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Banu Arun, MD: Hello. I'm Dr Banu Arun from the University of Texas MD Anderson Cancer Center, in the department of breast medical oncology and the Clinical Cancer Genetics Program. Welcome to Medscape's InDiscussion series on advanced and metastatic breast cancer. Today we'll discuss germline testing and access to genetic counseling and testing, and their treatment implications for patients with metastatic breast cancer. First, let me introduce my guest, Dr Nadine Tung. Dr Tung is a professor of medicine at Harvard Medical School. She is a medical oncologist from Beth Israel Deaconess Medical Center in Boston, part of Dana-Farber/Harvard Cancer Center. Dr Tung specializes in managing patients with breast cancer with a clinical and research focus on patients with hereditary breast cancer, and she oversees the genetic testing service. Welcome to InDiscussion.
Nadine Tung, MD: Thank you so much. It's such a pleasure to be here.
Arun: I like to ask each of my guests what they believe is the most relevant issue in advanced and metastatic breast cancer today.
Tung: I think it is personalizing therapy for patients. The days of using one algorithm to treat all patients with breast cancer are really over. Identifying appropriate targets appropriate for a specific patient is optimal, whether it's PIK3CA or an ESR1 mutation or human epidermal growth factor receptor 2 (HER2) expression in a tumor that's HER2 negative. The same is true for patients who have an inherited BRCA1 or BRCA2 mutation. We hope these more specific therapies are going to be more effective and hopefully less toxic, as in the poly-(ADP-ribose) polymerase (PARP) inhibitors we're going to talk about today.
Arun: Which patients with breast cancer should be offered or recommended to have germline genetic testing?
Tung: In the early-stage setting, there is controversy. The American Society of Breast Surgeons advocates that all patients with breast cancer should be offered genetic testing, whereas the National Comprehensive Cancer Network (NCCN) is a bit more limited and advocates testing all women with breast cancer who, for example, are diagnosed at age 50 or younger, are Ashkenazi Jewish, have triple-negative breast cancer, or have bilateral breast cancer, as well as all men with breast cancer. But otherwise, for women diagnosed beyond age 50, they need some relevant family history of pancreatic cancer or ovarian, breast, or prostate cancer. Today, we're talking about the metastatic setting. It's really important to stress that in the metastatic setting, the National Comprehensive Cancer Network (NCCN) Guidelines recommend that all patients with HER2-negative breast cancer should be offered germline genetic testing. NCCN has recommended this ever since 2019 based on the OlympiAD and the EMBRACA trials demonstrating the benefit of PARP inhibitors.
Arun: How does knowing a patient has a germline BRCA1 or BRCA2 mutation impact treatment of a patient with metastatic breast cancer? Can you elaborate on the OlympiAD and EMBRACA studies? Who was included and what were the results?
Tung: The OlympiAD and the EMBRACA trials were phase 3 trials in patients with germline BRCA1 or BRCA2 mutations who had metastatic HER2-negative breast cancer. The single-agent PARP inhibitor olaparib was compared in one trial and talazoparib in the other trial with nonplatinum chemotherapy of the physician's choice. This was first-line chemotherapy all the way up to third-line chemotherapy. About half the patients in the trial had triple-negative disease and about half had ER-positive, HER2-negative disease. For the estrogen receptor (ER)–positive disease, patients had received endocrine therapy and they were deemed endocrine resistant. Of note, at that time in history, only about 5% of patients had seen a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Nevertheless, the primary endpoint was progression-free survival (PFS) in both trials. Both trials were successful, demonstrating a significant improvement in PFS with a hazard ratio of about 0.55 in both trials, a median PFS improvement of about 2 months, and the PARP inhibitors were also associated with a better health-related quality of life in both trials — much less toxicity than the chemotherapy. Finally, I'd say there was no demonstrated improvement in overall survival, which was a secondary endpoint for both trials. But in an exploratory analysis, at least for the OlympiAD trial, they did find that for patients who received the olaparib as first-line treatment, there was a suggestion of a significant improvement in overall survival when compared with chemotherapy. The bottom line and message is to try to use a PARP inhibitor as early as possible in the treatment of metastatic disease for those with inherited BRCA mutations and breast cancer. Banu, can you remind everybody how PARP inhibitors work? It's such a novel therapy.
Arun: PARP inhibitors are drugs that can trap the PARP1 protein at the single-strand break DNA lesion and disrupt its catalytic cycle, ultimately leading to replication for progression and consequent double-strand breaks. Dr Tung, can you discuss the fact that patients were not randomized to platinum-based chemotherapy in these trials? What do we know about platinum efficacy in BRCA-related breast cancers? Do PARP inhibitors work after platinum?
