Uncovering Clinical Risk Factors for T-DXd Pneumonitis in Metastatic Breast Cancer

In patients with metastatic breast cancer, pretreatment interstitial lung abnormalities (ILAs) and human epidermal growth factor receptor 2 (HER2)–low breast cancer are major risk factors for pneumonitis related to treatment with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), according to data from a retrospective cohort study published in Breast Cancer Research.¹

Pretreatment ILAs, which can represent an early form of idiopathic interstitial lung disease (ILD),¹ were the strongest predictor of T-DXd pneumonitis in the study, with significant associations observed in both univariate- (HR, 17; 95% CI, 6.5-46) and multivariate-adjusted Cox proportional hazard models (HR, 10.56; 95% CI, 3.8-29.31; P < .0001). Low HER2 status was also significantly associated with pneumonitis in both univariate (HR, 4.00; 95% CI, 1.43-11.11) and adjusted models (HR, 0.30; 95% CI, 0.09-0.96; P = .042).

“The mechanisms whereby ILAs predispose to pneumonitis and other lung toxicities after cancer therapies remain unclear, but [one] possibility is that the alveolar epithelium in individuals with ILAs may be more vulnerable to damage,” the authors hypothesized.¹

Other significant risk factors identified in univariate models included a history of autoimmune disease, baseline shortness of breath, more lines of prior therapy, prior immune checkpoint inhibitor treatment, and triple-negative breast cancer.

Furthermore, in examining the association between pneumonitis and mortality, no fatal cases of pneumonitis were observed in the cohort that directly led to death. However, pneumonitis development was associated with increased mortality in the unadjusted model (HR, 2.5; 95% CI, 1.2-5.0). The Kaplan-Meier curves depicting overall survival trends by pneumonitis status showed a marked separation of curves after 1 year of T-DXd treatment.

T-DXd is an FDA-approved HER2-targeted antibody-drug conjugate indicated for unresectable or metastatic hormone receptor–positive, HER2-low/ultralow breast cancer. The agent has gained recent traction in the metastatic breast cancer space with an FDA breakthrough designation in July 2025 and a priority review of its supplemental biologics license application for its combination with pertuzumab (Perjeta) in HER2-positive breast cancer.

Despite the agent’s approval and efficacious activity in the DESTINY-Breast series of clinical trials, there is also evidence of associated pulmonary toxicities such as pneumonitis, which could potentially be fatal if left untreated.² T-DXd plus pertuzumab has a Prescription Drug User Fee Act target action date in the first quarter of 2026. Understanding the risk factors for T-DXd pneumonitis is crucial for developing and mobilizing proactive prevention and management approaches, as the agent’s application could expand to a new population of patients with breast cancer.

“Further mechanistic studies are needed to understand whether HER2 expression in the lung increases the risk for T-DXd pneumonitis, and whether other ILA or ILD risk markers may be relevant to predict individuals at high risk for T-DXd pneumonitis,” wrote the study authors on future areas for investigation.¹

Data Collection and Cohort Characteristics

Investigators collected electronic health record data of 203 female patients with metastatic breast cancer who were treated with T-DXd between 2020 and 2024 and had at least 3 months of follow-up.

The median age of the cohort was 55 years (IQR, 47-65). Approximately half (50%) of patients were HER2 positive, and 32% were considered HER2 low. Of the total cohort, 9.4% developed pneumonitis. The makeup of pneumonitis cases by grade was 32%, 37%, 26%, and 5% for grades 1, 2, 3, and 4, respectively.

REFERENCES

1. Azhar M, Soto F, Su A, et al. Incidence and risk factors for pneumonitis due to trastuzumab deruxtecan in metastatic breast cancer: a retrospective cohort study. Breast Cancer Res. 2025;27(1):197. doi:10.1186/s13058-025-02151-1

2. Henning JW, Brezden-Masley C, Gelmon K, et al. Managing the risk of lung toxicity with trastuzumab deruxtecan (T-DXd): a Canadian perspective. Curr Oncol. 2023;30(9):8019-8038. doi:10.3390/curroncol30090582