Identification of gene expression profiling to predict pathologic response of rectal carcinoma after preoperative chemoradiotherapy

Background: The pathologic response after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer is a clinically relevant issue because a better survival and a lower rate of local recurrence has been reported for ‘‘responders’’ as compared with ‘‘non responders’’. Aim of this study was therefore to identify a set of discriminating genes that can be used for discriminate responders or nonresponders after CRT using microarray technology. Patients and Methods: Eighty consecutive patients with mid-low rectal cancer (up to 11 cm from the anal verge) were considered. Patients underwent preoperative CRT (conventional long-course radiotherapy with a total dose of at least 45 Gy and 5-FU- based chemotherapy) followed by radical surgery 6-8 weeks later. Indication for CRT were: age between 18 and 75 years, clinical TNM stage II/III (transmural and/or lymph node infiltration) as assessed by transrectal ultrasonography and pelvic magnetic resonance imaging or multislice computed tomography. For 43 of them, pre-treatment biopsies showing a cancer cellularity of at least 70% were available, these patients were included in the study. Tumor regression grade (TRG) was scored according to the modified Mandard classification. Tumors showing a TRG1-2 were considered responders, whereas those showing a TRG3-5 were considered nonresponders. Gene expression profiles were obtained using human Affimetrix 133Aplus Gene Chip. Results: Ninenteen patients showed a TRG1-2 (responders) and the remaining twentyfour a TRG3-5 (nonresponders). Responders and nonresponders showed significantly different expression levels for 19 genes (P<.001). Starting from these 19 probset we selected the logistic model maximizing the Akaike information criterion. With this approach a list of four discriminating genes was found: XRCC3 ( X-ray repair gene), RAB7, RAB6A and interleukine 12 (IL12). Performance was 95% accuracy by Leave One Out Cross Validation. In order to confirm these data, XRCC3 and IL12 expression was investigated by using real time PCR. Also using this analysis, both XRCC3 and IL12 were found to be overexpressed in responders compared to nonresponders. Conclusions: Our findings suggest that gene expression profiles using microarray technology may be able to predict the pathologic response after preoperative CRT for rectal cancer. XRCC3 and IL12 seem to play a significant role in the physiopathology of response to CRT.