Impact of cardiometabolic health on treatment outcomes in early-stage triple-negative breast cancer receiving chemoimmunotherapy

BACKGROUND: Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and pivotal trials of pembrolizumab with neoadjuvant chemotherapy (KEYNOTE-522) underrepresent patients with cardiometabolic comorbidities. We evaluated how metabolic dysfunction affects treatment tolerability, pathologic complete response (pCR), and overall survival (OS) in routine care. METHODS: We conducted a retrospective cohort study of women with early-stage triple-negative breast cancer (TNBC) treated with the KEYNOTE-522 regimen at the Cleveland Clinic between January 1, 2020, and March 31, 2025. Metabolic syndrome was defined using a constellation of cardiometabolic risk factors consistent with criteria proposed by the American Heart Association and the National Heart, Lung, and Blood Institute, adapted to available real-world clinical data (BMI, HbA1c in place of fasting glucose, hypertension, chronic kidney disease, HDL < 50 mg/dL, triglycerides > 150 mg/dL; ≥3 criteria). Data included demographics, tumor characteristics, treatment details, cardiometabolic comorbidities, CTCAE-graded adverse events, pathologic complete response (pCR), and overall survival (OS). Kaplan-Meier methods estimated survival; logistic regression evaluated predictors of pCR; Cox proportional hazards models assessed OS. Median follow-up was 28.8 months. RESULTS: Among 222 patients with early-stage TNBC treated with the KEYNOTE-522 regimen, 55 (24.8%) met criteria for metabolic syndrome. Patients with metabolic syndrome were older (median 65 vs. 55 years, p = 0.0004) and more frequently Black (43.6% vs. 18.0%). Cardiometabolic comorbidities were more prevalent, including obesity (85.5% vs. 35.9%), diabetes (72.7% vs. 7.8%), hypertension (69.1% vs. 24.6%), CKD (21.8% vs. 4.8%), low HDL (83.6% vs. 12.0%), and elevated triglycerides (58.2% vs. 6.0%) (all p < 0.001). Dose reductions were more frequent among patients with metabolic syndrome (32.7% vs. 20.4%), with similar treatment discontinuation rates. pCR rates did not differ significantly (72.7% vs. 68.9%, p = 0.62), and no cardiometabolic factors independently predicted pCR. With median follow-up of 28.8 months, metabolic syndrome was associated with worse overall survival. Hypertension (HR 3.83, 95% CI 1.47-9.96, p = 0.006) and diabetes (HR 3.07, 95% CI 1.33-7.08, p = 0.009) were independent predictors of mortality. CONCLUSION: Cardiometabolic comorbidities, particularly hypertension, were associated with poorer survival and greater treatment intolerance despite preserved pCR. Systematic cardiometabolic assessment and proactive management should be integrated into TNBC care.