Personalized prophylactic antiemetic regimens for the control of chemotherapy-induced nausea and vomiting by pharmacogenetic analysis of three receptors genes: HTR3A, HTR3B, TACR1

BackgroundContemporary prophylactic antiemetic regimens have improved the control of chemotherapy-induced nausea and vomiting (CINV). However, many patents still have suboptimal control with over 50% still suffering from nausea. We postulate that an individuals pharmacogenetic profile may aid in optimizing the use of antiemetic prophylaxis. This study aimed to correlate the genetic determinants of individual patients with the efficacy of the prophylactic antiemetic regimens each received. MethodsBreast cancer patients who were enrolled in 2 previously reported prospective antiemetic studies consented for the present pharmacogenetic study. Prior to highly emetogenic doxorubicin and cyclophosphamide (AC) (neo)adjuvant chemotherapy, they received a combination of antiemetic prophylaxis: regimen A and B were respectively aprepitant/ondansetron/dexamethasone with or without olanzapine; regimen C was netupitant/palonosetron/dexamethasone. Effectiveness of antiemetic regimens were mainly assessed by complete protection rate (CP) rates. Patients genotypes in 3 genes, HTR3A, HTR3B and TACR1, were analyzed. FindingsHomozygous TT (p.129Tyr) genotype of a non-nonsynonymous variant (rs1176744) in HTR3B and homozygous GG of rs3821313 genotype in TACR1 had better outcome with regimen B (when olanzapine was combined with aprepitant/ondansetron/dexamethasone). Digenic interaction analysis further reveals interaction between rs1176744 (HTR3B) and rs3821313 (TACR1). Patients who were both homozygote T of rs1176744 and homozygote G of rs3821313 achieved the highest CP rate with regimen B (10/12 patients; 83%), in contrast to only 29% (7/24 of patients) given regimen A (p= 0.0027). Patients who were homozygote for G alleles in both rs1176722 of HRB3A and rs3821313 of TACR1 showed the poorest response to regimen A with CP rate of 17% (2/12), while patients given regimen B had the highest CP rate of 70% (7/10) (p= 0.0159). The findings were confirmed upon logistic regression adjusted for clinical factors. InterpretationThe present study confirmed our hypothesis that among Chinese breast cancer patients who received AC, the selection of optimal antiemetic prophylaxis may be aided by assessing an individuals pharmacogenetic profile. It also highlights a new phenomenon of digenic interaction that has not been known before for pharmacogenetic analysis. FundingThis study was supported by an education grant from Madam Diana Hon Fun Kong Donation for Cancer Research. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlthough contemporary antiemetic prophylaxis has improved control of chemotherapy-induced nausea and vomiting among cancer patients receiving highly emetogenic AC chemotherapy, complete protection (CP) is achieved in less than 60% of patients while nearly 50% still experience nausea. Does determination of genetic constitution enable selection of the most effective antiemetic prophylaxis? Added value of this studyBy applying pharmacogenomic study, homozygous TT of rs1176744 genotype of HTR3B and homozygous GG of rs3821313 genotype in TACR1 were found to have better CP rates when olanzapine is being combined with aprepitant/ondansetron/dexamethasone. Digenic interaction analysis further reveals significant interaction between these genes. Olanzapine-containing regimen yielded the highest CP rates among patients who were both homozygote T of rs1176744 and homozygote G of rs3821313. Similar findings were also observed for patients who were homozygote G in both rs1176722 of HRB3A and rs3821313 of TACR1. Implications of all the available evidenceAmong patients who received highly emetogenic AC chemotherapy, assessment of patients genetic constitution can enable appropriate selection of the most optimal antiemetic prophylaxis.