Abstract P4-03-02: Casting a wide net: Finding actionable results in non-breast cancer (BC) genes on multi-gene panel testing (MGPT) in a BC cohort
Authors: Culver S , Kipnis L , Stokes S , Bychkovsky B , Scheib R , Rana H , Garber J 
Published: May 2019

Background: MGPT for hereditary cancer syndromes allows for concurrent analysis of genes associated with many different cancer types. This may lead to the identification of unexpected mutations in genes with no BC link. The objective of this study was to examine the landscape of pathogenic mutations in a BC cohort who underwent MGPT, to assess if there was clinical suspicion for identified mutations and if the results would affect subjects' medical management.

Methods: Retrospective review of subjects with BC seen at a single institution who underwent MGPT from 1/1/15- 5/31/18 was conducted. MGPT was defined as testing of more than the 9 genes associated with BC (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53). Deidentified pedigrees were analyzed by genetic counselors to determine whether there was clinical suspicion of the presence of the mutations using national testing guidelines or clinical diagnostic criteria.

Results: Among 3044 subjects, 365 (12%) were found to have one pathogenic mutation in at least one cancer susceptibility gene. Subjects with mutations in APC I307K, moderate-penetrance BC genes (NBN, RAD50, BARD1), and MUTYH were excluded from further analysis. We identified 52 pathogenic mutations in genes not typically associated with risk for BC in 51 (2%) subjects (table 1). There was clinical suspicion for the identified mutation in 17 (33%).

Table 1:Non-BC gene mutation landscape Number of MutationsClinical Suspicion (%)Lynch syndrome117 (64%)MLH110MSH221MSH632PMS254Ovarian181 (6%)BRIP1*111RAD51C40RAD51D30SHDx62 (33%)SDHA*30SDHC*32Other156 (40%)FH10HOXB13*32MITF32NF142VHL40CDKN2A21 (50%)Total5217 (33%)*Contains individuals that also have a mutation in a BC susceptibility gene

Conclusion: Of 3044 BC patients who underwent MGPT, 2% were found to have a pathogenic gene mutation that would have been missed by a smaller BC gene panel. Medical or surgical management would be affected by the MGPT result in 86% of subjects. Only 6% of subjects with genetic risk for ovarian cancer had a family history of this disease. The single FH and 3 of 4 VHL mutations are only associated with disease in the biallelic state; these findings do not affect the subjects' care, but have implications for reproductive risk. The HOXB13 mutations were found in female subjects only, but would have implications for their male relatives. NF1 mutations are associated with BC risk, but were included in this analysis due to a historically distinct clinical phenotype. Only 50% of NF1+ subjects had a clinical diagnosis or family history of NF1. In all cases, cascade testing was offered to at-risk family members, allowing for cancer and reproductive risk stratification and management. This study demonstrates how comprehensive MGPT can provide a more complete and personalized cancer risk assessment for BC patients and their families.

Citation Format: Culver S, Kipnis L, Stokes S, Bychkovsky B, Scheib R, Rana H, Garber J. Casting a wide net: Finding actionable results in non-breast cancer (BC) genes on multi-gene panel testing (MGPT) in a BC cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-02.