Genetic risk factors for chemotherapy-induced nausea and vomiting in patients with cancer receiving cisplatin-based chemotherapy
Younger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30–50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response.
This study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study’s efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR0–24) and delayed (CR24–120) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables.
Multivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74–72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14–11.58; p = 0.029) were significant predictors of CR0–24. No significant association of CR24–120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis.
ERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy.
Clinical trial information: UMIN 000009335
KeywordsChemotherapy-induced nausea and vomiting (CINV) ERCC1 polymorphism Cisplatin Granisetron Palonosetron Aprepitant
We wish to thank all the patients and medical staff who participated in this study.
Compliance with ethical standards
Written informed consent was obtained from the patients separately from the consent provided for the previously reported phase III trial. This study was approved by each participating institute’s institutional review board, and it complied with the provisions of the Declaration of Helsinki and local laws and regulations.
Conflicts of interest
The authors declare that they have no conflicts of interest.
- 1.Hickok JT, Roscoe JA, Morrow GR, King DK, Atkins JN, Fitch TR (2003) Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer 97(11):2880–2886. https://doi.org/10.1002/cncr.11408 CrossRefPubMedGoogle Scholar
- 2.Glaus A, Knipping C, Morant R, Böhme C, Lebert B, Beldermann F, Glawogger B, Ortega PF, Hüsler A, Deuson R (2004) Chemotherapy-induced nausea and vomiting in routine practice: a European perspective. Support Care Cancer 12(10):708–715. https://doi.org/10.1007/s00520-004-0662-x CrossRefPubMedGoogle Scholar
- 3.Molassiotis A, Saunders MP, Valle J, Wilson G, Lorigan P, Wardley A, Levine E, Cowan R, Loncaster J, Rittenberg C (2008) A prospective observational study of chemotherapy-related nausea and vomiting in routine practice in a UK cancer centre. Support Care Cancer 16(2):201–208. https://doi.org/10.1007/s00520-007-0343-7 CrossRefPubMedGoogle Scholar
- 4.Schmoll HJ, Aapro MS, Poli-Bigelli S, Kim HK, Park K, Jordan K, von Pawel J, Giezek H, Ahmed T, Chan CY (2006) Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 17(6):1000–1006. https://doi.org/10.1093/annonc/mdl019 CrossRefPubMedGoogle Scholar
- 5.Chawla SP, Grunberg SM, Gralla RJ, Hesketh PJ, Rittenberg C, Elmer ME, Schmidt C, Taylor A, Carides AD, Evans JK, Horgan KJ (2003) Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer 97(9):2290–3000. https://doi.org/10.1002/cncr.11320 CrossRefPubMedGoogle Scholar
- 6.Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, Raftopoulos H, Grunberg SM, Gabriel M, Rodgers A, Bohidar N, Klinger G, Hustad CM, Horgan KJ, Skobieranda F (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23(12):2822–2830. https://doi.org/10.1200/JCO.2005.09.050 CrossRefPubMedGoogle Scholar
- 7.Kitazaki T, Fukuda Y, Fukahori S, Oyanagi K, Soda H, Nakamura Y, Kohno S (2015) Usefulness of antiemetic therapy with aprepitant, palonosetron, and dexamethasone for lung cancer patients on cisplatin-based or carboplatin-based chemotherapy. Support Care Cancer 23(1):185–190. https://doi.org/10.1007/s00520-014-2339-4 CrossRefPubMedGoogle Scholar
- 8.Suzuki K, Yamanaka T, Hashimoto H, Shimada Y, Arata K, Matsui R, Goto K, Takiguchi T, Ohyanagi F, Kogure Y, Nogami N, Nakao M, Takeda K, Azuma K, Nagase S, Hayashi T, Fujiwara K, Shimada T, Seki N, Yamamoto N (2016) Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study. Ann Oncol 27(8):1601–1006. https://doi.org/10.1093/annonc/mdw220 CrossRefPubMedGoogle Scholar
- 9.Pollera CF, Giannarelli D (1989) Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer 64(5):1117–1122. https://doi.org/10.1002/1097-0142(19890901)64:5<1117::AID-CNCR2820640525>3.0.CO;2-R CrossRefPubMedGoogle Scholar
- 13.Tonato M, Roila F, Del Favero A (1991) Methodology of antiemetic trials: a review. Ann Oncol 2(2):107–114. https://doi.org/10.1093/oxfordjournals.annonc.a057871 CrossRefPubMedGoogle Scholar
