Abstract RF2-02: Pooled analysis of the BrighTNess, CALGB 40603 (Alliance), and GeparSixto clinical trials identifies the impact of neoadjuvant carboplatin on pCR and survival in early-stage triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with the lowest survival rate of all clinical subtypes of breast cancer, but patients who achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have a good prognosis. Results from the phase III KEYNOTE-522 trial established a new standard of care (SOC) for stage II-III TNBC, leading to US Food and Drug Administration approval in 2022 for the addition of carboplatin and pembrolizumab to NACT. Although the addition of carboplatin had previously been shown to increase pCR rates to NACT, it was not widely adopted as part of SOC NACT until its incorporation into both arms of KEYNOTE-522. Given the toxicities associated with carboplatin, there remains a need to better define its therapeutic benefit and to identify prognostic and predictive biomarkers of patient response and survival. Methods: We performed a pooled analysis of three randomized early-stage TNBC clinical trials that investigated the addition of carboplatin to NACT: BrighTNess (NCT02032277, n = 471), CALGB 40603 (NCT00861705, n = 351), and GeparSixto (NCT01426880, n = 262). We evaluated its impact on pCR, event-free survival (EFS), and overall survival (OS), and we explored germline BRCA1 and BRCA2 (gBRCA) mutation status as a potential biomarker. Additionally, we examined the prognostic and predictive value of eight published gene expression signatures (IgG, CD4, CD8, B-cell T-cell cooperativity, CD274, Immune1, Hypoxia core, VEGF). To analyze associations with pCR, we fit logistic mixed-effects regression models with study as a random effect. Associations with EFS and OS were evaluated using Cox proportional hazards models stratified by study. Multivariate models included age, tumor size, nodal status, gBRCA mutation status, and tumor grade as covariates. Results: For the pooled dataset (n = 1084), in multivariate models, the addition of neoadjuvant carboplatin was significantly associated with increased pCR rate (odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.41-2.55, p < 0.001) and EFS (hazard ratio [HR] = 0.71, 95% CI = 0.54-0.93, p = 0.01), but not OS (HR = 0.93, 95% CI = 0.65-1.31, p = 0.66). When considering only gBRCA mutant samples (n = 137), we found that the addition of carboplatin conveys a significant EFS benefit (HR = 0.50, 95% CI = 0.25-1.00, p = 0.05) but had no significant impact on pCR rate or OS. Among the eight gene expression signatures tested, all six immune signatures were associated with a higher pCR rate in multivariate models, with Benjamini-Hochberg (B-H) adjusted p < 0.05. Four signatures (IgG, CD8, CD274, and Immune1) were associated with improved EFS and OS (B-H adjusted p < 0.05). However, no interaction between carboplatin and any tested signature was significantly predictive of pCR, EFS, or OS. Whole transcriptome analyses are ongoing to identify gene expression features that may predict response to neoadjuvant carboplatin. Conclusions: Within a pooled analysis of the BrighTNess, CALGB 40603, and GeparSixto clinical trials, we found that neoadjuvant carboplatin was associated with a significant improvement in pCR rate and EFS, but not OS. The addition of carboplatin significantly improved EFS in patients with gBRCA mutations despite not significantly improving pCR rate or OS. While many immune-related gene expression signatures were prognostic, none were predictive for benefit from neoadjuvant carboplatin. These findings support the inclusion of neoadjuvant carboplatin in SOC treatment of stage II-III TNBC and further emphasize the prognostic importance of the TNBC immune microenvironment. Support: P50-CA058223; https://acknowledgments.alliancefound.org. BrighTNess was funded by AbbVie and GeparSixto was funded by GSK. Citation Format: B. M. Felsheim, V. Nekljudova, L. A. Carey, J. Huober, A. Schneeweiss, S. M. Tolaney, M. Untch, C. S. Kuzma, A. Fernandez-Martinez, S. Rachakonda, R. Suresh, D. G. Stover, P. Rastogi, M. Darsow, D. E. Lake, H. S. Rugo, J. O’Shaughnessy, M. Golshan, A. D. Pfefferle, W. M. Sikov, O. Metzger, C. Denkert, C. E. Geyer Jr., C. M. Perou, S. Loibl. Pooled analysis of the BrighTNess, CALGB 40603 (Alliance), and GeparSixto clinical trials identifies the impact of neoadjuvant carboplatin on pCR and survival in 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 RF2-02.