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.