- 15.Molassiotis A, Aapro M, Dicato M, Gascon P, Novoa SA, Isambert N, Burke TA, Gu A, Roila F (2014) Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study. J Pain Symptom Manag 47(5):839–848. https://doi.org/10.1016/j.jpainsymman.2013.06.012 CrossRefGoogle Scholar
- 17.Kaiser R, Sezer O, Papies A, Bauer S, Schelenz C, Tremblay PB, Possinger K, Roots I, Brockmöller J (2002) Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20(12):2805–2811. https://doi.org/10.1200/JCO.2002.09.064 CrossRefPubMedGoogle Scholar
- 18.Tremblay PB, Kaiser R, Sezer O, Rösler N, Schelenz C, Possinger K, Roots I, Brockmöller J (2003) Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol 21(11):2147–2155. https://doi.org/10.1200/JCO.2003.05.164 CrossRefPubMedGoogle Scholar
- 19.Fasching PA, Kollmannsberger B, Strissel PL, Niesler B, Engel J, Kreis H, Lux MP, Weihbrecht S, Lausen B, Bani MR, Beckmann MW, Strick R (2008) Polymorphisms in the novel serotonin receptor subunit gene HTR3C show different risks for acute chemotherapy-induced vomiting after anthracycline chemotherapy. J Cancer Res Clin Oncol 134(10):1079–1086. https://doi.org/10.1007/s00432-008-0387-1 CrossRefPubMedGoogle Scholar
- 22.Hammer C, Fasching PA, Loehberg CR, Rauh C, Ekici AB, Jud SM, Bani MR, Beckmann MW, Strick R, Niesler B (2010) Polymorphism in HTR3D shows different risks for acute chemotherapy-induced vomiting after anthracycline chemotherapy. Pharmacogenomics 11(7):943–950. https://doi.org/10.2217/pgs.10.67 CrossRefPubMedGoogle Scholar
- 23.Perwitasari DA, Wessels JA, van der Straaten RJ et al (2011) Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy. Jpn J Clin Oncol 41(10):1168–1176. https://doi.org/10.1093/jjco/hyr117 CrossRefPubMedGoogle Scholar
- 24.Tsuji D, Kim YI, Nakamichi H, Daimon T, Suwa K, Iwabe Y, Hayashi H, Inoue K, Yoshida M, Itoh K (2013) Association of ABCB1 polymorphisms with the antiemetic efficacy of granisetron plus dexamethasone in breast cancer patients. Drug Metab Pharmacokinet 28(4):299–304. https://doi.org/10.2133/dmpk.DMPK-12-RG-084 CrossRefPubMedGoogle Scholar
- 26.Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Su L, Christiani DC (2004) Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 10(15):4939–4943. https://doi.org/10.1158/1078-0432.CCR-04-0247 CrossRefPubMedGoogle Scholar
- 27.Suk R, Gurubhagavatula S, Park S, Zhou W, Su L, Lynch TJ, Wain JC, Neuberg D, Liu G, Christiani DC (2005) Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin Cancer Res 11(4):1534–1538. https://doi.org/10.1158/1078-0432.CCR-04-1953 CrossRefPubMedGoogle Scholar
- 29.Tsuji D, Yokoi M, Suzuki K, Daimon T, Nakao M, Ayuhara H, Kogure Y, Shibata K, Hayashi T, Hirai K, Inoue K, Hama T, Takeda K, Nishio M, Itoh K (2017) Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study. Pharmacogenomics J 17(5):435–440. https://doi.org/10.1038/tpj.2016.38 CrossRefPubMedGoogle Scholar
- 30.Stern RM, Koch KL, Andrews PLR (2011) Nausea: mechanisms and management. Oxford University Press, New YorkGoogle Scholar
- 31.Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T, Morita Y, Tamura T, Aoyama N, Hirai M, Kasuga M, Okumura K (2001) MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 18(10):1400–1404. https://doi.org/10.1023/A:1012244520615 CrossRefPubMedGoogle Scholar
- 32.Horinouchi M, Sakaeda T, Nakamura T, Morita Y, Tamura T, Aoyama N, Kasuga M, Okumura K (2002) Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: functional relevance to pharmacokinetics of digoxin. Pharm Res 19(10):1581–1585. https://doi.org/10.1023/A:1020433422259 CrossRefPubMedGoogle Scholar
- 33.Schwab M, Eichelbaum M, Fromm MF (2003) Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 43(1):285–307. https://doi.org/10.1146/annurev.pharmtox.43.100901.140233 CrossRefPubMedGoogle Scholar
- 35.Chen P, Wiencke J, Aldape K et al (2000) Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol Biomark Prev 9:843–847Google Scholar
- 36.Deloia JA, Bhagwat NR, Darcy KM et al (2012) Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum. Gynecol Oncol 126(3):448–454. https://doi.org/10.1016/j.ygyno.2012.05.006 CrossRefPubMedPubMedCentralGoogle Scholar