Dr Bardia talks about the role of biomarker testing and provides an overview of factors which may contribute to a clinician’s choice of treatment strategy for patients with ER+/HER- mBC.
Dr. Aditya Bardia: In the first-line setting, the management of ER-positive, HER2-negative metastatic breast cancer involves use of endocrine plus CDK4/6 inhibitor but patients have disease progression. In the second-line setting, at this time we use fulvestrant without other targeted therapies in the second-line setting. The challenge is that fulvestrant is given as an intramuscular shot, so can it be inconvenient for patients. As a single agent, the activity of fulvestrant is limited. Fulvestrant can be used with other targeted agents such as PI3 kinase inhibitor alpelisib or PIK3CA mutant ER-positive breast cancer in the second-line setting. That can be associated with toxicity including rash and diarrhea as well as hyperglycemia. Clinically, there's unmet need for better endocrine agents in this setting. A lot of interest in novel endocrine-based therapies in the second-line setting.
In terms of deciding between different therapies in the second-line setting, there are two broad factors that can help with treatment decision-making. The first is the molecular profile of the cancer. For example, if a tumor has PIK3CA mutation, there would be interest in using a PI3 kinase inhibitor along with endocrine therapy such as fulvestrant. The other factor is the amount of disease and presence of bone-only mets versus bone-plus visceral mets. In patients who have a lot of disease including visceral metastasis, sometimes we tend to consider chemotherapy in the second-line setting to control the disease. The other factor that comes into this decision-making is the duration that the patient was on endocrine plus a CDK4/6. If that duration is shot, you worry about endocrine-resistant disease, and sometimes, particularly in the presence of visceral metastasis chemotherapy such as capecitabine is utilized in this setting.
Biomarker testing is routinely done for a patient with metastatic breast cancer. The first biomarker is to look at ER-PR and HER2. That's usually done at the time of diagnosis of metastatic disease. The second category of biomarker would include genotyping, which can either be tissue-based genotyping or plasma-based genotyping. The idea here is to look at mutations. An actionable mutation in metastatic ER-positive breast cancer is PIK3CA because there's a PI3 kinase inhibitor that could be utilized in this setting. There are other alterations as well. For example, BRCA. A subset of metastatic breast cancers have somatic BRCA which is different from germline BRCA. In that setting, one could consider the use of a PARP inhibitor, usually in a clinical trial. Another similar alteration is PALB2. If PALB2 alteration is present, be it somatic or germline, there would be interest in using a PARP inhibitor. There's value in doing genotyping in metastatic disease including ER-positive breast cancer.
In terms of testing methods for genotyping, it can broadly be divided into two categories. Tissue-based genotyping and plasma-based genotyping. For tissue-based genotyping, that could be done in the metastatic specimen. Usually, that's preferred over primary breast cancer. For truncal alterations like PIK3CA, you can usually detect it in primary as well as metastatic disease but for some alterations that are acquired like ESR1 mutations, which are acquired mutations usually under selective pressure from aromatase inhibitors. Then the reason these mutations come up is because these mutations confer estrogen independence. The tumor is still dependent on the ER receptor in the ER pathway but becomes estrogen-independent and thus resistant to aromatase inhibitors. Because these are acquired alterations, it's best to detect them utilizing plasma-based genotyping because over time the tumor can evolve and it's tough to do repeated biopsies, but it can collect blood and utilizing blood, do plasma-based genotyping that can help with detection of these acquired alterations like ESR1. ESR1 mutations are important in ER-positive HER2-negative metastatic breast cancer because they confer resistance to aromatase inhibitors, but still would confer sensitivity to drugs that directly bind ER such as selective estrogen receptor degraders, even selective estrogen receptor modulators because these drugs directly bind to the ER and thus would still work in the ESR1 mutant setting.