecular Testing

A. Very useful in risk stratification based on the mutations noted (some mutations are unfavorable and some are favorable)

B. Certain genetic mutations have drugs that are effective against them, therefore provides information about targeted therapeutic options

C. In hematologic malignancies, can be used to also assess response to treatment

1. You can determine minimal residual disease or MRD

2. Can look for a gene mutation that was present in the original cancer clone and see if there is any amount of residual cancer left over on the order of 1 in a million cells

D. In solid cancers, used to determine presence of genetic changes that have prognostic and targeted treatment implications

1. BRAF V600E mutation in melanoma → BRAF inhibitor pill treatment

2. EGFR mutation in lung cancer → EGFR inhibitor pill treatment

III. How is molecular testing different than FISH?

A. Both require choosing probes and understanding what you are looking for before running the test

B. FISH (discussed in part 3!) reports out of 200 cells and provides information about only larger kilobase sized genetic changes (translocations, inversions, deletions)

C. Molecular testing analyzes a much larger number of cells and can detect changes at the single base pair level. Much more detailed and microscopic evaluation of genetic changes

IV. Single Gene Molecular Testing

A. Look for a specific gene mutation (i.e. EGFR for lung cancer, BRAF for melanoma, FLT3-ITD for AML)

B. Pros:

1. Faster turnaround time

2. Has a higher resolution and effective for detecting MRD

B. Cons:

1. Only looks for one genetic mutation as opposed to a panel like in NGS

2. Some diseases ideally require understanding of multiple mutations not just one for prognostication and treatment planning

V. Next Generation Sequencing (NGS)

A. Allows to sift through a larger part of the genome to identify a panel of mutations

B. Panel of mutations chosen is based on the clinical context

1. For example: NGS for acute myeloid leukemia is much different than NGS testing for lung cancer as each cancer has a much different genetic mutation profile

C. Overview of technical aspects of running NGS

1. Massively parallel sequencing meaning that many tiny primers are used and the areas that primers encode may be overlapping

2. A computer takes all of the smaller pieces and puts them together to determine the correct sequence

D. Pros:

1. Gives us an understanding of many different mutations present based on the panel chosen

2. Again, this has both prognostic and predictive treatment implications

E. Cons:

1. May find mutations of undetermined significance meaning we currently do not understand how these mutations will affect prognosis and treatment decisions

2. Very time consuming (~2-4 week turnaround time)

3. Costly

References:

1. https://jamanetwork.com/journals/jamaoncology/fullarticle/2734828 - Quick overview of NGS

2. https://ashpublications.org/blood/article/125/26/3996/34323/Minimal-residual-disease-diagnostics-in-acute - Look at table 1 to see the difference in sensitivity for MRD testing

3. https://www.oncotarget.com/article/27602/text/ - Emphasizes prognostic relevance of EGFR mutations in NSCLC

4. https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 - Phase 3 trial showed that targeted treatment for EGFR mutation in NSCLC was superior to chemotherapy

5. https://www.nejm.org/doi/full/10.1056/nejmoa1614359 - Phase 3 trial showed that targeted treatment of FLT3 mutation in AML improved outcomes

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In Part 3 of our Heme Path series, we break down the basics of immunohistochemistry (IHC)

Episode contents:

- What is immunohistochemistry?

- What are the pros and cons?

- How do we use this clinically?

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In Part 2 of our Heme Path series, we get into the details of cytogenetics (conventional karyotype and FISH)

Episode contents:

- What is "cytogenetics"?

- How do we use cytoenetic information clinically?

- What is the difference between the conventional karyotype and FISH?

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In Part 1 of our Heme Path series, we break down the logistics and applications of flow cytometry.

Episode contents:

- What is flow cytometry?

- How do we use this to identify cells?

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We strongly recommend you listen to our previous episodes metastatic lung cancer (Episodes 0032 and 0033) to better be able to follow along with this conversation. Key trials mentioned in this episode include:

CHECKMATE 227

KEYNOTE 024

Q:Do you send molecular testing (PDL1 and NGS) on the biopsy, peripheral blood or both?

