Integrating , and testing in patients with metastatic colorectal cancer.

AIM

To investigate the impact of thymidylate synthase (), and in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.

METHODS

Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. genotypes were identified with restriction fragment analysis PCR, while and mutation status was evaluated using real-time PCR assays. gene polymorphisms of each of the 3' untranslated region (UTR) and 5'UTR were classified into three groups according to the probability they have for high, medium and low expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.

RESULTS

The analysis recovered 89 patients with mCRC (46.1% metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of polymorphisms, and with clinicopathological parameters indicated that 3'UTR polymorphisms are associated with risk for disease progression and death ( < 0.05 and < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, < 0.06 respectively). Additionally, mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, < 0.05). The addition of irinotecan in 1 line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, < 0.01 respectively).

CONCLUSION

The genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.