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Clinical Genetic Features and Neoadjuvant Chemotherapy Response in HER2-Low Breast Cancers: A Retrospective, Multicenter Cohort Study

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The objective of this work is to reveal differences in clinical and genetic features, as well as neoadjuvant chemotherapy (NAC) response, between HER2-low and HER2-zero or HER2-positive breast cancers.

Patients and Methods

A total of 245 female patients with breast cancer were retrospectively enrolled from seven hospitals. Core needle biopsy (CNB) samples were collected before NAC and used for next-generation sequencing by a commercial gene panel. Clinical and genetic features, as well as NAC response, were compared between HER2-low and HER2-zero or HER2-positive breast cancers. The nonnegative matrix factorization (NMF) method was applied to cluster the C-Score of enrolled cases to reveal the intrinsic features of each HER2 subgroup.

Results

A total of 68 (27.8%) cases are HER2-positive, 117 (47.8%) cases are HER2-low, and 60 (24.5%) cases are HER2-zero. HER2-low breast cancers have a significantly lower pathologic complete response (pCR) rate than HER2-positive and HER2-zero breast cancers (p < 0.050 for all comparisons). Compared with HER2-low breast cancers, HER2-positive cases have higher rates of TP53 mutation, TOP2A amplification, and ERBB2 amplification, as well as lower rates of MAP2K4 mutation, ESR1 amplification, FGFR1 amplification, and MAPK pathway alteration (p < 0.050 for all comparisons). After clustering HER2-low cases by the NMF method, 56/117 (47.9%) are in cluster 1, 51/117 (43.6%) are in cluster 2, and 10/117 (8.5%) are in cluster 3. HER2-low cases in cluster 2 have the lowest pCR rate among the three clusters (p < 0.050).

Conclusions

HER2-low breast cancers have significant genetic differences from HER2-positive cases. Genetic heterogeneity exists in HER2-low breast cancers and impacts on NAC response in this subgroup.

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Acknowledgment

We thank Burning Rock Biotech (Guangzhou, China) for providing NGS detection and raw data analyses.

Funding

This study was supported by 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18012/ZYJC1035), Interdisciplinary Crossing and Integration of Medicine and Engineering for Talent Training Fund, West China Hospital, Sichuan University (ZYGX2022YGRH015), and Sichuan Provincial Natural Science Foundation Project (2022NSFSC1484).

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Author notes

  1. Libo Yang and Yuqiong Liu have contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610000, Sichuan Province, People’s Republic of China

    Libo Yang MD, PhD & Feng Ye PhD

  2. Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, 450002, Henan Province, People’s Republic of China

    Yuqiong Liu MS & Wencai Li MD, PhD

  3. Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei Province, People’s Republic of China

    DanDan Han MM & Yue** Liu MD, PhD

  4. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cellular & Molecular Diagnostic Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People’s Republic of China

    Sha Fu MD & Huan Wan BS

  5. Department of Pathology, ** Guo MD, PhD & Zhe Wang MD, PhD

  6. Department of Pathology, Department of Oncology/Institute of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, People’s Republic of China

    Longlong Bao MS & **aoyan Zhou MD, PhD

  7. Department of Molecular Pathology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, 350014, Fujian Province, People’s Republic of China

    Yi Shi PhD, Rongfang Huang MS & Gang Chen MD, PhD

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  1. Libo Yang MD, PhD
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Correspondence to Yue** Liu MD, PhD or Feng Ye PhD.

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Yang, L., Liu, Y., Han, D. et al. Clinical Genetic Features and Neoadjuvant Chemotherapy Response in HER2-Low Breast Cancers: A Retrospective, Multicenter Cohort Study. Ann Surg Oncol 30, 5653–5662 (2023). https://doi.org/10.1245/s10434-023-13311-y

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