Abstract PO5-13-02: BRCA mutational profiles of endocrine-resistant breast cancer

Abstract Background Around 75% of breast cancer (BC) patients have tumors expressing the treatment-predictive biomarker estrogen receptor α (ER) and are consequently offered endocrine therapy. One-third of these patients develop endocrine resistance, a majority with tumors that retain ER expression. For most cases, the resistance mechanism is still unknown, but mutational activity is a suggested mechanism. Germline BRCA mutations are well-known in BC and are found in approximately 23% of patients with triple-negative BC and in 5% of patients with ER+ BC. However, less is certain about the somatic variants, though studies have shown prevalences of around 3% in BC. This study aimed to examine the somatic BRCA mutational profiles of endocrine-resistant paired primary and relapse tumors. Methods A retrospective cohort of verified endocrine-resistant BC patients was collected at Karolinska University Hospital in Stockholm, Sweden. Patients diagnosed in 2008-2012 with an ER+ and human epidermal growth factor receptor 2 (HER2) negative primary tumor and a following ER+ and HER2- relapse tumor within five years of ongoing endocrine therapy were included (N=63). DNA was extracted from archived formalin-fixed paraffin-embedded relapse and primary tumor tissue and analyzed by panel sequencing. Tumor-free lymph nodes were used as germline normal samples. Results The analysis showed somatic BRCA mutational activity in 38.1% of the patients. Variants were present in 20.3% of primary tumors and 30.4% of relapse tumors. BRCA1 mutations were present in 11.9% of primary tumors and 21.4% of relapse tumors. BRCA2 variations were, in turn, seen in 11.9% of primary tumors and 14.3% of relapse tumors. The frequency of patients that had alterations in both the primary and relapse tumors was 3.2% for BRCA1 and BRCA2 respectively. Conclusion This study of a unique endocrine-resistant BC cohort shows a high presence and varying distribution of somatic BRCA mutations in both primary and even higher in relapse tumors. These results suggest that mutational testing for possible further treatment decisions may be relevant for patients exhibiting endocrine resistance, especially in the advanced setting. Citation Format: Emelie Karlsson, Caroline Schagerholm, Stephanie Robertson, Hosein Toosi, Emmanouil Sifakis, Johan Hartman. BRCA mutational profiles of endocrine-resistant breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-02.