Genetic associations with chemotherapy-induced nausea and vomiting: A genome-wide association study.

Abstract

12050 Background: Nausea and vomiting affect up to 80% of patients treated with chemotherapy, and the costs of healthcare utilization due to chemotherapy-induced nausea are estimated to cost over $6 billion each year in the United States. Existing antiemetic regimens targeting 5-HT3 and NK1 antagonists are suboptimal, as up to 40% of continue to report nausea despite antiemetic treatment. Further, existing risk prediction algorithms have poor discrimination. Methods: In this original research study, we conducted a genome-wide association study of genetic factors associated with patient- and clinician-reported nausea and vomiting at 24 hours after infusion (acute) and 5 days after infusion (delayed) in patients treated with moderately- or highly-emetogenic chemotherapy. Participants were recruited from five ORIEN centers: City of Hope, Moffitt Cancer Center, Ohio State University, Rutgers University, and University of Colorado-Denver. Patient-reported CINV was assessed using the MASCC Antiemesis Tool and clinician-reported CINV was assessed using Common Terminology Criteria for Adverse Events (CTCAE) ratings. The study cohort was divided into a training set (70% of the sample) and a test set (30% of the sample). Machine learning was used to evaluate the predictive performance of a polygenic score along with clinical variables, over and above models with clinical variables only. Areas under the curve (AUC) were used to compare the accuracy of each predictive model. Results: Participants (n=1,271) were 58 years of age on average (SD=13), and most were female (74%), White (97%), with breast cancer (41%). Half of participants (50%) had early stage cancer and most were treated with a guideline-concordant prophylactic regimen (70%). Any acute and delayed self-reported nausea was reported by 42% and 70% of participants, respectively. For acute nausea, one gene, C12orf50 , met the threshold for suggestive significance (P = 4.58 x 10 -6 ). For vomiting, the presence of the G allele at rs9712639 (nearest gene: OR7E23P ) was linked to an increased likelihood of clinician-reported acute vomiting (P = 1.83 x 10 -8 ). A further 11 SNPS reached the threshold for suggestive significance and were associated with both acute and delayed vomiting reported by clinicians; these were mapped to the FTLP18 gene. Polygenic scores did not improve predictive risk models based on clinical factors only. Conclusions: Results of our GWAS indicate that there are different genetic associations for acute and delayed nausea and vomiting, suggesting potentially distinct genetic factors underlying each outcome. However, regardless of outcome, genetic information did not significantly improve models predicting the development and intensity of CINV.