Differential response and survival across rarehistologic subtypes of triple-negative breast cancerfollowing neoadjuvant chemo-immunotherapy

Abstract
Special histologic subtypes of triple-negative breast cancer (TNBC) are biologically distinct, yet their outcomes in the immunotherapy era remain undefined. We analyzed 823 patients with early -stage TNBC treated with pembrolizumab plus chemotherapy in the multicenter real-world Neo-Real/GBECAM-0123 cohort. Histologies included invasive carcinoma of no special type (NST; n=762, 92.6%), metaplastic carcinoma (n=26, 3.2%), triple-negative lobular carcinoma (n=17, 2.1%), and other rare variants (n=18, 2.2%). Metaplastic carcinoma demonstrated significantly lower pathological complete response (pCR) rates compared with NST (17.4% vs 65.4%; OR 0.14, 95% CI 0.04–0.44; p
=0.001), suggesting relative resistance to chemo-immunotherapy, with a numerical trend toward
worse event-free survival (EFS) (HR 2.07, 95% CI 0.88 –4.88; p=0.094). Triple-negative lobular carcinoma achieved pCR rates comparable to NST (56.2%) but showed poorer 2-year EFS, with a significant association in the pre-surgical multivariable model (HR 4.25, 95% CI 1.50–12.06; p = 0.00
6), and a persistent trend after adjustment for pCR. This highlights the biological heterogeneity of TNBC and supports the investigation of histology-driven therapeutic strategies.