Abstract P4-06-02: Germline analysis of breast cancer patients with abnormal somatic results: Ancillary assessment or critical co-diagnostic?
Authors: Blanco AM , Yang S , Michalski ST , Ouyang K , Hamlington B , Fulbright J , Erhard K , Kang HC , Jacobs M , Koptiuch C , Vig H , Silver E , Benson C , Massingham L , Lincoln SE , Nussbaum RL , Hampel H , Esplin ED 
Published: February 2018

Abstract
Background: Tumor genetic testing (TGT) is increasingly used for planning cancer treatment and identifying appropriate clinical trials. Emerging literature shows that 4–12% of genetic variants identified on TGT are also present in the germline, conferring hereditary cancer risk. Germline genetic testing (GGT) guidelines were recently expanded to include the identification of a BRCA1/BRCA2 variant on TGT as an indication for germline analysis. We evaluated the diagnostic yield of current GGT guidelines by assessing the rate of pathogenic and likely pathogenic (P/LP) germline findings in a series of patients who had a variant identified on TGT and underwent GGT. Methods: We analyzed de-identified data from 185 sequential patients with various tumor types who had TGT and GGT. Personal and family histories were compared to all available NCCN guidelines for GGT. Results: Sixty-four of 185 patients (34.6%) had at least one P/LP germline variant, and among these patients, 42% (27/64) had variants in BRCA1/BRCA2. Variants in all but one patient (26/27) were also found on TGT. Fourteen of 27 (52%) patients had a personal diagnosis of cancer not typically associated with BRCA1/BRCA2, including colorectal (5), lung (3), and one each of cervical, cholangiocarcinoma, gastric, thymus, thyroid, and uterine. Furthermore, prior TGT results were the only reason GGT guidelines were met in 12 of 27 (44%) patients with germline BRCA1/BRCA2 variants. Among 34 patients with a personal history of breast or ovarian cancer, a P/LP germline variant was identified in nine (26%); the majority (5 of 9) were in non-BRCA1/BRCA2 genes including CDKN2A (1), FANCA (1), MUTYH (1), and PALB2 (2). Notably, the patient with the CDKN2A variant did not meet current breast cancer guidelines for GGT, and one patient with breast cancer and a germline BRCA2 mutation only met GGT guidelines due to prior TGT results. Discussion: Genetic testing guidelines have begun to reflect the opportunity for TGT to identify families at risk for hereditary cancer. Expanding GGT criteria to include TGT results is critical for capturing patients who may not otherwise receive GGT. Our data showed a substantial diagnostic yield in patients—including those with breast or ovarian cancer—who completed GGT after variant identification on TGT. Although current genetic testing guidelines capture the portion of these patients with a BRCA1/BRCA2 mutation identified with TGT, our data suggest that P/LP variants in other genes should also be considered during the evaluation of TGT results for subsequent GTG. Finally, the broad spectrum of tumor types with BRCA1/BRCA2 P/LP variants emphasizes the need for all clinicians, regardless of subspecialty, to be aware of current GTG recommendations when TGT identifies a BRCA1/BRCA2 variant and the potential implications of GTG, including targeted therapy, screening, prevention, and family testing.
Citation Format: Blanco AM, Yang S, Michalski ST, Ouyang K, Hamlington B, Fulbright J, Erhard K, Kang HC, Jacobs M, Koptiuch C, Vig H, Silver E, Benson C, Massingham L, Lincoln SE, Nussbaum RL, Hampel H, Esplin ED. Germline analysis of breast cancer patients with abnormal somatic results: Ancillary assessment or critical co-diagnostic? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-02.