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.

INTRODUCTIONWhile overexpression of syndecan-1 has been associated with aggressive breast cancer in the Caucasian population, the expression pattern of syndecan-1 in Asian women remains unclear. Triple-positive breast carcinoma, in particular, is a unique subtype that has not been extensively studied. We aimed to evaluate the role of syndecan-1 as a potential biomarker and prognostic factor for triple-positive breast carcinoma in Asian women.METHODS Using immunohistochemistry, staining scores of 61 triple-positive breast carcinoma specimens were correlated with patients' clinicopathological variables such as age, ethnicity, tumour size, histological grade, lymph node status, lymphovascular invasion, associated ductal carcinoma in situ grade, recurrence and overall survival. RESULTS Syndecan-1 had intense staining scores in triple-positive invasive ductal breast carcinomas when compared to normal breast tissue. On multivariate analysis, syndecan-1 epithelial total percentage and immunoreactivity score showed statistical correlation with survival (p = 0.02). CONCLUSIONThe intense staining scores of syndecan-1 and their correlation with overall survival in patients with triplepositive breast carcinoma suggest that syndecan-1 may have a role as a biological and prognostic marker in patients with this specific subtype of breast cancer.