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Clinical implications of HER2 mRNA expression and intrinsic subtype in refractory HER2-positive metastatic breast cancer treated with pan-HER inhibitor, poziotinib

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Abstract

Introduction

We explored clinical implication of intrinsic molecular subtype in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer (BC) with pan-HER inhibitor from a phase II clinical trial of poziotinib in refractory HER2+BC patients.

Methods

For this translational research correlated with phase II clinical trial, we performed an nCounter expression assay, using gene panel including 50 genes for PAM50 prediction and targeted deep sequencing.

Results

From 106 participants, we obtained 97 tumor tissues and analyzed gene expression in 91 of these samples. Of 91 HER2+BCs, 40 (44.0%) were HER2-enriched (E) intrinsic molecular subtype, 17 (18.7%) of Luminal A, 16 (17.6%) of Basal-like, 14 (15.4%) of Luminal B and 4 (4.4%) of Normal-like. HER2-E subtype was associated with hormone receptor negativity (odds ratio [OR] 2.93; p = 0.019), 3 + of HER2 immunohistochemistry(IHC) (OR 5.64; p = 0.001), high mRNA expression of HER2 (OR 14.43; p = 0.001) and copy number(CN) amplification of HER2 (OR 12.80; p = 0.005). In genetic alterations, alteration was more frequently observed in HER2-E subtype (OR 3.84; p = 0.022) but there was no association between PIK3CA alteration and HER2-E subtype (p = 0.655). In terms of drug efficacy, high mRNA expression of HER2 was the most powerful predictor of poziotinib response (median progression-free survival [PFS): 4.63 months [high] vs. 2.56 [low]; p < .001). In a combination prediction model, median PFS of intrinsic subtypes except Her2-E with high HER2 mRNA expression without PIK3CA genetic alteration was 6.83 months and that of the remaining group was 1.74 months (p < .001).

Conclusion

HER2-E subtype was associated with hormone receptor status, HER2 IHC, CN and mRNA expression and TP53 mutation. In survival analysis, the information of level of HER2 mRNA expression, intrinsic molecular subtype and PI3K pathway alteration would be independent predictors to poziotinib treatment.

ClinicalTrials.gov identifier: NCT02418689.

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Funding

This study was sponsored by National OncoVenture (NOV) (NOV120101-203) and Hanmi Pharmaceutical Co., Ltd., Seoul, Korea. This work was supported by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) in 2020.

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Author notes

  1. Ji-Yeon Kim and Kyunghee Park have contributed equally to this study.

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea

    Ji-Yeon Kim & Yeon Hee Park

  2. Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Kyunghee Park

  3. Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University School of Medicine, Seoul, 03080, Korea

    Seock-Ah Im

  4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea

    Kyung Hae Jung

  5. Department of Internal Medicine, Yonsei Cancer Center, Seoul, 03722, Korea

    Joohyuk Sohn

  6. Center for Breast Cancer, National Cancer Center Hospital, Goyang, 10408, Korea

    Keun Seok Lee

  7. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 13620, Korea

    Jee Hyun Kim

  8. Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, 28644, Korea

    Yaewon Yang

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  1. Ji-Yeon Kim
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Correspondence to Yeon Hee Park.

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Supplementary file1 (DOCX 26 kb)

10549_2020_5891_MOESM2_ESM.tif

Supplementary file2 (TIF 84 kb) Supplementary Figure 1. Consort diagram and tissue status of exploratory biomarker analysis

10549_2020_5891_MOESM3_ESM.tif

Supplementary file3 (TIF 153 kb) Supplementary Figure 2. Univariate analysis according to (A) PIK3CA mutation (B) TP53 mutation (C) PIK3CA pathway alteration and (D) TP53 deleterious mutation

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Kim, JY., Park, K., Im, SA. et al. Clinical implications of HER2 mRNA expression and intrinsic subtype in refractory HER2-positive metastatic breast cancer treated with pan-HER inhibitor, poziotinib. Breast Cancer Res Treat 184, 743–753 (2020). https://doi.org/10.1007/s10549-020-05891-0

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