Discordance of HER2-low between primary tumors and matched distant metastases in breast cancer

Abstract Background: Novel antibody-drug conjugates (ADCs) show activity in HER2-low advanced breast cancer. We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative cohort (HER2-low and HER2-zero). Patients and Methods: The retrospective study included 191 consecutive paired samples of primary breast cancer (BC) and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic BC. The relationship was determined by cross-tabulation and calculation of Cohen's kappa coefficient. Results: The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n=78), metastatic samples 73.5% (n=86)]. The discordance rate between HER2 status of primary tumors and corresponding distant metastases was 49.6% (n=63) (kappa -0.003, 95%CI -0.15 - 0.15). Development of a HER2-low phenotype occurred most frequently (n=52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n=34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites (with the exception of lung/pleural metastases) and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (kappa 0.48, 95%CI 0.27 - 0.69) versus 50.5% (kappa 0.14, 95% CI -0.03 - 0.32)]. Conclusion: In HER2-negative BC, there is a significant discrepancy between primary tumor and distant metastases. In particular, for the HER2-low cohort, biopsy of metastases opens new therapeutic opportunities with novel ADCs such as trastuzumab-deruxtecan.