Insights From: Oliver Dorigo, MD, PhD, Stanford University Medical Center; Whitney Graybill, MD, MS, Medical University of South Carolina; Matthew Powell, MD, Washington University School of Medicine
Matthew Powell, MD: When I’m asked about molecular testing, usually for newly-diagnosed patients with ovarian cancer or patients I’m seeing for the first time, I’m very interested to see if they’ve been offered genetic testing. Do they have an inherited gene from their parents that would put them at an increased risk for developing cancers as a family member? But it also helps us to provide insight into their cancer to see if it would alter therapies. When using those molecular tests, if they were done several years ago, we might try to repeat them as we’ve expanded those panels to beyond BRCA1 and BRCA2. We’re also looking at tumor profiling. There’s a lot going on as far as actionable mutations beyond BRCA1 and BRCA2, a whole homologous recombination category of genes. There is a so-called BRCA-ness or BRCA-like phenomenon. I like to, when I talk about an ovarian cancer patient, include what their molecular status is as I communicate about that patient with other providers.
Oliver Dorigo, MD, PhD: We have, in general, embraced germline testing for all ovarian cancer patients. National organizations, including the American Society of Clinical Oncology, the Society of Gynecologic Oncology, and the NCCN guidelines really outline that testing should be done on patients who are newly diagnosed with ovarian cancer. It’s important information for the patient and her family, since we have measures to prevent the development of fallopian tube and ovarian cancers in those individuals who have predisposing germline mutations.
Somatic mutation testing in the tumor itself is certainly still under development. I personally use it to make decisions regarding targeted therapies. The identification of certain somatic mutations, particularly in the oncogenic pathway, might open up opportunities for treatment with drugs that are still mostly under development but important for us to pursue further. There are a number of clinical trials now that need information in the context of somatic mutations in order to enroll patients. The National Cancer Institute is conducting a trial at this point that is matching tumor mutations with targeted therapies. And in that context, somatic mutation testing is usually important. We cannot recommend it generally to all patients at this point, so somatic mutation testing still has to be individualized.
Whitney S. Graybill, MD, MS: In terms of doing germline BRCA testing versus HRD testing, I think there are definitely more data that support germline testing. We know that it’s more predictive and prognostic in terms of what we have studied thus far. So, I tend to order germline testing in the upfront setting for all my patients with newly diagnosed ovarian cancer. I think it’s also important that patients, if they didn’t have germline testing or have their tumors evaluated initially, go back and do that testing.
I think HRD testing can be important in certain groups of patients who are BRCA negative, where if they’re somatic mutation positive or HRD positive, they may have access to an agent or PARP inhibitor that they didn’t otherwise. And again, I think it can be helpful to let the patient know what kind of a clinical response they may expect with treatment.
I like to test in the upfront setting. If I have a patient who comes in with a newly diagnosed ovarian cancer, I discuss testing with them at that time. If there is a patient who had not previously been tested with recurrent disease, then I address it when available.
I tend to order panel testing as opposed to single-gene testing, because I think it gives us more information in general about what drugs a patient may be eligible for. I think the important thing to remember is that the more genes you test for, you’re going to find more genes that are deleterious but you’re also going to find more genes that have variations of uncertain significance, where we really don’t know what the clinical implication of a positive test might mean.
Matthew Powell, MD: I’m often asked about whether I order single-gene tests for molecular testing or multigene panels. We’ve really moved to multigene panels to provide us the most information and avoid that need for cascade-like testing, where I have to continue to wait on additional examples. Now with the way the tests are performed, it makes sense to order the full panel when we look beyond just BRCA1 and BRCA2 for the other group of genes that are responsible for inherited risk. Testing can also convey a unique sensitivity to PARP inhibitors when we see these categories of genes that are responsible for homologous recombination deficiency.