Heterogeneity of breast cancer metastases

Comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases

Julie M. Wu, Mary Jo Fackler, Marc K Halushka, Diana Weedman Molavi, M. Evangeline Taylor, Wen Teo Wei, Constance Griffin, John H Fetting, Nancy E. Davidson, Angelo Michael Demarzo, Jessica L. Hicks, Dhananjay Chitale, Marc Ladanyi, Saraswati Sukumar, Pedram Argani

Research output: Contribution to journalArticle

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) 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 inmetastases. 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.

Original languageEnglish (US)
Pages (from-to)1938-1946
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number7
DOIs
StatePublished - Apr 1 2008

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Methylation
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Therapeutics
erbB-2 Genes
Gene Amplification
Estrogen Receptors
Autopsy
Biomarkers
Cyclin D2
erbB-1 Genes
Progesterone Receptors
Cadherins
Cyclooxygenase 2
Epidermal Growth Factor Receptor
Proteins
Research Design
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Heterogeneity of breast cancer metastases : Comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. / Wu, Julie M.; Fackler, Mary Jo; Halushka, Marc K; Molavi, Diana Weedman; Taylor, M. Evangeline; Wei, Wen Teo; Griffin, Constance; Fetting, John H; Davidson, Nancy E.; Demarzo, Angelo Michael; Hicks, Jessica L.; Chitale, Dhananjay; Ladanyi, Marc; Sukumar, Saraswati; Argani, Pedram.

In: Clinical Cancer Research, Vol. 14, No. 7, 01.04.2008, p. 1938-1946.

Research output: Contribution to journalArticle

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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) 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 inmetastases. 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.",
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T1 - Heterogeneity of breast cancer metastases

T2 - Comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases

AU - Wu, Julie M.

AU - Fackler, Mary Jo

AU - Halushka, Marc K

AU - Molavi, Diana Weedman

AU - Taylor, M. Evangeline

AU - Wei, Wen Teo

AU - Griffin, Constance

AU - Fetting, John H

AU - Davidson, Nancy E.

AU - Demarzo, Angelo Michael

AU - Hicks, Jessica L.

AU - Chitale, Dhananjay

AU - Ladanyi, Marc

AU - Sukumar, Saraswati

AU - Argani, Pedram

PY - 2008/4/1

Y1 - 2008/4/1

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AB - 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 inmetastases. 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.

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