Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that targets human epidermal growth factor receptor 2 (HER2) and delivers a topoisomerase inhibitor payload. T-DXd has been effectively used to treat metastatic breast cancer but causes pneumonitis in 10–15% of cases. Risk factors associated with T-DXd pneumonitis are not well described.

What are the major clinical risk factors for T-DXd pneumonitis?

We conducted a retrospective study of women with metastatic breast cancer at our institution treated with T-DXd as standard of care between 2020 and 2024. We collected clinical data, including demographics, relevant review of symptoms, molecular subtypes, prior treatments, and pulmonary comorbidities, from the electronic health record. A thoracic radiologist reviewed pre-treatment scans for the presence of interstitial lung abnormalities (ILAs). Radiation exposure variables were obtained from an institutional database. Pulmonologists reviewed all cases for the development of pneumonitis. We used univariable and multivariable Cox proportional hazard models to measure the association of clinical variables with the development of pneumonitis.

Pneumonitis was observed in 19/203 patients (9.4%). In univariable analyses, pre-treatment shortness of breath (hazard ratio [HR] 3.9, 95% confidence interval [CI] 1.3–11.7), greater number of prior treatments (HR 1.2 per line, 95% CI 1.0-1.4), triple-negative breast cancer (HR 4.9, 95% CI 1.8–13.0), low HER-2 status (4.00 (95% CI: 1.43–11.11) and pre-treatment ILAs (HR 17, 95% CI 6.5–46) were associated with pneumonitis. In multivariable models, pre-treatment ILAs (HR 10.56, 95% CI 3.8-29.31, p < 0.0001) and HER2 (HR 0.30, 95% CI 0.09–0.96, p = 0.042) were the strongest predictors of pneumonitis, with a marginal association observed for V20 (HR 1.04, 95% CI 0.99–1.09, p = 0.081).

Pre-treatment ILAs and HER2-low breast cancer are major risk factors for T-DXd pneumonitis.