Abstract RF3-02: Gene Expression-based Subtyping of Early Triple-Negative Breast Cancer (TNBC) for Prediction of Response to Neoadjuvant Immune-chemotherapy in the NSABP B-59/GBG-96-GeparDouze Trial

Abstract Introduction: The NSABP-B59/GBG-96-GeparDouze trial study was designed to evaluate the value of adding atezolizumab to standard neoadjuvant chemotherapy in TNBC. As reported at the SABCS 2024 meeting, the addition of atezolizumab to neoadjuvant chemotherapy followed by adjuvant atezolizumab did not result in statistically significant improvement in event-free survival (EFS) over the control arm (Geyer et al. SABCS 2024, GS 3-05). Here, we report the first biomarker analyses for subtyping of triple-negative breast cancer and evaluation of predictive signatures, based on previous analyses that were performed in the GeparNuevo trial. Methods: We evaluated a total of 494 pre-therapeutic (pre-Tx) core biopsies for gene expression of 2549 genes using the HTG EdgeSeq system. For subtyping of tumors, we used the AIMS approach as well as the TNBC subtyping. Endpoints were pathological complete response (pCR) as well as EFS. Predefined gene expression signatures for immune genes, proliferation genes and stromal genes were used based on previous evaluations in the GeparNuevo trial (Denkert et al. Cell Rep. Med. 2024, PMID 39566464). Results: Based on classical AIMS subtyping of this TNBC cohort, the main subtypes were Basal-like (70.5%) and HER2-enriched (23.8%). With TNBC subtyping, the main subtypes were immunomodulatory (IM, 25.5%), Mesenchymal (23.9%), Basal-like-1 (BL1, 17.6%), Mesenchymal stem-like (MSL, 15.2%), Basal-like-2 (BL2, 10.1%) and Luminal androgen receptor (LAR, 7.7%). pCR rates for all subtypes were: IM (74.6%), M (38.1%), BL1 (58.6%), MSL (46.7%), BL2 (54.0%) and LAR (21.1%). The IM subtype had a similar pCR rate in both therapy arms (atezolizumab: 76.2% vs. placebo 73.02%). Numerically increased pCR rates in the atezolizumab arm were observed for BL2 (atezolizumab: 60.8% vs. placebo 48.2%) and LAR (atezolizumab: 31.3% vs. placebo 13.6%) Kaplan-Meier analysis showed significant differences for the six TNBC subtypes overall. Detailed EFS data for the separate subgroups will be presented. When considering a predefined gene set of 126 genes that had been defined in the GeparNuevo trial, with a focus on immune genes, proliferation genes and stromal genes, the expression of most immune and proliferation genes was significantly associated with pCR in both therapy arms. For EFS, a subset of immune genes including HLA-A, HLA-B and IL6R was significant only in the atezolizumab arm (with a positive test for interaction for IL6R; interaction p-value 0.017). In a combined analysis of the two endpoints pCR and EFS, a positive association between the expression of immune genes and improvement in both endpoints was confirmed, while expression of stromal genes was associated with reduced response and reduced survival. Conclusion: In this study we have observed a considerable heterogeneity of TNBC subtypes for pCR and EFS in the context of neoadjuvant immune-chemotherapy. We have been able to confirm previous results regarding the contribution of stromal genes, immune genes and proliferation genes to response to neoadjuvant immune-chemotherapy in TNBC. The similarities regarding predictive genes for pCR and prognostic genes for EFS suggest that the interaction between immune cells and tumor cells is relevant in the placebo-arm, as well. Expression of selected immune genes is significant only in the atezolizumab arm, these genes are candidates for further validations. Citation Format: C. Denkert, S. Rachakonda, T. Karn, A. Schneeweiss, C. Solbach, P. Rastogi, F. Moreno, T. Freeman, T. Link, J. Mouta, M. Reinisch, R. Meyer, Á. Rodríguez Lescure, V. Bjelic-Radisic, P. A. Fasching, M. Balic, M. Untch, K. Rhiem, J. Teply-Szymanski, K. Lüdtke-Heckenkamp, J. Huober, S. Morales, I. Blancas, J. Holtschmidt, V. Nekljudova, N. Wolmark, C. E. Geyer, S. Loibl. Gene Expression-based Subtyping of Early Triple-Negative Breast Cancer (TNBC) for Prediction of Response to Neoadjuvant Immune-chemotherapy in the NSABP B-59/GBG-96-GeparDouze Trial [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 RF3-02.