Abstract P4-02-24: Frequency of HER2-low status among patients with breast cancer and germline BRCA1/2 pathogenic variants

Abstract

Abstract Background: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has significantly improved survival outcomes among breast cancer (BC) patients with low expression of HER2 (HER2-low) as determined by immunohistochemistry. Since then, understanding the frequency of this condition in different scenarios became relevant to guide therapeutic strategies. In sporadic BC, around 60% of hormone receptor (HR) positive and 30% of HR negative tumors are classified as HER2-low. BRCA1/2-mutated breast cancers have distinct biology, with an enrichment of triple-negative breast cancer in patients with germline BRCA1 pathogenic variants (PVs), while luminal B-like tumors are common in those with germline BRCA2. Given these particularities, the objective of the study was to evaluate the frequency of HER2-low status among BC patients carrying germline BRCA1/2 (gBRCA1/2) PVs. Methods: An observational study was conducted to evaluate patients with a germline BRCA1/2 PVs diagnosed with breast cancer. Patients were treated between 1995 and 2024 in three oncologic centers. Electronic records and pathology reports were reviewed to collect data on demographic, clinic and pathologic features. HER2-low status was defined as immunohistochemistry +1 or +2 with a negative in-situ hybridization. Results: Ninety-three patients with breast cancer and a germline BRCA1/2 pathogenic variant were identified, with 59 having a BRCA1 PV (63.4%) and 34 a BRCA2 PV (36.5%). Triple-negative breast cancer occurred in 47% of the cases, while 44% were hormone receptor-positive HER2-negative. Only two patients had HER2-positive breast cancer. The median age at diagnosis was 40 years (18.5 - 69.2 years), and the majority of the patients had early-stage tumors (10.7% stage I, 47.3% stage II, 20.4% stage III), with only three patients with stage IV disease. The most frequent histological type was ductal carcinoma (82%), followed by lobular carcinoma (9%); histological grade 3 was observed in 61% of the cases. Among patients with triple-negative breast cancer, 17.8% of the tumors were HER2-low. Among those with hormone receptor-positive HER2-negative breast cancer, the proportion of HER2-low was 29.0%. Overall, HER2-low status was present in 19.4% and 26.9% of the BC from germline BRCA1 and BRCA2 PVs carriers, respectively. Conclusion: The HER2-low status occurred in a lower proportion in BRCA1/2-mutated BC patients in this cohort, compared to what was previously described in the literature for sporadic BC patient, both in HR negative and HR positive tumors. Additional studies are required to understand particularities of hereditary tumors in terms of the frequency of HER2-low status when samples of multiple tumor sites are evaluated as well as the frequency of HER2-ultralow since these conditions can also guide the use of targeted therapy with T-DXd. Citation Format: Ana Maria Ulbricht Gomes, Luciana Auresco, Renata Colombo Bonadio, Graziela Zibetti Dal Molin, Benedito Mauro Rossi, Debora de Melo Gagliato Jardim, Vanessa Petry, Laura Testa, Allyne Queiros Carneiro Cagnacci, Jennifer Thalita Targino dos Santos, Maria del Pilar Estevez-Diz, Rodrigo Guindalini. Frequency of HER2-low status among patients with breast cancer and germline BRCA1/2 pathogenic variants [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-02-24.