Abstract PS5-01-05: Unraveling KAdcyla (Trastuzumab emtansine; T-DM1) resistance in HER2+ advanced breast cancer geicam/2017-04-KATIA study: biomarker analyses

Abstract Background: T-DM1 remains a relevant therapeutic option for patients with HER2-positive metastatic breast cancer (HER2+ MBC), particularly for those who have previously received trastuzumab and taxane-based therapies. However, despite its clinical utility, the mechanisms underlying both primary and acquired resistance to T-DM1 remain largely uncharacterized, limiting the ability to optimize treatment strategies and identify patients most likely to benefit from this therapy. The aim was to characterize the mechanisms of resistance to T-DM1 in the KATIA study. Methods: The KATIA study (NCT03829306) was a prospective, multicenter study in progressive/recurrent HER2+ MBC patients treated with second-line T-DM1. Tumor and plasma samples were collected from 32 (100%) patients. Genomic profiling was performed on pre-treatment baseline (BL) metastatic tumors (n=18, 56%), and on liquid biopsies at BL (n=20, 62,5%) and at disease progression (n=12, 37,5%) using the FoundationOne CDx and FoundationOne liquid CDx assays (324-gene NGS panels; Foundation Medicine). Additionally, we analyzed a 77-gene NGS panel on circulating tumor DNA (AVENIO ctDNA Expanded Kit V2, Roche, n=31, 97%). HER2, Ki67, Estrogen and Progesterone Receptors (ER and PR) status and the tumor immune microenvironment markers (PD-L1, PD1, CD3, CD8, tumor-infiltrating lymphocytes) were analyzed on BL tumors (n=26, 81%) by immunohistochemistry (IHC). The Kaplan-Meier method estimated median progression free survival (PFS) and overall survival (OS). Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models and the p-values adjusted for multiple comparisons by the Bonferroni method. Results: Tumor BL mutations in CCDN1, FGF4 or FGF19 predicted better mPFS (CCDN1: 8.61 vs. 3.65 m., HR 0.19; 95% CI 0.04-0.92, p=0.039; FGF4: 8.77 vs. 3.84 m., HR 0.1; 95% CI 0.01-0.79, p=0.0298; FGF19: 8.61 vs. 3.65m., HR 0.19; 95% CI 0.04-0.92, p=0.039). On the contrary, GNAS mutations showed a trend towards worse mOS (6.67 vs. 17.45 m., HR 4.63; 95% CI 0.42-51.09, p=1). Tumor burden ctDNA analyses revealed that the presence of ≥3 BL mutations showed a trend towards worse mOS (14.23 vs. 22.87 m., HR 2.85; 95% CI 0.91-10.01, p=0.1032). BL ctDNA mutations in PIK3CA/TP53 (the most frequent mutated genes) also showed a trend towards worse mOS (14.55 vs. 22.87 m., HR 4.78; 95% CI 0.56-40.89, p=1), as well as mutations detected in the following signaling pathways: receptor tyrosine kinases (RTKs: 14.55 vs. 22.87 m., HR 3.15; 95% CI 0.62-16, p=1) and DNA damage response/TP53 (DDR/TP53: 14.55 vs. 22.87 m., HR 4.98; 95% CI 0.59-42.32, p=1). Similar results were observed for mutations detected in these pathways at the time of disease progression. Conclusions: Baseline tumor mutations in CCDN1, FGF4 or FGF19 genes were significantly associated with longer PFS in HER2+ MBC patients treated with second line T-DM1, suggesting their potential role as predictive biomarkers of treatment benefit. Citation Format: J. Albanell, J. García-Sáenz, B. Bermejo, A. Stradella, Y. Izarzugaza, A. Barnadas, E. Alba, J. Alonso-Romero, S. López-Tarruella, F. Henao-Carrasco, S. Zazo, F. Moreno, M. Martínez-Martínez, A. Vethencourt, H. Callata-Carhuapoma, J. Herranz, R. Caballero, M. Portela, F. Rojo. Unraveling KAdcyla (Trastuzumab emtansine; T-DM1) resistance in HER2+ advanced breast cancer geicam/2017-04-KATIA study: biomarker analyses [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-05.