Background: Contemporary 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 individual's 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. Methods: Breast 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. Findings: Homozygous 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. Interpretation: The 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 individual's pharmacogenetic profile. It also highlights a new phenomenon of digenic interaction that has not been known before for pharmacogenetic analysis.

WY has been involved in the CINV Network in Asia and has been a speaker of the CINV organized by Mundipharma. Mundipharma supported the study design of the netupitant, but had no role in the present analysis, data collection and analysis, decision to publish, or preparation of the manuscript. None of the other authors declare any conflict of interest. The statements presented in this paper are the sole responsibility of the authors. Patent filing related to this study is in progress for WY, SLM and NLS. Tang.

This study was supported by an education grant from Madam Diana Hon Fun Kong Donation for Cancer Research.

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Ethics committee of The Chinese University of Hong Kong gave ethical approval for this work

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All data relevant to the study are included in the article or uploaded as supplementary information. The data are available from the Comprehensive Cancer Trials Unit of the Department of Clinical Oncology, Chinese University of Hong Kong, but restrictions apply to the availability of these data. These data were used under permission for the current study, and so are not publicly available. Data are, however, available from the authors (WY and FM) upon reasonable request. Data will be made available for 15 years from the start of the clinical trials.