* Yield is highest from the tissue sample

* Peripheral blood (circulating DNA) samples are dependent on the burden of disease and so often the yield is lower

** One of the benefits is that it can be sent quickly and having a fast turn-around; Tissue samples are dependent on being able to schedule a biopsy

* Dr. West says he definitely sends this on a non-smoker with non-squamous lung cancer, as they are more likely to have molecular targets

* Dr. West has not personally adopted the idea of sending peripheral and tissue samples for NGS testing for everyone

Q: Do you ever use Ipi/Nivo in patients with PDL1 <50% (ref: CHECKMATE 227)?

* There are a lot of other options so he does not use this, as it is harder to predict the side effects with therapy like this

* “Chemo-free does not mean side-effect free”

Q: We understand there is a lack of randomized trial data on the use of consolidative radiation after IO based treatment in the metastatic setting. If patients have a good response to systemic treatment, when do you consider using consolidative radiation for cure?

* A systemic therapy that is effective that leaves you with oligo-residual disease, radiation can be considered for the right patient

** We need to balance what a radiation oncologist says he/she can radiate vs. what is actually the right thing to do

** Sometimes, it’s best to give the cancer some time to “declare itself”.

* A nuanced discussed, but it may be worth considering especially in patients who have disease that is

** (a) growing at a clinically meaningful rate

** (b) in patients with a few sites of disease, but otherwise great control

* This is much more effective in patients with driver mutations being treated with TKIs with oligo-residual disease

Q: Do you ever give chemo along with IO in patients with PDL1 >50%?

* KEYNOTE 024: First study to show that IO was superior to chemo in high PDL1 patients lead to an instant change in our approach

* More recent data suggests that there are differences between patients with PDL1 90% vs. someone at like 50, 60, or 70% (not all PDL1 >50% is created equal!)

* If there is a patient with a lot of cancer burden, a lot of symptoms, and rapid progression of disease, you don’t want to miss an opportunity to do what is best for the patient. There is always a chance that IO may not work as monotherapy. This is a case-by-case discussion, but in cases like this, he discusses with his patient about using chemo + IO

** Essentially attacking the cancer from multiple angles

Q: In patients with positive driver mutations who are initially stable on treatment, but then progress, do you repeat molecular testing at the time of progression? Do you ever treat with two TKIs at the same time?

* Dr. West referenced recent abstract at ESMO 2022 by Dr. Julien Mazieres from CHU de Toulouse in France who presented data regarding the use of MET inhibitor tepotinib with osimertinib:

** In the study, when screening for MET amplification, about 36% of patients were positive; at 9 months, the response rate was 54%

** One limitation of this study is that every company that tests for MET amplification has a different definition of what constitutes “amplification”

* Otherwise, there is mixed data about this

* Molecular testing is often done on repeat biopsies in many academic centers, but that is not universally true and not the standard of care

Q: TKIs have great CNS penetration. Let’s say a patient achieved a CR of CNS metastasis, but has progression of disease elsewhere. Do you continue the TKI?

* He prefers, in general, to continue TKI given great CNS penetration while adding chemotherapy for other systemic metastatic sites

** This is more expert opinion, not well-studied

* Flare phenomenon can happen, meaning that abruptly stopping TKI may allow a clone of the cancer to begin rapidly growing if this subset of disease is responsive of treatment

* Remember: Not all mutations are created equally

** You DO NOT want to give EGFR and/or ALK IO even if they have a high PDL1

** On the other hand, patients with KRAS and BRAFV600E do respond to IO treatment

About our guest:

Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women’s Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD

References:

https://www.nejm.org/doi/full/10.1056/nejmoa1606774 - KEYNOTE024

https://www.nejm.org/doi/full/10.1056/nejmoa1910231 - CHECKMATE227

https://oncology.medicinematters.com/esmo-2022/non-small-cell-lung-cancer/insight-2-tepotinib-osimertinib-advanced-nsclc/23480600 - ESMO 2022 abstract on tepotinib with osimertinib

https://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy - Episode 032

https://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy-stczg - Episode 033

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Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we begin to round out our NSCLC series with the first of two episodes where we interview Dr. Jack West from City of Hope!

