关键词: 乳腺癌, 肝转移, 肿瘤异质性, 预后, 分子分型

Abstract:

Background and purpose: Systematic treatment for breast cancer largely depends on the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Discordance in ER, PR and HER2 status between primary breast cancer and distant metastases has been observed in a proportion of patients in previous studies. Liver is one of the frequent metastatic sites of breast cancer. Currently, limited data are available on the receptor conversion between primary breast cancer and matched liver metastases. This study aimed to investigate the prevalence, risk factors and prognostic impact of receptor conversion between primary breast cancer and paired liver metastases. Methods: The data of breast cancer patients who had pathologically confirmed liver metastases from January 2013 to May 2020 at Fudan University Shanghai Cancer Center were retrospectively collected. A total of 353 patients with ER, PR and HER2 status available on both primary breast cancer and matched liver metastases were finally included in this study. ER, PR and HER2 status were interpreted according to the most updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. The evolution of receptor status and phenotype from primary to metastatic breast cancer was illustrated using Sankey diagrams. Kappa coefficient and McNemar’s test were used to assess the agreement on receptor status between primary breast cancer and liver metastases. The Kaplan-Meier curves were plotted and survival differences across each group were assessed by log-rank test. Multivariate analyses were performed based on the COX proportional hazard regression model. Results: The total discordance rate of ER, PR and HER2 was 19.5%, 39.4% and 4.8%, respectively (Kappa coefficient: 0.569, 0.258 0.876). In de novo stage Ⅳ patients, the discordance rate of ER, PR and HER2 was 15.2%, 28.3% and 2.2%, respectively. Multivariate analysis showed that previous endocrine therapy before liver re-biopsy was an independent risk factor of PR discordance. None of the variables of interest was found to be associated with discordance in ER or HER2 status. Additionally, 37.9% of the HER2-0 tumors converted to HER2-low. A trend of increase in triple-negative and decrease in hormone receptor (HR)+/HER2- cases were observed in liver metastases. Patients with HR+/HER2- primary breast cancer who converted to triple-negative in liver metastases had a significantly shorter overall survival (OS) than those with consistent HR+/HER2- subtype. Patients with the same subtype in liver metastases shared similar OS. Conclusion: This study confirmed discordance in ER, PR and HER2 status between primary breast cancer and liver metastases. The prognosis of breast cancer patients was determined mainly by the subtype in metastases rather than that in primary disease. Our study underlined the necessity of liver re-biopsy in de novo stage Ⅳ patients with liver metastases. Over one-third of HER2-0 patients converted to HER2-low in liver metastases after reassessment, which enabled them to be treated with new antibody-drug conjugate (ADC).

Key words: Breast cancer, Liver metastases, Tumor heterogeneity, Prognosis, Molecular subtype