No abstract

Radical radiotherapy with concurrent cisplatin-based chemotherapy is an established treatment for cervical cancer patients with stage FIGO IIB and higher. The tumor control can be achieved in 40-80% of patients, the treatment is associated with the risk of late postiradiation complications in 10 -15% of cases. Detection of the factors predictive for tumor control and late morbidity is a possible direction how to individualize radiotherapy dose and technique. The aim of our review is to summarize results of studies inquiring various molecular markers predicting tumor response to radiotherapy and a risk of late complications.A lot of candidate molecules were evaluated in histochemical studies: membrane receptors (EGFR, HER-2), cell cycle regulators (p53, p21), proliferative markers (Ki-67), hypoxia and angiogenetic factors (HIF, VEGF), HPV status, and others (COX-2), with promising results in some of them (HPV, HIF-1α, Ku80, ATM polymorphism).Microarray studies identified decades of genes with different expression in radiosensitive/radioresistant cervical tumors and sets of genes are able to comletely separate responding and nonresponding tumors, but these sets differ across studies. Further well designed studies will be necessary to achieve results matured for use in clinical practice.

Summary: Clinical oncologists have been focusing their efforts on attempting to define risk groups of patients with unusual biological reactions to the recommended therapy regimens using molecular biology techniques. The aims of our study were: (i) to find a design and validate a method for fast and reliable analysis of the D1853N (5557G>A) genetic polymorphism in the ATM (ataxia-telangiectasia mutated) gene; (ii) to use side-directed mutagenesis to generate ATM 5557A-positive DNA (reference ATM5557A DNA); and (iii) to analyze a group of patients suffering from cervical carcinoma with adverse responses to radiotherapy. The 5557A variant was found in three of twenty women (15%). Our data show that the prevalence of the 5557A allelic variant in cervical cancer subjects with adverse responses after irradiation probably does not differ from the prevalence common in Caucasians. A larger population study should confirm these preliminary results.

The purpose of our study was to evaluate a possible correlation between genetic polymorphisms in ATM and TGFB1 genes and late toxicity of chemoradiotherapy for locally advanced cervical cancer. Fifty five patients with FIGO stage IIB and higher without a disease recurrence with a mean follow up of 6 years were included. Late toxicity was assessed by EORTC/RTOG late toxicity criteria. Univariate and multivariate logistic regression model was used for statistical analysis. Degree of association between polymorphisms and late toxicity of chemotherapy was assessed on the basis of phi-coefficient (φ) as well. We did not find any association between 5557G>A polymorphism in the ATM gene or single TGFB1 polymorphisms and late toxicity. TGFB1 compound homozygosity (-1552delAGG, -509C>T, L10P) was a significant predictive factor of grade III-IV and any grade of complications in both univariate and multivariate logistic regression analyses and statistical significance of association between polymorphisms and late toxicity of chemoradiotherapy was confirmed also by the evaluation of phi-coefficient (φ). We conclude that haplotypes instead of single nucleotide polymorphic sites in the genes may better characterize the individual radiosensitivity.

Intensity of VEGF expression and depth of tumor invasion may be significantly negative predictors of disease-free survival in tongue cancer patients treated by brachytherapy alone. Predictive value of VEGF deserves evaluation in larger studies.