Abstract 4620: Assessing the impact of germline and somatic variants in breast cancer treatment
Authors: Jonathan V. Wooten, Santiago Avila, Becca Pollard, Sheila Rajagopal
Journal: Cancer Research (2025)

Abstract Germline genetic variants are hereditary DNA alterations, whereas cancer somatic variants originate in the tumor. For patients with breast cancer, treatment approvals focus on either germline or somatic data with no consideration of co-occurrence. As such, most clinical datasets lack either germline or somatic variant designation, and most molecular oncology datasets contain limited treatment information, focusing primarily on survival. Datasets that contain germline and somatic sequencing and treatment information are typically from single institutions, limiting their statistical power. This project seeks to aggregate datasets inclusive of germline and somatic sequencing and treatment information with the goal of starting to assess the effect of co-occurring variants on treatment response in breast cancer. We reviewed breast cancer datasets in CBioPortal and papers published in the past 15 years for germline and somatic sequencing with reported variants, treatment information, and associated responses. We identified 3 datasets: The Cancer Genome Atlas, The Metastatic Breast Cancer Project, and Fudan University Shanghai Cancer Center (BC cohort). We evaluated a total of 7 co-occurring gene pairs obtained from literature review: BRCA1 and BRCA2; BRCA2 and RB1, BRCA1 or 2 and TP53, PTEN, PIK3CA, MYC; and PALB2 and NOTCH2. We used the NIH Integrated Data Analysis Platform to harmonize variant calls across these datasets. For early-stage disease, we assessed disease-free survival (DFS) in response to the classes of chemotherapy or hormone therapy. For metastatic disease, we assessed duration of treatment response for specific treatments. We were able to assess one gene pair using our dataset – BRCA1/2 and TP53. Other gene pairs had 0-2 patients with co-occurring variants, limiting statistical analysis. We observed statistically significant differences in DFS among early-stage patients who received chemotherapy (Kruskal-Wallis test: &amp;lt;0.05), but observed patients with BRCA1/2 alone having shorter DFS relative to those with TP53 regardless of co-occurrence:No variants (n=212): Mean=33.32 months (SD=26.7 months)BRCA1/2 alone (n=141): Mean=18.32 months (SD=13.91 months)Co-occurring (n=10): Mean=49.17 months (SD=38.14 months)TP53 alone (n=95): Mean=41.45 months (SD=31.88 months) In the context of treatment, significantly more publicly available, better annotated data will be required to understand the influence of co-occurring variants, germline origin, and somatic origin on treatment response. In this preliminary analysis, we observed differential patterns of changes in treatment response based on the presence or absence of BRCA1/2 and TP53. These genes commonly co-occur – where co-occurrence is less common, we lacked power for our analysis. This question is under-addressed and may potentially influence treatment response and decision-making. Citation Format: Jonathan V. Wooten, Santiago Avila, Becca Pollard, Sheila Rajagopal. Assessing the impact of germline and somatic variants in breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4620.