Tumor heterogeneity between primary and paired recurrent breast cancer and its potential molecular mechanism.

Abstract

e13177 Background: Breast cancer serves as a type of highly heterogeneous tumor. Patients with heterogeneity between primary and recurrent breast tumors have distinct survival outcomes. The study aims to analyze the heterogeneity of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2-), and molecular subtype between primary and recurrent breast tumors and explore associated transcriptomic mechanisms. Methods: Patients and related clinicopathological information were collected from three cancer centers in China. Transcriptomic markers correlated to tumor heterogeneity were assessed in five tumor cell-clustered regions from primary breast tumor tissues using GeoMx digital spatial profiling. Multiple statistical analyses were performed to investigate the tumor heterogeneity and its correlation with overall survival (OS). Results: Totally, 238 breast cancer patients with complete information about ER, PgR, and HER2 in primary and recurrent tumors were analyzed. Discordance rate was respectively 13.1%, 25.6%, 10.1% and 46.1% in ER, PgR, HER2, and molecular subtype between primary and recurrent breast tumors. Visceral metastases have higher heterogeneity compared with other metastatic organs. Three upregulated and six downregulated genes intersected in patients with visceral metastases. Pathway analyses showed that the nine genes were significantly enriched in ferroptosis, necroptosis, intracellular sequestering of iron ion and ferroxidase activity, mainly mediated by the upregulated FTH1. OS was not significantly different between patients with concordant ER, PgR, HER2, and molecular subtype versus those with discordant characteristics in primary and recurrent tumors. In the patient population with recurrent tumors from visceral organs, patients with discordant PgR as compared to primary breast tumors had worse OS of 4.4 years versus 5.7 years in patients with concordant PgR (p = 0.04, HR = 0.53, 95%CI = 0.29-0.97). Conclusions: Tumor heterogeneity of ER, PR, HER2 and molecular subtypes exists between primary and recurrent breast tumors, as well as different metastases organs. Visceral metastases of the liver or lung obtain higher heterogeneity, where overexpressed FTH1 has the potential to be involved in the heterogeneity within visceral metastases. Discordant PgR in recurrent tumors from visceral organs leads to worse OS.