Molecular analysis of metaplastic breast carcinoma: high <i>EGFR</i> copy number via aneusomy

Gilbert, Judith A; Goetz, Matthew P.; Reynolds, Carol; Ingle, James N.; Giordano, Karin F.; Suman, Vera J.; Blair, Hilary; Jenkins, Robert B.; Lingle, Wilma L.; Reinholz, Monica M.; Adjei, Alex A.; Ames, Matthew M.

doi:10.1158/1535-7163.mct-07-0570

Cited by 66 publications

(66 citation statements)

References 34 publications

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“…The tumors were rich in mitotic figures with an average mitotic count of 31/10 HPFs. The histopathological features observed in our series are similar to the description in the previous studies (4,5,7,15,16,21,22). in addition, 3 cases had a central scar, 5 had central necrosis, 7 had geographic necrosis and 6 had a pushing growth pattern.…”

Section: Discussionsupporting

confidence: 89%

“…Therefore, an immunohistochemical panel, proposed by Carey et al, including estrogen receptor (Er), progesterone receptor (Pr), human epidermal growth factor receptor-2 (HEr2), epidermal growth factor receptor (EGFr) and cytokeratin 5/6 (CK 5/6), was widely accepted for use in identifying breast carcinomas with basal-like immunophenotype as defined by cDna microarrays (12). in the meantime, MCs have been shown to be a part of the spectrum of basal-like breast carcinomas, since they usually display a basal/myoepithelial and epithelial to mesenchymal molecular make-up (13,14), basal-like immunophenotype, and triple negativity and often show expression of EGFr, CK14 and CK5/6 (15,16).…”

Section: Introductionmentioning

confidence: 99%

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Metaplastic breast carcinomas and their relationship with basal-like phenotype

Çakır

Gönül²,

Uluoğlu³

2012

TJPATH

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Objective: Metaplastic carcinoma is a rare tumor showing high histological grade and low hormone receptor expression. it has pure epithelial and mixed types. Studies have suggested that metaplastic carcinomas may have a basal-like profile. our aim was to evaluate the clinicopathological features of 11 metaplastic carcinomas and determine their resemblance to basal-like breast carcinomas regarding their morphological and immunohistochemical profile. Material and Method:Eleven metaplastic carcinoma cases were reviewed for their histopathological features. all tumors but one were evaluated for the immunohistochemical expressions of the cytokeratin 5/6, cytokeratin 14 and epidermal growth factor receptor; and hormonal status was assessed.Results: Four of eleven cases were carcinoma with chondroid metaplasia, 3 were adenosquamous carcinoma, 2 were squamous cell carcinoma and 2 were carcinosarcoma. The mean patient age was 53 years and the mean tumor size was 5,1 cm. Histological grade was 3 for all with a nuclear grade of 3. average mitotic count was 31/10 high power fields. Four cases had a central scar, 5 had central necrosis and 7 had geographic necrosis. Tumor growth pattern was pushing in 6 cases and no carcinoma in-situ was identified in 5 cases. Seven of 10 patients had axillary lymph node metastasis. Seven of 10 cases were triple-negative (estrogen receptor-, progesterone receptor-, HEr2-) and 6 of them were positive for cytokeratin 5/6 and/or epidermal growth factor receptor, consistent with basal-like immunophenotype. Cytokeratin 14 was positive in 7 cases. Conclusion:Metaplastic carcinomas are large-sized, high-grade tumors with prominent nuclear pleomorphism and frequent mitosis. They rarely overexpress hormone receptors and HEr2 and generally have basal-like immunophenotype.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Çakır

Gönül²,

Uluoğlu³

2012

TJPATH

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“…[42], CD44 [43] and epidermal growth factor receptor (EGFR) [36]. In a minority of cases, they harbour EGFR gene amplification [8] or aneusomy [44]. Basal-like tumours may express genes characteristic of luminal epithelia, including cytokeratin 8/18, albeit at lower levels than luminal carcinomas, as well as KIT, which is expressed by luminal ER-negative epithelia [45].…”

Section: Class Discovery Studies: Moving Away From Histopathology?mentioning

confidence: 99%

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade

Weigelt

Baehner

Reis‐Filho

2009

The Journal of Pathology

395

355

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In the last decade, the development of microarrays and the ability to perform massively parallel gene expression analysis of human tumours were received with great excitement by the scientific community. The promise of microarrays was of apocalyptic dimensions, with some experts envisaging that it would be a matter of a few years for this technology to replace traditional clinicopathological markers in clinical practice and treatment decision-making. The replacement of histopathology by high-tech and more objective approaches to cancer diagnosis, prognostication and prediction was, at that time, a foregone conclusion. Ten years after the initial publications of translational research studies using microarrays, one cannot deny that this technology has changed the way breast cancer is perceived. It has brought the concept of breast cancer heterogeneity to the forefront of cancer research, and the fact that distinct subtypes of breast cancer are completely different diseases that affect the same anatomical site. Furthermore, it has led to the development of prognostic and predictive 'gene signatures', which are yet to be fully incorporated into clinical practice. Importantly, though, the prognostic and predictive power of microarrays has been shown to be complementary to, rather than a replacement for, traditional clinicopathological parameters. Here we endeavour to provide a fair and balanced assessment of what microarray-based gene expression analysis has taught us in the last decade and its contribution to breast cancer classification, prognostication and prediction.

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“…NET TMA sections (5 m) were analyzed by FISH for EGFR and HER-2/neu copy number by the Cytogenetics Shared Resource Laboratory, Mayo Clinic Rochester, as reported (Gilbert et al 2008). Thirty nuclei were scored per sample with quantitation of red signals (HER-2/neu or EGFR) and green signals (chromosome 17 centromere (CEP17) or chromosome 7 centromere (CEP7) respectively).…”

Section: Fish Analysis Of Gene Copy Numbermentioning

confidence: 99%

“…All neuroendocrine tumor tissues assessed for EGFR, KIT, PDGFRA, and KRAS mutations are listed, by case, in Supplementary Table S1. Mutational analyses of EGFR (exons 18, 19, and 21) were performed as previously described (Gilbert et al 2005); KIT mutational analyses (exons 9, 11, 13, and 17) were conducted as reported (Gilbert et al 2008).…”

Section: Fish Analysis Of Gene Copy Numbermentioning

confidence: 99%

Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors

Gilbert¹,

Adhikari²,

Lloyd³

et al. 2010

Endocrine-Related Cancer

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Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT ), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-b receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC 50 values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC 50 values of 428 nM, 2.8 mM, and 1 mM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.

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Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy

Cited by 66 publications

References 34 publications

Metaplastic breast carcinomas and their relationship with basal-like phenotype

Metaplastic breast carcinomas and their relationship with basal-like phenotype

The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade

Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors

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