Equivocal and Definite Interstitial Lung Abnormalities as Risk Factors for Trastuzumab Deruxtecan-Related Interstitial Lung Disease in Breast Cancer

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is effective for advanced breast cancer but is associated with interstitial lung disease (ILD). The clinical relevance of baseline interstitial lung abnormalities (ILAs), including subtle equivocal findings, remains unclear. METHODS: This retrospective cohort study included consecutive patients with advanced or recurrent breast cancer who initiated T-DXd at a tertiary hospital in Japan between June 2020 and May 2025. Baseline CT before T-DXd initiation was reviewed for ILAs and classified as no ILA, equivocal ILA, or definite ILA. The cumulative incidence of T-DXd-related ILD was estimated using a competing-risk approach. RESULTS: Among 156 patients, baseline ILAs were identified in 50 patients: 21 with equivocal ILA and 29 with definite ILA. T-DXd-related ILD occurred in 31 patients (20%), including 19 of 50 patients (38%) in the ILA group and 12 of 106 patients (11%) in the non-ILA group. Baseline ILA was associated with a higher cumulative incidence of T-DXd-related ILD (subdistribution hazard ratio, 3.56; 95% CI, 1.63-7.78; p = 0.001). No significant difference in T-DXd-related ILD risk was detected between the equivocal and definite ILA groups. This association remained consistent in the <1.5-mm CT subgroup. No significant differences in progression-free or overall survival were observed according to baseline ILA status. Among patients with baseline ILA, 33 of 50 had ILAs first detected during prior systemic anticancer therapy. CONCLUSIONS: Baseline ILAs, including equivocal findings, were associated with an increased risk of T-DXd-related ILD. ILAs were frequently first detected during prior systemic anticancer therapy before T-DXd initiation.