EGFR gene copy number alteration is a better prognostic indicator than protein overexpression in oral tongue squamous cell carcinomas
ABSTRACT Although epidermal growth factor receptor (EGFR) is particularly important in the pathogenesis of head and neck squamous cell carcinomas (HNSCCs), conflicting data have been reported on the correlation between EGFR copy number and survival and the association between EGFR copy number and protein expression. Anatomical site of the tumour in HNSCCs may likely contribute to the discordance of the above points as EGFR expression may differ between the sub-sites of HNSCCs. Thus, in this study, we focused on oral tongue squamous cell carcinomas (OTSCCs). To investigate the association between EGFR copy number alteration and overexpression and to determine which is the more reliable prognostic indicator, Fluorescence in situ hybridisation (FISH) and immunohistochemical staining (IHC) were performed at a single institution on samples from 89 patients with OTSCCs undergoing surgery as the primary treatment modality. Thirty-two (36%) of 89 cases demonstrated an EGFR copy number alteration. EGFR protein expression was found in all 89 cases, of which 82.0% showed overexpression. No significant correlation was found between gene copy number and protein overexpression. Gene copy number alteration was significantly associated with reduced disease-free survival (P=0.048) and overall survival (P=0.001). Multivariate Cox proportional hazards analysis demonstrated that EGFR copy number increase was significantly correlated with overall survival (P=0.001). EGFR copy number status is a more reliable indicator than protein overexpression of the survival rate in OTSCCs. FISH analysis of the EGFR status is useful in predicting poor prognosis in OTSCCs.
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ABSTRACT: Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of "common" head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far only antibodies against EGF-receptors are established in clinical practice.Laryngo-Rhino-Otologie 03/2012; 91 Suppl 1:S1-26. DOI:10.1055/s-0031-1297241 · 0.99 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the impact of expression of epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition factor (c-Met), and insulin-like growth factor receptor 1 (IGF-1R) protein on response to treatment and survival in patients with oral and oropharyngeal squamous cell carcinoma (SCC). EGFR, c-Met, and IGF-1R immunohistochemical (IHC) scores were generated based on the incidence and intensity of expression of the biomarkers evaluated in paraffin-embedded sections of biopsy specimens taken before treatment from 113 patients given neoadjuvant chemoradiotherapy followed by resection for primary locally advanced oral and oropharyngeal SCC. Correlations were assessed between the IHC of the biomarkers and the patients' clinicopathological variables using Spearman's rank test. Cox's regression models were used to evaluate the impact of EGFR, c-Met, and IGF-1R, expression on survival. Almost all the patients showed expression of EGFR, c-Met, and IGF-1R (99%, 100%, and 100%, respectively). None of the biomarkers examined predicted response to neoadjuvant chemoradiotherapy or were associated with survival. In multivariate analysis, age (p=0.05), alcohol consumption (p=0.03), and pathological size/extent of the primary tumour after neoadjuvant treatment (ypT) status (p=0.009) were significantly associated with recurrence-free survival. Age (p=0.02) and alcohol consumption (p=0.02) were independently associated with overall survival. Although none of the biomarkers evaluated could be used as prognostic indicators, their common expression suggested a strong rationale for targeting EGFR, c-Met, and IGF-1R in the treatment of oral and oropharyngeal SCC.British Journal of Oral and Maxillofacial Surgery 08/2012; 51(3). DOI:10.1016/j.bjoms.2012.06.009 · 1.13 Impact Factor
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ABSTRACT: Patients with locally advanced head and neck squamous cell carcinoma often experience relapse, the cause of poor survival statistics. Relapse occurs following the three main types of treatment, surgery with or without post-operative (chemo)radiotherapy, or chemoradiation (containing cisplatin). Cancer relapse can result from (i) outgrowth of residual tumour cells, sometimes with a number too small to be detected by routine histopathology or (ii) development of another carcinoma in a field of pre-neoplastic cells that has remained after treatment of the primary carcinoma. At this moment, clinical staging is not enough to identify patients who will develop relapse and who need tailored treatment. This review describes the latest knowledge of mechanisms of cancer relapse, addresses the biomarkers of potential interest detectable in the tissue of the tumour or its surgical margins and discusses three biomarkers, human papillomavirus, TP53 and epidermal growth receptor in more detail. Once a marker panel has been established, treatment should be focussed on the patients at risk of relapse by improved tailoring of existing treatment modalities. Also, the implementation of more targeting therapies based on the characteristics of the discovered markers should lead to better survival rates.Annals of Oncology 09/2012; 23 Suppl 10:x173-x177. DOI:10.1093/annonc/mds299 · 6.58 Impact Factor