ORIGINAL ARTICLE
Taxane treatment outcomes in histologically characterized Algerian lung cancer patients: a population-specific exploratory study of CYP3A4, CYP2C8, and ABCG2 variants
1
Laboratoire de Toxicologie, Environnement et Santé, LATES, USTO-MB, Oran, Université des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, Oran, Algeria
2
Ecole Supérieure en Sciences Biologique d’Oran (ESSBO), Oran, Algeria
3
Département de Pharmacie, Faculté de Médecine, Université Oran, Oran, Algeria
4
Service d’Oncologie, Etablissement Hospitalo-Universitaire d’Oran, Oran, Algeria
Submission date: 2026-01-25
Final revision date: 2026-05-11
Acceptance date: 2026-05-17
Online publication date: 2026-10-30
Publication date: 2026-10-30
Corresponding author
Ikram Saliha Benyahia
Laboratoire de Toxicologie, Environnement et santé, LATES, USTO-MB, Oran, Université des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB
Laboratoire de Toxicologie, Environnement et santé, LATES, USTO-MB, Oran, Université des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB
Pol J Pathol 2026;77(3)
KEYWORDS
lung cancerpharmacotoxicitygenetic polymorphismscytochromes P450ABCG2 transporterpersonalized medicine
TOPICS
ABSTRACT
Introduction:
Taxane-based chemotherapy remains a cornerstone of lung cancer treatment, but its clinical use is often limited by dose-dependent toxicities, particularly peripheral neuropathy. In this retrospective study of 110 Algerian patients with lung cancer, we evaluated the influence of germline polymorphisms, distinct from tumor somatic alterations, on treatment outcomes, while considering World Health Organization classified histological subtypes.
Material and Methods:
Based on their roles in taxane metabolism and transport, CYP2C8, CYP3A4, and ABCG2 were selected for analysis. Germline polymorphisms CYP2C8 c.416G>A, CYP3A4 g.392A>G, and ABCG2 c.421C>A were genotyped using TaqMan PCR, and their associations with treatment response, adverse events, and dose modifications were analyzed using SPSS, Epi Info 7, and R-Studio.
Results:
The results showed that the CYP2C8 c.416G>A polymorphism was not significantly associated with chemotherapy response or neuropathy incidence. The ABCG2 c.421C>A polymorphism was not significantly associated with treatment efficacy or peripheral neuropathy, but it was related to cumulative taxane exposure. The CYP3A4 g.392A>G polymorphism was associated with increased peripheral neuropathy severity. Adenocarcinoma histology was also significantly associated with treatment response (p = 0.01), underscoring the value of integrating histopathological and pharmacogenetic factors.
Conclusions:
These population-specific findings support further investigation of pharmacogenetic stratification in larger lung cancer cohorts.
Taxane-based chemotherapy remains a cornerstone of lung cancer treatment, but its clinical use is often limited by dose-dependent toxicities, particularly peripheral neuropathy. In this retrospective study of 110 Algerian patients with lung cancer, we evaluated the influence of germline polymorphisms, distinct from tumor somatic alterations, on treatment outcomes, while considering World Health Organization classified histological subtypes.
Material and Methods:
Based on their roles in taxane metabolism and transport, CYP2C8, CYP3A4, and ABCG2 were selected for analysis. Germline polymorphisms CYP2C8 c.416G>A, CYP3A4 g.392A>G, and ABCG2 c.421C>A were genotyped using TaqMan PCR, and their associations with treatment response, adverse events, and dose modifications were analyzed using SPSS, Epi Info 7, and R-Studio.
Results:
The results showed that the CYP2C8 c.416G>A polymorphism was not significantly associated with chemotherapy response or neuropathy incidence. The ABCG2 c.421C>A polymorphism was not significantly associated with treatment efficacy or peripheral neuropathy, but it was related to cumulative taxane exposure. The CYP3A4 g.392A>G polymorphism was associated with increased peripheral neuropathy severity. Adenocarcinoma histology was also significantly associated with treatment response (p = 0.01), underscoring the value of integrating histopathological and pharmacogenetic factors.
