00019606-200903000-00004ArticleDiagnostic Molecular PathologyDiagnostic Molecular Pathology© 2009 Lippincott Williams & Wilkins, Inc.18March 2009
p 30-33Effect of High Copy Number of HER2 Associated With Polysomy 17 on HER2 Protein Expression in Invasive Breast CarcinomaOriginal ArticlesShah, Sejal S. MD*; Wang, Yan MD, PhD†; Tull, Jamie BS*; Zhang, Shengle MD**Department of Pathology, SUNY Upstate Medical University, Syracuse, NY†Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital, China Medical University, Shenyang, ChinaFinancial interest and/or disclosure: None.Reprints: Shengle Zhang, MD, Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, WH 2319, Syracuse, NY 13210 (e-mail:
[email protected]).AbstractHER2 gene amplification by fluorescence in situ hybridization and protein expression by immunohistochemistry (IHC) have been used for prognosis and guiding treatment of invasive ductal carcinoma of the breast with trastuzumab. Accurate evaluation of HER2 status is important in the management of patients with candidacy for the HER2-targeting therapy. Despite previous studies, effects of polysomy of chromosome 17, at which HER2 is located, on HER2 protein expression remains controversial. In this study, we calculated the average copy numbers of HER2 and chromosome 17 (CEP17) per nucleus in 109 cases of invasive
breast carcinoma and analyzed their correlations with the HER2/CEP17 ratio and protein expression. As expected, there were close correlations between HER2 protein expression and the HER2/CEP17 ratio (CC: 0.49, P<0.001), along with the HER2 copy number per nucleus (CC: 0.48, P<0.001) and between the CEP17 copy number per nucleus and the HER2 copy number per nucleus (CC: 0.45, P<0.001). Correlation between the CEP17 copy number per nucleus and the HER2/CEP17 ratio was not significant (CC: 0.2, P>0.05). There was a weak, but statistically insignificant, correlation between the CEP17 copy number per nucleus and HER2 protein expression by IHC (CC: 0.26, P>0.05). The cases were then grouped on the basis of the amplification of the HER2 gene by fluorescence in situ hybridization. In the cases that showed no amplification, there was a significantly higher CEP17 copy number per nucleus in cases with strong HER2 protein expression (2.99) when compared with cases with weak (2.39) or absent (1.86) expression. In conclusion, a high HER2 gene copy number-associated polysomy 17 is a significant contributing factor in HER2 protein overexpression in unamplified invasive breast carcinomas. Cases without HER2 amplification, but carrying polysomy 17, should be further evaluated for HER2 protein overexpression by IHC. Those with polysomy 17-associated HER2 protein overexpression, like any other IHC+ ones, should be eligible candidates for trastuzumab therapy.The HER2 gene and its protein product, a 185-kDa receptor tyrosine kinase, are amplified and overexpressed in approximately 20% of human breast cancers.1,2HER2 gene amplification by fluorescence in situ hybridization (FISH) and protein overexpression by immunohistochemistry (IHC) are associated with poor prognosis and shortened disease-free survival.3HER2 status also predicts the therapeutic response of the patients to chemical agents and humanized monoclonal antibody trastuzumab.4,5 The patients with evidence of either HER2 overexpression or amplification are considered suitable candidates for the trastuzumab-associated therapy.6 Recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for HER2 assays recommend 2 algorithms for performing IHC and FISH.6 In algorithm for IHC, FISH should be performed if IHC is 2+ (equivocal). In algorithm for FISH, IHC should be performed if FISH is 1.8 to 2.0 (ratio, PathVysion) or 4.0 to 6.0 (gene copy, INFORM). Understanding the correlation between IHC and FISH is more important in view of the current recommendations in selecting appropriate assays and for data interpretation.Polysomy of chromosome 17 is frequent and can be identified in 20-40% of invasive breast carcinomas, depending on designation for polysomy.7 A high HER2 gene copy number associated with polysomy 17 has been reported as a contributing factor for HER2 protein overexpression.8,9 However, several other publications showed no effect of polysomy 17 on HER2 protein expression7 or was limited in a rather small group of cases.10,11 If polysomy 17 is an effective factor on IHC score, some positive IHC cases caused by the polysomy may be missed when following the algorithm for FISH.6 Therefore, it is imperative to further study the effect of polysomy 17 on HER2 expression.In this paper, we statistically analyzed 109 cases of invasive breast cancer from our hospital for correlations among the HER2/CEP17 ratio and HER2 gene amplification and protein expression, with focus on the effects of polysomy of chromosome 17.MATERIALS AND METHODSCase SelectionA retrospective study was conducted over 2 and a half years to reveal 109 cases of invasive ductal carcinomas of the breast (aged 26 to 93 y, median 58 y) that