HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

• Published in: BMC medicine 2022-03, Vol.20 (1), p.105-15, Article 105
• Main Authors: Tan, Ryan Shea Ying Cong, Ong, Whee Sze, Lee, Kyung-Hun, Lim, Abner Herbert, Park, Seri, Park, Yeon Hee, Lin, Ching-Hung, Lu, Yen-Shen, Ono, Makiko, Ueno, Takayuki, Naito, Yoichi, Onishi, Tatsuya, Lim, Geok-Hoon, Tan, Su-Ming, Lee, Han-Byoel, Ryu, Han Suk, Han, Wonshik, Tan, Veronique Kiak Mien, Wong, Fuh-Yong, Im, Seock-Ah, Tan, Puay Hoon, Chan, Jason Yongsheng, Yap, Yoon-Sim
• Format: Article
• Language: English
• Subjects: Analysis; Breast cancer; Breast Neoplasms - pathology; Care and treatment; Cohort Studies; Copy number variations; Diagnosis; DNA Copy Number Variations - genetics; ERBB2 neutral; Female; HER2-low breast cancer; Humans; METABRIC; Neoplasm Recurrence, Local; Prognosis; Risk factors; TCGA
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-022-02284-6

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). 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. 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. 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.