Association between HER family expression and clinical outcomes with trastuzumab deruxtecan (T-DXd) in patients with hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC).

1030 Background: T-DXd improves outcomes in HR+/HER2- mBC, yet response remains heterogeneous. Treatment selection is based on HER2 IHC. Preclinical models suggest signaling from HER family dimerization partners like EGFR drive resistance; specifically, EGFR overexpression impairs T-DXd internalization by favoring EGFR/HER2 heterodimerization. Because clinical data linking HER dimerization partners to T-DXd outcomes are limited, investigation is warranted to understand how expression of these partners may serve as predictive biomarkers. Methods: The Tempus Lens Platform was used to identify and analyze a cohort of patients (pts) with HR+/HER2- mBC treated with T-DXd (n = 224) and sacituzumab govitecan (SG) (n = 81, comparator) who underwent RNA (Tempus xR) and DNA (Tempus xT) sequencing within one year of treatment initiation. HER family gene expression ( EGFR/ERBB1, ERBB2/3/4 ) was quantified as transcripts per million (TPM) and reported as log2(TPM+1). High vs low groups were defined using median expression. Median real-world time to next treatment (rwTTNT) with T-DXd and real-world overall survival (rwOS) were calculated using Kaplan–Meier curves and compared using log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazards models. Results: The cohort (n = 305) had a median age of 60; 83% of pts’ race was reported as White, 9.6% Black or African American, 2.7% Asian, 7.6% Hispanic or Latino, and 4.3% unknown. Median HER family gene expression values were: ERBB1 ( EGFR ): 3.92; ERBB2 7.75; ERBB3 7.65; ERBB4 4.72. EGFR RNA expression was negatively correlated with ERBB2/3/4 (p < 0.0001). ERBB2/3/4 RNA expression was positively correlated with one another (p < 0.0001). Among pts treated with T-DXd, the EGFR -high group had shorter median rwTTNT (7.76 vs 13.25 months; HR = 2.17 95% CI 1.42-3.34, p < 0.001) and rwOS (13.71 vs 22.55 months, HR = 2.21; 95% CI 1.50-3.24, p < 0.001) compared to the EGFR -low group. In contrast, increased RNA expression of other HER family members was not associated with a significant difference in rwTTNT or rwOS. Among pts treated with SG, the EGFR -high group did not have significantly different rwTTNT (median 4.34 vs 5.56 months; HR = 1.30 95% CI 0.72-2.36, p = 0.4) or rwOS (median 14.47 vs 11.28 months; HR = 0.86, 95% CI 0.47-1.55, p = 0.6) compared with the EGFR -low group. Conclusions: Among pts with HR+/HER2- mBC treated with T-DXd, elevated EGFR , but not ERBB2/3/4 , RNA expression was associated with worse outcomes. EGFR overexpression did not modulate outcomes in pts treated with SG, highlighting a potential differential impact based on antibody target rather than payload. Further research is needed to confirm the utility of pre-treatment EGFR expression as a predictive biomarker for T-DXd treatment.