Polysomy 17 in HER-2/neu Status Elaboration in Breast Cancer: Effect on Daily Practice

Ma, Yan; Lespagnard, Laurence; Durbecq, Virginie; Paesmans, Marianne; Desmedt, Christine; Gomez-Galdón, Maria; Veys, Isabelle; Cardoso, Fátima; Sotiriou, Christos; Leo, Angelo Di; Piccart, Martine; Larsimont, Denis

doi:10.1158/1078-0432.ccr-04-2256

Cited by 96 publications

(77 citation statements)

References 42 publications

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“…Therefore, these cases did not fit within the HER2-amplified breast carcinoma category. 21,22 Taken together, a subgroup of borderline (2þ) breast carcinomas represented a majority of the cases with increased CEP17 copy number in our study, and only 13% of the cases showed HER2 gene amplification. This finding is in line with previous studies that confirmed that breast cancers with an equivocal IHC score (2þ) harbored CEP17 polysomy instead of HER2 gene amplification.…”

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confidence: 50%

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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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“…21 Our study indicates that determination of HER2 amplification status may show discordant results, depending on whether CEP17 copy number was taken into account. Indeed, more than one-third of the studied cases harboring >6 copies of the HER2 gene did not show HER2 gene amplification (ratio, >2.2).…”

mentioning

confidence: 77%

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

Vranić

Teruya

Repertinger

et al. 2010

Cancer

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“…Several investigators have shown that polysomy of chromosome 17 can account for a small subset of breast cancers showing 3 þ levels of HER2 immunostaining but no amplification by FISH when the HER2/chromosome 17 ratio is evaluated. [44][45][46] In the present study, of the 15 cases that were IHC 3 þ and FISH nonamplified, 8 had polysomy of chromosome 17 with HER2/CEP17 ratios that were less than 2. Therefore, a concordance rate of 95% or higher may well be biologically unattainable.…”

Section: Discussionmentioning

confidence: 43%

High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system

Gown¹,

Goldstein²,

Barry³

et al. 2008

Modern Pathology

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The American Society of Clinical Oncologists and College of American Pathologists have recently released new guidelines for laboratory testing of HER2 status in breast cancer, which require high levels (95%) of concordance between immunohistochemistry positive (3 þ ) and fluorescence in situ hybridization-amplified cases, and between immunohistochemistry negative (0/1 þ ) and fluorescence in situ hybridization-nonamplified cases; these required levels of concordance are significantly higher than those found in most published studies. We tested the hypothesis that a modification of the HER2 immunohistochemistry scoring system could significantly improve immunohistochemistry and fluorescence in situ hybridization concordance. A total of 6604 breast cancer specimens were evaluated for HER2 status by both immunohistochemistry and fluorescence in situ hybridization using standard methodologies. Results were compared when the standard immunohistochemistry scoring system was replaced by a normalized scoring system in which the HER2 score was derived by subtracting the score on the non-neoplastic breast epithelium from that on the tumor cells. Among the 6604 tumors, using a non-normalized immunohistochemistry scoring system, 267/872 (30.6%) of the immunohistochemistry 3 þ cases proved to be fluorescence in situ hybridization nonamplified, whereas using the normalized scoring system only 30/562 (5.3%) of immunohistochemistry 3 þ cases proved to be 'false positive'. The concordance rate between immunohistochemistry 3 þ and fluorescence in situ hybridizationamplified cases using the normalized scoring method was 94.7%, whereas the concordance using the non-normalized method was only 69.4%. Extremely high concordance between immunohistochemistry and fluorescence in situ hybridization assessment of HER2 status in breast cancer is achievable, but to attain this high level of concordance, modification of the FDA-approved immunohistochemistry scoring system is required.

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“…Several investigators have shown that polysomy of chromosome 17 can account for a small subset of breast cancers showing 3 þ levels of HER2 immunostaining but no amplification by FISH when the HER2/chromosome 17 ratio is evaluated. [69][70][71] The new ASCO-CAP guidelines mandate significant changes in HER2 testing in laboratories throughout the United States. As technical handling of tissue continues to be a significant factor in standardization of test quality, the new guidelines mandate fixation in 10% neutral-buffered formalin for a minimum of 6 h and a maximum of 48 h duration.…”

Section: Part 2: Human Epidermal Receptor Protein-2mentioning

confidence: 99%

Current issues in ER and HER2 testing by IHC in breast cancer

2008

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The presence of estrogen receptors (ERs), as detected by immunohistochemistry (IHC), is a weak prognostic marker of clinical outcome in breast cancer, but a strong predictive marker for response, for example, to tamoxifen-based therapy. As with all IHC markers, factors such as tissue fixation (both type and duration), the choice of antibody, and the threshold for interpretation of positive immunostaining can dramatically affect test accuracy and reproducibility. For example, optimal fixation for detection of ER requires at least 6-8 h in formalin, and the use of newer antibodies such as SP1 may identify additional patients who might benefit from hormonal therapy. Although the threshold for positivity may be as few as 1% of tumor cells showing nuclear signal, recent studies appear to demonstrate a dichotomization of ER IHC, with the vast majority of cases showing all positive or all negative results. This may be helpful in dictating the appropriateness of hormonal therapy, but quantification of ER by IHC, or other methods, may play a more important role in the future. Breast cancers with human epidermal receptor protein-2 (c-erbB-2; HER2) alterations are critical to identify because such tumors require unique treatment, including the use of targeted therapies such as trastuzumab. HER2 alterations at the DNA (amplification) and protein (overexpression) level usually occur in concert, and both fluorescence in situ hybridization (FISH) or IHC can be accurate methods to assess these alterations. However, recent studies have suggested that serious reproducibility issues exist in both FISH and IHC HER2 studies. To address this, a joint committee of both the American Society for Clinical Oncologists and the College of American Pathologists has promulgated new guidelines for HER2 testing. These include the following: (a) recommendations for tissue fixation for more than 6 and less than 48 h; (b) new scoring criteria, including a new threshold of 30% strong immunostaining for classification of 3 þ ; (c) introduction of the term 'equivocal' to characterize HER2 studies that are 2 þ by IHC and/or show HER2/chromosome 17 ratios of between 1.8 and 2.2 by FISH; (d) requirements for laboratories to validate HER2 assays, generally through the cross-testing of cases with another HER2 methodology, with laboratories required to attain 95% concordance for both positive and negative tests; (e) participation in HER2 proficiency testing.

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Polysomy 17 in HER-2/neu Status Elaboration in Breast Cancer: Effect on Daily Practice

Cited by 96 publications

References 42 publications

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

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

High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system

Current issues in ER and HER2 testing by IHC in breast cancer

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