Impact of CYP2C8 T>C rs10509681 Genetic Variation on Efficacy and Safety of Paclitaxel in Iraqi Women with Breast Cancer CYP2C8 & paclitaxel

Hiba Jalal Hatem (1), Atheer Majid Rashid Al-Juhaishi (2), Ahmed Abduljabbar Jawad Alaskari (3)
(1) Department of 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Kerbala, Kerbala, Iraq, Iraq,
(2) Department of Clinical Pharmacy, College of Pharmacy, University of Kerbala, Kerbala, Iraq, Iraq,
(3) Clinical Oncologist in Oncology Department, Imam Hassan Al-Mujtaba Hospital, Kerbala, Iraq, Iraq

Abstract

Background: Breast cancer is the leading cause of cancer mortality among Iraqi women, accounting for approximately 34.35% of all cancer-related deaths in this demographic. Paclitaxel is an antineoplastic medication that stabilizes microtubules and is extensively utilized in the treatment of various malignancies, including breast cancer. This study aimed to investigate the genetic variation in metabolizing enzyme CYP2C8 T>C (rs10509681) and evaluate the impact of this variation on the efficacy and safety of paclitaxel in Iraqi women with breast cancer.


Methods: This cross-sectional observational study involved 150 women diagnosed with breast cancer who were administered paclitaxel. During the second week of paclitaxel therapy, these women were evaluated individually using a questionnaire to gather demographic information, such as age and body mass index, as well as the likelihood and intensity of paclitaxel's adverse effects. Simultaneously, neutrophilia levels and breast cancer biomarkers (CA15.3 and CEA) were evaluated.


Results: The wild-type TT was detected in about 69% of breast cancer cases, with the mutant type CC(Bray,  #2) and the heterozygous type TC detected in about 10% and 21% of the cases, respectively. A significant association was found between the TT, TC, and CC genotypes and levels of the tumor markers CA 15-3 and CEA, as well as paclitaxel-related adverse effects (neutropenia, oral mucositis, peripheral neuropathy) in Iraqi breast cancer patients (P < 0.05).


Conclusion: Despite the small sample size and single-center design, the findings suggest that identifying the CYP2C8 T>C (rs10509681) genetic variations can impact treatment decisions in patients with breast cancer.

Full text article

Generated from XML file

References

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-63. PubMed PMID: 38572751. DOI: 10.3322/caac.21834.

Salih HH, Abd SY, Al-Kaseer E, Al-Diwan J. Cancer in Iraq, General View of Annual Report 2022. Journal of Contemporary Medical Sciences. 2024;10(6). DOI: 10.22317/jcms.v10i6.1676.

Kashyap D, Pal D, Sharma R, Garg VK, Goel N, Koundal D, et al. Global Increase in Breast Cancer Incidence: Risk Factors and Preventive Measures. Biomed Res Int. 2022;2022:9605439. PubMed PMID: 35480139. PMCID: PMC9038417. DOI: 10.1155/2022/9605439.

Chasib ZM, Gaaib JN. The Association of Five Novel Variants of TLR7 Gene with Some Biochemical Markers in Breast Cancer Patients from Iraqi Women. Karbala Journal of Pharmaceutical Sciences. 2024;15(24):124-35. DOI: 10.62472/kjps.v15.i24.124-135.

Hasan D. Diagnostic impact of CEA and CA 15-3 on chemotherapy monitoring of breast cancer patients. J Circ Biomark. 2022 Jan-Dec;11:57-63. PubMed PMID: 36381348. PMCID: PMC9644433. DOI: 10.33393/jcb.2022.2446.

Hossam Abdelmonem B, Abdelaal NM, Anwer EKE, Rashwan AA, Hussein MA, Ahmed YF, et al. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines. 2024 Jul 2;12(7). PubMed PMID: 39062040. PMCID: PMC11275228. DOI: 10.3390/biomedicines12071467.

Pernaute-Lau L, Morris U, Msellem M, Martensson A, Bjorkman A, Gil JP. Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar. Malar J. 2021 Feb 15;20(1):90. PubMed PMID: 33588856. PMCID: PMC7885591. DOI: 10.1186/s12936-021-03620-6.

Aquilante CL, Kosmiski LA, Bourne DW, Bushman LR, Daily EB, Hammond KP, et al. Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone. Br J Clin Pharmacol. 2013 Jan;75(1):217-26. PubMed PMID: 22625877. PMCID: PMC3555061. DOI: 10.1111/j.1365-2125.2012.04343.x.

Abouzeid HA, Kassem L, Liu X, Abuelhana A. Paclitaxel resistance in breast cancer: Current challenges and recent advanced therapeutic strategies. Cancer Treat Res Commun. 2025;43:100918. PubMed PMID: 40215760. DOI: 10.1016/j.ctarc.2025.100918.

