Caris Life Sciences® (NASDAQ: CAI), a leading AI-powered precision medicine company, has published a groundbreaking study in npj Breast Cancer titled, “Mechanisms of Resistance to Trastuzumab Deruxtecan in Breast Cancer Elucidated by Multiomic Molecular Profiling.” The research leverages large-scale real-world clinico-genomic data and Caris’s comprehensive multiomic profiling to reveal clinically relevant mechanisms of resistance to trastuzumab deruxtecan (T-DXd) in metastatic breast cancer, offering new insights into why patient responses vary and how resistance evolves over time.
T-DXd, an FDA-approved antibody–drug conjugate for HER2-positive and HER2-low metastatic breast cancer, often encounters resistance, leaving a critical knowledge gap in treatment outcomes. Caris scientists addressed this gap by combining real-world clinical data with detailed molecular profiling, including whole exome sequencing (WES) and whole transcriptome sequencing (WTS), enabling a population-level analysis of resistance pathways across DNA, RNA, and protein expression.
“In this large real-world analysis, clinical outcomes allowed Caris to pinpoint molecular features linked to treatment-specific survival,” said George W. Sledge, Jr., MD, Caris EVP and Chief Medical Officer. “Post-treatment molecular shifts reveal biologically plausible routes to acquired resistance, showing that RNA-level and multiomic profiling can provide actionable insights beyond standard HER2 classification to better stratify patients and guide therapies.”
The study examined 2,799 breast cancer patients treated with T-DXd. WTS analysis identified ERBB2 (HER2) and ABCC1 as the strongest transcriptomic predictors of T-DXd-specific overall survival. Higher ERBB2 expression was associated with improved outcomes, while higher ABCC1 expression correlated with poorer outcomes, regardless of HER2 status.
ABCC1 also demonstrated predictive value within HER2-defined subgroups. Post-treatment samples showed increased ABCC1 expression along with enriched mutations in ERBB2, NFE2L2, KEAP1, and TOP1, consistent with mechanisms of acquired resistance. Preclinical models further confirmed a functional role for ABCC1-mediated drug efflux in T-DXd resistance.
“This study demonstrates how population-scale, multiomic real-world data can drive high-impact translational discoveries,” said David Spetzler, MS, PhD, MBA, Caris President. “It reinforces the value proposition for patients and provides biopharma with actionable insights into resistance biology to guide next-generation drug development.”
About Caris Life Sciences
Caris Life Sciences® is a patient-centric AI TechBio company and precision medicine pioneer focused on transforming healthcare through comprehensive molecular profiling and advanced AI-driven analysis. By integrating whole exome and transcriptome sequencing with large-scale clinico-genomic datasets, Caris provides insights to improve early detection, diagnosis, therapy selection, and drug development. Headquartered in Irving, Texas, Caris has offices in Phoenix, New York, Cambridge (MA), Tokyo, and Basel, serving patients and partners globally.
