Aneusomy 17 in Breast Cancer: Its Role in HER-2/neu Protein Expression and Implication for Clinical Assessment of HER-2/neu Status

Wang, Sijian; Saboorian, M. Hossein; Frenkel, Eugene P.; Haley, Barbara; Siddiqui, Momin T.; Gokaslan, Sefik T.; Hynan, Linda S.; Ashfaq, Raheela

doi:10.1038/modpathol.3880505

Cited by 116 publications

(86 citation statements)

References 17 publications

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“…There have been several reports that cases with HER-2 overexpression without gene amplification mostly occurred in moderate positive cases (2 þ ) (Perez et al, 2002;Varshney et al, 2004), in line with this study. Various explanations of this discrepancy have been proposed: transcriptional or post-translational activation (Slamon et al, 1989), artifactual high sensitivity of IHC (Varshney et al, 2004), the presence of chromosome 17 polysomy (Wang et al, 2002) or the low detection rate of FISH analysis (Jacobs et al, 1999). We found one case of polysomy in 2 þ patients and two cases of polysomy in 1 þ patients, suggesting that the presence of chromosome 17 polysomy might be one explanation for the discrepancy between the HercepTest and FISH in oesophageal SCC.…”

Section: Discussionmentioning

confidence: 61%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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The utilisation of antitumour T cells induced by cancer vaccination with HER-2 peptides or antibodies (Herceptin) against HER-2, as immunotherapy for oesophageal cancer, is a novel and attractive approach. It is important to clarify the frequencies of HER-2 expression and gene amplification in patients with oesophageal squamous cell carcinoma (SCC) and to evaluate the relationship between HER-2 status and HLA haplotype, since the candidates for HER-2 peptide-based vaccination are restricted to a certain HLA haplotype. We determined the frequency of HER-2 expression using the HercepTestt for immunohistochemistry and HER-2 gene amplification by fluorescence in situ hybridisation (FISH) assay in oesophageal SCC (n ¼ 66). HER-2-positive tumours (1 þ /2 þ /3 þ ) analysed by a HercepTest were observed in 30.3% of all the patients and HER-2 gene amplification evaluated by FISH was observed in 11.0% of all the patients, in which all HercepTest (3 þ ) tumours were found to have gene amplification and three of six moderately positive (2 þ ) tumours showed gene amplification. Furthermore, HER-2-positive cells were present more diffusely and were larger within each tumour in the patients who were HercepTest 3 þ than those who were HercepTest 1 þ . Moreover, the survival rate in HER-2-positive group was significantly worse than that in HER-2-negative group. Also, the survival rate in the patients with HER-2 gene amplification was significantly worse than that without HER-2 gene amplification. In addition, oesophageal SCC patients with both HLA-A24-positive and HER-2-positive tumours (1 þ /2 þ /3 þ ) accounted for 26% of these cases, and both HLA-A2-and HER-2-positive tumours accounted for 18% of them.

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Section: Discussionmentioning

confidence: 61%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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“…[10][11][12][13] In a recently published series by Vanden Bempt et al, >40% of breast carcinomas were found to harbor increased CEP17 copy number.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 However, the reported frequency of CEP17 copy number alteration in breast cancer varies, depending on the study population, selection criteria, and the definition of chromosome 17 polysomy (CEP17). [10][11][12][13] In the literature, it is commonly assumed that an increase in CEP17 copy number is because of polysomy 17, and these terms have been used interchangeably. However, it is important to recognize that an increase in CEP17 signals does not necessarily represent a true polysomy (ie, gain of the entire chromosome), but rather may represent a focal pericentromeric gain or a partial polysomy.…”

