Pharmacogenomic profiling of the efficacy of gemcitabine monotherapy in metastatic pancreatic cancer: Subgroup analysis of the GENESECT study

AIM: In the GENESECT study, no significant gemcitabine (GEM) metabolism-related germline genetic polymorphisms (GPs) were identified because approximately 70% of patients received combination therapy with nab-paclitaxel, which has metabolic pathways different from GEM. The present study was a sub-analysis including only GEM monotherapy patients. METHODS: Of 159 patients analysed in the GENESECT study, only GEM-monotherapy patients were selected. The endpoints included carbohydrate antigen 19-9 (CA19-9) response (reduction ≥ 50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs. Analysed genes included those encoding GEM transporters and metabolic enzymes (SLC29A1, ABCC5, CDA, DCK, RRM1/2) and a tumour cell proliferation enzyme (COX-2). Screening and significance levels were set at 10% (univariable) and 5% (multivariable), respectively. RESULTS: Data for 50 patients were analysed. Genotype AA of ABCC5 1146A>G (rs7636910) showed a higher CA19-9 response rate than AG/GG (52.9% vs. 21.2%, p = 0.023) and remained significant in multivariable analysis (odds ratio: 6.255, p = 0.014). It also tended to be associated with longer PFS, but not significantly (hazard ratio [HR]: 0.464, p = 0.074). By contrast, although CA19-9 responses were not significantly associated with DCK -1205T>C (rs4694362), the TT/TC genotype was significantly associated with prolonged PFS compared with CC (median 127 vs. 48 days, p = 0.002), and this association remained significant in multivariable analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS. CONCLUSION: ABCC5 and DCK might be related to the efficacy of GEM treatment, but further research is needed.