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Genetic and Expression Analysis of HER-2 and EGFR Genes in Salivary Duct Carcinoma: Empirical and Therapeutic Significance

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Genetic and Expression Analysis of HER-2 and EGFR Genes in Salivary Duct Carcinoma: Empirical and Therapeutic Significance Published OnlineFirst April 14, 2010; DOI: 10.1158/1078-0432.CCR-09-0238 Clinical Human Cancer Biology Cancer Research Genetic and Expression Analysis of HER-2 and EGFR Genes in Salivary Duct Carcinoma: Empirical and Therapeutic Significance Michelle D. Williams1, Dianna B. Roberts2, Merrill S. Kies3, Li Mao3, Randal S. Weber2, and Adel K. El-Naggar1,2 Abstract Purpose: Salivary duct carcinoma overexpresses epidermal growth factor receptor (EGFR) and HER-2, although the underlying mechanisms remain undefined. Because of the potential utilization of these markers as treatment targets, we evaluated protein and gene status by several techniques to determine complementary value. Experimental Design: A tissue microarray of 66 salivary duct carcinomas was used for immunohis- tochemical analysis of HER-2 and EGFR expression (semiquantitatively evaluated into a three-tiered system), and fluorescence in situ hybridization for gene copy number, and chromosomes 7 and 17 ploidy status. Sequencing of exons 18, 19, and 21 of the EGFR gene for mutations was carried out. Result: For EGFR, 46 (69.7%) of the 66 tumors showed some form of EGFR expression (17 at 3+, 17 at 2+, 12 at 1+) but none gene amplification. Five (9.4%) of 53 tumors showed mutations in exon 18 (n = 3) and exon 19 (n = 2). Polysomy of chromosome 7 (average >2.5 copies/cell) was detected in 15 (25.0%) of 60 tumors (6 at 3+, 5 at 2+, 2 at 1+, 2 at 0+ expression) and correlated with poor 3-year survival (P = 0.015). For HER-2, 17 (25.8%) of 66 tumors expressed HER-2 (10 at 3+, 3 at 2+, 4 at 1+). Eight tumors showed HER-2 gene amplification (6 at 3+, 1 at 1+, 1 at 0+ protein expression). Chro- mosome 17 polysomy was found in 8 (15.7%) of 51 tumors; two had HER-2 expression (3+, 1+). Conclusion: Our study shows that salivary duct carcinomas (a) harbor EGFR gene mutations in a subset of tumors that may guide therapy, (b) pursue an aggressive clinical course in cases with chro- mosome 7 polysomy and high EGFR expression, and (c) with HER-2 gene amplification and protein high expression, may be selected for targeted therapy. Clin Cancer Res; 16(8); 2266–74. ©2010 AACR. Salivary duct carcinoma is a high-grade, clinically ag- hormonal and growth factors that are known to play a cen- gressive adenocarcinoma variant with remarkable pheno- tral role in the biology of breast cancers, including HER2 typic and biological resemblance to mammary high-grade and epidermal growth factor receptor (EGFR; refs. 5, 8). ductal carcinoma (Figs. 1A and 1C; refs. 1, 2). Patients However, the optimum methodology that best reflects with locally advanced, recurrent, and/or metastatic disease their functional level for therapeutic purposes remains a have limited therapeutic options and generally succumb to subject of debate. their disease. In the past two decades several individual Growth factors and their receptors play a central role in genes, markers of different cellular pathways, chromo- mammary ductal tumorigenesis and in other adenocarci- some alterations, and hormonal and growth factor nomas, but the expression levels alone fail to predict res- receptors have been evaluated in an effort to define the ponders to therapies (9). Several studies have shown that underlying molecular and biological pathways associated HER-2 gene amplification status has improved the identi- with their development and progression (1, 3–7). Several fication of possible responders to targeted therapy with of these studies have led to the characterization of certain trastuzumab (10–14). However, concurrent expression and gene amplification studies have identified a subset Authors' Affiliations: Departments of 1Pathology, 2Head and Neck of low and intermediate HER-2 gene expressions with high Surgery, and 3Head and Neck Medical Oncology, The University of gene amplification, suggesting that immunohistochemical Texas M.D. Anderson Cancer Center, Houston, Texas analysis alone leads to underestimation of patients eligible Note: Supplementary data for this article are available at Clinical Cancer for therapy (14, 15). Central to addressing this issue is Research Online (http://clincancerres.aacrjournals.org/). whether protein expression and gene amplification are Corresponding Author: Adel K. El-Naggar, Professor of Pathology and Head and Neck Surgery, The University of Texas M.D. Anderson Cancer mutually exclusive or complementary events in assessing Center, 1515 Holcombe Boulevard, Unit 085, Houston, TX 77030. Phone: the biological role of these factors for therapeutic stratifi- 713-792-3109; Fax: 713-792-5532; E-mail: [email