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