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Combined analysis of receptor expression reflects inter-and intra-tumor heterogeneity in HR+/HER2+ breast cancer

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Abstract

Background

Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5–10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched subtype in patients with HR+/HER2+ breast cancer.

Methods

First of all, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n = 141) and METABRIC (n = 104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. From this, we constructed a novel marker termed rH/E, which was calculated as ERBB2 expression quantity/(ESR1 expression quantity + 1). Secondly, we performed multiplex immunofluorescence (mIF) to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). When using mIF, rH/E was adjusted to prH/E, which was calculated as HER2-positive cells%/(ER-positive cells + 1)%.

Results

All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal B subtype was the most common, followed by the HER2-enriched and luminal A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2−, ER+/HER2+, ER−/HER2+, and ER−/HER2−. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, prH/E showed a significant prognostic association in the CAMS cohort.

Conclusions

This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+ breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

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Data availability

Data available from the authors upon reasonable request and with permission of National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in China.

Abbreviations

TCGA:

The Cancer Genome Atlas

METABRIC:

Molecular Taxonomy of Breast Cancer International Consortium

ERBB2/HER2:

Human epidermal growth factor receptor 2

ER:

Estrogen receptor

PR:

Progesterone receptor

ERBB3/HER3:

Human epidermal receptor 3

PI3K:

Phosphatidylinositol 3-kinase

TP53:

Tumor protein p53

mTORC1:

Mechanistic target of rapamycin complex 1

TNF-α:

Tumor necrosis factor-alpha

EMT:

Epithelial mesenchymal transition

RNA-seq:

RNA sequencing

DEGs:

Differentially expressed genes

IHC:

Immunohistochemistry

mIF:

Multiplex immunofluorescence

HE:

Hematoxylin–eosin

ROC:

Receiver operating characteristic

AUC:

Area under the receiver operating characteristic curve

HR:

Hormone receptor or hazard ratio

CI:

Confidence interval

DFS:

Disease-free survival

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Acknowledgements

The authors acknowledge and express their deepest gratitude to all participants of this study.

Funding

This work was supported by the National Key R&D Program of China (2018YFC0115204), the National Natural Science Foundation of China (81672634), the CSCO Pilot Oncology Research Fund (Y-2019AZMS-0377), the Capital Health Development Research Project (2018-2-4023), and the National Natural Science Foundation of China (82172650).

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Author notes

  1. Jie Ju and Feng Du have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Jie Ju, Song-Lin Gao, Yi-Ran Si, Nan-Lin Hu, Fang-Chao Zheng, Yi-Kun Kang, Zi-Xuan Yang, Fei Ma & Bing-He Xu

  2. Department of VIP Medical Services, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Jie Ju, Xue Wang, Jian Yue & Peng Yuan

  3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, 100142, China

    Feng Du

  4. School of Science, Auckland University of Technology, Auckland, 1010, New Zealand

    Dong-Xu Liu

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  1. Jie Ju
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Contributions

Study design: JJ, FD, D-XL and PY. Experiment: JJ and FD. Data collection: Y-RS, N-LH, D-XL, XW, JY, F-CZ, Y-KK, Z-XY, FM and B-HX. Data analysis: JJ, FD and S-LG. Draft writing: JJ, FD and PY. Final revision: PY. All authors read and approved the final version of the manuscript, and agreed with the order of presentation of the authors.

Corresponding author

Correspondence to Peng Yuan.

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The study was approved by the independent Ethics Committee/Institutional Review Board of CAMS (20/272-2468).

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Ju, J., Du, F., Gao, SL. et al. Combined analysis of receptor expression reflects inter-and intra-tumor heterogeneity in HR+/HER2+ breast cancer. Breast Cancer Res Treat 194, 221–230 (2022). https://doi.org/10.1007/s10549-022-06629-w

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