Gene Status in <i>HER2</i> Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

Sapino, Anna; Maletta, Francesca; Cantogno, Ludovica Verdun di; Macrì, Luigia; Botta, C.; Gugliotta, Patrizia; Scalzo, Maria Stella; Annaratone, Laura; Balmativola, Davide; Pietribiasi, Francesca; Bernardi, Paolo; Arisio, Riccardo; Viberti, L; Guzzetti, Stefano; Orlassino, Renzo; Ercolani, Cristiana; Mottolese, Marcella; Viale, Giuseppe; Marchiò, Caterina

doi:10.1634/theoncologist.2014-0195

Cited by 41 publications

(39 citation statements)

References 36 publications

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“…A recent study also showed that the percentage of Her-2 D-FISH equivocal cases was as high as 9.4% according to the ASCO/CAP 2013 guidelines [16], similar to our results. Several other studies also demonstarted a significant increase in the D-FISH equivocal cases after the ASCO/CAP 2013 guideline update [12,14,15,17,18]. In addition, our assay revealed the interpretation of D-FISH equivocal results with good reproducibility.…”

Section: Discussionsupporting

confidence: 63%

“…Multiplex ligation-dependent probe amplification (MLPA) may be of support in reassessing Her-2 gene status of D-FISH equivocal cases. A recent report suggested that MLPA could rule out Her-2 amplification in 75% of ISH-evaluated Her-2-equivocal carcinomas [14]. Her-2 mRNA expression analysis by quantitative reverse transcription-PCR (qRT-PCR) may also be of help to determine the status of Her-2 [21].…”

Section: Discussionmentioning

confidence: 99%

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Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines

Qian

Wen

Yang

et al. 2016

Breast Cancer Res Treat

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Dual-probe fluorescence in situ hybridization (D-FISH) is a widely accepted method to determine the gene amplification status of human epidermal growth factor receptor 2 (Her-2). In 2013, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on the Her-2 testing for invasive breast cancer (BCa). The interpretation criteria for D-FISH changed accordingly. In this study, we compared the Her-2 FISH statuses based on the 2013 and 2007 ASCO/CAP guidelines in 1931 cases of BCa with Her-2 D-FISH testing at our hospital. We analyzed the clinicopathologic features of cases with equivocal results by the 2013 ASCO/CAP guidelines. Although the guideline update significantly improved the detection rate of Her-2 amplification, it also significantly increased the rate of equivocal results, posing a dilemma for clinical management. The equivocal results had good reproducibility. The distribution of D-FISH equivocal cases did not correlate with Her-2 status by immunohistochemistry, suggesting that Her-2 D-FISH equivocality may not reflect Her-2 overexpression. Compared with Her-2 negative cases by D-FISH, Her-2 D-FISH equivocal cases had higher Ki-67 expression, higher histological grade, more frequent lymph node metastasis, and lower estrogen receptor α expression, indicating a group of BCa with worse prognosis. The clinical significance of Her-2 equivocal results by D-FISH warrants further investigation.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines

Qian

Wen

Yang

et al. 2016

Breast Cancer Res Treat

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“…Similar to our study, they reported an increase in equivocal cases when using the ASCO/CAP 2013 ISH algorithm (12.3%) compared with the ASCO/CAP 2007 ratio criterion (2.4%). 7 Additional evaluation of the data by Sapino et al 7 reveals that although only 2.4% of the 2007 cases were equivocal by ratio, 13.5% would have been equivocal by copy number alone using the 2013 guidelines or by the ❚Image 1❚ HER2 fluorescence in situ hybridization (FISH; dual-color PathVysion FISH assay) and immunohistochemical assessment of a representative equivocal breast carcinoma. A HER2 equivocal case from 2013 cohort demonstrates (A) HER2 (red signals) to CEP17 (green signals) ratio of 1.9 and HER2 copy number of 4.8 (DAPI counterstain; ×1,000) and (B) reflex HER2 immunohistochemistry (IHC) showing incomplete, weak to moderate membrane staining in more than 10% of tumor cells, scored as HER2 2+ (×40) (inset, IHC HER2 3+ control, ×40).…”

Section: Discussionmentioning

confidence: 99%

Impact of the 2013 ASCO/CAP HER2 Guideline Updates at an Academic Medical Center That Performs Primary HER2 FISH Testing

