Understanding PARP Inhibition in BRCA-Mutated Breast Cancer - Episode 9
Kristin E. Fleischmann-Rose, NP: Nadine, can you discuss what PARP [poly ADP ribose polymerase] inhibitors are and explain the rationale behind using this targeted therapy in patients with breast cancer and a BRCA mutation?
Nadine M. Tung, M.D.: Breast cancers in BRCA carriers actually have a weakness. They have an Achilles’ heel. Even though they’re growing, they lack the ability to fix or repair their damaged genetic material, their DNA. So the hypothesis was that if we give those patients a medication that creates more damaged DNA in the cancer cell, like a PARP inhibitor, that would overwhelm the breast cancer cell and it would die. And, in fact, this is what we know to be true now.
And we know that because there were two very large studies, one called OlympiAD using the PARP inhibitor olaparib, and one called EMBRACA using the PARP inhibitor talazoparib. And both of these studies were pretty identical. Patients with metastatic breast cancer who were BRCA carriers, who had HER2 [human epidermal growth factor receptor 2]-negative disease, were randomly assigned to either receive standard chemotherapy or to receive the PARP inhibitor.
What we learned is that the patients, the BRCA carriers who received the PARP inhibitors, had a longer time before their breast cancer progressed. They had twice as high a chance that their breast cancer would shrink, and this all came to pass with fewer side effects than with chemotherapy. And the BRCA carriers had a better quality of life with the PARP inhibitors. So, as a result of those two studies, both olaparib and talazoparib are now approved for treatment for BRCA carriers in the metastatic setting, and they’re being evaluated and studied for newly diagnosed BRCA carriers.
Kristin E. Fleischmann-Rose, NP: So you’d say that BRCA carriers are the ideal patients for PARP inhibitors? Are there any other patients who might benefit from PARP inhibitors?
Nadine M. Tung, M.D.: Well, we don’t know that yet. I think right now, the ideal breast cancer patient for PARP inhibitor is a BRCA carrier with metastatic HER2-negative breast cancer, just as was in those two studies. What we are learning is that the earlier that one gives a PARP inhibitor in the metastatic setting, the better: the higher the chance of shrinking the tumor, the longer before the tumor progresses. So for that patient with estrogen receptor-positive/HER2-negative breast cancer — if they’re a BRCA carrier, when they have completed their endocrine therapy or it’s no longer working, and they’re ready to move over to get chemotherapy — instead of chemotherapy I would use a PARP inhibitor. And for the triple-negative breast cancer patient who’s a BRCA carrier, I would reach for a PARP inhibitor instead of chemotherapy in the metastatic setting.
Kristin E. Fleischmann-Rose, NP: Let me ask you another question. When do you recommend testing for a BRCA mutation?
Nadine M. Tung, M.D.: We used to do the genetic testing for BRCA mutations really to determine whether a patient had an increased risk of cancers in the future. We were doing it for prevention, whether it was mastectomies or oophorectomies. And now I think the important point is, that knowing that a patient with breast cancer has a BRCA mutation really impacts treatment. And so it’s important not to forget to think about BRCA testing in patients with metastatic breast cancer. Now, certain guidelines say that every patient with metastatic breast cancer who has HER2-negative disease is eligible for BRCA testing.
I’m not sure we’re testing every single patient yet, but I think it’s a good reminder for clinicians to think about whether their patient with metastatic breast cancer has any criteria that would make one think about having a mutation: young age, triple-negative disease, or family history. So again, it’s very important not to miss those BRCA carriers, so we don’t deny them the opportunity of using a PARP inhibitor. And in fact, at Beth Israel Lahey Health, instead of three categories of breast cancer, we really do think of breast cancer in four categories, the fourth being those BRCA carriers. And that’s how we organize our research trials and the way we think about breast cancer.
I think you also asked me, Kristin, about patients other than those with breast cancer in whom PARP inhibitors are perhaps effective. I think it is worth noting that PARP inhibitors are now approved for patients with ovarian cancer, both for BRCA carriers and for all patients when they recur with their ovarian cancer, and also BRCA carriers with some other cancers. In pancreatic and prostatic cancer, there have been reports of responses even though they’re not FDA approved yet. So there are patients other than breast cancer patients for whom PARP inhibitors are appropriate.
Transcript Edited for Clarity