Conclusions:
These population-specific findings support further investigation of pharmacogenetic stratification in larger lung cancer cohorts.
REFERENCES (66)
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394 424.
2.
Nicholson AG, Tsao MS, Beasley MB, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol 2022; 17: 362 387.
3.
Zugazagoitia J, Enguita AB, Nuñez JA, Iglesias L, Ponce S. The new IASLC/ATS/ERS lung adenocarcinoma classification from a clinical perspective: current concepts and future prospects. J Thor Dis 2014; 6.
4.
Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the international association for the study of lung cancer. J Thorac Oncol 2021; 16: 1647 1662.
5.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015; 10: 1243 1260.
6.
Jaiyesimi IA, Leighl NB, Ismaila N, Alluri K, Florez N, Gadgeel S, et al. Therapy for Stage IV non-small cell lung cancer without driver alterations: ASCO living guideline, version 2023.3. J Clin Oncol 2024; 42: e23 43.
7.
Russo AE, Priolo D, Antonelli G, Libra M, McCubrey JA, Ferraù F. Bevacizumab in the treatment of NSCLC: patient selection and perspectives. Lung Cancer (Auckl) 2017; 8: 259 269.
8.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III Study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543 3551.
9.
Hicks JK, Howard R, Reisman P, Adashek JJ, Fields KK, Gray JE, et al. Integrating somatic and germline next-generation sequencing into routine clinical oncology practice. JCO Precis Oncol 2021; 5: PO.20.00513.
10.
Johnson ML, Sima CS, Chaft J, Paik PK, Pao W, Kris MG, et al. Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas. Cancer 2013; 119: 356 362.
11.
Hertz DL, Joerger M, Bang YJ, Mathijssen RH, Zhou C, Zhang L, et al. Paclitaxel therapeutic drug monitoring – International Association of Therapeutic Drug Monitoring and Clinical Toxicology recommendations. Eur J Cancer 2024; 202: 114024.
12.
Xu AP, Xu LB, Smith ER, Fleishman JS, Chen ZS, Xu XX. Cell death in cancer chemotherapy using taxanes. Front Pharmacol 2023; 14: 1338633.
13.
Sivadas SK, Das A, Vijayakumar N, Shaji N, Mangalath S, Pavithran K, et al. Genetic determinants of paclitaxel-induced peripheral neuropathy: a review of current literature. Drug Metab Rev 2025; 57: 190 207.
14.
Spratlin J, Sawyer MB. Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol 2007; 61: 222 229.
15.
Morris ME, Guan X. The role of transporters in drug delivery and excretion. In: Drug delivery. John Wiley & Sons Ltd., Hoboken 2016, 62 102.
16.
Stage TB, Bergmann TK, Kroetz DL. Clinical pharmacokinetics of paclitaxel monotherapy: an updated literature review. Clin Pharmacokinet 2018; 57: 7 19.
17.
Wu X, Xiong H. The role of pharmacogenetic-based pharmacokinetic analysis in precise breast cancer treatment. Pharmaceutics 2024; 16: 1407.
18.
Zhang Y, Wang Z, Wang Y, Jin W, Zhang Z, Jin L, et al. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. Peer J 2024; 12: e18636.
19.
Saiz-Rodríguez M, Almenara S, Navares-Gómez M, Ochoa D, Román M, Zubiaur P, et al. Effect of the most relevant CYP3A4 and CYP3A5 polymorphisms on the pharmacokinetic parameters of 10 CYP3A substrates. Biomedicines 2020; 8: 94.
20.
Werk AN, Cascorbi I. Functional gene variants of CYP3A4. Clin Pharmacol Ther 2014; 96: 340 348.
21.
McEvoy L, Cliff J, Carr DF, Jorgensen A, Lord R, Pirmohamed M. CYP3A genetic variation and taxane-induced peripheral neuropathy: a systematic review, meta-analysis, and candidate gene study. Front Pharmacol 2023; 14.
