Ovarian cancer represents 3.7% of all female cancers and is usually diagnosed in advanced stages with a poor prognosis, with overall survival being the worst of all gynecologic malignancies. Professional society guidelines include gene-specific risk reducing recommendations . While these guidelines incorporate decades of evidence for BRCA1 and BRCA2, guidelines are not as clear for other, less well-characterized genes associated with increased ovarian cancer risk. In this analysis, we evaluated the clinical presentation of over 3,000 women with PVs in BRIP1, RAD51C, or RAD51D identified by a multigene hereditary cancer panel. To our knowledge, this is the largest published study evaluating the ovarian cancer risk and age of onset associated with pathogenic variants in these moderate penetrance ovarian cancer-risk genes.
The data presented here for BRIP1, RAD51C, and RAD51D supports previous research demonstrating an increased risk of ovarian cancer for women with PVs in these genes. The prevalence of a personal or family history of ovarian cancer among women with PVs in BRIP1, RAD51C, or RAD51D was similar to that observed for women with PVs in BRCA1 or BRCA2 in this cohort. This supports a recent study that utilized a large clinical cohort to quantify gene-specific ovarian cancer risk. In this study, Kurian et al. demonstrated that BRIP1, RAD51C, and RAD51D are all significantly associated with ovarian cancer . Furthermore, the relative risk of ovarian cancer associated with RAD51C and RAD51D was comparable to BRCA2, with odds ratios for all three genes of approximately five . In addition, there was a substantial enrichment of PVs in these three genes among women with ovarian cancer compared to PV-negative women in this cohort. Collectively, this reiterates the importance of pan-cancer panel testing in women with ovarian cancer. Given the poor prognosis associated with this disease, identifying PVs in genes that confer an increased risk for ovarian cancer outside of BRCA1 and BRCA2 is critical for appropriate patient management.
NCCN guidelines recommend that women with PVs in ovarian cancer-risk genes consider RRSO . Given the psychological and medical complications of premature menopause, patients and providers must balance the timing of RRSO with the risk of ovarian cancer. For BRCA1, the risk of ovarian cancer at an early age has been well established. This was also observed here, where women with PVs in BRCA1 had the youngest median age at diagnosis. The median age at ovarian cancer diagnosis of women with a PV in BRIP1, RAD51C, or RAD51D was much older and more than three quarters of women with a PV in one of these three genes and a history of ovarian cancer was diagnosed after the age of 50. For BRIP1 and RAD51C, the median age at ovarian cancer diagnosis was after 60 years. This is comparable to what is seen in the general population, where about half of the women who are diagnosed with ovarian cancer are 63 years or older .
At the individual gene level in this cohort, one may determine that it is reasonable to delay RRSO until age 45–50 for women with a PV in a moderate penetrance ovarian cancer-risk gene. In addition, it may be reasonable to delay RRSO until age 50–55 for women with a BRIP1 or RAD51C PV, which is at a time when natural menopause typically occurs. Delayed RRSO in these women may minimize the vasomotor symptoms and cardiovascular risk associated with a premature menopause as well as its negative effect on bone metabolism, and possibly, cognition and longevity [15–17]. Overall, these data aid in supporting providers and their patients in the clinical decision-making process based on a more refined risk of ovarian cancer.
The data presented here also spur an interesting possible application of panel testing among women with ovarian cancer as a method to tailor treatment. Women with defects in the homologous recombination repair (HRR) pathway are more likely to benefit from DNA-damaging therapies, such as PARP inhibitors or platinum-based regimens [18, 19]. Previous research has shown that the presence of germline or tumor PVs in BRCA1 or BRCA2 predict benefit from such therapies among women with ovarian cancer [20, 21]. The presence of PVs in other genes in the HRR pathway, including BRIP1, RAD51C, or RAD51D, express a phenotype similar to BRCA-related HRR defects . This suggests that panel testing may help guide treatment selection for women with ovarian cancer by identifying PVs in BRIP1, RAD51C, or RAD51D .
While this study is informative, it is not without limitations. First, family history information was obtained from provider completed test request forms and may not be comprehensive. Given the size of this cohort, it was not feasible to confirm the reported family and personal history. In accordance with other data and to help minimize the impact of inaccuracies , family history was only considered for first- and second-degree relatives. In addition, our population was composed of women referred for genetic testing and is therefore enriched for individuals with a personal and family history of ovarian cancer. In order to avoid over-interpretation of the data for BRIP1, RAD51C, and RAD51D, we evaluated PV-negative women to provide an appropriate baseline for this elevated risk population. This characteristic should be considered when generalizing this study’s results.