Abstract P6-08-01: Comparison of recommendations for germline genetic testing in an unselected cohort of patients with breast cancer
Authors: Yadav Siddhartha , Hu Chunling , Hart Steven N. , Boddicker Nicholas , Polley Eric C. , Na Jie , Gnanaolivu Rohan , Lee Kun Y. , Olson Janet E. , Ruddy Kathryn J. , Couch Fergus J. 
Published: March 2020

Abstract
Purpose:
To determine the sensitivity of germline hereditary cancer genetic testing recommendations for detection of pathogenic mutations in breast cancer predisposition genes in an unselected cohort of breast cancer patients.
Patients and Methods: The study population included patients enrolled in a prospective breast cancer registry after being seen at Mayo Clinic for newly diagnosed breast cancer between 2004 and 2016. All patients were subjected to germline mutation testing for 12 known breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53). Results from testing of all breast cancer patients according to American Society of Breast Surgeons (ASBrS) genetic testing recommendations and patients meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing, based on age at diagnosis and personal and family history of cancer, were compared.
Results: Among the 4516 patients in the cohort, the median age at diagnosis of breast cancer was 57 years, 80.5% had estrogen receptor positive tumors, and 43% had a family history of breast cancer. All patients in the cohort met ASBrS criteria for hereditary cancergenetic testing, 2050 (45.4%) met NCCN criteria, 1892 (41.9%) did not meet NCCN criteria, and 574 (12.7%) patients could not be fully evaluated for NCCN testing criteria due to missing data. The frequencies of pathogenic variants in the cohort are shown in Table 1. Patients meeting NCCN criteria were more likely to carry a pathogenic variant compared to those who did not (9.8% vs. 3.8%, p&lt;0.001, Table 1). However, 72 (26.5%) out of the 272 patients with mutations in 12 breast cancer predisposition genes and 15 (12.4%) out of 121 with mutations in BRCA1/2 were overlooked when NCCN selection criteria alone were applied.
When testing was expanded to include all patients with breast cancer diagnosed at age ≤65 and/or meeting NCCN testing criteria, only 20 (7.4%) out of 272 mutation carriers in 12 breast cancer genes and 2 (1.6%) out of 121 BRCA1/2 mutation carriers were overlooked. However, this increased the number tested to detect one mutation carrier on average from 17 to 25 for BRCA1/2 and from 9 to 12 for the 12 breast cancer predisposition genes. In total, this age cutoff led to an increase in the number of patients tested by 28% while the number of patients in the cohort that need not undergo germline genetic testing was 20%.
Conclusions: Although NCCN criteria for BRCA1/2 germline genetic testing detect the majority of predisposition gene mutation carriers, a significant number of carriers are missed in an unselected cohort of breast cancer patients using these criteria. Expanding the current NCCN criteria to include all women with breast cancer diagnosed ≤ 65 years of age, will substantially improve the sensitivity of mutation testing, without the need for evaluation of all breast cancer patients.
Table 1: Comparison of frequency of germline mutations between patients who met and did not meet NCCN guidelines for germline genetic testing#Total, Meets ASBrS guidelines N=3942Meets NCCN guidelines, N=2050Did not meet NCCN guidelines, N=1892P-value€ NCCN vs non-NCCNPercent mutation carriers missed by NCCN criteria* BRCA1/2121 (3.1%)106 (5.2%)15 (0.8%)&lt;0.00112.4%6 High risk genes$150 (3.8%)120 (5.8%)30 (1.6%)&lt;0.00120.0%12 Breast cancer genes:272 (6.9%)200 (9.8%)72 (3.8%)&lt;0.00126.5%ATM45 (1.1%)32 (1.56%)13 (0.69%)28.9%BARD16 (0.2%)5 (0.24%)1 (0.05%)16.7%BRCA158 (1.5%)53 (2.59%)5 (0.26%)8.6%BRCA263 (1.6%)53 (2.59%)10 (0.53%)15.9%CDH16 (0.2%)3 (0.15%)3 (0.16%)50.0%CHEK267 (1.7%)41 (2.00%)26 (1.36%)38.8%NF10 (0.0%)0 (0.00%)0 (0.00%)0.0%PALB216 (0.4%)7 (0.34%)9 (0.48%)56.3%PTEN1 (0.0%)1 (0.05%)0 (0.00%)0.0%RAD51C6 (0.2%)6 (0.29%)0 (0.00%)0.0%RAD51D4 (0.1%)2 (0.10%)2 (0.11%)50.0%TP537 (0.2%)3 (0.15%)4 (0.21%)57.1%#: Patients who did not meet NCCN criteria excluded from analysis$: BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53;€: Fisher exact test comparing frequency of germline mutations between those who met NCCN guidelines and those who did not;*: Denominators for percentages are the total mutation carriers in respective categories.
Citation Format: Siddhartha Yadav, Chunling Hu, Steven N. Hart, Nicholas Boddicker, Eric C. Polley, Jie Na, Rohan Gnanaolivu, Kun Y. Lee, Janet E. Olson, Kathryn J. Ruddy, Fergus J. Couch. Comparison of recommendations for germline genetic testing in an unselected cohort of patients with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-01.