protected]. cation of patients with these tumors. Accordingly, initial doi: 10.1158/1078-0432.CCR-09-0238 immunohistochemical screening followed by gene ampli- ©2010 American Association for Cancer Research. fication analysis by fluorescence in situ hybridization 2266 Clin Cancer Res; 16(8) April 15, 2010 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst April 14, 2010; DOI: 10.1158/1078-0432.CCR-09-0238 EGFR and HER-2 Analysis in Salivary Duct Carcinoma M.D. Anderson Cancer Center formed this study. The cur- Translational Relevance rent WHO guidelines were used for classifying tumors as salivary duct carcinomas (30). A tissue microarray was crea- Our concurrent analysis, the most comprehensive ted using two 1.0-mm diameter cores consisting of repre- to date, of the expression and the genomic alterations sentative tumor from each paraffin block consisting of EGFR of the epidermal growth factor receptor ( )and tumor tissue fixed in 10% buffered formalin. The tissue mi- HER-2 receptor, defines the molecular alterations of croarray was used for immunohistochemistry and FISH these genes in salivary duct carcinomas for the biolo- evaluations. Pathologic findings, which included immuno- gical stratification of patients with these tumors. Both histochemistry, gene amplification, and mutational status, EGFR activating mutations (10%) in the gene and were compared with clinical factors that included gender, chromosome 7 polysomy (25%) were identified in a age, and stage along with clinical outcomes and were eva- subset of salivary duct carcinomas. These alterations luated by Fisher's exact test and χ2 based on the number of have correlated with tyrosine kinase inhibitor treat- comparative groups. A P value of 0.05 was considered ment response in different adenocarcinomas and significant. may potentially be applicable in salivary duct carcino- ma patients. Additionally, chromosome 7 polysomy Immunohistochemical analysis portends a poorer clinical outcome that trends with Immunohistochemical analysis for HER-2 and EGFR high EGFR expression. The finding of both overexpres- was done using the automated BOND MAX immunohis- sion of HER-2 and gene amplification defines a group tochemistry stainer by Vision Biosystems on 4-μm paraf- of patients who may benefit from targeted therapy fin sections of the tissue microarray material. In brief, with trastuzumab. The results of this study highlight following dewaxing, washing, and rehydration of the the spectrum of alterations in the EGFR family of slides through xylene and graded alcohols, Tris-EDTA receptors as potential targets for therapy in salivary buffer was used for antigen retrieval. Slides were subse- duct carcinomas. quently treated with 3% hydrogen peroxide to block endogenous peroxidase. Following incubation with the primary antibodies, HER-2 (clone e2-4001, mouse, (FISH) has been recommended for borderline cases in 1:300, Labvision) and EGFR (clone 31G7, mouse, 1:50, mammary carcinomas (14, 16). The correlation between Zymed), the secondary conjugate antibody was applied. the immunohistochemical expression and the genomic Finally, each specimen-containing slide was developed ′ status of the HER-2 gene in salivary duct carcinoma re- using the chromogen 3,3 -diaminobenzidine and coun- mains poorly defined secondary to the limited number terstained with hematoxylin. of tumors studied to date (14, 17–20). Immunohistochemically stained tumor sections for Recently, mutational analysis of the EGFR gene has HER-2 were evaluated for membranous expression: 3+, identified a subset of non–small cell lung carcinomas that strong complete in >10%; 2+, weak complete in >10%; responded to tyrosine kinase inhibitors (TKI; refs. 21–23). 1+, partial staining of tumor cells in >10%; 0, negative Other molecular alterations, including chromosomal or <10% staining. EGFR immunohistochemistry in tumor polysomy, may also play a role in the pathogenesis asso- cells was evaluated for membranous expression: 3+, strong ciated with this pathway (24–28). Because at least half of membrane staining in >10%; 2+, moderate membranous salivary duct carcinomas express EGFR (5, 29) and little is staining in >10%; 1+, weak membranous staining in known on the status of the EGFR expression, correlative >10%, 0, negative or <10% staining. assessment of these findings may determine the associa- tion between expression and underlying molecular factors, FISH μ including mutational and gene amplification status. A4- m paraffin section of the tissue microarray was Our objectives were to concurrently analyze, for the first analyzed by FISH using the manufacturer's recommended time, the expression and the genomic status of EGFR and standard methods for HER-2 [PathVysion HER-2 DNA HER-2 genes in a large cohort of salivary duct carcinomas. Probe Kit; HER-2 Spectrum Orange/centromere enhancer We used immunohistochemical
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