Προγνωστική αξία της έκφρασης των μοριακών δεικτών p53, p21, p27, cyclin D1, Ki67, EGFR και IGF-1R στο ακανθοκυτταρικό καρκίνωμα του στόματος και του στοματοφάρυγγα

Abstract

OOSCC, which is a subset of head and neck cancer, is a major cause of cancer-related deaths worldwide. The main risk factors for OOSCC are tobacco usage and alcohol abuse. In recent times, infection with high-risk types of human papillomavirus, especially type 16, has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinomas. Despite significant improvements in the treatment of OOSCC, the survival rate has remained essentially unchanged over the past decades. Recent advances in the understanding of head and neck cancer biology have allowed the development of novel molecular-targeted therapies that block dysregulated signaling pathways. In addition, improvements in proteomic and genomic technologies may enable the detection of novel cancer biomarkers that have the ability to predict treatment response and clinical outcome in patients with OOSCC.OOSCCs arise as a result of genetic changes and epigenetic abberations accumulating in a cell. These alterations eventually lead to inappropriate activity of cancer-associated signaling pathways that control cellular growth, apoptosis, angiogenesis and metastasis. The EGFR is almost universally expressed in head and neck cancer and its activation triggers downstream signaling cascades that play critical roles in carcinogenesis. Accumulated evidence suggests that the IGF-1R is expressed in the majority of head and neck cancers. Additionally, a crosstalk has been observed between the IGF-1R and the EGFR mainly through common downstream molecular pathways. The tumor suppressor gene TP53 is mutated in approximately 60-80% of head and neck cancers. The p53 protein is a transcription factor, which regulates genes involved in cell cycle arrest, DNA repair and apoptosis. Inactivation of p53 function by TP53 mutations abrogates normal cell-cycle checkpoints and apoptosis, thus creating a favourable setting for genomic instability and carcinogenesis. Cell-cycle dysregulation is a hallmark of cancer pathogenesis. Several lines of evidence suggest that the abnormal expression of the cell-cycle regulatory proteins p21, p27 and cyclin D1 promotes cell-cycle progression and cellular proliferation in head and neck cancer. The nuclear protein Ki67, which is expressed in cells during all active phases of the cell-cycle, is a useful marker of cellular proliferation, reflecting the total fraction of proliferating cells in a tumor.The aim of the present thesis was to determine the immunohistochemical expression of EGFR, IGF-1R, p53, p21, p27, cyclin D1 and Ki67 in pretreatment tumor biopsies from patients with locally-advanced OOSCC, and to investigate the association between the expression of these biomarkers and clinical outcome parameters, such as treatment response, overall survival and recurrence-free survival. EGFR, c-Met and IGF-1R immunohistochemical 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 receiving neoadjuvant chemoradiotherapy followed by radical resection for primary locally-advanced OOSCC. Almost all the patients showed expression of EGFR, c-Met, and IGF-1R (99%, 100% and 100%, respectively). There was a significant association between the IGF-1R and c-Met immunohistochemical expressions. None of the molecular markers examined predicted response to neoadjuvant chemoradiotherapy or were associated with survival. On multivariate analysis, age, alcohol consumption, and pathological size of the primary tumor after neoadjuvant treatment (ypT) were significantly associated with recurrence-free survival. Age and alcohol consumption were independently associated with overall survival. The expression of p53, p21, p27, cyclin D1, and Ki67 was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded pretreatment biopsies of 111 homogenously treated patients with OOSCC. We assessed the association between the expression of the biomarkers (analyzed as both dichotomized and continuous variables) and clinicopathological variables as well as survival outcome of patients. Biomarker overexpression on the basis of pre-selected cutoff points was seen in 59% of OOSCCs for p53, in 69% for p21, in 43% for p27, in 73% for cyclin D1, and in 49% of tumors for Ki67. None of the investigated biomarkers was able to predict response to neoadjuvant chemoradiotherapy or was associated with survival outcome. Advanced post-treatment pathologic TNM stage, pathological non-response of the primary tumor, and perineural invasion were the only factors having a significant negative effect on recurrence-free survival. Advanced post-treatment pathologic N stage, advanced post-treatment pathologic TNM stage, pathological non-response of the primary tumor, and perineural invasion had a significant negative impact on overall survival.In conclusion, our results suggest that the biomarkers EGFR, IGF-1R, p53, p21, p27, cyclin D1 and Ki67 have no impact on treatment response and survival in patients with OOSCC treated with preoperative chemoradiation. Nevertheless, the common expression of EGFR and IGF-1R suggested a strong rationale for targeting these biomarkers in the treatment of OOSCC.