Prognostic Value of Tumoral Thymidylate Synthase and p53 in Metastatic Colorectal Cancer Patients Receiving Fluorouracil-Based Chemotherapy: Phenotypic and Genotypic Analyses

Abstract

P r o g n o s t i c V a l u e o f T u m o r a l T h y m i d y l a t e S y n t h a s e a n d p 5 3 i n M e t a s t a t i c C o l o r e c t a l C a n c e r P a t i e n t s R e c e i v i n g F l u o r o u r a c i l -B a s e d C h e m o t h e r a p y : P h e n o t y p i c a n d G e n o t y p i c A n a l y s e sBy Marie-Christine Etienne, Maurice Chazal, Pierre Laurent-Puig, Nicolas Magné, Christophe Rosty, Jean-Louis Formento, Mireille Francoual, Patricia Formento, Nicole Renée, Emmanuel Chamorey, André Bourgeon, Jean-François Seitz, Jean-Robert Delpero, Christian Letoublon, Denis Pezet, and Gérard MilanoPurpose: The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid.Patients and Methods: Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively.Results: p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P ‫؍‬ .047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P ‫؍‬ .040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P ‫؍‬ .035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P ‫؍‬ .018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism.Conclusion: Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity. T HE BASIS OF THE chemotherapeutic strategy for the treatment of advanced colorectal cancer is currently broadening with the clinical emergence, among a plethora of potential candidates, of new active drugs such as irinotecan 1 and oxaliplatin. 2 It follows that fluorouracil (FU) is no longer the sole agent with significant antitumor activity in colorectal cancer. This new therapeutic context heightens the need for objective arguments when choosing the most active drug for a given colorectal tumor. Concerning FU itself 3 or new promising FU prodrugs such as capecitabine, 4 several tumoral candidates able to predict FU efficacy have been identified.Thymidylate synthase (TS), one of the key enz...

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

“…Patients with *2/*2 genotype have a good prognosis, but patients with *3/*2 genotype are sometimes included in the good prognosis group 27 and other times in the intermediate or bad prognosis group. 12,26 In a recent work, Uchida et al 29 reported that the loss of heterozygosity at the TS locus in tumor samples of colorectal cancer patients treated with fluoropyrimidine therapy affects tumor response and survival in those patients with a heterozygous TS*2/*3 genotype. In 17 of 22 of these heterozygous cases, a LOH was demonstrated in tumor tissues The authors reported that the response rate of the TS*2/loss tumor genotype patients was 80% and that only 1 of 7 tumors with a genotype of *3/loss showed a response.…”

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy

“…Therefore, the TS functional polymorphisms are under investigation for the possibility of optimising chemotherapy (Yong and Innocenti, 2007). Studies in patients with metastatic colorectal cancer showed that carriers of the TS 5 0 -UTR 3R (3G) and/or the TS 3 0 -UTR 6 þ alleles had adverse clinical outcomes (Pullarkat et al, 2001;Etienne et al, 2002;Park et al, 2002;Marcuello et al, 2004;Stoehlmacher et al, 2004;Martinez-Balibrea et al, 2007); however, such an association was not always detected (Lecomte et al, 2004;Jakobsen et al, 2005;Ruzzo et al, 2007a, b). Heterogeneity in clinical experimental conditions (Sorbye et al, 2007), in tumour burden (Köhne et al, 2002) and in genetic/molecular features in the presence of a multisite metastatic disease (Yokota, 2000) may explain variable results in these pharmacogenetic studies.…”

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

“…An association between the genotype of the TS enhancer region and response and toxicity with 5-FU-based therapy in patients with colorectal cancer has been reported previously. [29][30][31][32][33][34][35][36][37][38][39] : patients who are homozygous for the double-tandem repeat have a lower TS protein content and a higher likelihood of response, but a greater risk of toxicity. MTHFR is involved in the regeneration of 5 methyltetrahydrofolate from 5,10 methylenetetrahydrofolate.…”