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

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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.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

BC:

Breast cancer

HER2 + :

HER2-positive

TILs:

Tumor-infiltrating lymphocytes

FFPE:

Formalin-fixed, paraffin-embedded

SNV:

Single-nucleotide variants

CNAs:

Copy number alterations

ExAC:

Exome Aggregation Consortium

gnomAD:

Genome Aggregation Database

CNV:

Copy number variation

KEGG:

Kyoto encyclopedia of genes and genomes

GO:

Gene ontology

BP:

Biological process,

CC:

Cellular component

MF:

Molecular function

ECM:

Extracellular matrix

OS:

Overall survival

ADCC:

Antibody-dependent cytotoxic cells

IDC:

Invasive ductal carcinoma

FAK1 :

Focal Adhesion Kinase

RTK:

Receptor tyrosine kinases

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Author notes

  1. Chi Xu and Yahui Wang have contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Breast Surgery, Peking Union Medical College Hospital, Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Chi Xu, Ru Yao, Xi Shen, Yang Qu & Yidong Zhou

  2. Genecast Biotechnology Co., Ltd, Wuxi, Jiangsu, China

    Yahui Wang, Yuanyuan Hong, Lijia Wu, Zhuo Zhang, Wei Zhu, Ying Yang & Weizhi Chen

  3. Department of Pathology, Peking Union Medical College Hospital, Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Zhiyong Liang

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Contributions

CX and YW conceived and designed the study. YH and RY supervised and administrated the project. LW, XS, YQ, and ZZ conducted the experiments, and WZ, YY, and WC acquired and analyzed the data. YZ and ZL drafted the manuscript.

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Correspondence to Yidong Zhou or Zhiyong Liang.

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Supplementary file1 (TIF 13069 KB)—Fig. S1 Cluster heatmap of the DEGs in recurrent and non-recurrent HER2+ BC patients

10549_2023_6931_MOESM2_ESM.tif

Supplementary file2 (TIF 10910 KB)—Fig. S2 GSEA of Hallmark gene sets in recurrent and non-recurrent HER2+ BC patients. Significantly enriched signaling pathways were revealed by gene set enrichment analysis. At the top of the plot is the run enrichment score (ES) for the gene set, and the score at the peak (the score furthest from 0.0) represents the ES for the entire gene set. The middle section shows where the members of the genome appear in the sorted list of genes. The bottom portion of the plot shows that the value of the ranking metric decreases as the value of the ranking gene list reduces

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Xu, C., Wang, Y., Hong, Y. et al. Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment. Breast Cancer Res Treat 199, 603–615 (2023). https://doi.org/10.1007/s10549-023-06931-1

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