It’s All in the Genes:
Multi-gene Panels Increase Variant Yield and Treatment Options in Ovarian Cancer Patients
September 28, 2022
DELRAY BEACH, FL – Without effective early detection methods and lack of specific symptoms, ovarian cancer (OC) is often left undiagnosed until late in disease progression and risk of mortality is high. The National Comprehensive Cancer Network (NCCN) recommends that all ovarian cancer patients undergo germline testing, regardless of family history. In order to guide treatment, the germline panel should include BRCA1, BRCA2 and other genes with OC predisposition. “This seems to be the best approach as some studies showed that more than 30% of women with germline variants had no family history of breast or OC.”1
A new study, published in Cancers, showed the value of having more genes than just BRCA1/2 within the germline panel. The researchers identified 10 different OC predisposition gene (BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PMS2, RAD51C, RAD51D, and TP53) that would be sequenced within their patient sample. The results showed that “among the 95 OC patients analyzed…26 (27.4%) were carriers of rare germline variants in seven genes associated with genetic predisposition to OC (BRCA1, BRCA2, BRIP1, MSH6, RAD51C, RAD51D, and TP53).”1 The study suggests that using a multi-gene panel increases the chance of finding a pathogenic variant, while lowering sequencing costs and increasing the potential for variant-driven targeted therapies, clinical trial eligibility and the use of off-label therapy. In 2018, the FDA approved PARPi, like Olaparib, for use in patients with BRCA1/2 germline pathogenic variants. “HR deficient tumors due to deleterious variants in genes other than BRCA1 and BRCA2 may be sensitive to PARPi…RAD51C-deficient cancer cells were highly sensitivity [sic] to Olaparib, significantly inhibiting tumor growth…cell deficient in RAD51D were sensitive to Olaparib in a magnitude similar to the observed by silencing BRCA2.”1
Recently, the FDA has approved PARPi for metastatic castration-resistant prostate cancer with certain germline pathogenic variants, including RAD51C and RAD51D. “On the other hand, tumors with MMR deficiency display a phenotype of microsatellite instability, which is a predictive biomarker immunotherapy, allowing the FDA approval of the use of pembrolizumab, an anti-PD1 therapy, for the treatment of solid tumors with high microsatellite instability or MMR deficiency.”1 MRR genes include genes like, MLH1, MSH2, MSH6, and PMS2.
The researchers concluded that using a multi-gene panel to test for germline variants “enables the identification of clinically actionable germline variants in a significantly higher proportion of OC patients…which may be valuable information in patient with advanced disease that have run out of approved therapeutic options” or need more targeted therapies. Without multi-gene germline testing, OC patient mortality will continue to increase without the targeted treatments that these patients need.
- Barbosa A, Pinto P, Peixoto A, et al. Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2. Cancers (Basel). 2020;12(10):2834. Published 2020 Sep 30. doi:10.3390/cancers12102834