HR+ MBC: Genomic Testing and Treatment Guidance

Aditya Bardia, MD, MPH: We are in the era of precision oncology. The question of molecular testing often comes up for a patient with metastatic breast cancer. In the past, this was controversial. A few years ago at the San Antonio Breast Cancer Symposium, there was a debate session and the topic was should everyone with metastatic breast cancer have tumor genotyping? This is somewhat settled now in part because we have FDA [Food and Drug Administration] approval of a drug, a PI3K inhibitor, alpelisib, for patients with PI3KCA-mutant hormone receptor-positive metastatic breast cancer. Molecular testing should routinely be offered to a patient with hormone receptor-positive metastatic breast cancer because the results are actionable. Once patients receive first-line therapy with endocrine therapy, be it aromatase inhibitor or fulvestrant plus a inhibitor at the time of disease progression, if a patient has PI3KCA mutation, the next line should be fulvestrant plus a PI3K inhibitor alpelisib. Molecular testing is something that should routinely be done because it can have direct therapeutic implications for a patient with metastatic hormone receptor-positive breast cancer.

In terms of when molecular testing should be done and whether it should be a liquid biopsy, or tissue-based biopsy, or tissue-based genotyping, either is fine. You can either use a liquid biopsy or plasma-based genotyping or use tissue-based genotyping. In terms of when it should be done, when a patient [receives a diagnosis of] metastatic disease, it's common to do a tumor biopsy or a tissue biopsy to confirm the metastatic disease and also estrogen progesterone and HER2-receptor status. That is the time where the tissue could be sent for tumor genotyping. You already have the tissue biopsy. It could be sent for genotyping. If a patient has PI3KCA mutation, that'll be helpful for the future when the patient has disease progression on first line therapy. Sometimes the tissue is insufficient or the genotyping is not done initially. If that's the case, that's where liquid biopsies can be very helpful. You can send it either upfront or at the time of disease progression to first-line therapy; that is the time where liquid biopsy or plasma-based genotyping could be utilized. If a patient has PI3KCA mutation that's level one evidence it's actionable. You can also see other mutations by the use of plasma-based genotyping. Often there are clinical trials that are specific for certain mutations so if that mutation is seen for that patient, the patient could be triaged to that genotype-directed clinical trial.

In terms of actionable mutations in the setting of breast cancer, if you talk about actionable mutations for which we have therapies now, we have level one evidence for a PI3K inhibitor, alpelisib. Having said that there are a number of other actionable alterations or driver alterations for which we have targeted therapies, usually in the form of a clinical trial. For example, if a patient has AKT1 mutation, there are a couple of AKT inhibitors, such as patasertib, and capivasertib that are in clinical development in phase 1/2. Capivasertib is in phase 3 clinical trials. That's one option. If a patient has a HER2 mutation, there are number of drugs that target HER2 mutation. Neratinib is one, trastuzumab deruxtecan is another drug that targets HER2 mutation and there's a basket trial enrolling for patients with HER2- mutant cancers in general, including breast cancer. Another one is BRCA. Olaparib and talazoparib are FDA approved for germline BRCA mutant breast cancer, but a subset of breast cancers can a harbor somatic BRCA mutation. There are clinical trials looking at a PARP inhibitor for patients with somatic BRCA mutation. Similar to BRCA there's another alteration called PALB2, which is being evaluated in clinical trials in terms of looking at efficacy of PARP inhibition, because PALB2 is related to BRCA, and there's at least some evidence that PARP inhibitors might have efficacy in patients who have PALB2 mutations. Then there are other alterations as well, for example, NTRK [neurotrophic tyrosine receptor kinase] alterations for NTRK alterations. We have NTRK inhibitors that are FDA approved. For patients with a high tumor mutation burden, immunotherapy is FDA approved so there's value in doing genotyping because there are multiple drugs that could be utilized depending on the type of alteration that's seen.

Transcript edited for clarity.