had been evaluated for the HER2 gene by FISH and protein expression with IHC on formalin-fixed paraffin-embedded tissue.IHC analysis was performed on 5-μm section with a Food and Drug Administration (FDA)-approved pathway HER2 (4B5) rabbit monoclonal antibody (Ventana, Tucson, AZ) and streptavidin-biotin-peroxidase techniques on an automatic immunostainer BenchMark XT (Ventana, Tucson, AZ) with appropriate positive and negative controls. Immunoreactivity was graded as negative (0, 1+), weak positive or equivocal (2+), and strong positive (3+) by a FDA-approved scoring system.FISH was performed on 4-μm sections using the FDA-approved PathVysion HER2/neu DNA probe kit (Abbott Molecular, Des Plaines, IL) and paraffin pretreatment kit I (Abbott Molecular, Des Plaines, IL) as per the manufacturers' instructions. For each case, 40 invasive tumor cells were counted by 2 different scorers. The HER2 gene was considered amplified when the ratio was ≥2.0. Cases with ≥2.7 chromosome 17 per nucleus on average were considered as polysomy.The data of FISH and IHC were statistically calculated for their correlation coefficients (CC) and P values by Mann-Whitney Wilcoxon test.RESULTSCCs were calculated for 109 cases of invasive breast carcinomas. Not surprisingly, HER2 protein expression by IHC was well correlated with the HER2/CEP17 ratio and the HER2 copy number per nucleus with CC of 0.49 and 0.48, respectively (P>0.05) (Figs. 1, 2). The CEP17 copy number per nucleus was well correlated with the HER2 gene copy number per nucleus (CC: 0.45; P>0.05; P<0.01), but not with the HER2/CEP17 ratio (CC: 0.2; P>0.05) (Figs. 3, 4). CC between the CEP17 copy number and HER2 protein expression is slightly increased (0.26), but was not statistically significant (P>0.05) (Fig. 5).JOURNAL/dimp/04.03/00019606-200903000-00004/figure1-4/v/2021-02-17T200000Z/r/image-jpeg
Correlation of HER2/CEP17 ratio by FISH with HER2 expression by IHC. CC=0.49 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.JOURNAL/dimp/04.03/00019606-200903000-00004/figure2-4/v/2021-02-17T200000Z/r/image-jpeg
Correlation of HER2 copies/cell by FISH with HER2 expression by IHC. CC=0.48 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.JOURNAL/dimp/04.03/00019606-200903000-00004/figure3-4/v/2021-02-17T200000Z/r/image-jpeg
Correlation of HER2 copies/cell with CEP17 copies/cell by FISH. CC=0.45 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.JOURNAL/dimp/04.03/00019606-200903000-00004/figure4-4/v/2021-02-17T200000Z/r/image-jpeg
Correlation of HER2/CEP17 ratio with CEP17 copies/cell by FISH. CC=0.20 (P>0.05). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.JOURNAL/dimp/04.03/00019606-200903000-00004/figure5-4/v/2021-02-17T200000Z/r/image-jpeg
Correlation of HER2 expression by IHC with CEP17 copies/cell by FISH. CC=0.26 (P>0.05). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.Further correlations were analyzed after grouping the cases depending on the amplification of the HER2 gene by FISH (Table 1). In the amplified group, the CEP17 copy number per nucleus showed no apparent effect on the IHC scores. Among the unamplified group, the CEP17 copy number per nucleus was similar in cases with IHC score of 1+ or 2+, but seemed to be increased in cases with IHC score of 3+. For further clarification, the unamplified cases were divided into 3 groups on the basis of the IHC score: group 1 (0), group 2 (1+, 2+), and group 3 (3+) (Table 2). Interestingly, the average CEP17 copy number per nucleus was 1.86 for group 1, 2.39 for group 2, and 2.99 for group 3, and the differences among the 3 groups were statistically significant (P<0.01).JOURNAL/dimp/04.03/00019606-200903000-00004/table1-4/v/2021-02-17T200000Z/r/image-tiff Correlation of HER2 by IHC With CEP17 Copy Number in HER2 Positive and Negative Cases by FISHJOURNAL/dimp/04.03/00019606-200903000-00004/table2-4/v/2021-02-17T200000Z/r/image-tiff CEP17 Copy Number of Unamplified Cases in Groups with Different HER2 Expression and Statistic AnalysisDISCUSSIONAs expected, HER2 protein expression was well correlated with the HER2/CEP17 ratio and the HER2 copy number per nucleus. The CEP17 copy number was well correlated with the HER2 gene copy number, but not with the HER2/CEP17 ratio. We regrouped the cases on the basis of amplification of the HER2 gene by FISH because of our observation of weak correlation between the CEP17 copy number per nucleus and HER2 protein expression by IHC (CC: 0.26). Although the effect of polysomy 17 on HER2 expression has been studied previously, it still remains controversial. Although Bose et al8 and Farabegoli et al9 reported that polysomy 17 was a significant contributing factor in HER2 protein expression, Downs-Kelly et al7 suggested that polysomy 17 in absence of gene amplification did not have a significant influence on HER2 protein expression. On the other hand, studies by Lal et al10 and Varshney et al11 showed that influence of polysome 17 was only in the group with strong HER2 expression (3+).In our study, there