Abstract P3-07-06: Guideline-based multi-gene panel (MGP) testing for germline pathogenic variants among patients diagnosed with breast cancer: Regional perspectives
Authors: Abdel-Razeq Hikmat , Almasri Rama , Abujamous Lama , Al-Masri Mahmoud , Allah Majd Hamed , Tamimi Faris , Edaily Sarah , Abuhijla Fawzi , Salama Osama , Abdulelah Hazem , Bater Rayan 
Published: March 2022

Background: Genetic testing and genetic counseling for patients with breast cancer are routinely practiced as recommended by many professional societies and international guidelines including the National Comprehensive Cancer Network (NCCN). In addition to its major impact on cancer prevention, knowledge generated may impact cancer management, too. In this study, we evaluate the prevalence and patterns of germline mutations among at-risk breast cancer patients using commercially available next generation sequencing (NGS)-based multi-gene panel (MGP). Patients and Methods: Consecutive at-risk breast cancer patients, as recommended by the NCCN guidelines, were offered genetic testing using a 20-gene NGS-based panel performed at a reference genetic lab. Prior to testing, patients underwent extensive counseling by one of the investigators or their primary oncologist. Genetic variants were classified as benign or likely benign (negative), pathogenic or likely pathogenic (positive) or variants of uncertain significance (VUS). Clinical and pathological data were obtained from patients’ medical records, and detailed familial lineage for three generations was obtained by a cancer genetic counselor. Results: Between November 2019 and March 2021, a total of 714 patients were enrolled, the median age (range) was 39 (19-78) years. Among the whole group, 91 (12.7%) patients had pathogenic/likely pathogenic variants, mostly in BRCA1 and BRCA2 (n=50, 54.9%). However, 41 (45.1%) had pathogenic variants in genes other than BRCA1 or BRCA2; mostly in TP53, PALB2, CHECK2, BRIP2, ATM and MSH6.Mutation rates were significantly higher among a group of 182 women diagnosed at any age, with one or more close relatives with breast cancer (18.7% compared to 10.7%, p=0.007), and among 287 younger patients (diagnosed at age ≤ 50 years) with one or more close relatives with breast, ovarian, pancreatic, or prostate cancer (Gleason score ≥7); 17.1% vs. 9.8%, p=0.008. Additionally, patients with triple-negative disease (n=92) had higher pathogenic mutations; 17.4% vs. 12.1%, p=0.03. Variants of uncertain significance (VUS) were observed among 213 (29.8%) and majority (n=160, 75.1%) were in genes other than BRCA1 or BRCA2. Conclusions: Pathogenic mutations in genes other than BRCA1 or BRCA2 are relatively common and could have been missed, if genetic testing was restricted to BRCA1 or BRCA2. Patients with triple-negative disease and those with additional positive family history, have the highest mutation rates. On the other hand, expanding genetic testing using MGP resulted in a significantly higher rate of VUS, a finding that may increase the anxiety of patients and physicians, alike.

Citation Format: Hikmat Abdel-Razeq, Rama Almasri, Lama Abujamous, Mahmoud Al-Masri, Majd Hamed Allah, Faris Tamimi, Sarah Edaily, Fawzi Abuhijla, Osama Salama, Hazem Abdulelah, Rayan Bater. Guideline-based multi-gene panel (MGP) testing for germline pathogenic variants among patients diagnosed with breast cancer: Regional perspectives [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-06.