Determining true HER2 gene status in breast cancers with polysomy by using alternative chromosome 17 reference genes: implications for anti-HER2 targeted therapy.

Abstract

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.

• Authors: Chun Hing Tse, Harry C Hwang, Lynn C Goldstein, Patricia L Kandalaft, Jesse C Wiley, Steven J Kussick, Allen M Gown
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 31 Pg. 4168-74 (Nov 01 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21947821 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Cep170 protein, human
• Microtubule-Associated Proteins
• Phosphoproteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Algorithms
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (analysis, genetics)
• Breast Neoplasms (chemistry, drug therapy, genetics)
• Chromosomes, Human, Pair 17 (genetics)
• Female
• Gene Amplification
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, erbB-2 (drug effects)
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Microtubule-Associated Proteins
• Middle Aged
• Molecular Targeted Therapy
• Phosphoproteins (analysis, genetics)
• Receptor, ErbB-2 (analysis, genetics)
• Tumor Suppressor Protein p53 (analysis)