Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in patients with HER2+ early breast cancer (EBC).

Abstract

Background: In HER2+ early breast cancer (EBC), we investigated tumor and immune changes during neoadjuvant treatment and their impact on residual disease (RD) biology and prognostic implications across 4 neoadjuvant studies of trastuzumab with or without lapatinib, and with or without chemotherapy: CALGB 40601, PAMELA, NeoALTTO and NSABP B-41.

Patients and methods: We compared tumor and immune gene expression changes during neoadjuvant treatment and their association with with event-free survival (EFS) by uni- and multivariable Cox regression models in different cohorts and timepoints: 452 RD samples at baseline including 169 with a paired RD, and biomarker changes during neoadjuvant therapy, evaluating model performance via the c-index.

Results: Analysis of 169 paired tumor samples revealed a shift in intrinsic subtype proportions from HER2-Enriched at baseline (50.3%) to Normal-like (49.1%) followed by Luminal A (18.9%) in RD. This luminal phenotypic change was supported by decreased correlation to the HER2-Enriched centroid, ERBB2, and HER2 amplicon genes and increased correlation to the Luminal A centroid (Wilcoxon-test p-value < 0.001). Additionally, RD showed relative immune activation marked by significant increases in B cell, CD8 T cell, and NK cell signatures (Wilcoxon-test p-value < 0.05). In multivariable Cox models, intrinsic subtypes at baseline provided more prognostic information, while immune gene expression signatures provided more prognostic information in RD. Notably, the best multivariable EFS model (c-index = 0.77) integrated the IgG signature from RD samples (adjusted hazard ratio 0.45, 95% CI 0.30-0.67, adjusted p-value 0.002).

Conclusions: In patients with HER2+ EBC and RD, tumor biomarkers provide more prognostic information at baseline. In contrast, immune biomarkers perform better for EFS prognosis in RD.