PURPOSE: High-throughput arrays are opening new opportunities for our understanding of the molecular aberrations underlying the outcome of colorectal cancer (CRC) in response to specific therapies. The aim of the present study was to evaluate whether genome-wide DNA copy number profiles of CRC specimens can predict the clinical outcome to irinotecan and 5-fluorouracil (5-FU) or pemetrexed treatments.

EXPERIMENTAL DESIGN: High-resolution DNA copy number profiles were obtained by 44K oligonucleotide-based array-comparative-genomic-hybridization (aCGH). DNA was isolated from formaldehyde-fixed paraffin-embedded primary tumors of 34 patients with advanced CRC, treated within a randomized phase II trial of pemetrexed+irinotecan (ALIRI) vs. leucovorin-modulated-5-FU + irinotecan (FOLFIRI).

RESULTS: Unsupervised hierarchical cluster analysis of the aCGH data revealed two clusters significantly correlated with response status (P=0.03). Most frequently observed chromosomal aberrations (>50%) in the 9 responders were losses of 18q (78%), losses of 18p (72%), 8p22-p23.1 (56%), and 17p11.2 (67%), and gains of 20p13-q13.3 (73%), the whole chromosome 13 (78%), 7p11.2-22.3 (56%), and 8q24.21 (56%). After multiple correction gains in 8q24.21and in 20p13-q13 as well as losses of 18p and 17p11 were significantly associated with response. The analysis of patients categorized for different treatments showed that tumors of patients with better response after FOLFIRI had specific profiles of chromosomal aberrations, including significantly more losses at chromosome 18, fewer losses at chromosome 17, and more gains at chromosomes 20 and 8. Similar results were observed in the ALIRI arm. However, in contrast to the results observed in the patients treated in the ALIRI arm, response to FOLFIRI was correlated with a higher number of losses at chromosome 1, including the 1p36 region (P<0.001). The aberrations in this region were also significantly different in the non-responders in the ALIRI (N=15) vs FOLFIRI (N=10) arm (P=0.02). However, due to the small sample size of the ALIRI and FOLFIRI groups, the relevance of these findings should be interpreted with caution

CONCLUSIONS: Genome-wide DNA profiling of CRC revealed several genomic loci, of which the copy number status may serve as predictive marker for clinical outcome after the commonly used FOLFIRI regimen, and large prospective studies are ongoing. Some of these aberrations, but also other specific aberrations, affected the activity of the pemetrexed-irinotecan combination, and should be further studied to explain the biological basis of response to these drugs and optimize their use.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2146.