Tissue biomarkers (BIOM) in colon cancer (COC): The translational study on the randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) to 5-FU/FA in stage II-III COC patients (pts)

Abstract

4022 Background and Aims: PETACC 3 is a large adjuvant trial with 3,005 COC pts. The value of BIOM in COC in adjuvant setting is still a matter of debate because of lack of large data sets. We took advantage of PETACC 3 to assess P53, SMAD4, thymidylate synthetase (TS), telomerase (HTERT) expressions, UGT1A1 genotype, KRAS and BRAF mutations, microsatellite instability (MSI), 18q and 8p LOH with regard to their prognostic and predictive value and their individual interactions on a very large homogeneous cohort of COC pts. In addition we investigated the association between UGT1A1 genotype and occurrence of diarrhoea and Gd 4 neutropenia. Methods: 1,564 formalin fixed paraffin embedded (FFPE) tissue blocks of PETACC 3 pts were prospectively collected and 5–20μ sections cut. DNA from normal (Nor) and tumoral (Tu) tissue was extracted after section microdissection. P53, SMAD4, TS and HTERT were assessed by immunohistochemistry (IHC); MSI was typed with 10 markers, KRAS exon 2 and BRAF exon 15 mutations by allele specific real time PCR on Tu DNA; 18q and 8p LOH by typing multiple SNPs by pyrosequencing on Nor/Tu DNA; UGT1A1 genotypes by PCR and fragment sizing on Nor DNA. Prognostic/predictive value of each BIOM is analysed by Cox regression for disease free survival and by logistic regression for specific toxicity. Associations between any 2 categorized BIOM and between each BIOM and each known prognostic variable are tested by chi-square tests. Results: DNA of 1405 pts was extracted and successfully analyzed in 97.1% for KRAS, 98.6% for BRAF, 94% for 18q LOH, 93.6% for MSI, 86% for UGT1A1, 8p LOH is still ongoing. Of 1530 pts slides IHC analysis was successful in 94.5% for P53, 94.2% for SMAD4, 82.9% for TS, 53.9% for HTERT. The clinical database was made available in Nov 06 and statistical analysis started on Dec 11th 2006. Conclusion: This is the largest multicenter centrally coordinated tissue BIOM study performed in COC to date. The high success rate of analysis shows that large prospective BIOM studies can be performed on routine FFPE material. Final results on the prognostic/predictive value of each molecular BIOM will be available at the meeting. No significant financial relationships to disclose.