Case 2: 34-year-old woman with TNBC
Elizabeth A. Mittendorf, MD, PhD: Our second case is a 34-year-old woman who presented with a palpable breast mass and mild back pain. This breast tissue was biopsied and showed a poorly differentiated invasive ductal carcinoma. It was triple negative breast cancer. Germline staging PET [positron emission tomography] scan and FDG [F-fluorodeoxyglucose] avid lesions were identified in bone, lung and mediastinal lymph nodes. She performed routine chemical analyzes in other laboratories, and they were generally within normal limits, although there was a slight elevation in ALK-phosphatase. She had a lung biopsy to confirm metastatic disease, and similar to our previous case, she was tested for PD-L1. But in this case, it was PD-L1 negative. She had no significant family history, but given her young age and triple negative breast cancer, she was advised to undergo genetic counseling or genetic testing. In fact, her germline test was positive for a BRCA pathogenic variant. Before we get into the details of how we might approach this patient, David, could you briefly discuss what germline testing is versus somatic testing? What differences are we looking for?
David G. Hicks, MD: The germ line test would look in the blood. A germline mutation carrier basically has that mutation in every cell in their body. You can therefore take it in a blood sample. The somatic mutation test would be a mutation acquired in the tumor during tumor development. In particular, triple negative breast cancers carry numerous somatic mutations. We are increasingly being asked to do next-generation tumor sequencing and whole genome sequencing, more commonly known as the solid tumor panel. A solid tumor panel is where we have 81 potential genes of interest that we are looking for in the tumor.
This can be done from blocks of paraffin embedded tissue from the pathology lab. There are implications for both. In the future, we may see genetic testing on every patient with metastatic breast cancer and somatic mutation testing on many tumors.
Elizabeth A. Mittendorf, MD, PhD: Yes. Before we jump into this specific case, I told you that this patient is a BRCA carrier of mutations, so that’s clearly going to guide the therapy we’re going to recommend – Ruta, what is your practice in evaluating breast cancer patients for genetic counseling, or genetic testing in general? What are you doing at Rush University Medical Center in Chicago?
Ruta Rao, doctor of medicine: For anyone aged 60 or under with a new diagnosis of triple negative breast cancer, whether metastatic or at an early stage, we refer to genetic testing. In addition, we also do this for patients with a strong family history. We have a genetic counselor in all of our tumor boards so that we can always ask ourselves the question: do you think this patient would be a candidate for a genetic test? Specifically, for those patients with metastatic triple negative breast cancer, it is important to think about testing them all, as we have targeted therapy which we know has some benefit in patients who have the germ line. BRCA1 or BRCA2 mutations. We don’t want to miss this potential patient. This patient has been tested very appropriately, but I would consider testing almost all triple-negative metastatic people for germline mutations.
Elizabeth A. Mittendorf, MD, PhD: This is going a tangent, but I ask the question because we see it in our practice. A few years ago, the American Society of Breast Surgeons recommended that all people with breast cancer undergo genetic testing. What are your thoughts on this?
Ruta Rao, doctor of medicine: We have a little trouble covering the genetic tests of some patients, so part of it: the financial part. We don’t want to add to the financial toxicity these patients experience, especially if their family history doesn’t suggest it. But yes, this recommendation does exist. It’s one of those things that we will all have to watch out for in the years to come. We may test all breast cancer patients for germline mutations.
Elizabeth A. Mittendorf, MD, PhD: You said it was appropriate. I suggest having this specific patient tested for our mutation. I guess you said this because this patient has a BRCA mutation, so it’s really going to impact your treatment recommendations. If we look at the slides we put together for this case, the first slide shows the 2 phase 3 studies that were done on PARP inhibitors and patients with a BRCA1– or BRCA2– mutated metastatic breast cancer. The 2 trials are OlympiAD and EMBRACA. OlympiAD looked at agent olaparib. EMBRACA looked at agent talazoparib. If we look at the next slide, the first 1 is the diagram, and the second slide is the results of the studies. For both trials, the primary endpoint was progression-free survival. What we are seeing is that there was an advantage in the administration of the PARP inhibitor over the chemotherapy chosen by the doctor. The third slide we have for this case looks at extended follow-up, specifically for the OlympiAD trial, which looked at olaparib. We see that for the general population, the median overall survival was 19.3 months vs. approximately 17 months. There is no statistically significant difference in survival in the general population. Additionally, there have been no new safety signals with this more extensive tracking. But we have some interesting data when you think about whether a patient has ever had chemotherapy. I am going to stop my remarks there and ask you: Given the data from OlympiAD and EMBRACA, how are you going to treat this young woman in our case?
Ruta Rao, doctor of medicine: We would ideally like to start with a PARP inhibitor in a patient like this. She’s naive about chemotherapy. We saw that his tumor tested negative for PD-L1 via the SP142 test. We don’t really think about immunotherapy in this patient, although I have a question for David: is this the kind of patient for whom, because she was tested with SP142 and was negative, you would recommend that his tumor be retested with 22C3?
David G. Hicks, MD: I think so. Particularly if the pembrolizumab treatment option was a potential part of her therapy. About 30% of patients will be negative for SP142 but positive for 22C3, so it is possible that it is positive. This is what our medical oncologists tell us, our institution. If 1 is negative, please test the other 1.
Ruta Rao, doctor of medicine: In our practice, we would do the same. Back to this patient. Even if we assume that she is tested via both tests for PD-L1 and is negative, a PARP inhibitor would be an excellent choice for her as overall survival was higher for patients who had not received previous chemotherapy.
Elizabeth A. Mittendorf, MD, PhD: That was the conclusion on the last slide we showed. In the OlympiAD trial, for patients who had not had previous chemotherapy, median overall survival was approximately 23 months for those receiving olaparib versus approximately 15 months for those receiving chemotherapy. The EMBRACA study – the last slide in this series for this patient – does not appear to show that there is a statistically significant difference in overall survival. The 2 trials are so similar, but they are a little different. How do you collect the data to determine if you are going to give olaparib versus talazoparib?
Ruta Rao, doctor of medicine: This is a difficult question. Obviously, the drugs were not compared directly. Some of them are: What have you used before? What do you use most comfortably? What are you most comfortable with dealing with side effects? Both drugs have strong Phase 3 data and approval in this setting.
Transcription edited for clarity.