Management of Advanced HER2-Positive Breast Cancer and Brain Metastases Guideline Update

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.