Molecular Testing in Ovarian Cancer

EP: 1.Case Overview: A 67-Year-Old Woman With Ovarian Cancer

EP: 2.Predictors of Recurrence in Ovarian Cancer

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EP: 3.Molecular Testing in Ovarian Cancer

EP: 4.Options for Maintenance Therapy in Ovarian Cancer

EP: 5.Clinical Trials in Ovarian Cancer Maintenance: PRIMA and NOVA

EP: 6.Platinum Sensitivity vs Resistance and Treatment Selection in Ovarian Cancer

EP: 7.Future Directions in Ovarian Cancer

Chirag Shah, MD, MPH: This question of tumor testing and germline testing is about what type of testing we use and for whom do you get what test. It has been a moving target over the past few years. We have certainly come a long way in our understanding of the genetics and the Fanconi anemia pathway through the hard work of investigators and discovering that, in addition to BRCA, there are other mutations that can occur, both germline inherited or within the tumor that predispose a patient to the development of these cancers.

Our current pathway is to obtain germline testing for all women who are diagnosed with epithelial, ovarian, primary peritoneal, or fallopian tube cancers. This is consistent with NCCN [National Comprehensive Cancer Network] Guidelines, which suggest that all patients should obtain germline tumor testing. The subsequent pathway is then dependent on your germline testing results. If the patient is known to have a germline tumor test that is positive, then the need for molecular testing somewhat obviated, at least in the initial setting. Based on the results of the germline tumor test, we then reflexively decide to do molecular testing. If a patient is germline BRCA1 or BRCA2 negative, tumor testing can then be obtained. There are a number of tumor tests that are commercially available, and there are institutional tumor tests. We are predominantly speaking about HRD [homologous recombination deficiency], which has been demonstrated to be present in about 50% of somatic samples or tumors that are found of this type, and it also includes the tumor BRCA mutations. In addition, it is present in tumors that have large-scale translocations, telomeric allelic imbalance, and then loss of heterozygosity [LOH], which are the scars that result in tumors that have deficient DNA repair. This can be quantified by these assays and then used as an actionable target for determining if patients might derive additional benefit from a molecule such as a PARP inhibitor.

The primary benefit is that it can help you be consistent with FDA approvals and decide what medication or combination of medications you might consider for maintenance therapy. It is also incredibly useful for counseling our patients in terms of what the prognostic implications of the addition of maintenance therapy might mean for them. Essentially, the pathway that we employ is to begin with germline tumor testing, and the patient usually goes through the process of referral to genetic counselors. Once we obtain those results, we will move forward with tumor testing. There are additional benefits to tumor testing outside the LOH or HRD status; the discovery of mutations that might be actionable targets for therapy in the recurrent setting is also useful. For patients who do not receive PARP inhibition up front or who are not started on that medication initially, it may help us to define their benefit in subsequent lines of therapy.

Transcript edited for clarity.

Case: A 67-Year-Old Woman With Ovarian Cancer

Initial Presentation

• A 67-year-old female presented with abdominal discomfort and modest weight loss
• PMH: unremarkable, postmenopausal; no known family history of cancer
• PE: diffuse tenderness to abdominal palpation, abdominal bloating
• ECOG PS 0

Clinical Work-up

• Pelvic exam with transvaginal ultrasound showed a left ovarian mass
• Chest/abdomen/pelvis CT with contrast revealed a left adnexal 5-cm mass, pelvic and inguinal lymph node involvement, no pleural effusion
• Paracentesis (1200cc) cytology confirmed high-grade epithelial ovarian cancer
• Germline molecular testing: HRD+, BRCA1/2-
• CA-125, 360 U/mL
• Diagnosis: Stage 4, high-grade epithelial ovarian cancer

Treatment

• Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
• IP/IV paclitaxel/cisplatin; CR
• Niraparib maintenance was initiated