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

474 Background: KRAS mutation represents the only validated biomarker used in clinical practice for selection of metastatic colorectal cancer (mCRC) candidates for therapy with the anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies. Previous studies conducted in small cohorts of patients suggested that HER2, the major EGFR partner, could modify the sensitivity to anti-EGFR agents. Aim of the present study was to investigate the role of HER2 gene status in a cohort of mCRC patients treated with cetuximab or panitumumab. Methods: 266 chemorefractory mCRC patients treated with cetuximab or panitumumab alone or in combination with chemotherapy were collected in an international consortium effort. HER2 gene status was analyzed using the dual-color FISH assay LSI HER2/neu-CEP17 (PATHVYSION, Abbott) in one central lab, whereas KRAS/BRAF mutations were investigated locally. HER2 gene amplification was defined as the presence of a ratio between HER2 gene and chromosome 17 centromere > 2. Results: An objective response to anti-EGFR therapy (complete or partial response according to RECIST criteria) was observed in 79/266 (29%) of patients. Twelve cases (4.5%) showed the classical pattern of HER2 gene amplification (R>2) in the whole tissue (>80% of tumor cells). By matching HER2 gene status with clinical response we observed that HER2 gene amplification was significantly related to therapy resistance (p<0.0001). Moreover, analysis of follow-up data indicated that HER2 gene amplification was significantly associated with a worse progression free survival (PFS, p=0.0025) and with a trend for a worse overall survival (p=0.062). Similar associations were also observed in the KRAS/BRAF wild-type patients. Conclusions: Data from this large retrospective study suggest that HER2 gene status evaluated by FISH may represent an additional marker useful for the prediction of mCRC patients’ response to EGFR-targeted therapies, in line with very recent evidence. In particular, patients with HER2 gene amplification seem to be resistant and show a shorter PFS. Future studies are needed to deeply investigate the clinical and biological meaning of HER2 gene status deregulation in mCRC.

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Comparison of Silver-Enhanced in situ Hybridization and Fluorescence in situ Hybridization for HER2 Gene Status in Breast Carcinomas

Journal of Breast Cancer ◽

10.4048/jbc.2009.12.4.235 ◽

2009 ◽

Vol 12 (4) ◽

pp. 235 ◽

Cited By ~ 9

Author(s):

Jun Kang ◽

Gui Young Kwon ◽

Young-Hee Lee ◽

Gyungyub Gong

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Breast Carcinomas ◽

Her2 Gene ◽

Gene Status

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Determining True HER2 Gene Status in Breast Cancers With Polysomy by Using Alternative Chromosome 17 Reference Genes: Implications for Anti-HER2 Targeted Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2011.36.0107 ◽

2011 ◽

Vol 29 (31) ◽

pp. 4168-4174 ◽

Cited By ~ 85

Author(s):

Chun Hing Tse ◽

Harry C. Hwang ◽

Lynn C. Goldstein ◽

Patricia L. Kandalaft ◽

Jesse C. Wiley ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Reference Genes ◽

Copy Number ◽

Retinoic Acid Receptor ◽

Chromosome 17 ◽

Breast Cancers ◽

Her2 Gene ◽

Polysomy 17 ◽

Gene Status

Purpose The ratio of human epidermal growth factor receptor 2 (HER2) to CEP17 by fluorescent in situ hybridization (FISH) with the centromeric probe CEP17 is used to determine HER2 gene status in breast cancer. Increases in CEP17 copy number have been interpreted as representing polysomy 17. However, pangenomic studies have demonstrated that polysomy 17 is rare. This study tests the hypothesis that the use of alternative chromosome 17 reference genes might more accurately assess true HER2 gene status. Patients and Methods In all, 171 patients with breast cancer who had HER2 FISH that had increased mean CEP17 copy numbers (> 2.6) were selected for additional chromosome 17 studies that used probes for Smith-Magenis syndrome (SMS), retinoic acid receptor alpha (RARA), and tumor protein p53 (TP53) genes. A eusomic copy number exhibited in one or more of these loci was used to calculate a revised HER2-to-chromosome-17 ratio by using the eusomic gene locus as the reference. Results Of 132 cases classified as nonamplified on the basis of their HER2:CEP17 ratios, 58 (43.9%) were scored as amplified by using alternative chromosome 17 reference gene probes, and 13 (92.9%) of 14 cases scored as equivocal were reclassified as amplified. Among the cases with mean HER2 copy number of 4 to 6, 41 (47.7%) of 86 had their HER2 gene status upgraded from nonamplified to amplified, and four (4.7%) of 86 were upgraded from equivocal to amplified. Conclusion Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.

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475 Determination of HER2 Gene Status and Chromosome 17 Polysomy in Penile Carcinoma and Association With HER2 Protein Levels

European Journal of Cancer ◽

10.1016/s0959-8049(12)71148-6 ◽

2012 ◽

Vol 48 ◽

pp. S114-S115

Author(s):

A.M.T. Silva ◽

I.W. Cunha ◽

F. Ayala ◽

G.C. Guimaraes ◽

A. Lopes ◽

...

Keyword(s):

Penile Carcinoma ◽

Chromosome 17 ◽

Her2 Gene ◽

Her2 Protein ◽

Protein Levels ◽

Gene Status

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Detection of HER2 Amplification in Breast Carcinomas: Comparison of Multiplex Ligation-Dependent Probe Amplification (MLPA) and Fluorescence In Situ Hybridization (FISH) combined with Automated Spot Counting

Analytical Cellular Pathology ◽

10.1155/2006/741586 ◽

2006 ◽

Vol 28 (4) ◽

pp. 151-159

Author(s):

Elna Moerland ◽

Rens L. H. P. M. van Hezik ◽

Toine C. J. M. van der Aa ◽

Mike W. P. M. van Beek ◽

Adriaan J. C. van den Brule

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Gene Amplification ◽

Her2 Status ◽

Her2 Amplification ◽

Breast Carcinomas ◽

Her2 Gene ◽

Her2 Gene Amplification ◽

Dependent Probe

In this study the detection of HER2 gene amplification was evaluated using Fluorescence In Situ Hybridization (FISH; PathVysion) in comparison with Multiplex Ligation-dependent Probe Amplification (MLPA), a PCR based technique. These two methods were evaluated on a series of 46 formalin fixed paraffin embedded breast carcinomas, previously tested for protein overexpression by HercepTest (grouped into Hercep 1+, 2+ and 3+). HER2 gene amplification (ratio ≥ 2.0) by FISH was found in 9/10, 10/30 and 0/6 in IHC 3+, 2+ and 1+/0 cases, respectively. Digitalized automated spot counting performed with recently developed CW4000 CytoFISH software was 100% concordant with manual FISH scoring. Using MLPA 18/46 samples showed a clear HER2 amplification. Comparing MLPA and IHC showed the same results as for FISH and IHC. All but one FISH positive cases (18/19) were confirmed by MLPA for the presence of the gene amplification. The overall concordance of detection of Her2 gene amplification by FISH and MLPA was 98% (45/46). Furthermore, both the level of amplification and equivocal results correlated well between both methods. In conclusion, MLPA is a reliable and reproducible technique and can be used as an either alternative or additional test to determine HER2 status in breast carcinomas.

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