22.
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 5080.
23.
Kolesar JM, Breunig A, Miller J, Stephenson P, McLeod H, Marsh S, et al. CYP3A5*3 and CYP3A4*1B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers. J Clin Oncol 2004; 22: 2016 2016.
24.
Zhou LP, Yao F, Luan H, Wang YL, Dong XH, Zhou WW, et al. CYP3A4*1B polymorphism and cancer risk: a HuGE review and meta-analysis. Tumour Biol 2013; 34: 649 660.
25.
Subhani S, Jamil K, Atilli S. Association of CYP3A4*1B and CYP3A5*3 genetic polymorphisms with lung cancer and its impact on taxane metabolism in Indian population. Acta Med Int 2015; 2: 19.
26.
Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 2008; 112: 2709 2712.
27.
Bahadur N, Leathart JBS, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol 2002; 64: 1579 1589.
28.
Kaspera R, Naraharisetti SB, Evangelista EA, Marciante KD, Psaty BM, Totah RA. Drug metabolism by CYP2C8.3 is determined by substrate dependent interactions with cytochrome P450 reductase and cytochrome b5. Biochem Pharmacol 2011; 82: 681 691.
29.
Safar Z, Kis E, Erdo F, Zolnerciks JK, Krajcsi P. ABCG2/BCRP: variants, transporter interaction profile of substrates and inhibitors. Exp Op Drug Metab Toxicol 2019; 15: 313 328.
30.
Nakamura T, Yamamori M, Sakaeda T. Pharmacogenetics of intestinal absorption. Curr Drug Deliv 2008; 5: 153 169.
31.
Hasanabady MH, Kalalinia F. ABCG2 inhibition as a therapeutic approach for overcoming multidrug resistance in cancer. J Biosci 2016; 41: 313 324.
32.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247.
33.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215.
34.
Joshi M, Liu X, Belani CP. Taxanes, past, present, and future impact on non-small cell lung cancer. Anticancer Drugs 2014; 25: 571.
35.
Min HY, Lee HY. Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch Pharm Res 2021; 44: 146 164.
36.
Cui H, Arnst K, Miller DD, Li W. Recent advances in elucidating paclitaxel resistance mechanisms in non-small cell lung cancer and strategies to overcome drug resistance. Curr Med Chem 2020; 27: 6573 6595.
37.
Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F. Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos 2002; 30: 438 445.
38.
Muth M, Ojara FW, Kloft C, Joerger M. Role of TDM-based dose adjustments for taxane anticancer drugs. Br J Clin Pharmacol 2021; 87: 306 316.
39.
Wopat H, Harrod T, Brem RF, Kaltman R, Anderson K, Robien K. Body composition and chemotherapy toxicity among women treated for breast cancer: a systematic review. J Cancer Surviv 2024; 18: 1356 1369.
40.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N En J Med 2002; 346: 92 98.
41.
Echepare M, Picabea B, Arricibita A, Teijeira Á, Pasquier A, Zandueta C, et al. DSTYK inhibition sensitizes NSCLC to taxane-based chemotherapy. J Thor Oncol 2025; 20: 345 365.
42.
Lamba JK, Fridley BL, Ghosh TM, Yu Q, Mehta G, Gupta P. Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small-cell lung cancer. Pharmacogenomics 2014; 15: 1565 1574.
43.
Björn N, Jakobsen Falk I, Vergote I, Gréen H. ABCB1 variation affects myelosuppression, progression-free survival and overall survival in paclitaxel/carboplatin-treated ovarian cancer patients. Basic Clin Pharmacol Toxicol 2018; 123: 277 2787.
44.
Taniguchi R, Kumai T, Matsumoto N, Watanabe M, Kamio K, Suzuki S, et al. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. J Pharmacol Sci 2005; 97: 83 90.
45.
