Moving Molecular Testing to the Frontlines of Ovarian Cancer

Mihaela C. Cristea, MD

High-grade serous and endometrioid carcinomas are predominantly driven by deficiencies in homologous recombination, whereas less common histologic subtypes are largely driven by genetic alterations. However, every patient, irrespective of histologic subtype, should have access to molecular testing to determine whether a germline or somatic mutation is present, said Mihaela C. Cristea, MD.

Cristea, an associate clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, emphasized the use of molecular testing over tumor testing in a presentation during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer as tumor testing cannot distinguish between a germline or somatic alteration.

Germline Mutations

BRCA mutations are among the most common germline mutations and are found in approximately one-fifth of patients with ovarian cancer, said Cristea. While BRCA1 is more common than BRCA2 and carries a higher cumulative risk of ovarian cancer, both confer sensitivity to PARP inhibition.

Lynch syndrome, although rare, carries up to a 24% risk for developing ovarian cancer; however, this is mainly restricted to endometrioid and clear-cell histologies.

“The mark for Lynch syndrome is not ovarian cancer. It’s colorectal and uterine cancer, but we need to think about this in the setting of ovarian cancer, especially if the tumor is low-grade endometrioid or clear-cell,” stressed Cristea.

Additional genes involved in the homologous recombination deficiency (HRD) pathway include, BARD1, BRIP1, RAD51C, RAD51D, and PALB2, the latter 3 of which are actively accruing to basket trials.

Instead of sequencing each individual gene with traditional targeted sequencing, next-generation sequencing allows for the assessment of several genes at once, including BRCA1/2, PALB2, BARD1, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6.

In terms of recommendations, the National Comprehensive Cancer Network, the Society of Gynecologic Oncology, and ASCO concur that genetic testing and counseling should be made available to patients with a diagnosis of epithelial, ovarian, tubal, and peritoneal cancers, even in the absence of family history.

However, despite consensus guidelines, adherence to testing remains low at approximately 30%, said Cristea.

Somatic Mutations

Somatic mutations are less common in ovarian cancer, representing approximately 7% of the overall population. Commonly typified are genomic loss of heterozygosity, a common marker of HRD, and microsatellite instability—high (MSI–H) status, for which single-agent pembrolizumab (Keytruda) is indicated in the recurrent setting.

Myriad’s myChoice HRD assay, although not yet on the market, has proven its utility in clinical trials. For example, by assessing a patient’s loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions in the phase III NOVA trial, investigators were able to discern between loss of DNA repair function and intact DNA repair function, and therein a patient’s amenability to PARP inhibition.

Bringing HRD companion diagnostics to market would aid clinicians in identifying the approximately 50% of patients with HRD high-grade serous cancers who are likely to benefit from PARP inhibitors, currently indicated as:

• Monotherapy for the treatment of recurrent germline/somatic BRCA-positive ovarian cancer (olaparib [Lynparza] and rucaparib [Rubraca])
• Maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer following a partial response (PR) or complete response (CR) to platinum therapy (niraparib [Zejula], olaparib, rucaparib)
• Maintenance therapy in patients with germline/somatic BRCA-positive ovarian cancer who are in PR/CR to first-line platinum-based chemotherapy

However, clinical implications go beyond high-grade serous cancers, explained Cristea. For example, rare histologies, such as low-grade serous endometrioid and clear-cell carcinomas, are more likely to harbor mutations in the mitogen-activated protein kinase pathway, commonly reflected by mutations in KRAS, BRAF, and HER2.

“These are not frequent situations,” said Cristea. “Most of these histologies represent 5% or less of ovarian patients, but these histologies do not respond very well to chemotherapy. It is in this setting that molecular testing is more rewarding because we can identify various targets.”

Testing should be performed by a validated Clinical Laboratory Improvement Amendments-approved center.

“All patients should undergo germline BRCA mutation testing, and after SOLO-1, all patients should undergo somatic mutation testing when they are newly diagnosed,” said Cristea.

In the recurrent setting, evaluation of MSI or mismatch repair proteins and HRD testing should also be ordered pending financial feasibility, she concluded.