# Association Between Single-Nucleotide Polymorphism and Trastuzumab Deruxtecan-Induced Interstitial Lung Disease in Breast Cancer Using the Japonica Array NEO

## TL;DR

This study explores how genetic differences might help predict which breast cancer patients are at higher risk of a dangerous side effect from a cancer drug called trastuzumab deruxtecan.

## Contribution

The study identifies a specific genetic variant associated with lung toxicity in patients treated with trastuzumab deruxtecan.

## Key findings

- Baseline clinical factors alone cannot reliably predict the risk of interstitial lung disease from trastuzumab deruxtecan.
- A specific genetic variant, rs12625311, was found to be significantly associated with the development of lung disease in patients treated with the drug.

## Abstract

Trastuzumab deruxtecan is an effective treatment agent for a wide range of cancers, including those with low human epidermal growth factor receptor 2 expression. However, it can cause interstitial lung disease, a side effect that may sometimes be life-threatening, often requiring treatment interruption. Currently, the prediction of patients at a higher risk of developing this complication is difficult. In this study, we examined whether patient background factors, such as age, kidney function, or treatment dose could explain the risk of developing lung disease. Additionally, we explored whether inherited genetic differences might play a role. Our data did not demonstrate that common clinical factors alone were not sufficient to identify high-risk patients. However, our genetic analysis suggested that certain genetic variations may influence individual susceptibility. These findings indicate that trastuzumab deruxtecan-induced lung toxicity is complex and may depend on both treatment effects and patient-specific factors, supporting future research on more personalized risk assessments.

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.