Tung: We know that platinum is a very active agent for treating triple-negative breast cancers that develop in BRCA carriers. In fact, we know from the trial TBCRC009 and some other studies that among patients with triple-negative breast cancers, those that are BRCA mutation carriers are more sensitive to platinum chemotherapy than patients with triple-negative breast cancer who are non–BRCA mutation carriers. In one other trial, the TNT trial, which treated patients with metastatic triple-negative disease in the first-line setting, we saw that for BRCA carriers, platinum was superior to taxane chemotherapy, while there was no difference in the response between platinum and taxanes for those who did not have an inherited BRCA mutation. But Banu, you asked me about cross-resistance between PARP inhibitors and platinum. Most data show that in BRCA carriers who have ovarian cancer, if the patient's tumor has progressed while receiving platinum chemotherapy — a tumor that's truly platinum refractory — there is little hope of a response to a PARP inhibitor. The data we have in breast cancer are more limited, but at least one trial, the ABRAZO trial, looks similar. On the other hand, BRCA carriers with breast cancer who have been treated in the past with platinum chemotherapy but for whom the cancer is not refractory can still benefit from olaparib or talazoparib. Both the OlympiAD and the EMBRACA trials allowed patients to have received prior platinum as long as metastatic disease had not developed within 12 months of the platinum exposure or if platinum had not been received in the metastatic setting and the tumor grew while the patient was receiving platinum. In OlympiAD, almost 29% of the patients had received prior platinum, and they also benefited from PARP inhibitors. We have to distinguish between just having received prior platinum and having a tumor that's truly refractory to platinum.
Arun: What are the most common side effects of PARP inhibitors, and how are they managed?
Tung: Let me focus on olaparib and talazoparib since they are the two PARP inhibitors that are approved for breast cancer. I'd say the most common side effect that patients experience is mild nausea. It's generally mild. It generally resolves after a few months if it even occurs. We use the standard antiemetics to treat the nausea. Anemia is more common than neutropenia or thrombocytopenia with these two PARP inhibitors. The anemia can develop several months into the treatment, so clinicians really have to watch the patient's lab work even after several months of being on the PARP inhibitor. It's typically managed easily with a transfusion and then a dose reduction. I've not found the anemia to be a problem in general. I do think the anemia is a bit worse with talazoparib and definitely has to be watched. This is because myelodysplastic syndrome (MDS) and acute leukemia have small but definite side effects that can occur. But if a patient has anemia that persists despite a dose reduction or despite transfusions, it's appropriate to work up the patient for MDS or acute leukemia. Banu, can you talk a little bit about combining chemotherapy with a PARP inhibitor? In particular, I'm thinking about the BROCADE3 trial that combined veliparib with chemotherapy. Can you remind us about that trial? Who was in it and what were the results?
Arun: Yes, the BROCADE3 trial is a little bit different than the OlympiAD and the EMBRACA trial in that patients with germline BRCA1 and BRCA2 mutations in a metastatic setting were randomized to chemotherapy vs chemotherapy plus a PARP inhibitor. We don't have a single PARP inhibitor arm in this study. In this study, the disease-free survival was significantly improved in patients who received carboplatin-Taxol plus the PARP inhibitor veliparib vs the control arm, which was carbo-Taxol. Unfortunately, as in the OlympiAD and the EMBRACA trial, the overall survival was not different amongst these patients. But what we saw in the study was that even at 3 years, the PFS was maintained to be significant in patients who received the chemotherapy plus the PARP inhibitor veliparib. Further, the objective response rate was also significantly higher in the chemotherapy plus veliparib group.
Tung: I thought it was interesting that in both arms of the BROCADE3 trial, patients received on average about 11 cycles of chemotherapy of carboplatin-Taxol, and the PFS curve seemed to separate after that point when the chemotherapy stopped. To me, it raised a question as to whether the improvement in the PFS seen with veliparib was more a result of using the PARP inhibitor as maintenance therapy after chemotherapy — similar to how BRCA carriers are treated with ovarian cancer or pancreatic cancer — rather than truly demonstrating a benefit of combining a PARP inhibitor with platinum-based chemotherapy. I was really struck by how long the PFS was even in the chemotherapy arm in BROCADE3, which was about 12-and-a-half months, increasing to 14-and-a-half months with the veliparib. That is in comparison to only 7 or 8 months when talazoparib or olaparib were used alone in OlympiAD and EMBRACA. Of course, we know the dangers of cross-study comparison. We have to remember that in BROCADE3, all of the patients were treated in the first-line setting, whereas in OlympiAD and EMBRACA, they could be treated up to the third-line setting. It does raise the question as to whether platinum-based chemotherapy followed by a PARP inhibitor could be superior to just a PARP inhibitor alone — although, of course, chemotherapy has so many more toxicities. Banu, I'd like to get your thoughts about the undertesting that's going on — how low the frequency of testing is, how few patients in the metastatic setting actually get germline testing, and the access to genetic testing. What are your thoughts about how to approach this problem?
