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Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter,
Masahiro Hatori1,2, Daiki Tsuji2, Kenichi Suzuki3
1Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
Background:
Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy.
Methods:
This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%.
Results:
In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019).
Conclusions:
Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.
Insights
Germline genetic polymorphisms in gemcitabine metabolism genes did not significantly impact treatment response in metastatic pancreatic cancer. However, COX-2 gene variations were linked to overall survival, suggesting a role in tumor proliferation.
Area of Science:
- Oncology
- Pharmacogenomics
- Cancer Genetics
Background:
- Individual responses to anticancer drugs vary due to genetic differences.
- Germline mutations' impact on chemotherapy efficacy remains understudied.
- Focus on gemcitabine pharmacokinetics and transporter gene polymorphisms in pancreatic cancer.
Purpose of the Study:
- Investigate associations between germline polymorphisms of gemcitabine-related genes and treatment outcomes.
- Evaluate the impact on carbohydrate antigen 19-9 (CA 19-9) response and overall survival (OS).
- Analyze outcomes in metastatic pancreatic cancer patients receiving gemcitabine-based chemotherapy.
Main Methods:
- Multicenter, prospective, observational study of 159 metastatic pancreatic cancer patients.
- Genotyping of 13 polymorphisms in gemcitabine metabolic and transporter genes.
- Logistic regression analyses to assess associations with CA 19-9 response and OS.
Main Results:
- Patients with CA 19-9 response showed significantly longer OS (372 vs. 241 days; p=0.007).
- RRM1 and RRM2 polymorphisms showed a non-significant trend towards association with CA 19-9 response and OS.
- COX-2 -765G>C polymorphism was significantly associated with OS (HR=2.031; p=0.019), but not CA 19-9 response.
Conclusions:
- Gemcitabine pharmacokinetic gene polymorphisms did not significantly correlate with treatment efficacy.
- COX-2 gene polymorphisms, potentially involved in tumor proliferation, may influence overall survival in pancreatic cancer patients.
- Further research into COX-2's role in pancreatic cancer progression is warranted.
