Abstract P6-06-01: The changing paradigm of hereditary cancer testing: Comparison of tests in 497 women with breast cancer evaluated at an NCI designated cancer center

The Hereditary Cancer Program at Vanderbilt-Ingram Cancer Center (VICC) was established in mid-2012 and provides cancer genetic services to patients and family members who are at risk for family cancer syndromes. During this time, the testing paradigm has markedly shifted from testing a small number of genes to a larger multi-gene set. HYPOTHESIS AND METHODS: We hypothesized that multi-gene testing would identify a higher rate of pathogenic mutations in breast cancer patients than the standard BRCA1/2 testing paradigm. To test this notion, we examined the records of 641 women with breast cancer seen in our clinic from July 2012 through Dec 2014 and tabulated the test outcome in women tested for BRCA1/2 only and women who had multi-gene panels. Patient characteristics were compared between the two groups. RESULTS: Excluding 17 (3%) women with a known familial mutation and the 127 (20%) women who did not proceed with testing, 497 women had usual Sanger BRCA1/2 (189; 38%) or a multi-gene NGS testing (308; 62%). 40 (13%) women were found to have a pathogenic mutation using the multi-gene panel compared to 13 (6%) women who had a restricted BRCA1/2 sequencing (P=0.035, Fishers Exact Test). The 13 women with Sanger BRCA1/2 were younger at diagnosis (40.6 vs 48 yrs) and more likely to have triple negative (TN) disease (38% vs 18%) compared to the 40 women diagnosed with multi-gene panels. TN disease was not confined to BRCA1 carriers, however, as 3 of 7 TN patients had a mutation in BRCA2, PALB2, and ATM, respectively. Thus, 29% (2/7) of our triple negative patients would not have been identified without multi-gene panels. In addition to BRCA1 (6; 15%) and BRCA2 (5; 12.5%), 6 women had mutations in ATM (15%), 7 in CHEK2 (17.5%), 6 in MUTYH (15%), 4 in PALB2 (10%), 2 in TP53 (5%), and 1 each in FANCC, PMS2, RAD51D and XRCC2 (2.5% each). 105 patients (35%) who did not have a deleterious mutation on a multi-gene panel were found to have one or more variants of uncertain significance (VUS) compared to 4 patients who underwent BRCA1/2 testing alone (4/189; 2%). There was a significant difference between providers when ordering hereditary cancer testing, with MD or NP ordering panel testing at a greater rate compared to Genetic Counselors (72% vs 53%; P CONCLUSION: We have examined the outcomes of genetic tests for 497 women with breast cancer during a time of great change in the approach to testing. Our study supports the paradigm that multi-gene panels will identify additional pathogenic mutations in genes other than BRCA1/2, which could increase clinical efficiency and improve patient outcomes. However, our study also found a high VUS rate in this group of patients, which will require additional clinical time to track for potential changes in pathogenicity. Future studies will focus on potential differences in management for patients found to have alterations on multi-gene tests. Citation Format: Wiesner GL, Lewis S, Holt J, Morgan RH, Riddle DA, Trump SA, McReynolds K. The changing paradigm of hereditary cancer testing: Comparison of tests in 497 women with breast cancer evaluated at an NCI designated cancer center. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-06-01.