are no significant differences in the CEP17 copy number among the groups with an IHC score of 1+ and 2+. However, the group with an IHC score of 3+ had a higher CEP17 copy number (Table 1). With appropriate regrouping and statistic analysis (Table 2), our results demonstrate that group 3 (IHC 3+) had significantly higher CEP17 copy numbers (average 2.99) than group 2 (IHC 1+ and 2+; average 2.39; P<0.01). The findings are similar to previous observations from Lal et al10 and Varshney et al.11 In addition, our results show that the group 1 (IHC 0) had the lowest CEP17 copy number 1.86 (P<0.01). Our analysis shows definite effect of chromosome 17 polysomy on HER2 protein expression and should, therefore, be considered in the interpretation of HER2 FISH and IHC assays. In current practice, the patients with either HER2 overexpression (3+) or amplification (≥2) are considered suitable candidates for the trastuzumab-associated therapy.6 If IHC is performed first following the algorithm for IHC,6 candidates with HER2 overexpression will not be missed. However, if FISH assay is performed first, the cases without HER2 amplification, but with polysomy 17-associated protein overexpression, may be missed. Therefore, IHC should be performed for those with negative HER2 amplification, but carrying polysomy 17. Although only approximately 5% of unamplified cases show HER2 protein overexpression, it is important to accurately evaluate the HER2 status for patient management.6 In consideration of cell truncation on tissue sections, 2.7 copies per nucleus rather than ≥3.0 is defined as polysomy in our test. The CEP17 copies of 5 cases in group 3 are all above 2.7, ranging from 2.8 to 3.3. It seems reasonable that 2.7 copies per nucleus are used as the cut-off value for polysomy.If the HER2 copy number per nucleus is used, like INFORM probe (Ventana), for evaluating the cases in group 3, 3 cases are below 4.0 HER2 copy number per nucleus (negative) and 2 cases are between 4.0 and 6.0 (equivocal). Obviously, this method could miss the cases with polysomy-associated HER2 protein overexpression as well.Studies12,13 showed that polysomy 17, unlike HER2 amplification, was not associated with bad tumor behavior or poor prognosis. A recent article from Hofmann et al14 demonstrated that the response rate to trastuzumab in the patients with IHC3+/FISH+ was 23% (16/68), whereas in those with IHC3+/FISH− it was 42%(3/7). Interestingly, among these 3 responders in the IHC3+/FISH− group, 2 of them were polysomy 17. In addition, high gene copy numbers of epidermal growth factor receptor associated with polysomy 7 (no amplification) in lung and colon cancer have been proven to be useful predictive factors for epidermal growth factor receptor-targeting therapies including antibodies.15,16HER2 protein overexpression associated with polysomy 17, therefore, should be a predictive factor for the benefit of trastuzumab as well. Hofmann et al also suggested that polysomic cases without HER2 amplification should be retested by strictly standardized IHC.In summary, a high HER2 gene copy number associated with polysomy 17 is a significant contributing factor in HER2 protein overexpression. Cases without HER2 amplification, but carrying polysomy 17, should be further precisely evaluated for HER2 protein overexpression by IHC. Those with polysomy 17-associated HER2 protein overexpression, like any other IHC+ ones, should be eligible candidates for trastuzumab therapy.REFERENCES1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182.[Context Link][CrossRef][Medline Link]2. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712.[Context Link][CrossRef][Medline Link]3. Carr JA, Havstad S, Zarbo RJ, et al. 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Correlation of HER2/CEP17 ratio by FISH with HER2 expression by IHC. CC=0.49 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.
Correlation of HER2 copies/cell by FISH with HER2 expression by IHC. CC=0.48 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.
Correlation of HER2 copies/cell with CEP17 copies/cell by FISH. CC=0.45 (P<0.01). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.
Correlation of HER2/CEP17 ratio with CEP17 copies/cell by FISH. CC=0.20 (P>0.05). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.
Correlation of HER2 expression by IHC with CEP17 copies/cell by FISH. CC=0.26 (P>0.05). CC indicates correlation coefficient; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. Correlation of HER2 by IHC With CEP17 Copy Number in HER2 Positive and Negative Cases by FISH CEP17 Copy Number of Unamplified Cases in Groups with Different HER2 Expression and Statistic AnalysisEffect of High Copy Number of <em xmlns:mrws="http://webservices.ovid.com/mrws/1.0">HER2</em> Associated With Polysomy 17 on <em xmlns:mrws="http://webservices.ovid.com/mrws/1.0">HER2</em> Protein Expression in Invasive Breast CarcinomaShah Sejal S. MD; Wang, Yan MD, PhD; Tull, Jamie BS; Zhang, Shengle MDOriginal ArticlesOriginal Articles118p 30-33
