Možnosti predikcie rezistencie k neoadjuvantnej konkomitantnej chemorádioterapii u pacientov s lokálne pokročilým karcinómom konečníka

POSSIBILITIES OF RESISTANCE PREDICTION TO NEOADJUVANT CONCOMITANT CHEMORADIOTHERAPY IN THE TREATMENT ALGORITHM OF PATIENTS WITH RECTAL CARCINOMA Backgrounds: Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It can reduce tumor volume, thus increases a feasibility of sphincter-sparing surgery, shows less acute toxicity, improves local control rate. It is based on fluoropyrimidines (5-fluorouracil, capecitabine) with concurrent radiotherapy. The aim of our study was to identify nonresponders (NR) pretherapeutically. Patients, methods: 170 patients with LARA who were treated by neoadjuvant concomitant chemoradiotherapy in Masaryk Memorial Cancer Institute from 2001 to 2008, were enrolled into our study. At the base of the tumor response to neoadjuvant therapy (evaluted as TRG according to Mandard), we divided patiens into two groups: responders (R, good response to neoadjuvant therapy, TRG 1-2) and nonresponders (NR, non/minimum response to neoadjuvant therapy, TRG 4-5). At the selected group of 17 patients, gene expression levels of 440 genes were obtained by low-density oligonucleotide microarrays. As well, immunohistochemical protein expression of selected molecules: EGFR, Akt-1, Akt-2, p-Akt-Thr-308, p-Akt-Ser-473, Bcl-2, CD29, TP53, MDM2 were provided at the tumor samples of R and NR (n=64-72), before starting the neoadjuvant therapy. Results: As negative clinico-pathological predictive parameters of tumor´s response to neoadjuvant therapy (evaluated by TRG according to Mandard) are these parametres: low rectal tumors up to 5 cm from anocutaneous line, initial size of tumor more then 45 mm, reduction of radiotherapy. Negative predictors of survival (DFS and OS) were: low grade of tumor, elevation of tumor marker CA 19-9 up to the norm of 40 kU/l before starting the neoadjuvant therapy (border statistical significance to DFS, p=0,063), elevation of tumor markers CEA and CA 19-9 up to the norm (for CEA up to the value of 4,6 µg/l) after neoadjuvant therapy. To DFS parameter, negative predictors are: inicial size of tumor more then 45 mm, worse TRG after neoadjuvant therapy, presence of lymphonodes´ metastasis after neoadjuvant therapy, absence of downstaging in T/N parameter, elevation of tumor marker CEA up to the norm before starting the neoadjuvant therapy. Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 8 genes (RB1, RBBP4, HYOU1, JUNB, MDM4, CANX, MMP2, TCF7L2) significantly upregulated in NR. More, using immunohistochemistry, we discovered that positive expression of EGFR protein was associated with worse response to neoadjuvant therapy, the association showed statistical significance. Patients´ tumors who had negative protein expression of CD29 had better response to neaodjuvant therapy (borderline statistical significance, p=0,057). Conclusion: We know that we cannot make definitive conclusions from our results, on the other side our observations are in concordance with biological function of found molecular predictors. From this point of view we can suggest that these molecules are suitable candidate of resistence prediction to neoadjuvant concomitant chemoradiotherapy in patiens with locally advanced rectal adenocarcinoma.