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. 2023 Jun;199(3):603-615.
doi: 10.1007/s10549-023-06931-1. Epub 2023 Apr 21.

Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment

Chi Xu #  1 , Yahui Wang #  2 , Yuanyuan Hong  2 , Ru Yao  1 , Lijia Wu  2 , Xi Shen  1 , Yang Qu  1 , Zhuo Zhang  2 , Wei Zhu  2 , Ying Yang  2 , Weizhi Chen  2 , Yidong Zhou  3 , Zhiyong Liang  4
Affiliations

Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment

Chi Xu et al. Breast Cancer Res Treat. 2023 Jun.

Abstract

Purpose: To determine the genetic and immune features associated with the recurrence of human epidermal growth factor receptor2-positive (HER2 +) breast cancer (BC) after trastuzumab-based treatment.

Methods: A retrospective cohort study of 48 patients who received trastuzumab-based treatment was divided into recurrent and non-recurrent groups according to clinical follow-up. Baseline samples from all 48 patients were analyzed for genetic variation, HLA allele type, gene expression, and immune features, which were linked to HER2 + BC recurrence. Statistics included logistic regression models, Kaplan-Meier plots, and Univariate Cox proportional hazards models.

Results: Compared with the non-recurrent group, the extracellular matrix-related pathway and 3 Hallmark gene sets were enriched in the recurrent group. The infiltration levels of immature B cells and activated B cells were significantly increased in the non-recurrent group, which correlated remarkably with improved overall survival (OS) in two other published gene expression datasets, including TCGA and METABRIC. In the TCGA cohort (n = 275), activated B cells (HR 0.23, 95%CI 0.13-0.43, p < 0.0001), and immature B cells (HR 0.26, 95%CI 0.12-0.59, p < 0.0001). In the METABRIC cohort (n = 236), activated B cells (HR 0.60, 95%CI 0.43-0.83, p = 0.002), and immature B cells (HR 0.65, 95%CI 0.47-0.91, p = 0.011). Cox regression suggested that immature B cells and activated B cells were protective factors for outcome OS.

Conclusions: Aberrant activation of multiple pathways and low baseline tumor-infiltrating B cells are related to HER2 + BC trastuzumab-based recurrence, which primarily affects the antitumor activity of trastuzumab.

Keywords: HER2-positive breast cancer; Innate anti-PD-1 resistance signature; Recurrence; Trastuzumab; Tumor-infiltrating B cells.

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