Case 2: Stage III, High-Grade Serous Epithelial Ovarian Cancer

Experts in gynecologic oncology review the case of a 71-year-old woman who is diagnosed with stage III, high-grade serous epithelial ovarian cancer, and comment on their approach to genetic testing in the frontline setting.

Thomas C. Krivak, MD: Moving on to our second case, this is a patient with stage III, high-grade serous epithelial ovarian cancer. At her initial presentation, she is a 71-year-young woman who presents with progressive abdominal discomfort, bloating, early satiety, and she has new onset constipation as well as some weight loss. Past medical history is significant for, she is postmenopausal and has some osteoarthritis. On physical examination, she has right lower quadrant tenderness on palpation. She weighs about 200 lb, and she has a good functional status with an ECOG status of 1.

Her clinical evaluation shows on pelvic exam as well as ultrasound that she has about a 4.5- to 5-cm ovarian mass. CT scan of the chest, abdomen, and pelvis shows a right adnexal mass with lymph node involvement as well as ascites. Through paracentesis, we have 1200 cc of fluid, which confirms high-grade serous epithelial ovarian cancer. She gets germline testing that’s noted to be BRCA1/2 wild type. CA [cancer antigen]-125 was elevated at 335 U/mL. She’s diagnosed with stage III, high-grade serous ovarian carcinoma, again not uncommon for us to see in our clinics.

I know we’ve talked about genetic testing, and it’s going to be important that we’re always going to be thinking about germline testing, tumor testing for all these patients because we want to deliver personalized care. Again, would you perform next-generation sequencing [NGS], HRD [homologous recombination deficiency] testing at this point? Which tests would you order? These are some of the questions that we need to think about?

Looking at some of the data, we always focus on BRCA1 and BRCA2, and there’s no doubt about it that those are important genes. But you can see these data by Barb Norquist, MD, looking at some of these other genes that have slightly lower penetrance but do have a role with respect to homologous recombination deficiency as well as possibly may place the patients at increased risk for cancer. The Fanconi genes RAD51, RAD50, BRIP1, ATM, and you can see on the right-hand side of the pie chart, about 50% of patients are going to have tumors that are homologous recombination proficient, 50% of patients will have tumors that are deficient. Looking at some of the causes: BRCA1/2 mutations, about 19%; the other homologous recombination genes, about 7%; and then HRD from other causes such as methylation, as well as other causes, will account for some of these patients having tumors that are HRD deficient.

Coming back to the myChoice tumor testing genomic instability, since this is the FDA-approved test for up front with respect to the PAOLA and PRIMA trials, it’s a different test in that it’s looking at LOH [loss of heterozygosity], telomeric allelic imbalance, and large-scale state transitions, as well as looking at a somatic mutation within the tumor. Then they add these scores to come up with a score of 42 or greater to be positive. Myriad Genetics is going to be making some changes to this test. But sometimes it’s important to figure out how they designed this test.

My understanding of how Myriad designed this test is they had numerous patients who had BRCA mutations, and then they looked at the scores and looked at LOH, large-scale state transitions, and telomeric allelic imbalance. And they tried to say if there was X number of patients, and you can see there was 790 who were BRCA intact and 270 with a BRCA mutation, they tried to capture 95% of those patients who were BRCA deficient. You can see that’s where they drew the line and said patients whose tumors were BRCA intact but fell into that range, those were the patients who had homologous recombination deficiency or genomic instability by what they have.

You can see here on the right, genomic instability positive, tumor BRCA negative, it’s going to be a positive for genomic instability or HRD. Any tumor that’s BRCA positive generally is going to be genomic instability positive. And people who have a germline or somatic mutation in general are going to be positive. You must have negative genomic instability and negative tumor testing for it to be a negative test. When you look at how Myriad designed their test and how Foundation Medicine moved the LOH percentage by looking at response, both are very valid tests, both very important tests but designed slightly differently with respect to how they’re going to report their scores.

At this point, she’s germline negative. We talked about the different tests. We’ve talked about this in the past with our other patient. What would you perform at this time for this patient? She’s BRCA wild type.

Cecelia H. Boardman, MD: Do we know that? Is that the first test we ordered?

Thomas C. Krivak, MD: Yes, she had germline testing that was negative.

Cecelia H. Boardman, MD: OK, because there are some people who speak to that financial toxicity piece, and obviously we’ve got guidelines that say germline testing should be done for all patients. But I’ve heard some clinicians argue, “Well, I don’t want to do that, or I think that that might be expensive, or I that might be stressful for the patient.” There are some people who argue maybe our first test should be HRD, and then of the patients who are HRD positive, then you can drill down whether that’s a germline or a somatic BRCA mutation or other genetic mutations. There are some people who argue if you do HRD testing alone, that gives you your highest yield of positive patients, it gives you your 50% who would be eligible for PAOLA. And then if you want to drill that down further to look for the germline status, you can do that. That’s another testing strategy that some people use that maybe fits in their own vision of not having excessive cost with diagnostics in the frontline setting.

Thomas C. Krivak, MD: Dr Chan?

John K. Chan, MD: That’s a good point. I generally order both tests, and I try to use our own mechanism or work with the Myriad company to do reflex testing. If they are germline negative based on NCCN, [National Comprehensive Cancer Network], I reflex to HRD testing. With respect to the NGS testing, which is the question that we have here, I generally save that for the recurrent setting. I try to obtain tests that I need only if it changes what I do, only if it changes my management. If the HRD and the germline mutation tests have already given me enough information to determine how I want to treat this patient in the upfront setting, I don’t order any unnecessary tests at that time. Now, when the patients recur and I want to put them on a clinical trial based on their biomarker testing, like the TAPUR trial, then I order the NGS and tailor their treatment.

Thomas C. Krivak, MD: Ashley, any thoughts on that?

Ashley Farione, PA-C: At this point, you’d probably send it for HRD for Myriad to see what her status is and then go from there.

Thomas C. Krivak, MD: Yes, HRD, I agree with you John and Ashley, that’s our decision tree. A couple of years ago at SGO [Society of Gynecologic Oncology annual meeting] they had a couple of plenaries that talked about testing the tumor, reflexing back, and doing what we do for colon cancer. I agree with the financial toxicity, but that cascade testing, testing other individuals, sisters, daughters, is important. I try to stress that importance. What is incredible is all of us sitting here talking about this. We have to try to communicate this information to a patient, which can be challenging at times, and I know it can be confusing for us as we talk about different strategies in how we approach this. It’s got to be confusing for the patient. It definitely takes a team to help get our patients through this.

Transcript Edited for Clarity

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