Abstract P3-07-02: Identification of potential germline variants (GV) on tumor comprehensive genomic profiling (CGP) in patients with advanced breast cancer (BC): BRCA1/2 and beyond
Authors: Tierno Marni B , Dougherty Kali C , Gornstein Erica , Pavlick Dean C , Schrock Alexa , Oxnard Geoff R 
Published: March 2022

Background Detection of pathogenic GVs in patients with BC has implications for both patients and their family members. Management options such as increased surveillance, chemoprevention, and surgical prophylaxis are available to GV carriers. Beyond BRCA1/2, GVs in the cancer susceptibility genes (CSGs) PALB2, ATM, and CHEK2 confer a 2-11-fold lifetime risk of BC. One opportunity CGP assays present is the potential to detect clinically-relevant GVs in addition to targetable somatic variants. While the Breast Cancer Association Consortium found that 5.2% of women with BC carried a GV in one of these five CSGs, we sought to describe the frequency of these potential GVs detected by CGP in a cohort of patients with advanced disease. Methods We reviewed an internal database of patients with advanced BC who underwent testing with a CGP panel using tissue (n= 20,109, FoundationOne® CDx) or plasma (n= 4,182, FoundationOne®Liquid CDx or FoundationOne®Liquid). Cases with a potential GV were identified by filtering base substitutions and short indels for inclusion in ClinVar as pathogenic or likely pathogenic and by variant allele frequency (VAF) based on an optimized assay-specific threshold, focusing on the select CSGs of BRCA1/2, PALB2, ATM and CHEK2. To enable follow-up of potential GVs, we implemented a new reporting “banner” to highlight select short variants in these CSGs. Predominant patient ancestry was inferred using a SNP-based classifier and Fisher’s exact test was utilized for comparison between groups. Results A total of 24,291 unique patients with primarily advanced BC had CGP results available for study, with common actionable findings including PIK3CA mutations (8,572, 35.3%), ESR1 mutations (3,289, 13.5%), and HER2 amplification (1,602, 6.6%). Focusing on the 5 CSGs, 16.4% of patients (3,986) had at least one pathogenic alteration detected in BRCA2 (1,153, 4.7%), ATM (969, 4.0%), CHEK2 (982, 4.0%) BRCA1 (849, 3.5%) or PALB2 (308, 1.3%); 1.1% of patients (263) harbored alterations in multiple CSGs. 50.7% (2,020/3,986) of patients with pathogenic alterations in these CSGs - 8.3% (2,020/24,291) of total patients with advanced BC - had an alteration meeting criterion as a potential GV. Variants in BRCA1 (511/919, 55.6%), BRCA2 (786/1,425, 55.2%), and PALB2 (201/376, 53.5%), more frequently met criteria as potential GVs than variants in CHEK2 (328/1,046, 31.4%) or ATM (265/1,100, 24.1%). In these five CSGs, 1,796/3,195 alterations detected on tissue CGP (56.2%) and 295/1,671 detected in plasma (17.7%) met criteria as a potential GVs. Ancestry analysis of 20,108 assessable BC patients tested using tissue CGP showed potential GVs in CHEK2 were more common in European vs non-European (1.7% vs 0.4%, p&lt;0.01) and potential GVs in PALB2 were more common in African vs non-African (1.4% vs 0.7%, p&lt;0.01) ancestries. Of 1,961 patients with BC tested over a 2-month period, 9.7% of reports (191) included a germline banner reporting a potential GV in one of these 5 CSGs and recommending consideration of referral for germline testing. Conclusion Potential pathogenic GVs in BRCA1/2, PALB2, ATM and CHEK2 were identified in 8.3% of patients with advanced BC tested utilizing CGP when filtering by VAF and ClinVar annotation. Highlighting these potential GVs with a report banner provides the opportunity for follow-up germline testing and genetic counseling for patients who otherwise may not have been referred for additional testing. These alterations were detected in both tissue and plasma CGP and in patients of varying ancestries. The potential for detection of potential GVs plus the detection of actionable driver and resistance mechanisms may add to the clinical value of CGP for patients with breast cancer.

Citation Format: Marni B Tierno, Kali C Dougherty, Erica Gornstein, Dean C Pavlick, Alexa Schrock, Geoff R Oxnard. Identification of potential germline variants (GV) on tumor comprehensive genomic profiling (CGP) in patients with advanced breast cancer (BC): BRCA1/2 and beyond [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 P3-07-02.