Germline pharmacogenetic variants associated with trastuzumab deruxtecan-induced interstitial lung disease in
A Arenas1, C Saura2, M Alva-Bianchi3
1Pharmacogenomics and Tumor Biomarkers Group, Institute for Biomedical Research Sols-Morreale (IIBM) CSIC/UAM, Madrid, Spain.
Background:
Trastuzumab deruxtecan (T-DXd) has demonstrated substantial clinical benefit in patients with advanced human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer. However, treatment-related adverse events-particularly interstitial lung disease (ILD) or pneumonitis-represent a clinically relevant limitation. While UGT1A1 polymorphisms influence toxicity with other topoisomerase I inhibitor-based therapies, their role in T-DXd-related toxicity appears limited. The PROCURE project aimed to investigate germline pharmacogenetic variants beyond UGT1A1 associated with T-DXd-induced ILD.
Materials And Methods:
The PROCURE project is a multicenter translational study conducted across 26 Spanish institutions. Germline DNA from patients with advanced HER2-positive or HER2-low breast cancer treated with T-DXd was genotyped using the Infinium Global Diversity Array enriched for pharmacogenomic variants. A candidate gene approach was applied to 14 genes involved in drug metabolism, transport, pharmacodynamics, and immune-mediated drug hypersensitivity. Logistic regression models were used to evaluate associations with ILD/pneumonitis.
Results:
A total of 290 patients with clinical and genotyping data were included in the analysis. The median age was 58 years (range, 34-94 years). After a median follow-up of 18.3 months [95% confidence interval (CI): 15.4-20.5], the cohort registered 33 ILD cases (incidence of 11.4%). The strongest association signals mapped to variants within the human leukocyte antigen (HLA) region, with the top single nucleotide polymorphism near HLA-F (rs9258213; OR 6.8, 95% CI 2.6-17.9, P = 9.5 × 10-5). Additional associations were observed in SLCO1B1 and CYP3A4, genes involved in T-DXd transport and metabolism.
Conclusions:
This study identifies host genetic variation within the HLA locus and drug pharmacokinetic pathways as potential contributors to T-DXd-induced ILD in patients with advanced breast cancer. Although no definitive pharmacogenomic predictor was identified, these findings provide insights into the biological mechanisms underlying this toxicity and support further investigation of pharmacogenomic biomarkers to improve risk stratification and guide personalized T-DXd therapy.
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