Association between ABCB1 genetic polymorphisms with treatment outcomes in patients with metastatic pancreatic cancer.

BACKGROUND: Gemcitabine plus nanoparticle albumin-bound-paclitaxel (GnP) therapy cause sometimes severe neutropenia in all the treatment period, which was reported to association with overall survival (OS). However, the relationship between pharmacokinetics-related genetic polymorphisms and both OS and early severe neutropenia in patients with metastatic pancreatic cancer receiving GnP therapy has not been adequately examined. We aimed to examine the associations between pharmacokinetic genetic polymorphisms involved in GnP, early severe neutropenia, and OS in Japanese patients with metastatic pancreatic cancer treated with GnP as first-line chemotherapy. METHODS: This multicenter prospective observational study enrolled 122 patients with metastatic pancreatic cancer who received GnP therapy. Twenty-two genetic polymorphisms related pharmacokinetics of GnP including ABCB1 were analyzed. Multivariable logistic regression and time-dependent Cox proportional hazards models were used to evaluate associations between these genotypes and early severe neutropenia up to day 14 and OS after applied inverse probability of treatment weighting. The significance level was set at 5%. RESULTS: Patients who developed early severe neutropenia had significantly longer median OS (523 vs. 249 days; adjusted hazard ratio [HR], 0.47; 95% confidence interval, 0.26-0.85; p = 0.012). The combination of ABCB1 rs2032582 non-GG and rs1045642 non-CC were significantly associated with severe neutropenia (adjusted odds ratio, 2.75; p = 0.020) and OS (adjusted HR, 0.56; p = 0.017). CONCLUSIONS: Early-onset severe neutropenia could be associated with prolonged OS in patients with metastatic pancreatic cancer treated with GnP. The combination of ABCB1 rs2032582 non-GG and rs1045642 non-CC may help predict the risk of severe neutropenia and OS. TRIAL REGISTRATION: UMIN 000012720.