Heterogeneity of Breast Cancer Metastases: Comparison of Therapeutic Target Expression and Promoter Methylation Between Primary Tumors and Their Multifocal Metastases

Abstract

Purpose: A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done. Experimental Design: We did rapid autopsies (postmortem intervals,1-4 hours) on10 consenting patients who died of MBC.We constructed single-patient tissue microarrays from the patients' archived PBC and multiple different MBCs harvested at autopsy, which were immunohistochemically labeled for multiple biomarkers. Methylation of multiple gene promoters was assessed quantitatively on dissected PBC and MBC samples. Results: Extensive heterogeneity was observed between PBC and their paired MBC, as well as among multiple MBC from the same patient. Estrogen and progesterone receptors tended to be uniformly down-regulated in metastases. E-cadherin was down-regulated in a subset of the MBC of one case.Variable overexpression in MBC compared with the PBC was observed for cyclooxygenase-2 (five cases), epidermal growth factor receptor (EGFR; four cases), MET (four cases), and mesothelin (four cases). No case strongly overexpressed HER-2/neu by immunohistochemistry, but eight cases showed variable protein expression ranging from negative to equivocal (2+) in different MBC. In one case, variable low-level HER-2/neu gene amplification was found. EGFR and METoverexpression were restricted to the four basal-type cancers. EGFR protein overexpression did not correlate with EGFR gene amplification. Multigene promoter hypermethylation of RASSF1a, HIN1, cyclin D2,Twist, estrogen receptor a, APC1, and RARb was overall very similar in the PBC and all MBCs in all cases. Conclusions: Therapeutic targets identified in the PBC or even some MBC may not reflect targets present in all metastatic sites.

Expression of wingless-type mouse mammary tumor virus integration site family pathway effectors in lymphatic and hepatic metastases of patients with colorectal cancer: Associations with the primary tumor

“…Similar findings were reported by Wu et al (21) comparing the therapeutic target expression and promoter methylation between primary breast tumors and their multifocal metastases. Notably, the study showed that therapeutic targets identified in the primary breast tumors do not reflect targets present in the metastatic sites.…”

HER2 status in a population-derived breast cancer cohort: discordances during tumor progression

“…Tumor cell heterogeneity has been observed in some series and could explain discordances in HER2 status between primary tumor and recurrence [25,26]. According to Wu et al primary tumors, as well as recurrences, are heterogeneous, with foci with variable morphology and marker expressions.…”

Seize the opportunity

“…In metastatic breast cancer, it has been demonstrated that expression of estrogen/progesterone receptors and EGFR may be significantly different in metastatic lesions than in the primary tumor, which may impact therapeutic decisions. 37 In addition to this advanced disease setting, patients receiving neoadjuvant therapy may be good candidates for molecular testing of FNA samples. Such patients may demonstrate a complete pathologic response to the therapy upon surgical resection, with minimal or no residual tumor, placing increased importance on the molecular characterization of the initial biopsy.…”