Pathologic complete response in rare histologic subtypes of early-stage triple-negative breast cancer in the era of immunotherapy.

593 Background: The addition of immunotherapy (IO) to chemotherapy has improved outcomes in early-stage triple-negative breast cancer (eTNBC). Rare histologic subtypes, like lobular and metaplastic, are managed using the same treatment algorithms as ductal TNBC but historically have been associated with worse outcomes. Whether the benefits of IO extend to these rare subtypes in real-world practice remains unclear. Methods: We used the National Cancer Database to retrospectively identify patients diagnosed with stage II-III TNBC who received neoadjuvant therapy from 2021 to 2022, after FDA approval of IO for eTNBC. TNBC was categorized as ductal, lobular, metaplastic or other. Logistic regression was used to assess pathologic complete response (pCR) stratified by IO use. All models were controlled for key demographic and clinicopathologic factors. Results: We identified 17,006 patients with stage II–III TNBC (mean age 55.0 years). Most patients had ductal histology (91.1%), with smaller proportions of metaplastic (2.5%), and lobular (1.9%). Overall, 11,132 (65.5%) patients received IO and achieved a higher pCR rate than those who did not receive IO (45.2% vs 33.1%). pCR rate differed significantly by histologic subtype treated with neoadjuvant chemotherapy, both with and without IO. Among patients who received IO, pCR rate was highest in ductal TNBC (47%) and was significantly lower in lobular (18.9%) and metaplastic (17.6%) tumors (p<0.001). Similarly, in patients who did not receive IO, ductal TNBC had the highest pCR rate (34.6%) with metaplastic and lobular subtypes having lower pCR rates (12.5% and 14.3%, respectively; p<0.001). After covariate adjustment, all non-ductal subtypes had significantly lower odds of pCR compared to ductal TNBC regardless of receipt of IO. This was most notable for metaplastic TNBC with an odds ratio OR of 0.19 (95% CI 0.10–0.33) with IO and OR 0.13 (95% CI 0.04–0.44) without IO. Lobular TNBC was also associated with significantly lower odds of pCR in IO-treated patients (OR 0.50, 95% CI 0.28–0.90) with similar trends observed in patients treated without IO. Conclusions: In this national real-world cohort, we demonstrate that despite the adoption of neoadjuvant IO for eTNBC and improved pCR rates overall, rare histologic subtypes continue to experience inferior treatment outcomes. Metaplastic and lobular TNBC had persistently low pCR rates, regardless of IO use. These results highlight the urgent need for novel therapeutic strategies and dedicated clinical trials for these rare histologic subtypes.