Biomarkers and Molecular Subtypes in Primary Breast Tumors and Metastases: Associations with Liver Metastases and Outcome

Abstract

Although discordant expression of biomarkers between a primary tumor and metastasis may significantly alter disease biology, personalization of therapy and prognosis after recurrence is mainly determined based on the primary tumor biomarker status. This study aimed to evaluate the prognostic relevance of metastasis-specific biomarkers and identify an estrogen receptor (ER) positive liver metastasis-specific gene signature. A cohort of 304 women with locally advanced and metastatic breast cancer was studied. ER, progesterone receptor (PR), HER2 and Ki67 expression were quantified in primary tumors (N = 217) by immunohistochemistry and in situ hybridization on tissue microarrays, and molecular subtypes were assigned according to the St Gallen guidelines 2013. In addition, fine-needle aspirates of metastases (N = 91) were transcriptionally profiled and intrinsic subtypes were determined using the PAM50 classifier. Overall, the expression of biomarkers and molecular subtypes was stable during tumor progression. However, amongst discordant cases, loss of expression at recurrence was significantly observed for ER [81% (17/21), P = 0.007] and PR [78% (32/41), P < 0.001]. Luminal A was the most unstable subtype, frequently changing to luminal B, albeit statistically non-significant [86% (6/7), P = 0.16]. Importantly, ER and molecular subtype at recurrence were both independent prognostic factors for post-recurrence survival (P < 0.01). Furthermore, hepatic recurrence was associated with the poorest survival and ER positive liver metastases displayed a distinct gene expression profile characterized by down-regulation of extracellular matrix and stroma-related genes. Interestingly, this liver-metastasis signature was prognostic for relapse-free and overall survival in hormone receptor positive primary disease, especially within the luminal A subtype. These results confirm that significant conversion of pathological biomarkers occurs across tumor progression stages and reveals the independent prognostic value of ER and molecular subtype at recurrence. In addition, a liver-metastasis signature with prognostic utility within the luminal A subtype was identified.