Abstract 2606: Absence of transcriptomic signature of response to chemotherapy in metastatic colorectal carcinoma patients

Abstract

Abstract Using whole genome tumour gene expression profiling in patients treated for metastatic colorectal cancer, we attempted to define a signature able to discriminate between responders and non-responders to first-line chemotherapy. A total of 42 patients were prospectively included between 2003 and 2006. They all suffered from histologically proven colorectal adenocarcinoma and were metastatic at the time of diagnosis. All of them gave informed consent to the study. They were treated in first line with 5-fluorouracil (according to the de Gramont regimen in most cases) associated either with irinotecan (FolFiri regimen, 180 mg/m2 every two weeks, 22 pts) or with oxaliplatin (FolFox 4 regimen, 85 mg/m2, 20 pts) according to physician's decision. Response was evaluated using WHO criteria every 2 months after initiation of chemotherapy and patients were assigned to complete response (1 pt), partial response (24 pts), stable disease (13 pts) or progressive disease (4 pts). From a tumour sample obtained at surgery (18 pts) or by biopsy (24 pts) and kept in RNA later, we extracted and purified total RNA. Gene expression profiling was performed by Cogenics using microarrays from Applied Biosystems (Human Genome Survey Microarray v2.0). We used three different methods for supervised data analysis: analysis of variance, SAM (statistical analysis of microarrays) and Limma (Bioconductor). We compared responders to non-responders in the whole set of patients and in the subsets of patients who received either irinotecan or oxaliplatin. With none of the three methods we were able to obtain a stable signature, i.e. a group of genes consistently associated with response to chemotherapy. On the contrary, we obtained very homogeneous gene expression profiles which were even difficult to clusterise using a non-supervised approach. These negative results show that the determinants of response to chemotherapy should be sought not only in the tumour molecular characteristics, but also among the processes leading to drug availability to the tumour (drug dose, drug disposition, etc.). Especially, the relatively low dose of irinotecan which is of standard use in Europe does not allow to recruit all the responders who could be identified at higher dosage, given the sharp dose-efficacy curve that has been identified long ago for this drug. 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 2606.