Postigo-Corrales F, Beltran-Videla A, Lazaro-Sanchez AD, Hurtado AM, Conesa-Zamora P, Arroyo AB, et al. Docetaxel Resistance in Breast Cancer: Current Insights and Future Directions. Int J Mol Sci. 2025 Jul 23;26(15). PubMed PMID: 40806254. PMCID: PMC12346647. DOI: 10.3390/ijms26157119.

Gote V, Nookala AR, Bolla PK, Pal D. Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue. Int J Mol Sci. 2021 Apr 28;22(9). PubMed PMID: 33925129. PMCID: PMC8125767. DOI: 10.3390/ijms22094673.

Sati P, Sharma E, Dhyani P, Attri DC, Rana R, Kiyekbayeva L, et al. Paclitaxel and its semi-synthetic derivatives: comprehensive insights into chemical structure, mechanisms of action, and anticancer properties. Eur J Med Res. 2024 Jan 30;29(1):90. PubMed PMID: 38291541. PMCID: PMC10826257. DOI: 10.1186/s40001-024-01657-2.

Meng Z, Chen J, Xu L, Xiao X, Zong L, Han Y, et al. Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS. Curr Drug Metab. 2024;25(5):330-9. PubMed PMID: 39039675. DOI: 10.2174/0113892002308509240711100502.

Gradishar WJ, Moran MS, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022 Jun;20(6):691-722. PubMed PMID: 35714673. DOI: 10.6004/jnccn.2022.0030.

Limenh LW, Tessema TA, Simegn W, Ayenew W, Bayleyegn ZW, Sendekie AK, et al. Patients' Preference for Pharmaceutical Dosage Forms: Does It Affect Medication Adherence? A Cross-Sectional Study in Community Pharmacies. Patient Prefer Adherence. 2024;18:753-66. PubMed PMID: 38558832. PMCID: PMC10981379. DOI: 10.2147/PPA.S456117.

Yanagihara F, Okura H, Ichikawa H, Shirakawa T, Pan Y, Tu B, et al. Development of an automated chemiluminescent immunoassay for cancer antigen 72-4 and the evaluation of its analytical performance. Pract Lab Med. 2023 Mar;34:e00308. PubMed PMID: 36713933. PMCID: PMC9879778. DOI: 10.1016/j.plabm.2023.e00308.

Ba Y, Shi Y, Jiang W, Feng J, Cheng Y, Xiao L, et al. Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association. Cancer Biol Med. 2020 Nov 15;17(4):896-909. PubMed PMID: 33299642. PMCID: PMC7721096. DOI: 10.20892/j.issn.2095-3941.2020.0069.

Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am. 2008 Jan;52(1):61-77, viii. PubMed PMID: 18154865. PMCID: PMC2266835. DOI: 10.1016/j.cden.2007.10.002.

Zhang X, Chen WW, Huang WJ. Chemotherapy-induced peripheral neuropathy. Biomed Rep. 2017 Mar;6(3):267-71. PubMed PMID: 28451384. PMCID: PMC5403454. DOI: 10.3892/br.2017.851.

Mohammed HH, Abdul-Reda U, Abo-Almaali HM. Effect of Genetic Polymorphism of CYP2C8 Enzyme on the Montelukast Therapy Responses in Iraqi Asthmatic Children. Karbala Journal of Pharmaceutical Sciences. 2024;15(24):146-55. DOI: 10.62472/kjps.v15.i24.146-155.

Alrawi N. A review on breast cancer in Iraq and future therapies insights. Baghdad Journal of Biochemistry and Applied Biological Sciences. 2022;3(01):4-16. DOI: 10.47419/bjbabs.v3i01.64.

Abu Samaan TM, Samec M, Liskova A, Kubatka P, Busselberg D. Paclitaxel's Mechanistic and Clinical Effects on Breast Cancer. Biomolecules. 2019 Nov 27;9(12). PubMed PMID: 31783552. PMCID: PMC6995578. DOI: 10.3390/biom9120789.

Camara MD, Zhou Y, De Sousa TN, Gil JP, Djimde AA, Lauschke VM. Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences. Hum Genomics. 2024 Apr 22;18(1):40. PubMed PMID: 38650020. PMCID: PMC11034136. DOI: 10.1186/s40246-024-00610-y.

Hertz DL, Roy S, Motsinger-Reif AA, Drobish A, Clark LS, McLeod HL, et al. CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel. Ann Oncol. 2013 Jun;24(6):1472-8. PubMed PMID: 23413280. PMCID: PMC3660078. DOI: 10.1093/annonc/mdt018.

