The Impact of Genetics on Outlook in Ovarian Cancer
A review of the impact that genetic testing and familial risk have on ovarian cancer and how the treatment plan can change.
PUBLISHED October 18, 2019
Shubham Pant, M.D.: Can you share a little of your experience, Doña, with this familial risk and genetic testing?
Doña Harman: I am a BRCA1 carrier. And I didn’t have a sense of guilt. I felt like a light bulb went on, because as I look back in my father’s family, there was cancer everywhere. For me, I really saw it as, “Oh, OK, now the family needs to know, because there’s something we can do.” There are maybe genetic components to lots of cancers. We just happen to know about this one. And there are therapies that can be targeted toward it, so I felt fortunate in that way. But I did want to bring up one thing. You were talking about the hereditary test that people take. It’s interesting, I did one of those, and I tested negative for the BRCA1 in that test, but I’m not negative.
Ramez N. Eskander, M.D.: It’s superimportant and very practical nowadays because these direct-to-consumer tests are available. But what people don’t realize is that they may test for one specific mutation.
Doña Harman: Like a hot spot mutation.
Ramez N. Eskander, M.D.: You got it, the most common mutations in these cohorts of patients and not test for others. So you may be negative for that, but that doesn’t mean there’s no alternate mutation that exists. I’ve had patients walk in and say, “No, no, I know I’m not BRCA mutated. Look, I did this commercial test, and it says I’m not.” And then you have to go through the process of explaining why that’s not a definitive test and what else we need to consider.
Shubham Pant, M.D.: Right, Dr. Eskander. That’s a very important point. Can you expand on that a little? Maybe can you expand a little on the BRCA1 gene? It’s a long gene. There are different mutations that can happen. Some are variants of unknown significance. Not every BRCA, BRCA1 mutation is pathogenic.
Ramez N. Eskander, M.D.: Correct.
Shubham Pant, M.D.: Can you expand on that a little, so people watching this can understand?
Ramez N. Eskander, M.D.: Sure, certainly. As you mentioned, a gene is a large piece of information, and abnormalities and mutations can occur in several places in a gene. It may not impact the function of the gene with a specific mutation or alteration. When you do genetic testing, they test the gene to look for mutations, and if it’s a reputable company, they’re testing the gene and essentially looking in the areas where they see most frequent aberrations or alterations covering a large portion, if not the entirety, of the gene depending on where it’s being done.
Variants of undetermined significance, or VUSs are not reflective of a pathogenic alteration. And it’s also really important because I’ve had patients come in and say, “I was told to have an operation to get a double mastectomy or to get my ovaries removed.” But there’s no pathogenic alteration in the BRCA. It’s a variant of undetermined significance, meaning we don’t have enough information to guide intervention based on that. In the future we may, but right now we wouldn’t. When you do have genetic testing, this is where either the physician, if they’re doing it on their own, has to be invested in explaining the results and really going over things. Or you have to have a good genetic counselor who partners with you who can do that. Because what you don’t want is a patient who has information that they can’t interpret, that they don’t know how to interpret, or unfortunately they get misinformation somewhere else.
Shubham Pant, M.D.: Right. And these are very complicated things. The way I sometimes explain it is, there’s a bus and there’s a driver on the bus and there are passengers. Some of the BRCA could be passengers, but they’re not driving the bus. They’re not driving the cancer, and you may end up taking out the passenger, but the bus is still driving along. And that’s very important for patients to know. Tell me a little, Dr. Eskander, if you are BRCA1- or BRCA2-positive, is your prognosis different from somebody who is BRCA1- or BRCA2-negative? Does it affect their survival, and is it a more aggressive cancer or a less aggressive cancer? Do people tend to live longer or shorter?
Ramez N. Eskander, M.D.: What we know is that patients who are BRCA mutation carriers are more sensitive to platinum agents in general. And the backbone of therapy for ovarian cancer historically was a combination of platinum and paclitaxel. And we also saw that patients who had BRCA mutations, yes, could have a longer disease response and remission.
Most recently, and probably some of the most exciting data that we’ve seen in gynecologic oncology as far back as I can remember, are the data looking at frontline PARP inhibitor therapy in BRCA-mutated patients. That was presented almost a year ago today at ESMO [European Society for Medical Oncology] and then subsequently led to regulatory approval. But the reason it was so exciting is we were able to show that in patients who had a BRCA mutation who was diagnosed and completed initial therapy and then got put on a PARP inhibitor, over 60% of those patients did not have a disease recurrence three years out from their diagnosis, which is a very dramatic improvement over what we see in historical baseline controls and in the control arm of that clinical trial.
We know that BRCA-mutation status is important for the patient and their family. We know now that it’s important and really relevant with treatment, prognosis, and counseling. Because the conversation I have with a BRCA-mutation patient can be very different from one I have with a non-BRCA-mutation carrier based on these data looking at these new drugs and the efficacy of these drugs in this patient population.