We strongly recommend you listen to our previous episodes on early stage lung cancer (Episodes 026 and 029) to follow along in this discussion. Key trials mentioned in this episode include:

ADAURA Trial

IMPOWER010

CHECKMATE816

Q: We’ve previously discussed that adjuvant cisplatin doublet chemotherapy is used for tumors > 4cm and/or nodal involvement. Given that PD-L1 status and EGFR status can also potentially change adjuvant therapy choices, how do you employ these tests in your practice?

* Different approaches at every center/with different thoracic oncologists.

* Dr. West does NOT recommend sending broad NGS testing on everyone if it is not going to change management.

* It it may influence management, at the very least, PDL1 and EGFR should be performed because of implications on adjuvant treatment options (See Episode 026 for treatment discussions):

** ADAURA Trial: Adjuvant Osimertinib x3 years for EGFR+ patients

** IMPOWER010: In patients with PDL1 >50%, patients did better with 1 year of immunotherapy (atezolizumab) after adjuvant therapy

* In patients with higher risk disease, can consider sending broad NGS, particularly looking for ALK and other mutations; remember that EGFR and ALK+ patients do NOT respond to immunotherapy well. This is important because we don’t want to give someone side effects that they would not otherwise had (these patients are getting treatment adjuvantly AKA after their disease is already resected!)

Q: What are limitations of the ADUARA Trial?

* The ADUARA suggested disease-free survival advantage with use of osimertinib, but we don’t know final overall survival data yet.

*Limitations:

** Three years of therapy

** Very expensive drug

** More data presented at ESMO 2022 on efficacy; Dr. West stated that there appears to be drop off in survival after stopping drug. Overall survival data not yet available

* Just because patients can get osimertinib does NOT mean that they are not eligible for chemotherapy

**Adjuvant chemotherapy for patients provides long-term benefit

** JBR.10 Trial: Older trial, but showed that patients who got adjuvant treatment (in this case vinorelbine plus cisplatin) had prolonged disease-free and overall survival in early-stage non–small-cell lung cancer.

** Follow up study suggested that EGFR+ patients trended towards longer survival

Q: What are your thoughts on Checkmate 816 with the use of neoadjuvant nivolumab in addition to the platinum doublet? Do you think pathologic CR was an appropriate surrogate endpoint for the trial?

* Complete path CR is a new end-point, but it does correlate with PFS. We cannot always for traditional endpoints, such as overall survival data, to mature because doing so may result in us withholding therapy that may be very beneficial.

* Biggest benefit to neoadjuvant treatment is that more patients are able to get the full regimen. Many have complications after surgery and never are able to then get/benefit from chemotherapy. Supported by data from NATCH trial

Q: What are your thoughts on induction chemoradiation vs. chemotherapy alone?

* Dr. West prefers to not use radiation pre-operatively, with some exception (for instance, pancoast tumor)

Tune in next week for part 2 of this discussion!

About our guest:

Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women’s Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD

References:

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext - IMPOWER 010 Trial

https://www.nejm.org/doi/full/10.1056/NEJMoa2027071- ADAURA Trial

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032958/ - NATCH Trial

https://www.nejm.org/doi/pdf/10.1056/NEJMoa043623 - JBR.10 Trial

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033998/ - Follow up to JBR.10 Trial looking at influence of EGFR status on chemotherapy response

https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816

https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s - Episode 026

https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s-6xae9-ws6nt-ntn8g - Episode 029

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

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Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we continue our discussion on metastatic non-small cell lung cancer, focusing on NSCLC with driver mutations.

* The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:

- Important to complete staging (discussed in prior episodes) to determine the extent of disease

- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options

- If your molecular testing is identified in a driver mutation gene, there are targeted options for this!

