Abstract:

Objective To analyze the distribution of UDP-glucuronosyltransferase1A1（UGT1A1） gene polymorphisms in Chinese Han patients with metastatic colorectal cancer（mCRC）， and to evaluate correlations between UGT1A1 gene polymorphisms and toxicity and efficacy of irinotecan（CPT-11） combined with fluorouracil（5-FU） regimen in patients with mCRC. Methods Chinese Han patients with mCRC in the multicenter phase Ⅱ study were treated with FOLFIRI regimen（CPT-11 180mg／m² iv）and IFL regimen（CPT-11 125mg／m² iv）. UGT1A1*28 and UGT1A1*6 genotypes were determined by direct sequencing. Effect of UGT1A1 gene polymorphisms on toxicity， efficacy and survival of chemotherapy were analyzed. ResultsA total of 192 patients were enrolled， and 189 patients were detected UGT1A1 gene polymorphisms. The rates of wild type， unit point mutation and two points mutation of UGT1A1 were 37.6％， 43.9％ and 18.5％. Treatment options included FOLFIRI or IFL regimens. One hundred and eightythree cases were eligible for toxicity evaluation， incidence of grade 3-4 neutropenia was 266％（51／183）， and grade 3-4 late diarrhea rate was 15.1％（29／183）. Patients with two points mutation had significantly higher incidence of grade 3-4 late diarrhea than patients with wild type（26.5％ vs. 9.0％， P=0.021）. Grade 2-4 late diarrhea rates of UGT1A1*28 wide type， UGT1A1*28 heterozygote and UGT1A1*28 homozygous were 29.6％， 37.5％ and 88.9％，showing significant differences（P＜0.05）. Grade 4 neutropenia rate of UGT1A1*28 homozygous was higher than that of UGT1A1*28 wide type（33.3％ vs. 9.6％）， with no significant difference（P=0.07）. Additionally， poor ECOG status and higher dose intensity of CPT-11 also significantly increased irinotecanrelated toxicity. One hundred and fiftyeight patients were evaluatable for efficacy and response rate was 20.9％. Better response rate was found in patients with two points mutation of UGT1A1 compared with wild type of UGT1A1（33.3％ vs.15.3％）， with no significant difference（P=0.063）. Multiple regression analysis showed treatment duration has a significant impact on treatment outcomes. Less than 6 weeks treatment had significantly increased risk of disease progression（OR=6.106，95％CI： 1.680-22.197， P=0.006）. Prognostic factors were ECOG status， treatment duration and regimens， but not UGT1A1 gene polymorphisms. Conclusion Chinese Han mCRC patients with two points mutation of UGT1A1 were associated with higher incidence of irinotecanrelated toxicity and better response， but treatment duration shortened due to toxicity might impair theefficacy， and it is worth further investigation.