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

• Published in: Clinical cancer research Vol. 14; no. 7; pp. 1938 - 1946
• Main Authors: WU, Julie M, FACKLER, Mary Jo, HICKS, Jessica L, CHITALE, Dhananjay, LADANYI, Marc, SUKUMAR, Saraswati, ARGANI, Pedram, HALUSHKA, Marc K, MOLAVI, Diana W, TAYLOR, M. Evangeline, WEI WEN TEO, GRIFFIN, Constance, FETTING, John, DAVIDSON, Nancy E, DE MARZO, Angelo M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2008
• Subjects: Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - analysis; Breast; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; DNA Methylation; Female; Gene Expression; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Mammary gland diseases; Medical sciences; Metastasis; Methylation; Middle Aged; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Pharmacology. Drug treatments; Promoter Regions, Genetic; Rapid autopsy; Tissue Array Analysis; Tumors; Breast disease; Targeting; Transcription promoter; Targeted therapy; Breast cancer; Metastasis; Malignant tumor; Gene expression; Mammary gland diseases; Heterogeneity; Primary; Methylation; Comparative study; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4082

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) on 10 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 MET overexpression 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 α, APC1 , and RARβ 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.