*Driver mutations are predictive of response to an oral therapy and a LACK of response to immune therapy (particularly in EGFR and ALK mutated patients)

* EGFR Mutation:

- Pay attention to the types of mutation in EGFR (not all are the same):

-- Exon 19 deletion

-- Exon 19 L858R

-- Exon 21 T790M

-- Exon 20 Insertion (Osimertinib [see below] cannot be used for this mutation)

- Osimertinib is first-line standard of care for patients with EGFR

-- Used to be a second-line agent. Many patients with EGFR mutations receiving earlier generation TKIs would develop resistance and when these tumors were sequenced, they would have Exon 21 T790M mutations. Osimertinib was effective even with this mutation and had superior overall survival data compared to chemotherapy (AURA3 Trial)

--Now it is used in first-line setting for patients with EGFR mutation based on the FLAURA trial

--- In this study, patients received osimertinib as first line vs. older generation EGFR-targeting TKIs (erlotinib or gefitib) and Osimertinib had better outcomes:

---- Showed that the median OS was 38.6 months with Osi vs. 31.8 months; also improved brain penetration! 

---- Also effective in patients with metastatic disease to the brain:

----- Only 6% of patients had CNS progression with Osi vs. 15% with others

- What if a patient is on Osi and later develops new brain mets?

-- If there is progression within just the brain (and good control in other sites of the body) you can refer patient to Radiation Oncology for SRS

-- Remember, based on discussion with Dr. Osmundson in our RadOnc lectures (Episode 028), it is important to HOLD Osimertinib if patient is going to get radiation to minimize the side effects

- What is patient had progression of disease in several sites throughout the body?

-- Management is less straightforward.

-- In many of these cases, you can consider:

--- Consolidative radiation - If small amounts of disease

--- Changing therapy - If there has been widespread progression; likely would change to chemotherapy (without IO, since lower predictive response to IO with EGFR mutation)

---- No clear guidelines if you should continue the TKI

---- Remember that IO + TKIs can cause increased risk of side effects, such as pneumonitis and hepatitis. DO NOT DO THIS!

* ALK Mutation:

- There are many options for ALK mutations

-- The first generation drug is crizotinib

--- Lots of side effects —> “It is crazy to start with crizotinib”

--- Studies for later generation TKIs were compared to crizotinib

-- Many people today will use third generation ALK-inhibitor alectinib (Important trials: ALEX Trial and J-ALEX Trial)

--- With alectinib, PFS 34.8 months, RR 83%, less CNS progression (12% vs 45%)

--- 5 year OS rate 62.5%

- What to do with disease progression while on ALK inhibitor?

-- In ALK, you can actually switch to another ALK inhibitor and many will respond well

--- Of course, with each change, you may expect not as great of a response

* Lots of other mutations!

- TFOC recommends just looking these up!

-- Link to NCCN Guidelines on NSCLC; Page 41 has full list!

- Another way to think about this, when do we NOT do TKIs as first line:

-- KRAS G12C

-- EGFR Exon 20 Insertion

-- HER2

- How do you counsel a patient when considering/starting a TKI?

-- Patients with highest chance of having a targeted mutation are younger non-smokers with adenocarcinoma

-- Set expectations: great outcomes overall, but still not a cure.

-- Remembering the drugs: All TKIs usually end in “-nib”

-- In general, the way we recommend remembering this: “Fatigue, GI, Derm (skin/nail changes)”; rarely pneumonitis

References:

* AURA3 Trial - https://www.nejm.org/doi/full/10.1056/NEJMoa1612674

Established osimertinib was better than chemo for patients with EGFR mutation and acquired Exon 21 T790M resistance mutation

* FLAURA Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1713137

Established osimertinib as first-line agent for patients with EGFR mutation

* ALEX Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1704795

Helped establish alectinib as superior for ALK mutations compared to crizotinib

* J-ALEX Trial - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltext

Helped establish alectinib as superior for ALK mutations compared to crizotinib

* NCCN Guidelines on NSCLC - https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

Instagram: @TheFellowOnCall

Listen in on: Apple Podcast, Spotify, and Google Podcast

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Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we start our discussion on metastatic non-small cell lung cancer, focusing on NSCLC without driver mutations.

