Abstract PO4-01-05: The prognostic importance of biological pathway enrichment patterns in trastuzumab-treated early HER2-positive breast cancer

Abstract Background: Biological tumor signatures of HER2-positive breast cancer may impact patients’ response to HER2 targeted treatment and are important to investigate since there is a need for both escalation and de-escalation of HER2-directed treatments. We aimed to examine subgroups of HER2-positive tumors based on different biological pathway enrichment patterns and their prognostic value. Materials and methods: In a retrospective cohort of 388 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, 356 HER2-positive FFPE samples were successfully analyzed for gene expression patterns using the Human nCounter Breast Cancer 360 panel (Nanostring Technologies). The raw data underwent extensive quality control and normalization in the nSolver software v. 4. 0 and its Advanced Analysis Module v. 2. 0 (NanoString Technologies). Unsupervised hierarchical agglomerative clustering was performed on pathway enrichment of nSolver customized biological process. Survival analysis for recurrence-free survival of pathway-driven clustered patients was examined using Kaplan-Meier and multivariable Cox regression models. Results: Four subgroups of patients with different biological pathway enrichment patterns were observed. The subgroup with the combination of low stromal and low immune biological pathways (Lowₛtromal/Lowᵢmmune) had a significantly worse prognosis than the Highₛtromal/Lowᵢmmune subgroup (RFS HR: 0. 4; CI: 0. 2-0. 9, p=0. 02) and Lowₛtromal/Highᵢmmune subgroup (RFS HR: 0. 4; CI: 0. 2-0. 9, p=0. 03). In addition, the subgroup with upregulation of both stromal and immune pathways (Highₛtromal/Highᵢmmune) showed a better response to trastuzumab than the Lowₛtromal/Lowᵢmmune subgroup even if not statistically significant (HR: 0. 4; CI: 0. 2-1. 0, p=0. 06). Moreover, the clusters of upregulated immune pathways showed the highest levels of tumor infiltrating lymphocytes. Conclusions: In this trastuzumab-treated early HER2-positive breast cancer cohort, we observed four subgroups with different biological pathway enrichment patterns. The subgroup with the combination of low stromal and low immune biological pathway enrichment was associated with a poorer prognosis than those mainly enriched with either stromal or immune pathways. This study shows the diversity of biological signatures within HER2-positive breast cancer, and results could potentially be used in future studies of HER2 target treatments. External validation is motivated. Citation Format: Caroline Rönnlund, Qiao Yang, Caroline Schagerholm, Theodoros Foukakis, Irma Fredriksson, Xinsong Chen, Stephanie Robertson, Emmanouil Sifakis, Johan Hartman. The prognostic importance of biological pathway enrichment patterns in trastuzumab-treated early HER2-positive breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84 (9 Suppl): Abstract nr PO4-01-05.