Gréen H, Söderkvist P, Rosenberg P, Mirghani RA, Rymark P, Lundqvist EÅ, et al. Pharmacogenetic studies of paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol Toxicol 2009; 104: 130 137.
46.
Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001; 11: 597-607.
47.
Bergmann TK, Brasch-Andersen C, Gréen H, Mirza M, Pedersen RS, Nielsen F, et al. Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenomics J 2011; 11: 113 120.
48.
Leskelä S, Jara C, Leandro-García LJ, Martínez A, García-Donas J, Hernando S, et al. Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmaco-genomics J 2011; 11: 121 129.
49.
Marcath LA, Kidwell KM, Robinson AC, Vangipuram K, Burness ML, Griggs JJ, et al. Patients carrying CYP2C8*3 have shorter systemic paclitaxel exposure. Pharmacogenomics 2019; 20: 95 104.
50.
Tsukada C, Saito T, Maekawa M, Mano N, Oda A, Hirasawa N, et al. Functional characterization of 12 allelic variants of CYP2C8 by assessment of paclitaxel 6α-hydroxylation and amodiaquine N-deethylation. Drug Metab Pharmacokinet 2015; 30: 366 373.
51.
Sharma P, Singh N, Sharma S. Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum-based doublet chemotherapy. J Gene Med 2023; 25: e3460.
52.
Campa D, Müller P, Edler L, Knoefel L, Barale R, Heussel CP, et al. A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis. Int J Cancer 2012; 131: 2920 2928.
53.
Sun NK, Huang SL, Chang PY, Lu HP, Chao CCK. Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response. Oncotarget 2014; 5: 11939 11956.
54.
Sun NK, Huang SL, Lu HP, Chang TC, Chao CCK. Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: analysis of the androgen receptor. Oncotarget 2015; 6: 27065 27082.
55.
Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol 2012; 83: 1084‑1103.
56.
Xu WW, Liu D yu, Cao Y chun, Wang X yun. GE11 peptide-conjugated nanoliposomes to enhance the combinational therapeutic efficacy of docetaxel and siRNA in laryngeal cancers. Int J Nanomed 2017; 12: 6461 6470.
57.
Morisaki K, Robey RW, Özvegy-Laczka C, Honjo Y, Polgar O, Steadman K, et al. Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol 2005; 56: 161 172.
58.
De Graan AJM, Elens L, Sprowl JA, Sparreboom A, Friberg LE, van der Holt B, et al. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 2013; 19: 3316 3324.
59.
Apellániz-Ruiz M, Lee MY, Sánchez-Barroso L, Gutiérrez-Gutiérrez G, Calvo I, García-Estévez L, et al. Whole-exome sequencing reveals defective CYP3A4 variants predictive of paclitaxel dose-limiting neuropathy. Clin Cancer Res 2015; 21: 322 328.
60.
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. J Pharm Pharmacogn Res 2025; 13: 955 967.
61.
Hu Y, Girdenyté M, Roest L, Liukkonen I, Siskou M, Bällgren F, et al. Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy. Fluids Barriers CNS 2024; 21: 13.
62.
Powell NR, Shugg T, Ly RC, Albany C, Radovich M, Schneider BP, et al. Life-threatening docetaxel toxicity in a patient with reduced-function CYP3A variants: a case report. Front Oncol 2022; 11.
63.
Frederiks CN, Lam SW, Guchelaar HJ, Boven E. Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: a systematic review. Cancer Treat Rev 2015; 41: 935 950.
64.
Hussaini SA, Waziri B, Dickens C, Duarte R. Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review. Pharmacogenomics 2024; 25: 329.
65.
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; 18: 40.
66.
Piriyapongsa J, Chumnumwat S, Kaewprommal P, Triparn K, Suvichapanich S, Udomsinprasert W, et al. Pharmacogenomic landscape of the Thai population from genome sequencing of 949 individuals. Sci Rep 2024; 14: 30683.
| eISSN: | 2084-9869 |
| ISSN: | 1233-9687 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