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confidence: 99%

Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

Vranić

Teruya

Repertinger

et al. 2010

Cancer

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BACKGROUND:The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas using fluorescent in situ hybridization methods. Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2-positive tumors as those with >6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio >2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17. METHODS: Seventy-two breast carcinoma cases with reported polysomy of chromosome 17 (3 CEP17 signals on average) by fluorescent in situ hybridization were identified, and the corresponding HER2 immunohistochemistry was obtained. The HER2 status of the archived samples was reviewed, and the tumors were recategorized according to the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines. RESULTS: The average CEP17 copy number for the group was 4.5 (range, 3.0-10.4). Thirty-three (45.8%) cases had >6 copies of HER2 per nucleus. Twenty-one cases (29.2%) qualified as HER2 gene amplified using the HER2/CEP17 ratio (>2.2) guideline. All these cases had >6 HER2 signals, which represented 63.6% of all cases with >6 HER2 signals. HER2 protein expression showed significant positive correlations with both HER2 gene copy number and HER2/CEP17 ratio (P < .01, r s ¼ 0.56 and 0.64, respectively). CONCLUSIONS: Increased CEP17 signals detected in invasive breast carcinomas may lead to discordant interpretation of gene amplification in a significant proportion of the cases, depending on which criterion (ratio vs absolute number) is used for interpretation. However, increased gene dosage (>6 HER2 genes or HER2/CEP17 ratio >2.2), regardless of the evaluation method, is positively correlated with HER2 protein expression. Cancer 2011;117:48-53.

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“…The cutoff number for determining oncogene amplification by CISH was empirically defined as six copies per cell based on the observation that most cases with polysomy of chromosome 17 fall into three to five signals per nucleus. 12,17 However, aneusomy of chromosome 17 is common in breast cancer 12,18,[21][22][23][24] and polysomy with 45 copies of chromosome 17 per nucleus is not rare. 17 These cases would be scored erroneously as low amplification while there is no actual amplification present.…”

Section: Discussionmentioning

confidence: 99%

Reliability of chromogenic in situ hybridization for detecting HER-2 gene status in breast cancer: comparison with fluorescence in situ hybridization and assessment of interobserver reproducibility

2005

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Accurate determination of HER-2 status is important in the management of patients with breast cancer, especially in determining their eligibility for trastuzumab therapy. Fluorescence in situ hybridization (FISH) has been regarded as the gold standard method for detecting HER-2 gene amplification. Recently, chromogenic in situ hybridization (CISH), in which HER-2 is detected by a peroxidase reaction and the gene copies are determined by regular bright-field microscopy, has emerged as a potential alternative to FISH. However, this method requires validation before it can be adopted into clinical practice. In this study, we evaluated 80 cases of invasive breast carcinoma by CISH, compared the results with those obtained by FISH, and assessed interobserver reproducibility among three observers. We found that agreement among the three pathologists on the CISH-determined HER-2 status was achieved in 73 cases (91%), all of which had results matching the corresponding FISH results: 54 nonamplified and 19 amplified. Of the 19 amplified cases, 13 were scored unanimously as high-level amplification; six had a minor scoring discrepancy (ie, low-level vs high-level amplification). A major scoring discrepancy (ie, nonamplification vs amplification) was found in the remaining seven cases, three of which were amplified and four of which were nonamplified by FISH. Two of the latter cases had a polysomy of chromosome 17. The cases that caused scoring difficulty were those with an equivocal or borderline signal number against a high background. Overall, there was nearly perfect agreement between the CISH and corresponding FISH results, and interpretation of CISH results were highly reproducible among the three pathologists. We conclude that, in general, HER-2 status can be reliably assessed by CISH. Confirmatory FISH is recommended in cases with equivocal or borderline CISH copy numbers.

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Aneusomy 17 in Breast Cancer: Its Role in HER-2/neu Protein Expression and Implication for Clinical Assessment of HER-2/neu Status

Cited by 116 publications

References 17 publications

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

Reliability of chromogenic in situ hybridization for detecting HER-2 gene status in breast cancer: comparison with fluorescence in situ hybridization and assessment of interobserver reproducibility

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