* The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:

- Important to complete staging (discussed in prior episodes) to determine the extent of disease

- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options

* Choosing a treatment is based on:

- Histology - cannot use pemetrexed or bevacizumab in squamous cell

- Platinum - Carboplatin is usually used (as opposed to our prior discussions about using Cisplatin because of LACE pooled analysis data)

-- Why is Cisplatin not a great idea? Cisplatin should not be used if patients have (***high yield to know cisplatin eligibility criteria!!***):

--- Poor performance status

--- Patients with eGFR <60

--- If a patient has baseline hearing loss

--- If a patient has baseline neuropathy

--- Patients with NYHF class III+

--If patient is getting “palliative” / non-curative setting, you want to spare patients these terrible potential side effects

-Immunotherapy - All patients with mNSCLC should have IO considered for treatment, unless they have contraindications. Considerations include:

-- Patients with EGFR and ALK mutations - patients with these mutations do NOT respond well to IO so should not use

-- TPS score:

--- Patients with score >50% can get IO monotherapy (spared chemotherapy)

---- KEYNOTE 024: approval for pembrolizumab monotherapy in patient with PDL1>50%

----- Study compared pembro to platinum doublet

----- OS 70% vs. 50% at one year

---- IMPOWER110: approval for atezolizumab monotherapy

----- Study compared atezo to chemotherapy

----- OS 64.9% vs 50% at 12 months

--- Patients with score <50% can get IO + chemotherapy

---- KEYNOTE 189: Showed that the addition of Pembrolizumab to carboplatin/pemetrexed followed by pembro/pemetrexed maintenance in mNSCLC with adenocarcinoma histology had impressive benefits

---- Carbo/taxol/pembro for squamous histology

--- Lots of other trials, check out NCCN for a comprehensive list

* Putting this all together:

- In PDL1 >50% WITHOUT SYMPTOMS: IO alone

- In PDL1 >50% WITH SYMPTOMS: Chemo + IO

- In PDL1 <50%: 

-- Lots of options, but usually some combination of chemotherapy + IO

-- Many people use Pembro, as it was first to market

* Management of mNSCLC to the brain:

- Recommend discussion with radiation oncology about role of SRS

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

Instagram: @TheFellowOnCall

Listen in on: Apple Podcast, Spotify, and Google Podcast

Love what you hear? Tell a friend and leave a review on our podcast streaming platforms!

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we round out our discussion of early stage lung cancer treatment!

* When deciding if a patient can get surgery upfront or not, remember the three “Fellow on Call” criteria for early stage lung cancer:  

- Mass invading other structures or mediastinum

- Central lymph nodes (single digit)

- Tumor >7 cm

* If surgery is NOT an option at this time, where do we go from here?

- Treat with upfront concurrent definitive chemoradiation

- Treat with “induction” chemotherapy or induction concurrent chemoradiation

**If surgery is/may be possible**

*What are the goals of “induction” treatments? 

- Eradicate microscopic disease

- Improved local control, possibly shrinkage

- Adding radiation may allow you to downstage tumor or lymph nodes to have a possible improvement in surgical outcomes

* What sorts of discussions are being had a thoracic tumor board in patients with newly diagnosed early stage NSCLC? 

- Is the patient a surgical candidate?

- If the patient is not a surgical candidate, then what are the options:

--Definitive concurrent chemoradiation (usually) followed by immunotherapy

---Pearl 1: Always choose this if surgeon thinks the patient is unresectable in general even with an induction approach

---Pearl 2: Always choose this if 2 out of 3 criteria we discussed above are met

---Pearl 3: Always choose this if N3 disease

- “Induction” regimen with either chemotherapy alone or concurrent chemoradiation followed by surgery

* What’s the idea behind “induction” chemo or chemoradiation? 

- There is a chance that patients with these high risk features may already have micrometastatic disease, so treatment upfront can help address that

- There is a chance that after surgery, patient may suffer deconditioning, which may preclude the use of chemo +/- radiation (up to 90% of patients are often eligible for chemoradiation before surgery; this drops to ~60% after surgery)

- Local disease control to achieve the best possible surgical outcome (R0 resection) and also prevent any microscopic residual disease from then having the opportunity to spread systemically, especially in areas where the mass may be adjacent to many blood vessels or lymph nodes

* What to treat with in the neoadjuvant setting?

