Role of Molecular Testing in Advanced Ovarian Cancer
An expert in ovarian cancer reviews best practices for molecular testing in patients with advanced ovarian cancer and the implications of testing results for treatment selections.
Ramez Eskander, MD: Considering patients with advanced stage epithelial ovarian cancer, we take multiple things into account when we think about prognosis and treatment. Thankfully over the last several years we have learned a lot more about the molecular drivers and what we call biomarkers that help us predict response and treatment efficacy. In this case the patient did not have a germline BRCA mutation or an identifiable somatic BRCA mutation, and when we looked at homologous recombination deficiency [HRD], there was no evidence of HRD on assessment. In context of the above, we know that these patients usually respond to frontline systemic chemotherapy, even those patients with advanced stage disease, stage 3 or stage 4 disease, at primary diagnosis. Approximately 80% will achieve a complete response [CR] or go into remission following primary surgery and systemic chemotherapy, whether that’s given as neoadjuvant chemotherapy, or interval surgery, or ultimately chemotherapy after primary surgery; remission is an expectation in many patients. Unfortunately, however, we know that most of these patients will develop disease recurrence. And this patient is an example of that scenario, where we have a patient who had a complete response to primary treatment but had a 1-year disease-free interval and then recurred. And we know when disease recurs, the goal is disease control with a preservation of quality of life because it’s hard to cure patients once the disease has recurred. That may evolve with time as we continue to make therapeutic breakthroughs, but at this juncture the goals of therapy are focused on disease control with preservation and a good quality of life and performance status.
Molecular testing has emerged as a critically important paradigm in the treatment of patients with epithelial ovarian cancer. We think about this as several pillars that support this intervention. No. 1 is every patient should have germline BRCA testing who has an epithelial ovarian cancer. This is relevant to the patient at maintenance therapy in the front line, following the publication and presentation of the SOLO-1 data. And these could essentially lead to dramatic improvements in oncologic or cancer outcomes. But it’s also critically important for first degree relatives because if the patient is found to have a germline BRCA mutation, those individuals should be tested. If they are found to have a mutation, they can have risk-reducing surgery, which could prevent the development of cancer in the first place and potentially be lifesaving. It’s also important to do somatic testing of the tumor. And this is relevant because there’s a difference. Germline mutations are inherited from parents to children. Somatic mutations are what we say is acquired. They evolve over time sporadically in tissue leading to a tumor. You could have a patient who is germline BRCA wild type but has a somatic BRCA mutation. And what we’ve learned from the clinical trials that we’ve conducted is that the somatic and the germline patients behave similarly when they’re treated with PARP inhibitors as a novel therapy, meaning there’s a tremendous benefit in clinical outcome there. Germline BRCA testing and somatic BRCA testing are very important to do at the front line at initial diagnosis because of the implications on therapy.
What’s also emerged as a relevant and important part of this process is the assessment of homologous recombination deficiency. And what that is, it’s a way for us to look at a genomic signature that suggests dysfunction with homologous recombination repair. And this is essentially helping inform us of patients who may benefit from a PARP maintenance strategy, either as a monotherapy or in combination in the front line or even in the recurrent settings. We have germline BRCA testing, we have somatic BRCA testing, and then we have homologous recombination deficiency assessment, which can all be performed in the first line because of the importance in patient treatment decision-making. Now we all are aware that there are larger NGS [next-generation sequencing] panels that can be submitted. There can still be relevant data from those. It is uncommon, but you may have a patient with ovarian cancer in some histologies who is mismatch repair proficient but can be found to be MSI [microsatellite instability] high or have a high tumor mutational burden. And those patients may potentially benefit from immunotherapy with an immune checkpoint inhibitor. You can find an NTRK fusion, and they can be on NTRK-targeting agents. Those are very uncommon to be identified but could potentially be identified and actionable in the patient’s treatment. I would venture to say that molecular testing is an important part of the care of these patients. There are multiple relevant molecular testing results that will impact maintenance therapy and counseling in the front line, and those can't be overlooked. Then there are also NGS testing results that could inform theoretically frontline treatment, or possibly treatment at recurrence, or eligibility enrollment in clinical trials looking at novel targeted agents.
When we talk about genetic testing and molecular testing, it’s also important to recognize that patients who are found to have a germline BRCA mutation should be appropriately referred to genetic counselors so that they can have a comprehensive discussion about the implications for them with respect to alternate solid tumors. But they can also have a larger conversation with family members who may have appropriate questions to ask about the implications for their own testing and testing results. And it’s also important because we talk about repeat testing through the paradigm of disease. At this juncture, the data don’t suggest that there’s much evolution in the NGS mutations in tumors with subsequent testing. However, we also identified that there could be BRCA reversion mutations and BRCA mutation carriers, or we can identify in some patients the acquisition of mutations that weren’t present previously. Again, this is not common, but these have been reported.
This transcript has been edited for clarity.
Case:A 64-Year-Old Woman With Ovarian Cancer
Initial Presentation
- A 64-year-old woman presented with abdominal bloating, low back pain, early satiety and progressive fatigue
- PMH: hysterectomy 5 years ago for benign indication; hypothyroidism managed medically; generalized anxiety disorder managed medically
- PE: diffuse lumbosacral pain with movement; abdominal tenderness and significant abdominal distension with a fluid weight consistent with ascites; unintentional weight loss of 8 lbs
- ECOG PS 1
Clinical work-up
- Pelvic ultrasound showed a ~5-cm complex left ovarian mass
- Chest/abdomen/pelvis CT revealed a complex pelvic mass and was also notable for abdominal ascites, omental cake, and retroperitoneal and inguinal adenopathy
- Paracentesis (1200cc) cytology confirmed high-grade serous ovarian cancer
- Omental biopsy histology also confirmed high-grade serious ovarian cancer
- Germline molecular testing: BRCA1/2wt
- Somatic testing: BRCA1/2 negative; HRD proficient
- CA-125, 360 U/mL
- Diagnosis: Stage III, high-grade serous epithelial ovarian cancer
Treatment
- Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
- Carboplatin/paclitaxel q3 weeks for 6 cycles; CA-125 normalized; CR
- Bevacizumab maintenance
- At 1 year post treatment, CA-125 increased; imaging revealed progressive retroperitoneal adenopathy suggestive of recurrent disease; not deemed a candidate for secondary surgery
- Rechallenged with carboplatin/paclitaxel q3 weeks for 6 cycles; PR; predominantly enlarged lymph nodes
- Rucaparib monotherapy maintenance
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