HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis
Ryan Shea Ying Cong Tan,
Whee Sze Ong,
Kyung-Hun Lee,
Abner Herbert Lim,
Seri Park,
Yeon Hee Park,
Ching-Hung Lin,
Yen-Shen Lu,
Makiko Ono,
Takayuki Ueno,
Yoichi Naito,
Tatsuya Onishi,
Geok-Hoon Lim,
Su-Ming Tan,
Han-Byoel Lee,
Han Suk Ryu,
Wonshik Han,
Veronique Kiak Mien Tan,
Fuh-Yong Wong,
Seock-Ah Im,
Puay Hoon Tan,
Jason Yongsheng Chan,
Yoon-Sim Yap
Affiliations
Ryan Shea Ying Cong Tan
Division of Medical Oncology, National Cancer Centre Singapore
Whee Sze Ong
Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore
Kyung-Hun Lee
Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
Abner Herbert Lim
Cancer Discovery Hub, National Cancer Centre Singapore
Seri Park
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University
Yeon Hee Park
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University
Ching-Hung Lin
Department of Oncology, National Taiwan University Hospital
Yen-Shen Lu
Department of Oncology, National Taiwan University Hospital
Makiko Ono
Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research
Takayuki Ueno
Breast Surgical Oncology, Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research
Yoichi Naito
Department of Medical Oncology, National Cancer Center Hospital East
Tatsuya Onishi
Department of Breast Surgery, National Cancer Center Hospital East
Geok-Hoon Lim
Breast Department, KK Women’s and Children’s Hospital
Su-Ming Tan
Sing Health Duke-NUS Breast Centre
Han-Byoel Lee
Department of Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
Han Suk Ryu
Department of Pathology, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
Wonshik Han
Department of Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
Veronique Kiak Mien Tan
Sing Health Duke-NUS Breast Centre
Fuh-Yong Wong
Division of Radiation Oncology, National Cancer Centre Singapore
Seock-Ah Im
Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine
Puay Hoon Tan
Division of Pathology, Singapore General Hospital
Jason Yongsheng Chan
Division of Medical Oncology, National Cancer Centre Singapore
Yoon-Sim Yap
Division of Medical Oncology, National Cancer Centre Singapore
Abstract Background HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC). Methods Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH−) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH− status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS. Results ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82–0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76–0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85–0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79–0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83–0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78–0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH− and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59–0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found. Conclusions HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.
