Molecular and clinical insights of trastuzumab deruxtecan efficacy in advanced breast cancer

Amin H Nassar; Elias Bou Farhat; Hassan Abushukair; Michel Alchoueriy; Samer Salem; Marc Machaalani; Elio Adib; Elizabeth P Henske; Priyanka Babu; Toni K Choueiri; Mehrdad Rakaee; Lill-Tove Rasmussen Busund; Yamato Takabe; Shun-Fat Lau; Kerri Rall; Abdul Rafeh Naqash; Caroline Jansen; Xiao Wang; Pavan Challa; Paolo Tarantino; Ann H Partridge; Sara M Tolaney; David J Kwiatkowski; Eric P Winer

doi:10.1093/jnci/djaf344

Molecular and clinical insights of trastuzumab deruxtecan efficacy in advanced breast cancer

J Natl Cancer Inst. 2025 Dec 4:djaf344. doi: 10.1093/jnci/djaf344. Online ahead of print.

Authors

Amin H Nassar^{1

2}, Elias Bou Farhat², Hassan Abushukair^{3

4}, Michel Alchoueriy², Samer Salem², Marc Machaalani⁵, Elio Adib², Elizabeth P Henske², Priyanka Babu¹, Toni K Choueiri⁵, Mehrdad Rakaee^{2

6}, Lill-Tove Rasmussen Busund⁷, Yamato Takabe¹, Shun-Fat Lau¹, Kerri Rall¹, Abdul Rafeh Naqash^{3

4}, Caroline Jansen⁸, Xiao Wang¹, Pavan Challa¹, Paolo Tarantino⁵, Ann H Partridge⁵, Sara M Tolaney⁵, David J Kwiatkowski^{2

5}, Eric P Winer¹

Affiliations

¹ Division of Medical Oncology, Yale Cancer Center, New Haven, CT, United States.
² Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, MA, United States.
³ Division of Medical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
⁴ Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
⁵ Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
⁶ Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway.
⁷ Department of Clinical Pathology, University Hospital of North-Norway, Tromso, Norway.
⁸ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States.

PMID: 41418409
DOI: 10.1093/jnci/djaf344

Abstract

Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment paradigm for HER2-expressing breast cancer, including HER2-low disease. However, biomarkers associated with T-DXd activity remain poorly defined. We conducted a comprehensive analysis of clinical, genomic, and immune correlates of T-DXd outcomes to identify molecular determinants of therapeutic benefit and resistance.

Methods: We retrospectively analyzed 2 independent cohorts of patients with advanced breast cancer treated with T-DXd at Dana-Farber Cancer Institute and Yale Cancer Center between 2018 and 2024. We included patients with ≥2 tumor blocks with HER2 immunohistochemistry (IHC) assessments prior to T-DXd. Clinical data on 524 patients were manually reviewed, and genomic profiling and immune microenvironment assessments were performed on a subset of patients. Multivariable Cox proportional hazards models evaluated associations between molecular features and overall survival (OS) and time to next treatment (TTNT).

Results: Among 524 patients, HER2 IHC discordance between sequential tumor biopsies was observed in 20% of patients and was independently associated with significantly worse OS (hazard ratio [HR] = 0.67; P = .012) and TTNT (HR = 0.65; P = .002), resembling outcomes seen in HER2 0 tumors. Genomic analysis revealed that PTEN mutations correlated with inferior TTNT (HR = 2.2; q = 0.068), whereas ERBB2 amplifications predicted improved OS and TTNT. An inflamed tumor microenvironment determined by digital pathology was associated with significantly poorer TTNT outcomes (median TTNT = 5.5 months) compared with immune-desert phenotypes (median OS = 9.6 months, P = .03).

Conclusions: This study identifies HER2 IHC discordance and specific genomic and immune features as prognostic biomarkers of T-DXd efficacy. These findings warrant prospective validation and may inform biomarker-driven strategies to optimize T-DXd therapy in HER2-expressing malignancies.

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