Multiomic Real-World Data Predict Outcomes in Metastatic Breast Cancer

Large-scale clinico-genomic analysis has identified novel transcriptomic predictors of survival and mechanisms of acquired resistance in patients with metastatic breast cancer treated with the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). The study, published in npj Breast Cancer, suggests that multiomic profiling, including whole exome sequencing and whole transcriptome sequencing, offers prognostic value beyond standard immunohistochemistry (IHC) for HER2.^1,2

Researchers from Caris Life Sciences analyzed a cohort of 2799 patients with mBC who received T-DXd. The study identified HER2 and ABCC1 (MRP1) as the most significant transcriptomic predictors of drug-specific overall survival (OS). While higher HER2 expression was associated with improved clinical outcomes, elevated ABCC1 expression correlated with significantly poorer OS, regardless of the patient’s established HER2 status.

Uncovering Mechanisms of Resistance

The clinical utility of T-DXd has expanded significantly following the landmark DESTINY-Breast04 trial (NCT03734029), which established the ADC as a standard of care for HER2-low mBC.³ However, primary and acquired resistance remain significant clinical hurdles.

The study utilized real-world data to pinpoint molecular shifts in tumors following treatment. Analysis of post-treatment samples revealed a marked increase in ABCC1 expression and a higher prevalence of mutations in HER2, NFE2L2, KEAP1, and TOP1. These findings align with known biological pathways of resistance, specifically involving drug efflux and altered payload targets.^1,2

"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 executive vice president and chief medical officer, in a news release.¹ "Posttreatment molecular shifts further reveal biologically plausible routes to acquired resistance, underscoring that RNA-level and multiomic profiling can provide actionable insights beyond standard HER2 classification to better stratify patients and inform therapies."

Clinical Implications for ADC Sequencing

The identification of ABCC1 as a predictor of poor response is particularly relevant for the management of patients who may be candidates for sequential ADC therapy. Current clinical practice often involves transitioning between T-DXd and other agents, such as sacituzumab govitecan (Trodelvy).

The Caris study’s finding that ABCC1—a known multidrug resistance protein—mediates resistance to fam-trastuzumab deruxtecan-nxki provides a potential biological rationale for why some patients fail to respond to sequential topoisomerase I inhibitor-based ADCs.

The Role of Comprehensive Profiling

Standard-of-care HER2 testing via IHC and in situ hybridization capture protein expression and gene amplification but may fail to reflect the dynamic transcriptomic landscape of a metastatic tumor. The authors argue that the integration of artificial intelligence-driven multiomics into clinical practice can fill this gap.

"This study demonstrates how population-scale, multiomic real-world data can drive high impact translational discoveries, reinforcing the value proposition for patients and equipping biopharma with actionable insights into resistance biology to guide next–generation drug development," said David Spetzler, MS, PhD, MBA, president of Caris, in the news release.¹

REFERENCES

1. Caris Life Sciences' real-world data uncovers metastatic breast cancer patient responses and resistance to trastuzumab deruxtecan. News release. Caris Life Sciences. January 28, 2026. Accessed January 29, 2026. https://tinyurl.com/mvvtza4d

2. Sledge GW, Xiu J, Mahtani RL, et al. Mechanisms of resistance to trastuzumab deruxtecan in breast cancer elucidated by multi-omic molecular profiling. NPJ Breast Cancer. 2025 Dec 20;12(1):1. doi: 10.1038/s41523-025-00868-y. PMID: 41422323; PMCID: PMC12774910.

3. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.