Detection of antibody-drug conjugate-induced interstitial lung disease using circulating cell-free DNA

Abstract

Background: The increasing use and anticipated future adoption of antibody-drug conjugates (ADCs) present a significant challenge in identifying and monitoring patients for the development of potentially fatal drug-induced interstitial lung disease (ILD). We sought to apply a tissue-specific methylation analysis of circulating cell-free DNA (cfDNA) to measure lung damage in patients with trastuzumab deruxtecan (T-DXd)-related ILD.

Patients and methods: We describe a patient with metastatic human epidermal growth factor receptor 2 (HER2)-positive endometrial cancer who developed ILD during T-DXd treatment. Blood samples collected at the time of ILD diagnosis, after recovery, and following rechallenge were studied for lung damage using lung-specific methylation markers in cfDNA. To validate the findings, we also tested plasma samples from an additional cohort of patients with HER2-positive metastatic breast cancer treated with T-DXd.

Results: In patients with HER2-positive metastatic cancer treated with T-DXd, the presence of an active ILD, as assessed clinically and using chest computed tomography, was associated with increased levels of lung-derived cfDNA.

Conclusions: This proof-of-concept study demonstrates that liquid biopsy can be developed as a valuable tool for detecting and monitoring ADC-related ILD. Its low cost and simplicity make it a potential alternative to current imaging methods, warranting further clinical development.

Keywords: HER2; antibody–drug conjugate; breast cancer; early detection; interstitial lung disease; liquid biopsy.

Figure 1

Correlation between CT imaging and lung-derived cfDNA. (A) Chest CT at the same level during the clinical course showing the initial diagnosis of interstitial lung disease (day 1), repeated scan after nearly 2 months following clinical and radiologic improvement (day 52), and marked inflammation with malignant effusions soon after rechallenge with T-DXd (day 74). (B) Levels of lung-derived cfDNA measured as cumulative genome equivalents (GE) at various time points. Below are the total levels of cfDNA in plasma, roughly equal at all time points. cfDNA, cell-free DNA; CT, computed tomography; T-DXd, trastuzumab deruxtecan.

Figure 2

Lung-derived cfDNA analysis in patients with metastatic breast cancer treated with T-DXd. cfDNA, cell-free DNA; GE, genome equivalents; ILD, interstitial lung disease; T-DXd, trastuzumab deruxtecan.