Muller

Marotti

Memoli

et al. 2015

American Journal of Clinical Pathology

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“…This is important, because previous studies have suggested that neoplasms with increased HER2 copy number respond to anti-HER2 treatment in a manner that is largely independent of Cep17 counts, even when HER2 copy number is in the equivocal range. 7,9,10,13 Furthermore, other studies, including that of Muller and colleagues, suggest a trend toward higher grade and higher Ki-67 counts among ISH equivocal cases when comparing cases identified by 2013 criteria with those defined by 2007 criteria. 7,9,14 The implication of these findings is that the equivocal group defined by 2013 criteria (unlike the 2007 defined cohort) may in fact be enriched in patients who may benefit from anti-HER2 or combination therapy in the adjuvant or neoadjuvant setting.…”

mentioning

confidence: 88%

“…7,9,10,13 Furthermore, other studies, including that of Muller and colleagues, suggest a trend toward higher grade and higher Ki-67 counts among ISH equivocal cases when comparing cases identified by 2013 criteria with those defined by 2007 criteria. 7,9,14 The implication of these findings is that the equivocal group defined by 2013 criteria (unlike the 2007 defined cohort) may in fact be enriched in patients who may benefit from anti-HER2 or combination therapy in the adjuvant or neoadjuvant setting. 5,7,15 And because the 2013 criteria also tend to shift a subset of 2007 defined ISH equivocal into the positive category, [5][6][7]9,15 the net result of increased ISH equivocal rates may in fact be an improvement in overall patient care.…”

mentioning

confidence: 88%

Is “Polysomy” in Breast Carcinoma the “New Equivocal” inHER2Testing?

Swanson

Yang

2015

Am J Clin Pathol

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It is reasonable to assume that the ultimate purpose of evidence-based consensus guidelines in pathology practice is to improve patient care. When the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) convened an expert panel to consider recommendations for HER2 testing in breast cancer, the HER2 testing landscape was more a mosaic of random color and form than a coherent composition. Despite using common immunohistochemistry (IHC) and in situ hybridization (ISH) tools, each with defined interpretative criteria, diagnostic laboratories were unable to achieve levels of interlaboratory concordance that could provide a meaningful level of confidence in the reliability of HER2 test results. This lack of clear concordance was complicated by overall positive rates of up to 30% (despite an expected rate closer to 12%-16%), and this separation of actual performance from expected values reflected both unacceptably high levels of false-positive and false-negative results. 1,2 The first published ASCO/ CAP guideline recommendations, although perhaps a flawed redefinition of the original HER2 IHC interpretative criteria, largely reiterated interpretative guidelines created and validated for initial companion testing for trastuzumab clinical validation trials while incorporating separately approved interpretative schemes for HER2 and dual HER2/Cep17 ISH modalities. 2 The improvement in laboratory performance following release of these guidelines in 2007 was thus less likely related to interpretive guidelines than to those elements of testing that related to preanalytic factors, tissue selection, assay validation, and emphasis on reflex testing for equivocal results. Whatever the basis, substantial improvement in testing performance did occur: overall positive rates aligned more closely with expected values, false-positive and false-negative rates decreased, and concordance both between laboratories and (when comparing different testing modalities) within laboratories also improved. 1 With the release of updates to these original recommendations, the ASCO/CAP panel took pains to create a testing environment that could further minimize falsenegative results, with the understanding that, given the overall benefit of anti-HER2 therapy and the relatively low toxicity of those treatments, false-positive results were much less of a concern. The restructured guidelines, in essence, emphasized sensitivity over specificity. 3 The question, though, is whether these updates, presented in 2013, actually improved the practice of HER2 testing or, more important, improved the quality of care received by patients with breast carcinoma.In a systematic critical review of the guideline updates, Rahka and colleagues 4 correctly identified areas of concern related to the evidentiary basis for changes in IHC interpretative criteria. They also made the prediction that the change in the definition of an IHC 2+ positive results in a larger number of IHC equivocal cases with a corresponding increase in reflex ISH...

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Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction-Based Method

Cited by 41 publications

References 36 publications

Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines

Assessment of dual-probe Her-2 fluorescent in situ hybridization in breast cancer by the 2013 ASCO/CAP guidelines produces more equivocal results than that by the 2007 ASCO/CAP guidelines

Impact of the 2013 ASCO/CAP HER2 Guideline Updates at an Academic Medical Center That Performs Primary HER2 FISH Testing

Is “Polysomy” in Breast Carcinoma the “New Equivocal” inHER2Testing?

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