215P Impact of HER2 low on survival in patients treated with standard therapies in advanced breast cancer

Abstract

Breast cancer (BC) pioneered precision medicine with immunohistochemistry (IHC) defined subtypes and early advent of targeted therapies. Trastuzumab deruxtecan (T-DXd) has expanded traditional HER2 definitions to include HER2-low (H2L) tumors, defined as HER2 IHC score of 1+ (>10% cells stained), or as 2+ (>10%) and negative in-situ hybridization (ISH) assay. Studies suggest H2L BC is not a separate clinical entity, strongly determined by hormone receptor (HR) status. We sought to understand the impact of H2L on current standards of care (SOC). Retrospective analysis was performed on 24,824 advanced BC with available genomic, transcriptomic, subtyping, and treatment data. Tumors were tested at Caris Life Sciences via NextGen DNA Sequencing (592 gene panel or whole exome) and RNA (whole transcriptome). BC subtypes were defined by IHC/ISH per accepted definitions. PD-L1 was determined by IHC (SP142 immune cells [IC] ≥ 1%). CODEai, a real-world evidence database was used to access clinical outcomes from insurance claims data, with Kaplan–Meier estimates for overall survival (OS) and 95% CI calculated from time of first treatment to last contact. Patients with HR positive (HR+)/H2L tumors treated with CDK4/6 inhibitors (n=1,348) had similar OS compared to pts with HR+/HER2 0 (n=3,027; 1,179 vs 1,105 days; HR=0.89, CI 0.82–0.98, p=0.012). 27.2% of HR+/H2L pts had activating PIK3CA mutations. Among HR+ PIK3CA mutated tumors, H2L pts treated with alpelisib showed no difference in OS (n=27; 342 days) vs. HER2 0 alpelisib treated pts (n=42; 566 days, HR=1.23, CI 0.66 – 2.29, p=0.517), with limited sample size. 13.9% of H2L TNBC pts were PDL-1+. Pts with H2L PD-L1+ TNBC BC treated with immune checkpoint inhibitors (ICI; atezolizumab, pembrolizumab, nivolumab; n=49) showed improved OS vs. HER2 0 (n=233; 991 vs 524 days; HR=0.61, CI 0.37–0.99, p=0.046). HR+/H2L BC pts treated with SOC endocrine therapy demonstrate no difference in OS compared to HER2 0, and thus, should exhaust endocrine therapy options before initiating T-DXd or chemotherapy until indicated by prospective trials. Combinations of T-DXd plus ICI in PDL1+ H2L BC may be promising opportunities for further investigation.