- Platinum containing regimens (“platinum doublets”):

-- Carboplatin + paclitaxel

-- Cisplatin + etoposide

-- Cisplatin + gemcitable

-- Cistplain + pemetrexed

- Can combine this with radiation

* How does the data about chemotherapy+IO in the neoadjuvant setting fit in here (CHECKMATE 816)?

- In patients with Stage IIB to IIIA (8th edition) WITHOUT EGFR or ALK mutation, treatment with NEOADJUVANT chemotherapy q3w x3 cycles (most got cisplatin based therapy) + nivolumab 360mg q3w x3 cycles resulted in improved event free survival (31.6 months vs. 20.8 months) AND pathological complete response was 24.0% vs. 2.2%

- Current NCCN guidelines state that if nivolumab is used in neoadjuvant setting, it should not be used in adjuvant setting

- There is still uncertainty about how this fits into treatment compared to “traditional” neoadjuvant approaches with chemo+/-radiation

*So after neoadjuvant treatment, does everyone go to surgery?

- Always re-assess the status of the disease; if there is progression of disease, then will go to definitive chemoradiation

- Discuss with surgeons to confirm if the patient is still a surgery candidate

* If patient undergoes surgery, then what?

- If patient got neoadjuvant therapy and an R0, then they are done with treatment

- If R0 resection was not able to achieved, then either radiation “boost” to the area (if they previously got radiation), a course of radiation (if they just got induction chemo) or re-resection

- We discuss the adjuvant setting in more detail in Episode 026 (https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s)

** If surgery is not possible**

* If patient cannot go through to surgery Definitive chemoradiation:

- Same chemotherapy agents as above, but treatment course is longer.

- For instance, for NSCLC, total 60Gy in 2Gy divided fractions (5 days/week, 6 weeks of treatment) with chemotherapy

* Additional therapy after chemoradiation (PACIFIC Trial) 

- Found that “consolidation” durvalumab 44% PFS 18 months vs 20% 5year survival benefit 40% vs. ~30% without treatment

References:

https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 - NCCN Lung Cancer guidelines

https://www.nejm.org/doi/full/10.1056/nejmoa1709937 - PACIFIC Trial (NEJM 2017)

https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 (NEJM 2022)

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

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Lung cancer specialized testing in NSCLC:

What do we do if we biopsy a suspected metastatic lesion?

* Immunohistochemistry (IHC):

**Confirm if it is metastatic NSCLC

**Confirms the histology of the NSCLC (such as adenocarcinoma vs. squamous cell)

**Used to determine the type of chemotherapy that can be administered for treatment

*PDL1 testing:

**PDL1 is a protein expressed by certain cancer cells allowing them to evade the immune system (“fake mustache analogy”).

**Also confirmed by IHC

**This protein is targetable!

**Often measured as:

***Total protein expression (TPS): The number of positive tumor cells divided by the total number of viable tumor cells multiplied by 100%

***Composite protein expression (CPS): The number of positive tumor cells, lymphocytes and macrophages, divided by the total number of viable tumor cells multiplied by 100%

*Molecular testing:

**We discuss this in detail in Episode 005

**Genetic information from the tissue sample

**Always better to get sample from soft tissue than from bone

**Why is this important?

***To be able to identify “driver mutations”

****What is it? Important mutations that may be “driving” oncogenesis

****Many of these have drugs that directly target these mutations

Prognostic vs. predictive biomarkers:

*Prognostic biomarkers: Mutations or changes that give information about the cancer’s overall outcome regardless of therapy

*Predictive biomarkers: Mutations that provide information about how a cancer may respond to a particular drug

Cell-free DNA (AKA “liquid biopsy”):

*Special tests that can detect microscopic amounts of cancer cell DNA within the patient’s blood which may also be used to find prognostic/predictive biomarkers

*Ongoing studies to see if this can be used to find relapse of disease

Please visit our website (TheFellowOnCall.com) for more information

Twitter: @TheFellowOnCall

Instagram: @TheFellowOnCall

Listen in on: Apple Podcast, Spotify, and Google Podcast