Abstract PS4-07-06: Independent validation of TNBCDX, a 15-gene genomic risk stratification tool for early-stage triple-negative breast cancer

Abstract Background: TNBCDX is a 15-gene composite biomarker (10-gene immune module, 4-gene proliferation signature, ERBB2 and clinical variables) for predicting pathological complete response (pCR) and recurrence risk in early-stage triple-negative breast cancer (TNBC). In Martin et al. (Ann Oncol 2024), TNBCDX was retrospectively validated in 527 patients (pts) from the WSG-ADAPT-TN, MMJ-CAR-2014-01 and NeoPACT cohorts—each receiving neoadjuvant taxane-based therapy without anthracycline/cyclophosphamide (AC)—where it independently stratified pCR rates, distant recurrence-free survival (DRFS) and overall survival (OS) after adjustment for pCR status and tumor-infiltrating lymphocytes (TILs). We now assess TNBCDX in 164 consecutive pts from two Spanish academic centers, 127 treated with sequential AC→taxane-carboplatin± pembrolizumab. Methods: Baseline pre-treatment formalin-fixed, paraffin-embedded tumor samples were collected retrospectively from pts with stage I-III TNBC treated at Clinic Barcelona Comprehensive Cancer Center (n=108) and Hospital 12 de Octubre, Madrid (n=56). Keynote-522 backbone regimen (AC-taxane-carboplatin) with and without pembrolizumab was used in 47 pts and 80 pts, respectively. Gene expression profiling was performed on the TNBCDX standardized platform. TNBCDX pCR and risk scores were calculated centrally, blinded to outcomes. Associations with DRFS, OS, and pCR were evaluated using Kaplan-Meier analyses and multivariable Cox and logistic regression models adjusted for age, stage, and TILs. Results: Median age was 56.2 years (range 27.3-84.9). Ductal morphology predominated (88.4%), followed by metaplastic (3.7%), apocrine (1.8%), and lobular (1.2%). Most tumors were high grade (68%), cT2 (59%), and cN0 (56%). Median TILs was 15% (range 0-90%). Nearly all pts (97.6%) received neoadjuvant taxane-carboplatin regimens—79.3% with AC and 36.6% with immunotherapy—achieving a 53% overall pCR rate. At a median follow-up of 44.5 months, there were 16 DRFS events and 15 deaths. Among the 127 pts treated with Keynote-522 backbone regimen, those receiving pembrolizumab (n=47) had a pCR rate of 53.7% versus 60.0% in those who did not (n=80) (p=0.562). The distribution of the TNBCDX pCR score was 32.9% low, 28.7% medium, and 38.4% high. High versus low TNBCDX pCR score was associated with higher pCR rates (65.5% vs 38.8%; odds ratio=6.51; 95% CI 1.45-3.41; p=0.019). The TNBCDX risk score classified 45.7% as low-risk and 54.3% as high-risk. High versus low TNBCDX risk score was independently associated with shorter DRFS (hazard ratio [HR]=5.12; 95% CI 1.58-16.50; p=0.006) and shorter OS (HR=5.56; 95% CI 1.51-20.5; p=0.010). Higher TILs predicted pCR (OR=1.03; 95% CI 1.01-1.05; p=0.005) but were not significantly associated with DRFS or OS (both p>0.05). Conclusions: In this independent cohort, TNBCDX pCR and risk scores were significantly associated with pCR and differential survival outcomes—independently of pCR status and systemic therapy. These data underscore the value of TNBCDX for tailoring systemic therapy intensity in early-stage TNBC. Citation Format: F. Braso-Maristany, E. Ciruelos, E. Seguí, J. Montes, P. Tolosa, M. Rey, F. Pardo, R. Sánchez-Bayona, L. Lema, M. Cobos, P. Blasco, P. Galván, L. Parilla, R. Moreno, G. Riu, I. Garcia-Fructuoso, R. Gómez-Bravo, M. Bergamino, F. Schettini, A. Madariaga, B. Adamo, M. Muñoz, M. Marín-Aguilera, L. Manso, L. Paré, T. Pascual, M. Vidal, A. Prat, M. Alva. Independent validation of TNBCDX, a 15-gene genomic risk stratification tool for early-stage triple-negative breast cancer [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 PS4-07-06.