Arun: Thank you, Nadine. This is a very important question, and I think there is a lot more we can do as oncologists and other healthcare providers. We now have evidence that germline testing results can impact a patient's treatment in the metastatic setting and also the adjuvant setting, so it is more important than ever that we think about genetic testing. The OlympiAD trial that has showed that germline BRCA-positive patients' overall survival is actually increased with 1 year of olaparib vs placebo. However, older studies, from more than 4 or 5 years ago, have shown that less than 50% of breast cancer patients who are eligible for genetic testing are actually offered testing and undergo testing. We can spend another hour discussing what the barriers are, but the most important thing is that we providers should be thinking of genetic testing as part of a multidisciplinary approach. When we see our patients, we think about surgery, radiation therapy and medical oncology. We order biomarkers, ER, progesterone receptor, and HER2/neu testing. We think about whether ordering BRCA testing should be automatic. Now, it might not be for everyone and we are not saying that everyone should be tested, but as in the most recent NCCN Guidelines, if we believe we are going to use this information for therapeutic interventions, then any metastatic breast cancer patient and any high-risk early breast cancer patient should be offered genetic testing with or without counseling. I'm saying this very carefully because the testing guidelines for this population are so direct that, for example, we at MD Anderson — since you ask — are implementing an approach where providers can order the test themselves and positive patients are then counseled by a genetic counselor. I acknowledge that each institution is different. There are different operational dynamics in the clinical centers. I also know we don't have genetic counselors everywhere in some community oncology settings. We have to think a little bit outside the box. But again, unlike in the older days, genetic testing will have an impact on patients' treatments and outcomes.
Tung: I couldn't agree with you more, Banu. You've made such excellent points. One of them, just to reiterate, is that we teach the fellows and our colleagues that as soon as a patient has metastatic disease, we are programmed to think about the three subtypes: HER2 positive, triple negative, and ER positive HER2 negative. We're looking up trials for that. We always teach that there is a fourth group, which are those with BRCA or other genetic mutations — particularly BRCA. If you think about it that way, it forces you to ask if you did germline genetic testing. That might be the treatment that's most appropriate. The second point about testing is what you said about needing the information so quickly. We have to have some informed consent perhaps without elaborate counseling because we need the material. Just as we do tumor testing, we need the germline testing to make decisions. I agree with you. We're doing oncologist-led testing. Some patients prefer videos and some patients prefer written material. Some just want to know that this testing is important for their treatment. And we're going to send the testing and do far more counseling if it comes back positive. I agree 100%.
Arun: Thank you, Nadine. Thank you so much for these comments. Among patients with metastatic breast cancer, we've talked about PARP inhibitors only for patients with germline BRCA1 and BRCA2 mutations. What about somatic BRCA1 and BRCA2 mutations and other gene mutations?
Tung: Right now, olaparib and talazoparib are only approved for patients with germline BRCA mutations and breast cancer. There have been data demonstrating excellent activity for olaparib and talazoparib for BRCA carriers with germline PALB2 mutations or tumors that have acquired somatic BRCA mutations in patients who do not have inherited BRCA mutations as in the olaparib expanded trial, TBCRC 048, which we published in the Journal of Clinical Oncology in 2020. Interestingly, NCCN just updated their guidelines for treating metastatic breast cancer and now they do say to consider these indications, namely germline PALB2 mutations or somatic BRCA mutations. However, PARP inhibitors do not yet have FDA approval for these patients. It's not clear what insurance companies will cover.
Arun: Today we talked to Dr Nadine Tung about how all patients with HER2/neu negative metastatic breast cancer should be tested for germline BRCA mutations before chemotherapy administration. We talked about PARP inhibitors as early in treatment as possible after endocrine therapy for ER-positive breast cancer. We talked about how the toxicity profile of PARP inhibitors is better than chemotherapy and the quality of life for patients is better. We also touched base on access to genetic counseling and testing and incorporation earlier in the multidisciplinary management of breast cancer. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on advanced and metastatic breast cancer. This is Banu Arun for InDiscussion.
Resources
Stage IV (Advanced or Metastatic) Breast Cancer
ESR1 Mutations in Breast Cancer
BRCA Gene Mutations: Cancer Risk and Genetic Testing
PARP and PARG Inhibitors in Cancer Treatment
Consensus Guideline on Genetic Testing for Hereditary Breast Cancer
Triple Negative Breast Cancer: A Thorough Review of Biomarkers
NCCN Guidelines® Insights: Breast Cancer, Version 4.2021
Olaparib for Metastatic Breast Cancer in Patients With a Germline BRCA Mutation
Talazoparib in Patients With Advanced Breast Cancer and a Germline BRCA Mutation
Management of Hormone Receptor-Positive, HER2-Negative Early Breast Cancer
Endocrine Therapy for ER-Positive/HER2-Negative Metastatic Breast Cancer
The Emerging CDK4/6 Inhibitor for Breast Cancer Treatment
Platinum-Based Systematic Therapy in Triple-Negative Breast Cancer
Carboplatin in BRCA1/2-Mutated and Triple-Negative Breast Cancer BRCAness Subgroups: The TNT Trial
Taxanes for Adjuvant Treatment of Early Breast Cancer
Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer
Myelodysplastic Syndrome (MDS)
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Cite this: Germline Testing, Access to Genetic Counseling, and Treatment Implications in Advanced and Metastatic Breast Cancer - Medscape - May 02, 2023.
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