Pre-treatment Lung Abnormalities Emerge as Major Risk Factor for T-DXd Pneumonitis in Metastatic Breast Cancer

A retrospective cohort study has identified pre-treatment interstitial lung abnormalities (search)Search disease (ILAs) as the strongest predictor of pneumonitis (search)Search disease in metastatic breast cancer (search)Search disease patients receiving fam-trastuzumab deruxtecanView drug details (T-DXdView drug details), with implications for patient selection and monitoring as the antibody-drug conjugate's use expands.

The study, published in Breast Cancer Research, analyzed 203 female patients with metastatic breast cancer (search)Search disease treated with T-DXdView drug details between 2020 and 2024. Pre-treatment ILAs emerged as the most significant risk factor, with patients showing a 17-fold increased risk in univariate analysis (HR, 17; 95% CI, 6.5–46) and a 10.56-fold increased risk after multivariate adjustment (HR, 10.56; 95% CI, 3.8–29.31; P <.0001).

HER2 Expression Level Influences Pneumonitis Risk

Surprisingly, the study revealed that HER2 (search)Search target-low breast cancer was associated with increased pneumonitis (search)Search disease risk compared to HER2-positive disease. In univariate analysis, low HER2 status showed a 4-fold increased risk (HR, 4.00; 95% CI, 1.43–11.11), while adjusted models confirmed the association (HR, 0.30; 95% CI, 0.09–0.96; P =.042). Patients with ER/PR negative, HER2-low tumors demonstrated more than a 6-fold increase in pneumonitis risk.

"The risk of pneumonitis (search)Search disease could also be potentiated by the presence of subclinical fibrosis in the form of ILAs," the study authors noted. "Our data demonstrates that lower HER2 (search)Search target expression by the primary tumor increased the risk for T-DXdView drug details pneumonitis suggesting the possibility that the risk for pneumonitis might be higher in HER2-low breast cancer due to more off-target delivery of the deruxtecan payload."

Clinical Outcomes and Mortality Impact

Among the 203 patients studied, 9.4% developed pneumonitis (search)Search disease, with grade distribution of 32% grade 1, 37% grade 2, 26% grade 3, and 5% grade 4 cases. While no fatal pneumonitis cases occurred, pneumonitis development was associated with increased mortality in unadjusted models (HR, 2.5; 95% CI, 1.2–5.0). Kaplan-Meier survival curves showed marked separation after one year of T-DXdView drug details treatment.

Notably, only 21% of patients who developed pneumonitis (search)Search disease achieved complete radiological resolution, and nearly half showed no appreciable improvement despite treatment interventions.

Mechanistic Insights and Additional Risk Factors

The study authors hypothesized that ILAs, which can represent early forms of idiopathic interstitial lung disease (search)Search disease, may make alveolar epithelium more vulnerable to damage. "The mechanisms whereby ILAs predispose to pneumonitis (search)Search disease and other lung toxicities after cancer therapies remains unclear, but one possibility is that the alveolar epithelium in individuals with ILAs may be more vulnerable to damage," researchers explained.

Additional risk factors identified in univariate models included history of autoimmune disease, baseline shortness of breath, greater lines of prior therapy, prior immune checkpoint inhibitor treatment, and triple-negative breast cancer (search)Search disease. After adjustment, mean lung radiation dose also showed association with pneumonitis (search)Search disease risk.

Clinical Implications for Expanding Indications

These findings carry particular significance as T-DXdView drug details continues to expand its clinical applications. The FDA-approved HER2 (search)Search target-targeted antibody-drug conjugate recently received breakthrough designation and priority review for combination with pertuzumabView drug details in HER2-positive breast cancer, with a target action date in the first quarter of 2026.

"Understanding the risk factors for T-DXdView drug details pneumonitis (search)Search disease is crucial for developing and mobilizing proactive prevention and management approaches as the agent's application potentially expands to a new population of breast cancer patients," the researchers emphasized.

Study Methodology and Limitations

The retrospective analysis included patients with at least three months of follow-up, with a median age of 55 years. Approximately 50% of patients were HER2 (search)Search target-positive, while 32% were HER2-low. Pneumonitis (search)Search disease diagnosis was made by experienced pulmonologists, and all pre-treatment scans were reviewed by a dedicated thoracic radiologist.

The authors acknowledged limitations including the retrospective design, low prevalence of ILAs (5% of patients), and reliance on PET-CT imaging rather than dedicated chest CT in some cases. Despite these limitations, the study represents the largest series examining T-DXdView drug details pneumonitis (search)Search disease risk factors in breast cancer patients.

The researchers called for further mechanistic studies to understand whether HER2 (search)Search target expression in lung tissue influences pneumonitis (search)Search disease risk and to identify additional ILA or ILD risk markers for predicting high-risk individuals.