Personalized Prophylactic Antiemetic Regimens for Control of Chemotherapy-Induced Nausea and Vomiting by Pharmacogenetic Analysis of Three Receptor Genes: HTR3A, HTR3B, TACR1.

PURPOSE: Contemporary prophylactic antiemetic regimens have improved the control of chemotherapy-induced nausea and vomiting (CINV). However, over 50% of patients still suffer from nausea. This study aimed to correlate the genetic determinants of individual patients with the efficacy of three prophylactic antiemetic regimens. METHODS: Patients with breast cancer in two previously reported prospective antiemetic studies consented for the present pharmacogenetic study. Before high-emetogenic doxorubicin and cyclophosphamide (AC) (neo)adjuvant chemotherapy, they received a combination of antiemetic prophylaxis: regimen A and regimen B were, respectively, aprepitant/ondansetron/dexamethasone with or without olanzapine; regimen C was netupitant/palonosetron/dexamethasone. The effectiveness of antiemetic regimens was mainly assessed by complete protection (CP) rates. Patients' genotypes in three genes, HTR3A, HTR3B and TACR1, were analyzed. RESULTS: Patients who were homozygous TT (p.129Tyr) of a non-nonsynonymous variant in HTR3B rs1176744 and homozygous GG of TACR1 rs3821313 had better outcome with regimen B. Digenic interaction analysis further reveals interaction between rs1176744 and rs3821313. Homozygotes TT of rs1176744 and homozygotes GG of rs3821313 achieved the highest CP rate with regimen B (10/12 patients; 83%), in contrast to only 29% (7/24) with regimen A (P = .0027). Homozygotes GG in both HTR3A rs1176722 and TACR1 rs3821313 showed the poorest response to regimen A with a CP rate of 17% (2/12), whereas patients given regimen B had the highest CP rate (70%; 7/10; P = .0159). The findings were confirmed upon logistic regression adjusted for clinical factors. CONCLUSION: The present study confirmed our hypothesis that among Chinese patients with breast cancer who received AC, the selection of optimal antiemetic prophylaxis may be aided by assessing an individual's pharmacogenetic profile. It also highlights a novel digenic interaction that has not been known before for pharmacogenetic analysis.