Neoadjuvant Chemo-Immunotherapy Yields Survival Comparable to Upfront Surgery in Metaplastic Breast Cancer: A National Cancer Database Analysis

OBJECTIVE: Metaplastic breast carcinoma (MpBC) is a rare and aggressive subtype of breast cancer, often characterized by triple-negative (TN) receptor status and a limited response to standard chemotherapy. The optimal treatment strategy remains undefined. This study evaluates overall survival (OS) in patients with TN-MpBC treated with neoadjuvant chemotherapy (NAC) or neoadjuvant chemo-immunotherapy (NACIO) compared with upfront surgery using the National Cancer Database. METHODS: A retrospective cohort analysis was conducted using the National Cancer Database to identify patients diagnosed with stage I-III TN-MpBC between 2010 and 2022 and treated with NAC, NACIO, or upfront surgery. Primary endpoints included OS, pathologic complete response (pCR), and breast conservation rates. Continuous variables were analyzed using the Wilcoxon rank-sum test, and categorical variables were assessed with the chi-squared or Fisher's exact test. Survival was estimated using the Kaplan-Meier method. Breast conservation and pCR were analyzed using logistic regression, and OS was analyzed using a Cox proportional hazards model. RESULTS: Of 4953 patients, 3429 (69.2%) underwent upfront surgery, 1232 (24.9%) received NAC, and 292 (5.8%) received NACIO. No significant difference in OS was observed between NACIO and surgery-first approaches (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.51-1.27; p = 0.3), but NAC was associated with a 37% increased risk of mortality compared with upfront surgery (HR 1.37; 95% CI 1.21-1.56; p < 0.001). NACIO was associated with a 62% higher likelihood of achieving pCR than was NAC (odds ratio [OR] 1.62; 95% CI 1.11-2.38; p = 0.013). The rate of breast conservation was not significantly different between NACIO and upfront surgery (OR 0.8; 95% CI 0.61-1.05; p = 0.11), but patients receiving NAC were 27% less likely to undergo breast-conserving surgery than were those undergoing upfront surgery (OR 0.73; 95% CI 0.63-0.84; p < 0.001). Stage significantly modified the association between treatment strategy and breast conservation (pooled Wald test, p = 0.022). CONCLUSION: In patients with TN-MpBC, NACIO demonstrated survival outcomes comparable to those with upfront surgery and improved pCR rates compared with NAC. These findings suggest that integrating immunotherapy into neoadjuvant treatment may offer clinical benefit, warranting further prospective investigation. However, findings should be interpreted cautiously given the baseline stage differences between the treatment groups and the potential for residual confounding inherent to retrospective database studies.