Prediction of sensitivity of locally advanced rectaladenocarcinomas to neoadjuvant combined therapy withfluoropyrimidines and concomitant radiotherapy by low-densityoligonucleotide arrays

PURPOSE: Rectal cancer prognosis is favorable for surcigally cured patients in early stages of disease. With increasing staging and lymph node positivity of the rectal cancer also local reccurence rates are increased (20 to 60%) and the surcigal intervention which is the major treatment modality is supplied by adjuvant or neoadjuvant chemoradiotherapy. Recently, neoadjuvant and concomitant administration of chemoradiotherapy is prefered because of its several advantages eg. less acute toxicity, increased radiosensitivity due to more oxygenated cells and mainly decrease of tumor volume (downstaging) allowing subsequent more conservative sphincter-sparing surgery. Unfortunately, only about one third of patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy have evidential benefit characterized by complete pathological remission (pCR: ypT0 ypN0) or only minimal microscopic residues. Molecular characterization of sensitive patients should assist to oncologists in treatment decision by selecting those patients who will have benefit from neoadjuvant chemoradiotherapy. PATIENTS AND METHODS: Eleven patients with locally advanced rectal adenocarcinomas neoadjuvantly treated with combined therapy based on fluoropyrimidines and concomitant radiotherapy were included to our pilot study. After therapy were five patients characterized by complete pathological remission, tumors of another six patients were not affected by therapy and stage of disease remains unchanged. Surgical microexcisions of bioptic samples were done before initiation of therapy. Total RNA was extracted from each frozen tumor specimen and relative gene expression levels of 440 genes known to be involved in cancer biology were obtained by low-density oligonucleotide microarrays from 11 rectal cancer samples. RESULTS: Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 7 genes (anti-apoptotic lipocalin 2, oncogene JUNB, cell cycle regulator RB1, p53-binding protein MDM4, calnexin, peroxisome proliferator-activated receptor delta PPARD, mucinlike adhesion molecule CD24) with significantly up-regulated expression in primary tumors of patients with poor response to therapy. In subsequent cluster analysis this group of genes was able to discriminate good from poor response cases. CONCLUSION: Our preliminary data suggest that low-density oligonucleotide microarray technology should contribute to a better understanding of rectal cancer resistance at molecular level, and facilitate prediction of tumor response to concomitant chemoradiotherapy. Supported by IGA MZ CR NR/9076.