Overall survival by genomic profile in HER2-positive (HER2+) metastatic breast cancer (mBC): A large US clinico-genomic database study.

1045 Background: Over the past few years, the landscape of treatment for HER2+ breast cancer has evolved significantly. Multiple active 1L treatment options have emerged, including T-DXd plus pertuzumab, maintenance palbociclib or tucatinib, providing an opportunity to tailor treatment according to the disease profile. This study aims to describe real-world treatment patterns and evaluate overall survival (OS) in a modern cohort of patients with HER2+ mBC, with sub-analysis by genetic profile of the disease. Methods: This retrospective study used the Flatiron Clinico-Genomic database (CGDB), where each patient received at least one Foundation Medicine next generation sequencing (NGS) test along the course of disease. Adults (≥18 years) diagnosed with HER2+ mBC between 1 January 2018 and 31 March 2024 (one year prior to the data cutoff) were included. OS was examined using the Kaplan-Meier method, with descriptive analyses by genetic alteration. Results: Among 7,933 mBC patients who underwent NGS profiling, 732 (9.2%) patients with HER2+ mBC were included. The median age at diagnosis was 59 years (range: 23-85); 68.3% had hormone receptor positive disease, and 37% had de novo mBC. Patients received a median of 3 lines of therapy (range: 1–14). The use of anti-HER2 antibodies ranged from 59.4% to 33.6% across 1L through 5L. Trastuzumab deruxtecan was prescribed more often in later lines (23.9% for 3L, 19.6% for 4L, and 23.0% for 5L) compared to 2L and 1L (11.3% and 4.2%). Similarly, the use of anti-HER2 tyrosine kinase inhibitors increased in later lines. The median (95% CI) OS for the entire population was 48 (41.6-53.1) months, with notable differences based on the detection of key genetic alterations. Patients with mutations in DNMT3A (14.2%), ARID1A (11.9%), MLL2 (10.9%), and CHEK2 (9%) had numerically longer mOS (64 49.5-NE, 51.4 35.8-69.4, 51.4 36.1-68.9, 51.4 40.1-NE months, respectively) while patients with mutations in BRCA1 (6.6%), CDH1 (10.9%), BRCA2 (10.9%), PIK3CA (37.4%), TP53 (59.6%), ERBB2 (11.5%), and ATM (12.7%) experienced numerically shorter mOS (36 25.0-56.3, 40.1 28.0-70.1, 40.1 34.1-62.5, 40.1 35.2-46.9, 40.6 35.9-48.7, 43.3 36.2-58.9, 44.3 36.5-62.8 months, respectively). Conclusions: The present study provides key insights into clinico-genomic characteristics, modern treatment patterns and OS for HER2+ mBC patients in the US. Although survival was 4 years in the overall cohort, patients with mutations in key DNA repair genes (BRCA1, BRCA2, ATM, TP53), in CDH1, PIK3CA or ERBB2 experienced a numerically worse prognosis, representing key unmet needs for drug development.