Messaoudi M, Pakstis AJ, Boussetta S, Ben Ammar Elgaaied A, Kidd KK, Cherni L. CYP2C gene polymorphisms in North African populations. Mol Biol Rep. 2024 Nov 12;51(1):1145. PubMed PMID: 39532754. DOI: 10.1007/s11033-024-10093-8.

Lee JS, Park S, Park JM, Cho JH, Kim SI, Park BW. Elevated levels of serum tumor markers CA 15-3 and CEA are prognostic factors for diagnosis of metastatic breast cancers. Breast Cancer Res Treat. 2013 Oct;141(3):477-84. PubMed PMID: 24072270. DOI: 10.1007/s10549-013-2695-7.

Attia HRM, Kamel MM, Ayoub DF, Abd El-Aziz SH, Abdel Wahed MM, El-Fattah SNA, et al. CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients. Sci Rep. 2024 Apr 4;14(1):7922. PubMed PMID: 38575662. PMCID: PMC10995116. DOI: 10.1038/s41598-024-58104-9.

Rozalem Moretti N, de Moura Moreira B, Pimentel Braz I, Caroline de Oliveira Barretto I, Ayumi Zanoni Chiba AL, Augusta Grigoli Dominato A, et al. CYP450 gene polymorphisms and the risk of taxane-induced neurotoxicity in breast cancer patients: a systematic review and meta-analysis. Biomarkers. 2025 Jun;30(4):315-26. PubMed PMID: 40560854. DOI: 10.1080/1354750X.2025.2522892.

Yue D, Ng EWH, Hirao H. Hydrogen-Bond-Assisted Catalysis: Hydroxylation of Paclitaxel by Human CYP2C8. J Am Chem Soc. 2024 Nov 6;146(44):30117-25. PubMed PMID: 39441858. PMCID: PMC11544615. DOI: 10.1021/jacs.4c07937.

Hertz DL, Roy S, Jack J, Motsinger-Reif AA, Drobish A, Clark LS, et al. Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy. Breast Cancer Res Treat. 2014 May;145(1):245-54. PubMed PMID: 24706167. PMCID: PMC4256153. DOI: 10.1007/s10549-014-2910-1.

Kus T, Aktas G, Kalender ME, Demiryurek AT, Ulasli M, Oztuzcu S, et al. Polymorphism of CYP3A4 and ABCB1 genes increase the risk of neuropathy in breast cancer patients treated with paclitaxel and docetaxel. Onco Targets Ther. 2016;9:5073-80. PubMed PMID: 27574448. PMCID: PMC4990373. DOI: 10.2147/OTT.S106574.

Green H, Khan MS, Jakobsen-Falk I, Avall-Lundqvist E, Peterson C. Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer. J Pharm Sci. 2011 Oct;100(10):4205-9. PubMed PMID: 21702053. DOI: 10.1002/jps.22680.

Crawford J, Herndon D, Gmitter K, Weiss J. The impact of myelosuppression on quality of life of patients treated with chemotherapy. Future Oncol. 2024;20(21):1515-30. PubMed PMID: 38587388. PMCID: PMC11441072. DOI: 10.2217/fon-2023-0513.

Jena S, Hasan S, Panigrahi R, Das P, Mishra N, Saeed S. Chemotherapy-associated oral complications in a south Indian population: a cross-sectional study. J Med Life. 2022 Apr;15(4):470-8. PubMed PMID: 35646189. PMCID: PMC9126462. DOI: 10.25122/jml-2021-0342.

Alvarado AT, Bolarte-Arteaga M, Pineda-Pérez M, Li-Amenero C, Chávez H, Bendezú MR, et al. CYP3A4* 20, CYP3A4* 22, CYP2C8* 3 and SLCO1B1 as genetic biomarkers to predict peripheral neuropathy induced by paclitaxel and docetaxel: A systematic review. Journal of Pharmacy and Pharmacognosy Research. 2025;13(3):955-67. DOI: 10.56499/jppres24.2125_13.3.955.

Authors

Hiba Jalal Hatem
hiba.jalal@s.uokerbala.edu.iq (Primary Contact)
Atheer Majid Rashid Al-Juhaishi
Ahmed Abduljabbar Jawad Alaskari
1.
Hatem HJ, Al-Juhaishi AMR, Alaskari AAJ. Impact of CYP2C8 T>C rs10509681 Genetic Variation on Efficacy and Safety of Paclitaxel in Iraqi Women with Breast Cancer: CYP2C8 & paclitaxel. Arch Breast Cancer [Internet]. [cited 2026 Jan. 12];13(1). Available from: https://archbreastcancer.com/index.php/abc/article/view/1198

Article Details