Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing

Abstract

Background Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013–May 2019 were included (N = 631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~ 3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~ 2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years for BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D. Conclusions These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45–50 in RAD51D PV carriers and possibly until age 50–55 in BRIP and RAD51C PV carriers.

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

“…It is well-established that PVs in BRCA1 confer an increased risk of OC at an early age. Nevertheless, the age at diagnosis in this patient is more consistent with the mean age at diagnosis of those women with PVs in other susceptibility genes, such as BRIP1 , RAD51C , or RAD51D —even with those defined for sporadic cases (63 years or older) [ 32 ]. Intriguingly, she was diagnosed at 81 years of age, very much older than the median ages for BRCA1 -positive or RAD51C -positive women (53 and 61 years old, respectively) [ 32 ].…”

“…Nevertheless, the age at diagnosis in this patient is more consistent with the mean age at diagnosis of those women with PVs in other susceptibility genes, such as BRIP1 , RAD51C , or RAD51D —even with those defined for sporadic cases (63 years or older) [ 32 ]. Intriguingly, she was diagnosed at 81 years of age, very much older than the median ages for BRCA1 -positive or RAD51C -positive women (53 and 61 years old, respectively) [ 32 ]. This patient is also a carrier of two VUS in BLM and MLH1 , so we cannot rule out whether these VUS variants or other external factors might play roles as modifiers of the phenotype.…”

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway

“…For BRIP1 GPV carriers, the NCCN clinical practice guidelines in oncology recommend that RRSO should be considered from age 45 to 50 years or earlier based on a specific family history of early-onset EOC [ 45 , 46 , 72 ] ( Table 1 ). Although the lifetime risk of EOC in BRIP1 GPV carriers seems to be sufficient to justify considering RRSO, there is currently no evidence to make a firm recommendation on the optimal age for this procedure.…”

“…Although the lifetime risk of EOC in RAD51C/RAD51D GPV carriers seems to be sufficient to justify considering RRSO, there is insufficient evidence to make a firm recommendation regarding the optimal age for this procedure. Reportedly, the median age at diagnosis for RAD51C/RAD51D GPV carriers with EOC is 62 and 57 years old [ 72 ]. Therefore, the age at which to begin consultation for surgery may change as more evidence is accumulated.…”

Hereditary gynecologic tumors and precision cancer medicine

“…RRSO is currently recommended for carriers of BRIP1 , RAD51C , and RAD51D mutations from the age of 45–50 years. Some are cautious about premenopausal RRSO because the onset age of OC in these moderate‐risk gene carriers is higher than that of BRCA1 101 . As there are also reports of peritoneal cancer in BRIP1 variant carriers, 102 peritoneal cancer and HBOC should be considered.…”