Markers of Toxicity for Chemotherapy in Colorectal Cancer
The summaries of product characteristics of only two drugs used in CRC have been modified to include warnings recommending genotyping before prescription to prevent or decrease associated ADRs. Research during the last 10 years has provided us with a large amount of data on the pharmacogenetics of adverse reactions in CRC patients receiving chemotherapy. However, as no conclusive findings are available, these results cannot be transferred to clinical practice. Most studies present the same limitations: low patient numbers, heterogeneous groups and different criteria for considering a polymorphism to be 'associated with toxicity'. Studies performed in recent years with large populations have generally reported negative results, and conclusions are heterogeneous. Consequently, evidence for applying pharmacogenetic testing to prevent chemotherapy-induced ADRs in CRC patients is lacking. Even in the case of UGT1A1*28 for irinotecan and DPYD*2A for fluoropyrimidines, no consensus has been reached in large cohorts. Nevertheless, trends have been confirmed in several studies. Considering the intrinsic variability in treatments, toxicity and statistical validations, we can be optimistic about the future application of pharmacogenetic tests in this field. It seems unlikely that a 100% positive or negative predictive value will be obtained in pharmacogenetics testing for ADRs in patients with CRC. However, considering the high number of drugs and combinations of drugs that can be administered, knowing the probability of developing an ADR to a specific drug could prove extremely useful for oncologists. Therefore, we consider that testing for DPYD*2A and UGT1A1*28 is justified before administration of fluoropyrimidines and irinotecan, respectively. Finally, GWAS studies with large patient populations are a promising tool, especially in CRC, where the results of many candidate gene-association studies have been poorer than expected.
Conclusion & Future Perspective
The summaries of product characteristics of only two drugs used in CRC have been modified to include warnings recommending genotyping before prescription to prevent or decrease associated ADRs. Research during the last 10 years has provided us with a large amount of data on the pharmacogenetics of adverse reactions in CRC patients receiving chemotherapy. However, as no conclusive findings are available, these results cannot be transferred to clinical practice. Most studies present the same limitations: low patient numbers, heterogeneous groups and different criteria for considering a polymorphism to be 'associated with toxicity'. Studies performed in recent years with large populations have generally reported negative results, and conclusions are heterogeneous. Consequently, evidence for applying pharmacogenetic testing to prevent chemotherapy-induced ADRs in CRC patients is lacking. Even in the case of UGT1A1*28 for irinotecan and DPYD*2A for fluoropyrimidines, no consensus has been reached in large cohorts. Nevertheless, trends have been confirmed in several studies. Considering the intrinsic variability in treatments, toxicity and statistical validations, we can be optimistic about the future application of pharmacogenetic tests in this field. It seems unlikely that a 100% positive or negative predictive value will be obtained in pharmacogenetics testing for ADRs in patients with CRC. However, considering the high number of drugs and combinations of drugs that can be administered, knowing the probability of developing an ADR to a specific drug could prove extremely useful for oncologists. Therefore, we consider that testing for DPYD*2A and UGT1A1*28 is justified before administration of fluoropyrimidines and irinotecan, respectively. Finally, GWAS studies with large patient populations are a promising tool, especially in CRC, where the results of many candidate gene-association studies have been poorer than expected.
Source...