Abstract Background: Compared to immune-high TNBC, immune-low TNBC has lower pathologic complete response (pCR) rates and higher recurrence rates after neoadjuvant chemoimmunotherapy. Development of more effective therapies for immune-low early- stage TNBC is an area of unmet clinical need. Bispecific antibodies targeting PD-1/PD-L1 plus vascular endothelial growth factor (VEGF) are being evaluated in advanced TNBC. In this study we examined the prognostic role of an angiogenesis pathway expression signature in immune-high and immune-low early-stage TNBC treated with chemoimmunotherapy. Methods: 107 patients with TNBC treated with neoadjuvant chemoimmunotherapy (Carboplatin + Docetaxel + Pembrolizumab X 6 cycles) on the phase II NeoPACT trial (NCT03639948) with available pre-treatment +/- residual tumor whole exome RNA sequencing were included. Stromal tumor-infiltrating lymphocytes (sTILs) were scored by standard criteria, and tumors were defined as immune-high (Im-High; sTILs ≥30%) or immune-low (Im-Low; sTILs 30%). A previously published 10-gene angiogenesis signature score was computed from RNA sequencing data, and samples were classified as angiogenesis-high (Ang-High) or angiogenesis-low (Ang-Low) based on receiver operator characteristic analysis. Angiogenesis signature was tested for prediction of pCR in Im-High and Im-Low groups. Logistic regression was used to examine the independent prognostic utility of sTILs and angiogenesis signature for pCR. Impact of angiogenesis category on event-free survival (EFS) was assessed by Kaplan-Meier method, with groups compared by log-rank test. Results: 50/107 tumors (47%) were classified as Im-High, and 65/107 (61%) classified as Ang-High. Angiogenesis and sTILs were inversely correlated (P0.001); compared to Im-High tumors, a higher proportion of Im-Low tumors were Ang-High (43% vs 74%, P=0.002). Angiogenesis signature was inversely associated with pCR both as a continuous variable (P=0.023) and when assessed as high/low categories (pCR 46% vs 75% in Ang-High vs Ang-Low; odds ratio OR 0.29, P=0.003). When included in a joint model with sTILs, angiogenesis was independently predictive of pCR (OR=2.48, P=0.046), and the two markers combined predicted pCR more accurately compared to each individually (AUC 0.676 for sTILs, AUC 0.642 for angiogenesis, and AUC 0.720 for joint model). Numerically lower EFS was noted in patients with Ang-High compared with Ang-Low tumors (3-year EFS 81% vs 94%, P=0.087). Dual classification based on both sTILs and angiogenesis was highly prognostic, with the highest pCR (83%) in the Im-High/Ang-Low group, lowest pCR (36%) in Im-Low/Ang-High group, and intermediate pCR in Im-High/Ang-High (68%) and Im-Low/Ang-Low (60%) groups, P0.001. Paired analysis of pre-treatment and residual tumor showed increased angiogenesis expression in residual disease compared to pre-treatment samples in both Im-High (P=0.005) and Im-Low tumors (P0.001). Conclusions: Correlative analysis from the NeoPACT trial shows that angiogenesis plays an important role in primary resistance to chemoimmunotherapy, and that this impact is independent of immune upregulation. Patients with Im-High/Ang-Low tumors experienced a pCR rate exceeding 80%, and those with Im-Low/Ang-High tumors had pCR rates below 40%. Furthermore, paired pre-treatment/residual tumor analysis shows that induction of angiogenesis appears to be an escape mechanism contributing to acquired chemoimmunotherapy resistance, irrespective of immune status. These findings lay a strong biological rationale for targeting VEGF in addition to PD-1/PD-L1 in combination with chemotherapy in early-stage TNBC. Citation Format: P. Sharma, R. Yoder, J. M. Staley, R. Salgado, R. Madan, H. Pathak, A. K. Godwin, D. Koestler, Q. J. Khan, J. O'Shaughnessy, S. R. Stecklein. Angiogenesis contributes to chemoimmunotherapy resistance in immune-high and immune-low triple-negative breast cancer (TNBC): Biomarker analysis of the NeoPACT 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 PD6-06.
Sharma et al. (Tue,) studied this question.