Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases.
OBJECTIVE
A comprehensive comparison of biomarker expression between patients' primary breast carcinoma (PBC) and their metastatic breast carcinomas (MBC) has not been done.


METHODS
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 alpha, APC1, and RARbeta 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.
Wu
Julie M
JM
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Fackler
Mary Jo
MJ
Halushka
Marc K
MK
Molavi
Diana W
DW
Taylor
M Evangeline
ME
Teo
Wei Wen
WW
Griffin
Constance
C
Fetting
John
J
Davidson
Nancy E
NE
De Marzo
Angelo M
AM
Hicks
Jessica L
JL
Chitale
Dhananjay
D
Ladanyi
Marc
M
Sukumar
Saraswati
S
Argani
Pedram
P
D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor