Association Between Single-Nucleotide Polymorphism and Trastuzumab Deruxtecan-Induced Interstitial Lung Disease in...

Background/Objectives: Trastuzumab deruxtecan (T-DXd) is an effective antibody-drug conjugate for human epidermal growth factor receptor 2-expressing solid tumors; however, interstitial lung disease (ILD) remains a clinically significant adverse event. Although both clinical characteristics and genetic susceptibility have been implicated in drug-induced ILD, the factors specifically associated with T-DXd-induced ILD remain unclear. This study aimed to evaluate clinical and genetic factors associated with the development of ILD in patients treated with T-DXd. Methods: We retrospectively analyzed the clinical data of 54 patients treated with T-DXd. The baseline clinical and treatment-related characteristics of patients with ILD and those without were compared. Genome-wide single-nucleotide polymorphism (SNP) analyses with genotype imputation and targeted candidate SNP analyses were performed to evaluate genetic susceptibility. Results: ILD occurred in 15 patients (27.8%), with a median time to onset of 215 days (range, 48-1187). None of the baseline clinical or treatment-related factors were significantly associated with ILD development. Genome-wide analyses did not reveal any significant SNPs after correcting for multiple testing. Contrarily, a targeted analysis focusing on SNPs previously associated with drug-induced ILD identified one variant rs12625311 that was significantly associated with ILD in this cohort. Conclusions: In this exploratory study, baseline clinical characteristics alone were insufficient to discriminate the risk of ILD among patients treated with T-DXd. Although no high-penetrance genetic variants were identified, candidate-based genetic analyses suggested that host genetic factors may contribute to ILD susceptibility. Integrating genetic information with clinical assessment may help refine the risk stratification for T-DXd-induced ILD in future studies.