Abstract Background Special histological types (SHT) of triple-negative breast cancer (TNBC) exhibit distinct biological behavior and treatment responses. However, due to their rarity, patients with SHT are underrepresented in clinical trials. We aimed to evaluate the effectiveness of pembrolizumab (P) combined with neoadjuvant chemotherapy (NCT) in patients with SHT of TNBC. Methods We analyzed data from patients with TNBC and SHT enrolled in the Neo-Real/GBECAM-0123 study—a multicenter, real-world study including patients treated with neoadjuvant P+NCT across ten cancer centers since July 2020. Effectiveness outcomes included pathologic complete response (pCR) and event-free survival (EFS). Results Of the 727 patients included to date in the Neo-REAL study, 646 (88.9%) had TNBC of no special type (NST), 51 (7%) SHT, 4 (0.6%) undifferentiated, and 26 (3.6%) unknown histology. Among the SHT group, 20 metaplastic, 16 lobular, and 15 other subtypes (9 apocrine, 3 micropapillary, 2 neuroendocrine, and 1 medullary). Patients with lobular, metaplastic, and other SHT tumors were older than those with NST (median ages: 58, 51, 49, and 44 years, respectively; p = 0.001). Grade 3 tumors were more frequent in NST (76%) and metaplastic (84%) subtypes than in lobular (50%) and other SHT tumors (50%) (p = 0.019). A high Ki-67 index (≥50%) was also more common in NST tumors (76%) compared to metaplastic (52%), lobular (53%), and other SHT tumors (36%) (p 0.001). Tumor stage distribution was similar across groups. Disease progression during P+NCT was significantly higher in the metaplastic group (33%) compared to NST (3%) and lobular tumors (0%) (p = 0.001). However, all but one patient with progression in the metaplastic group underwent surgery. pCR and EFS rates are presented in the Table. pCR rates were markedly lower in metaplastic tumors compared to NST and lobular subtypes. With a median follow-up of 22 months, 83 events of disease recurrence or death were recorded. Lobular and metaplastic tumors were associated with significantly lower 2-year EFS compared to NST. These differences remained significant in a multivariable Cox regression including tumor grade and stage. Conclusion Patients with SHT of TNBC had worse outcomes with neoadjuvant pembrolizumab plus chemotherapy compared to those with NST tumors. Metaplastic carcinoma was associated with lower pCR and a trend tower lower EFS rates. Although lobular carcinoma had pCR rates similar to NST, an unfavorable EFS was also observed in this group. These results underscore the urgent need for developing new tailored therapeutic strategies for these rare and aggressive subtypes of TNBC. Citation Format: R. Barroso-Sousa, L. Testa, P. Mandó, M. C. Tavares, N. C. Nunes, G. Cordoba, F. Waisberg, F. C. Balint, I. M. de Sousa, M. O. Andrade, M. C. Gouveia, F. Madasi, J. Bines, R. P. Ferreira, D. D. Rosa, C. L. Santos, M. R. Monteiro, Z. S. de Souza, D. Assad-Suzuki, C. dos Anjos, D. M. Gagliato, A. U. Gomes, B. M. Zucchetti, A. Ferrari, M. L. de Brito, M. F. Monteiro, P. A. Signorini, N. J. Gomes, C. Gallina, S. Sanches, P. M. Hoff, M. Estevez-Diz, R. C. Bonadio. Rare but Resistant: Neoadjuvant Chemoimmunotherapy in Special Histological Subtypes of Triple-Negative Breast Cancer — Insights from the Neo-Real/GBECAM-0123 Study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-04.
Hermelink et al. (Tue,) studied this question.