Abstract
PURPOSETubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives.PATIENTS AND METHODSIn this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver.RESULTSWe identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before.CONCLUSIONWe overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
Highlights
Knowledge Generated Our study explored three methods for the identification and genetic testing of deceased patients with ovarian cancer for pathogenic variants in hereditary risk genes
There was provision within the TRACEBACK study to facilitate testing of living probands (Data Supplement), here, we evaluate the implications of genetic testing in the deceased ovarian cancer population
17,000 women were diagnosed with invasive high-grade nonmucinous ovarian cancer (HGNMOC) in Australia between 2000 and 2016.21,22 On the basis of the reported testing rates from this period in two Australian studies[8,23] and data captured by participating research studies, we estimated that 12,000 patients missed genetic testing
Summary
Prevention strategies in individuals at increased genetic risk of cancer offer important opportunities to reduce cancer incidence and mortality. This is relevant for tubo-ovarian cancer (referred to as ovarian cancer). Pathogenic germline variants in BRCA1 and BRCA2 (BRCA1/2) confer a cumulative risk for ovarian cancer by age 80 years of 44% and 17%, respectively.[1]. RAD51C, RAD51D, PALB2, BRIP1, and genes involved in DNA mismatch repair, are associated with a moderately increased risk of between 5% and 12%.2-5. In the absence of reliable early detection, prevention of ovarian cancer remains the most effective means to reduce disease impact, as the majority of patients have advanced-stage cancer at diagnosis, which is associated with high rates of relapse and mortality RAD51C, RAD51D, PALB2, BRIP1, and genes involved in DNA mismatch repair, are associated with a moderately increased risk of between 5% and 12%.2-5 In the absence of reliable early detection, prevention of ovarian cancer remains the most effective means to reduce disease impact, as the majority of patients have advanced-stage cancer at diagnosis, which is associated with high rates of relapse and mortality.
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