Oral Mucositis as a Predictor of Systemic Complications and Mortality in Breast Cancer Patients Treated with Antibody–Drug Conjugates: A Real-World Cohort Study

Background/Objectives: Oral mucositis (OM) is a recognized toxicity of antibody–drug conjugates (ADCs), but its long-term systemic implications are unknown. We assessed long-term systemic complications and mortality associated with OM in patients with breast cancer treated with monoclonal antibodies and antibody–drug conjugates (mADCs). Materials and Methods: This retrospective cohort study used TriNetX data from 88 healthcare organizations. Adults with breast cancer receiving mADCs with (n = 1784) or without (n = 61,616) OM (ICD-10-CM K12.31) were 1:1 propensity score-matched on race, external causes of morbidity, ECOG performance status, and body mass index (1784 per cohort). Outcomes included volume depletion, fluid/electrolyte disorders, respiratory and circulatory disease, malaise/fatigue, pain, dysphagia, and all-cause mortality, assessed from 1 day after the index event using risk differences, Kaplan–Meier analysis, and Cox hazard ratios (HRs). Results: Patients with OM had higher risks of fluid/electrolyte disorders (39.1% vs. 32.1%), respiratory disease (48.5% vs. 39.0%), circulatory disease (63.7% vs. 51.2%), pain (16.1% vs. 11.7%), dysphagia (10.4% vs. 8.2%), and mortality (26.1% vs. 19.3%), with HRs (no OM vs. OM) of 0.664–0.753 (log-rank p ≤ 0.002 for all). Volume depletion and malaise/fatigue showed no significant absolute risk differences but significant survival differences (HR 0.824 and 0.855). Recurrent event counts did not differ. Conclusions: In patients with breast cancer treated with mADCs, OM was associated with greater long-term systemic morbidity and mortality after propensity score matching. OM may serve as a marker of systemic vulnerability, supporting routine oral health assessment and oncology–dentistry collaboration during ADC therapy, with implications for toxicity management as ADC use expands.