Thesis (M.Sc. in Pharm.)--Chulalongkorn University, 2016

Gemcitabine-platinum chemotherapy is the treatment of choice for unresectable cholangiocarcinoma, however, the response rate is still low and varies among individuals. Several studies have been investigated the biomarkers which can predict the response of treatment, but results are controversial. This is a cohort study to assess the association of RRM1, ERCC1, and CTR1 polymorphisms with response and toxicities of gemcitabine-platinum chemotherapy in unresectable cholangiocarcinoma patients. DNA from 33 patients were extracted and genetic polymorphisms were assessed by Taqman allelic discrimination assay. After third cycles of chemotherapy, treatment response and toxicities were evaluated according to RECIST version 1.1 and CTCAE version 4.03, respectively. The response rate and tumor control rate for 31 evaluable patients was 9.7% and 71%, respectively. There were no association between genetic polymorphisms and response rate as well as tumor control rate. The results showed that CTR1 polymorphisms were related with risk of alkaline phosphatase increasing (p=0.035). For further analysis, genetic polymorphisms were combined to observe their effects. RRM1 and CTR1 polymorphisms was related with risk of neutropenia (p=0.039) and severity of leukopenia (p=0.048). ERCC1 polymorphism in combination with CTR1 polymorphism (CC/GG) was associated with response rate (p=0.018). Carriers of CT/GT showed higher risk of neutropenia (p=0.024) and weight loss (p=0.010) than carrier of the other genotypes. Our results suggest that genetic polymorphism combinations were related with toxicities and may be potential biomarkers for unresectable cholangiocarcinoma patients treated with gemcitabine-platinum regimen.