Abstract P2-09-04: Implementation of next generation cancer gene panel testing in a large HMO
Authors: Haque R , Alvarado M , Ahmed SA , Chung J , Tiller GE 
Published: May 2016

Abstract
Background: Next generation cancer gene panel testing is fairly new in clinical practice. Little is known about the diagnostic yield of multigene cancer panel testing in community based hospitals.
Objective: To describe characteristics of a diverse cohort who underwent high/moderate risk multigene panel testing for either a personal or a family history of cancer in a large health plan, and report the proportion of pathogenic/likely pathogenic variants (PV/LPV) and variants of unknown clinical significance (VUS) by race/ethnicity.
Methods: Subjects included all 586 female patients who were referred for genetic counseling and underwent multigene panel testing between July 2014 and January 2015. Based on a literature review, the custom-designed high/moderate risk gene panel included 20 cancer susceptibility genes (described below). All tests were performed by the same commercial laboratory (GeneDx).
Results: Of the 586 women, 78 (13.3%) tested positive PV/LPV316 (53.9%) tested negative; and 192 (32.8%) carried one or more VUS. Age at testing ranged from 22-81 years (median 50 years). More women with PV/LPV results tended to be obese than those who tested negative (39.7% vs. 31.2%), and had greater comorbidity (Charlson Index of &gt;3, 35.9% vs. 33.2%).
Of 586 women, 305 (52.0%) had a cancer diagnosis, mainly first primary breast cancer (n=290, 95.1%), while some also had a second primary breast cancer (n=67, 11.4%). Of the 305 women with cancer, 131 (42.9%) were diagnosed prior to the multigene testing implementation (1987-2013), while 174 (57.1%) were diagnosed after implementation.
The cohort was diverse in terms of race/ethnicity: Western/Northern European (31.2%), Latina/Caribbean (30.0%), Asian (14.8%), African-American (7.2%), Ashkenazi Jewish (6.3%), Native American (5.9%), and other (14.9%) (percent exceeds 100% due to mixed race/ethnicity). Of the 192 women who carried a VUS, 60.4% were Western/Northern European, and 46.4% were Latina/Caribbean. Pathogenic or likely pathogenic mutations were higher in Latina /Caribbean women (37.2%), followed by Western/Northern European (26.7%), and African (10.3%). We identified a total of 84 pathogenic mutations among the 78 women with PV/LPV in the following genes: BRCA1 (n=22), BRCA2 (n=17), MUTYH (n=16; all heterozygous), CHEK2 (n=9), ATM (n=4), PALB2 (n=4), PMS2 (n=3), MLH1 (n=2), VHL (n=2), and one mutation in each of the following genes: APC, CDH1, PTEN, TP53, and STK11. VUS were detected in 192 patients (32.7%) of the 586 tested. VUS in ATM (n=57), APC (n=32) and CHEK2 (n=25) comprised 59.4% of all VUS detected.
Discussion: The large percent of VUS was surprising, given that our panel included only high/moderate risk cancer genes. The over-representation of BRCA1/2 among all mutations (45.1%) likely reflected a greater proportion of patients referred for genetic counseling with a personal and/or family breast cancer history. Given that 35% of our positive results were dominant-acting pathogenic or suspected pathogenic mutations, our results suggest that multigene cancer panel testing is an appropriate method for detecting germline mutations in a high-risk cohort in a managed care setting.
Citation Format: Haque R, Alvarado M, Ahmed SA, Chung J, Tiller GE. Implementation of next generation cancer gene panel testing in a large HMO. [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 P2-09-04.