Abstract PS8-14: Pathogenic variants in hereditary cancer syndrome genes are prevalent among breast cancer patients not meeting various ex-U.S. genetic testing guidelines
Authors: Nielsen Sarah M , Beitsch Peter , Whitworth Pat , Decker Emily , Rickers Natalie , Sroka Hana , Narravula Alekhya , Esplin Ed D , Nussbaum Robert L. 
Published: February 2021

Background:Therapeutic and risk management options have expanded for patients harboring pathogenic variants (PVs) in cancer predisposition genes. Historically, testing costs and clinical implementation challenges led to restrictive testing guidelines in many countries. Increasing evidence demonstrates that narrow criteria will miss patients with potentially actionable PVs and broader testing is a cost-effective way to identify patients (and their family members) with PVs. Here we assess the efficacy of multiple international testing guidelines in identifying breast cancer patients with clinically actionable PVs.

Methods:We reanalyzed a prospective cohort of breast cancer (BC) patients referred by their providers for multigene germline genetic testing (PMID: 30526229) 50% of which met U.S. testing criteria, by design. The is a cohort of U.S.-based patients, primarily Caucasian of Northern European ancestry. We applied testing guidelines from Australia, U.K. and 2 Canadian provinces (Ontario, British Columbia) to this cohort to determine their efficacy in selecting patients with PVs. These countries were chosen because of their single-payer healthcare model and their similar ethnic distribution to the U.S. Analysis focused on yield of PVs in high risk (&gt;4x risk compared to general population) breast/ovarian (BC/OV) cancer genes.

Results:Table 1 displays the distribution of in criteria (IC) vs. out of criteria (OOC) patients by country/testing criteria. Over 75% of patients in each country/province analyzed were OOC. Rates of PVs were similar between IC and OOC patients across countries. Existing Canadian, Australian and U.K. criteria missed up to 30% of patients with high risk PVs (Table 1). The majority (&gt;80%) of PVs in OOC patients were in genes with published management guidelines.

Conclusions:In our cohort, select ex-U.S. testing criteria identified &lt;30% of patients with PVs, while almost half of OOC patients harbored clinically relevant, potentially actionable mutations. These data suggest expanding certain international testing criteria would allow better identification and improved management for many patients diagnosed with breast cancer across the globe, and their families via cascade testing. This study also suggests additional research is needed to evaluate the efficacy of additional provincial and international criteria, including cost-effectiveness analyses, to inform future guideline updates.

Table 1. Findings in IC vs. OOC patientsOverallIn criteria Out of criteriaCountry/providenceGuidelineTotal n of cohortIC (% of total cohort)OOC (% of total cohort)Total PV IC (% of IC cohort)Total PV OOC (% of OOC cohort)High risk^ PVs (% of total PVs)High risk^ PVs (% of total PVs)U.S.NCCN953473 (49.6)480 (50.4)43 (9.1)40 (8.3)22 (26.5)8 (9.6)OntarioMOHLTC953210 (22.0)743 (78.0)18 (8.6)65 (8.7)5 (6.0)25 (30.1)B.C.BCHCP953203 (21.3)750 (78.7)24 (11.8)59 (7.9)9 (10.8)19 (22.9)AustraliaeviQ953180 (18.9)773 (81.1)19 (10.6)64 (8.3)12 (14.5)18 (21.7)U.K.NICE*826**127 (14.7)736 (85.3)11 (8.7)64 (8.7)6 (7.2)22 (26.5)US, United States; B.C., British Columbia; UK, United KingdomNCCN, National Comprehensive Cancer Network v. 2017MOHLTC, Ministry of Health and Long Term Care BCHCP, BC Provincial Health Services Authority Hereditary Cancer Program NICE, National Institute for Health Care Excellence*testing eligibility requires &gt;10% BRCA mutation detection rate, typically assessed by BOADICEA model in the UK but for this cohort risk estimates were only available via BRCAPro ** BRCAPro scores were not available for the full cohort ^Includes BRCA1, BRCA2, PALB2, TP53, RAD51C, RAD51D, MSH6

Citation Format: Sarah M Nielsen, Peter Beitsch, Pat Whitworth, Emily Decker, Natalie Rickers, Hana Sroka, Alekhya Narravula, Ed D Esplin, Robert L. Nussbaum. Pathogenic variants in hereditary cancer syndrome genes are prevalent among breast cancer patients not meeting various ex-U.S. genetic testing guidelines [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-14.