Abstract PS4-07-14: Germline BRCA Mutations and Chemo-Immunotherapy Predict Pathologic Complete Response in Triple-Negative Breast Cancer: Insights from a Resource-Limited Setting

Abstract Introduction: Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, often diagnosed at a younger age and associated with limited therapeutic options. Despite advances in systemic therapy, long-term outcomes remain suboptimal, particularly in resource-limited settings. This study aims to characterize the clinical features, germline mutation patterns, and survival outcomes of TNBC patients treated in Jordan, with a focus on real-world response to neoadjuvant chemo-immunotherapy and the prognostic value of germline genetic findings. Methods: This retrospective cohort study included patients diagnosed with TNBC between 2003 and 2023 at King Hussein Cancer Center. Demographic, clinical, pathological, and treatment-related data were extracted from medical records. All patients underwent germline genetic testing as part of their workup. Pathological complete response (pCR; defined as ypT0/is, ypN0), event-free survival (EFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Multivariable logistic regression was performed to identify independent predictors of pCR. Results: A total of 526 patients with TNBC were included, predominantly Jordanian (473, 89.9%), with a median age at diagnosis of 45 years (range: 36-54). Notably, 165 patients (31.4%) were diagnosed before the age of 40, indicating a high proportion of young patients. A personal history of non-breast malignancy was reported in 35 patients (6.6%), and 11 (2.1%) had a prior diagnosis of breast cancer with a different hormone receptor profile. A positive family history of cancer was documented in 407 patients (77.4%). At presentation, 494 patients (94.0%) had non-metastatic disease, including 283 (52.7%) with locally advanced tumors. Histopathological analysis revealed invasive breast carcinoma of no special type (NST) in 434 patients (82.5%), with grade 3 histology in 422 cases (80.2%). HER2-low status was identified in 95 patients (18.1%). Germline genetic testing revealed pathogenic or likely pathogenic (P/LP) variants in 117 patients (22.2%), most commonly BRCA1 (77 patients, 65.8%) and BRCA2 (31 patients, 26.5%). Among the 494 non-metastatic patients, 337 (68.2%) received neoadjuvant therapy, including 74 (21.9%) who received chemo-immunotherapy. This was associated with a significantly higher pCR rate compared to chemotherapy alone (59.5% vs. 39.9%; OR: 2.2, p = 0.003). In multivariable analysis, both neoadjuvant immunotherapy (OR: 2.18, p = 0.006) and the presence of P/LP mutations (OR: 1.95, p= 0.017) were independently associated with increased odds of achieving pCR, while age, HER2 status, tumor grade, and clinical stage were not significant predictors. Mastectomy was performed in 281 patients (56.9%), and among those with P/LP variants, 60.8% underwent risk-reducing contralateral mastectomy and 51.6% had bilateral salpingo-oophorectomy. After a median follow-up of 55.8 months, the 5-year event-free survival (EFS) among patients who presented with non-metastatic disease was 74.2% (95% CI: 70.0%-78.7%). In subgroup analysis, 5-year EFS was similar in patients with P/LP variants and those without; 77.5% (95% CI: 68.6%-87.6%) compared to 73.1% (95% CI: 68.3%-78.2%), p= 0.205. Conclusion: This study highlights the clinicopathologic diversity and outcomes of TNBC patients in a Middle Eastern population. A notable proportion carried BRCA1/2 mutations, supporting routine genetic testing. Adding immunotherapy to neoadjuvant chemotherapy improved pCR rates. Long-term outcomes were favorable, with no survival differences by mutation status. Citation Format: T. Al-Batsh, F. Tamimi, M. Horani, B. Sharaf, H. Bani Hani, L. El Saket, A. Issa, Z. Muhanna, O. Almuhaisen, O. Mahafdah, A. Shammout, M. El-Atrash, M. Abunasser, H. Abdel-Razeq. Germline BRCA Mutations and Chemo-Immunotherapy Predict Pathologic Complete Response in Triple-Negative Breast Cancer: Insights from a Resource-Limited Setting 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 PS4-07-14.