TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members

Abstract

Purpose: Tubo-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 methods: In 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.

Results: We 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.

Conclusion: We 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.

FIG 1.

TRACEBACK probands and samples. Schematic representation of the three ascertainment methods used to identify and test high-grade nonmucinous ovarian cancer probands, diagnosed in Australia between the years 2000 and 2016. Genetic testing of deceased probands (n = 824) is reported here, with information available for the living probands ascertained to the study (n = 265) in the Data Supplement. ^aSome exceptions were made for deceased probands diagnosed outside 2000-2016 for NOK referral (Data Supplement). ^bPredominately normal tissue was obtained from surgical tumor samples and included both FFPE and fresh-frozen biospecimens (Data Supplement). FFPE, formalin-fixed paraffin-embedded; HGNMOC, high-grade nonmucinous ovarian cancer; NOK-R, Next of Kin–referred; QC, quality control.

FIG 2.

Detected C4/C5 variants (PVs). An overview of the clinical and genomic features of 84 of 787 (11%) deceased probands with PVs, including one proband with two PVs, both in BRCA2 (one frameshift and one nonsense [given in ^a]). ACS, Australian Cancer Study; AOCS, Australian Ovarian Cancer Study; Carcinoma NOS, Carcinoma not otherwise specified; FFPE, Formalin-fixed paraffin-embedded; HGEn, High-Grade Endometrioid; HGNMOC, high-grade nonmucinous ovarian cancer; HGS, High-Grade Serous; NOK-R, Next of Kin–referred; Opal, Ovarian Cancer Prognosis and Lifestyle Study; PV, pathogenic variant.

FIG 3.

Frequency of PVs in the 787 deceased probands stratified by (A) method of ascertainment, (B) age at diagnosis, and (C) years of diagnosis. Group differences for categorical variables were examined using the chi-square test (GraphPad Prism 8.4 for Windows). ACS, Australian Cancer Study; AOCS, Australian Ovarian Cancer Study; NOK-R, Next of Kin–referred; OPAL, Ovarian Cancer Prognosis and Lifestyle Study; PV, pathogenic variant.

FIG 4.

Identification of recipients for research results. A stepwise representation of the feedback of PVs to date: (A) outcome of the feedback process to the NOK of deceased probands who self-referred into the study and (B) outcome for feedback to 77 NOKs of deceased probands ascertained via clinic-based recruitment and existing research studies. Created using BioRender. GC, Genetic clinician; NOK-R, next of kin–referred; PV, pathogenic variant.