Abstract P5-09-03: Expanded panel testing superior to BRCA1/2 and breast cancer panel in patients with breast cancer
Authors: Beitsch P , Whitworth P , Baron P , Rosen B , Compagnoni G , Simmons R , Smith LA , Holmes D , Brown E , Gold L , Clark P , Coomer C , Grady I , Barbosa K , Riley L , Kinney M , Lyons S , MacDonald H , Kahn S , Ruiz A , Patel R , Curcio L , Esplin E , Yang S , Michalski S 
Published: May 2019

Background: The testing of hereditary breast and ovarian cancer (HBOC) patients for BRCA1/2 only was established years ago to identify patients with clinically actionable variants and limit the economic burden. However, the cost of genetic testing has plummeted, and the number of breast cancer-risk genes with management guidelines has expanded. We created a community-based registry to test all breast cancer patients. A primary objective of this registry included accruing and comparing patients who did and did not meet NCCN guidelines and determining if providing all breast cancer patients with comprehensive multi-gene panel testing yields additional clinical value than testing BRCA1/2 alone.

Methods: An IRB-approved multicenter prospective registry was initiated with 20 community-based and academic breast sites, selected to insure geographic and ethnic diversity. Consecutive patients ages 18-90 with current or prior breast cancer were offered testing with an 80-gene panel (Invitae, San Francisco, CA). HIPAA-compliant case report forms collected patient diagnosis, test results, and physician recommendations made after test results.

Results: Over 1,000 patients were enrolled and data on 911 have been analyzed to date. Median age of patients is 60.5 (range 22 to 93). 56.0% were recently diagnosed with breast cancer. Of these patients, 50.54% met NCCN criteria, and 49.5% did not. 10.9% had history of a prior non-breast cancer. The pathogenic/likely pathogenic (P/LP) variant rate for patients on a comprehensive 80-gene panel was 8.9%. When restricted to a guidelines-based 11-gene breast cancer panel (BRCA1/2, ATM, CDH1, CHEK2, NBN, NF1, PTEN, STK11, TP53, PALB2), 4.9% had P/LP variants; when limited to BRCA1/2, 1.6% had P/LP variants. Of all patients with P/LP findings, 93% had variants in cancer-risk genes with established management recommendations (Table 1) and 80% had germline variants conferring eligibility for precision medicine-based cancer treatments, such as PARP inhibitors, through actively enrolling clinical trials.

Conclusions: This study demonstrates that comprehensive panel testing of breast cancer patients provides a higher yield of clinically actionable P/LP variants than BRCA1/2 testing alone. Limited panels may miss clinically relevant P/LP variants, leaving risk for preventable cancers undiscovered and unnecessarily restricting patients' treatment options. These results also suggest that variants in tumor suppressor genes, not previously thought related to breast cancer, may contribute to its etiology. A comprehensive panel strategy reveals untapped clinical utility and can impact breast cancer patient care by informing implementation of precision medicine treatment interventions and guiding long-term medical management and surveillance for patients and their family members.

 PatientsVariantsWith breast cancer management guidelines (including variants ATM*, BRCA1*, BRCA2*, CHEK2*, NBN*, NF1, PALB2*, TP53*)45 (56%)46 (55%)With cancer guidelines and clinical management implications (including variants BARD1*, FH, MITF, MSH6*, MUTYH*, PTCH1, RAD50*, RAD51C*, RAD51D*, RB1, RET, VHL)31 (38%)33 (39%)Evidence of actionability accruing (including variants BLM, DIS3L2, RECQL4)5 (6%)5 (6%)Totals8184*P/LP variants in these genes confer potential clinical trial eligibility, e.g. NCT02401347.

Citation Format: Beitsch P, Whitworth P, Baron P, Rosen B, Compagnoni G, Simmons R, Smith LA, Holmes D, Brown E, Gold L, Clark P, Coomer C, Grady I, Barbosa K, Riley L, Kinney M, Lyons S, MacDonald H, Kahn S, Ruiz A, Patel R, Curcio L, Esplin E, Yang S, Michalski S. Expanded panel testing superior to BRCA1/2 and breast cancer panel in patients with breast cancer [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 P5-09-03.