Amplification of the HER2 gene in breast cancers testing 2+ weak positive by HercepTest immunohistochemistry: false-positive or false-negative immunohistochemistry?

Barrett, Ciara; Magee, Hilary; O'Toole, Denise; Daly, Sinéad; Jeffers, Michael

doi:10.1136/jcp.2006.039602

Cited by 29 publications

(27 citation statements)

References 28 publications

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“…Unfortunately, only limited FISH data is available in 2+ immunostained specimens. As other have noted [21], disagreement between 2+ overexpression and amplification can occur in up to half of cases. In this study, only 5 of 13 (39%) of the 2+ immunostained specimens were found to have amplification by FISH.…”

Section: Discussionmentioning

confidence: 99%

HER-2/neu expression in primary and metastatic breast cancer

Lower

Glass

Blau

et al. 2008

Breast Cancer Res Treat

154

110

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Introduction Trastuzumab is a highly effective therapy for the treatment of HER-2/neu positive breast cancer. To maximize benefit and minimize unnecessary toxicity, patient selection is essential. Currently HER-2/neu analysis is routinely performed only for primary invasive breast cancers, and trastuzumab therapy is recommended based on primary analysis only. Methods Using immunohistochemistry, we performed a retrospective study comparing HER-2/neu expression in original primary to subsequent metastatic breast cancers. Results Tumors from 382 patients with metastatic breast cancer were studied. In 254 cases (66%) both primary and metastatic lesions were concordant. In 90 cases the primary lesion was HER-2/neu positive with the metastatic lesion negative; whereas, in 37 cases the primary lesion was HER-2/neu negative and the metastatic lesion positive. Primary HER-2/neu immunostaining was associated with a negative predictive value of 35.7%. Although all four groups were similar at diagnosis, survival differences were noted with the best survival experienced by patients with initial primary lesions HER-2/neu negative and subsequent metastatic lesions positive. Patients with hormone receptor and HER-2/neu positive primary lesions who received tamoxifen were more likely to have HER-2/neu positive metastasis. Conclusions The significant discordance between HER-2/neu expression in primary and metastatic tumors suggests that determination of HER-2/neu status in metastatic disease should be attempted.

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Section: Discussionmentioning

confidence: 99%

HER-2/neu expression in primary and metastatic breast cancer

Lower

Glass

Blau

et al. 2008

Breast Cancer Res Treat

154

110

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“…We believe that the prognostic significance of moderate HER2 (2C) expression needs to be reevaluated as a predictor for anti-HER2 therapy. Notably, intratumoral heterogeneity of the HER2 gene is a characteristic property of tumors with low and moderate HER2 expression and is associated with decreased DFS (Barrett et al 2007, Seol et al 2012. Therefore, HER2 overexpression without gene amplification should be further evaluated, and the determination of the HER2 status and in particular the predictive value of HER2 (2C) expression should be reconsidered.…”

Section: Discussionmentioning

confidence: 99%

Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer

Eggemann¹,

Ignatov²,

Burger³

et al. 2015

Endocrine-Related Cancer

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Overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis in breast cancer and predicts response to anti-HER2 therapy in breast cancer. The prognostic relevance of moderate expression of HER2 is unclear. Data of 9872 patients with primary nonmetastatic breast cancer from the cancer registries of Magdeburg and Halle, Germany, were analyzed retrospectively. A total of 5907 patients with complete data sets including follow-up were eligible for analysis. HER2 status was determined as recommended by international guidelines. Of 5907 patients investigated, 5023 (68.4%) had HER2 0 and 1C expression and 884 (12.0%) had HER2 (2C)/ HER2K expression. Patients with hormone receptor positive (HRC) and HER2 (2C) tumors had a shorter median disease-free survival (DFS; P!0.0001) and breast cancer specific survival (BCSS; PZ0.019) than HRC patients with HER2 (0/1C) tumors. Among patients with HRK breast cancer there was no significant difference between HER2 (2C) and HER2 (0/1C) tumors. In multivariate analysis after adjustment for other prognostic factors, HER2 (2C) status remained an unfavorable prognostic factor for DFS (hazard ratio (HR)Z1.217, 95% CIZ1.052-1.408; PZ0.008) but not for BCSS (HRZ1.045, 95% CIZ0.926-1.178; PZ0.474). The HER2 (2C) status is an unfavorable prognostic factor for survival of patients with HRC breast cancer. The impact of anti-HER2 therapy in this group of patients should be evaluated.

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“…2 The unreliability of current HER2 testing methods is illustrated by recent studies showing that some patients who tested negative for HER2 amplification by immunohistochemistry and FISH may still benefit from trastuzumab. 3,4 It has been proposed that this discrepancy is not because of misunderstanding the mechanism of action of the drug, but rather because of the inaccuracy of current testing methods. 5 Currently available FDA-approved FISH assays for the detection of HER2 gene amplification include an assay with a single probe for the HER2 gene and other assays with dual probes, one for the HER2 gene and another for the centromere of chromosome 17 (probe CEP 17, D17Z1).…”

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confidence: 99%

Clinical validation of an array CGH test for HER2 status in breast cancer reveals that polysomy 17 is a rare event

et al. 2009

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The HER2 gene is an important prognostic and therapeutic marker in newly diagnosed breast cancer. Currently, HER2 status is most frequently determined by immunohistochemical detection of HER2 protein expression on the cellular membrane surface or by fluorescence in situ hybridization analysis of HER2 gene copy number in fixed tissue using locus-specific probes for the HER2 gene and chromosome 17 centromere. However, these methods are problematic because of issues with intra-and inter-laboratory reproducibility and preanalytic variables, such as fixation time. In addition, the commonly used HER2/chromosome 17 ratio presumes that chromosome 17 polysomy is present when the centromere is amplified, even though analysis of the rest of the chromosome is not included in the assay. In this study, 97 frozen samples of invasive lobular and invasive ductal carcinoma, with known immunohistochemistry and fluorescence in situ hybridization results for HER2, were analyzed by comparative genomic hybridization to a commercially available bacterial artificial chromosome whole-genome array containing 99 probes targeted to chromosome 17 and the HER2/TOP2 amplicon. Results were 97% concordant for HER2 status, meeting the College of American Pathologists/ American Society of Clinical Oncology's validation requirements for HER2 testing. Surprisingly, not a single case of complete polysomy 17 was detected even though multiple breast cancer cases showed clear polysomies of other chromosomes. We conclude that array comparative genomic hybridization is an accurate and objective DNA-based alternative for clinical evaluation of HER2 gene copy number, and that polysomy 17 is a rare event in breast cancer.

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Amplification of the HER2 gene in breast cancers testing 2+ weak positive by HercepTest immunohistochemistry: false-positive or false-negative immunohistochemistry?

Abstract: Background: The majority of cases of breast cancer scoring HER2 weak positive (2+) on immunohistochemistry (IHC) using the HercepTest are not associated with amplification of the HER2/neu gene.

Cited by 29 publications

References 28 publications

HER-2/neu expression in primary and metastatic breast cancer

HER-2/neu expression in primary and metastatic breast cancer

Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer

Clinical validation of an array CGH test for HER2 status in breast cancer reveals that polysomy 17 is a rare event

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