Impact of ALDH1A1 and NQO1 Gene Polymorphisms on the Response and Toxicity of Chemotherapy in Bangladeshi Breast Cancer Patients

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2024 Jul 16

PMID 39012380

Authors

Md Siddiqul Islam

Ferdowsi Akter

Md Mosiqur Rahman

Md Rajdoula Rafe

Md Abdul Aziz

Salma Parvin

Abu Syed Md Mosaddek

Mohammad Safiqul Islam

Md Wahid Akter

Affiliations

Soon will be listed here.

Abstract

Purpose: Cyclophosphamide, Epirubicin/Doxorubicin, 5-fluorouracil (CEF or CAF) chemotherapy has long been a standard first-line treatment for breast cancer. The genetic variations of enzymes that are responsible for the metabolism of these drugs have been linked to altered treatment response and toxicity. Two drug-metabolizing enzymes ALDH1A1 and NQO1 are critically involved in the pathways of CEF/CAF metabolism. This study aimed to evaluate the effect of ALDH1A1 (rs13959) and NQO1 (rs1800566) polymorphisms on treatment response and toxicities caused by adjuvant (ACT) and neoadjuvant chemotherapy (NACT) where CEF/CAF combination was used to treat Bangladeshi breast cancer patients.

Methods: A total of 330 patients were recruited from various hospitals, with 150 receiving neoadjuvant chemotherapy and 180 receiving adjuvant chemotherapy. To extract genomic DNA, a non-enzymatic simple salting out approach was adopted. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect genetic polymorphisms. Unconditional logistic regression was used to derive odds ratios (ORs) with 95% confidence intervals (CIs) to study the association between genetic polymorphisms and clinical outcome and toxicity.

Results: A statistically significant association was observed between ALDH1A1 (rs13959) polymorphism and treatment response (TT vs. CC: aOR = 6.40, p = 0.007; recessive model: aOR = 6.38, p = 0.002; allele model: p = 0.032). Patients with the genotypes TT and CT + TT of the NQO1 (rs1800566) polymorphism had a significantly higher risk of toxicities such as anemia (aOR = 0.34, p = 0.006 and aOR = 0.58, p = 0.021), neutropenia (aOR = 0.42, p = 0.044 and aOR = 0.57, p = 0.027), leukopenia (aOR = 0.33, p = 0.010 and aOR = 0.46, p = 0.005), and gastrointestinal toxicity (aOR = 0.30, p = 0.02 and aOR = 0.38, p = 0.006) when compared to the wild CC genotype, while patients with the genotype CT had a significant association with gastrointestinal toxicity (aOR = 0.42, p = 0.02) and leukopenia (aOR = 0.52, p = 0.010). The TT and CT + TT genotypes of rs13959 had a significantly higher risk of anemia (aOR = 2.00, p = 0.037 and aOR = 1.68, p = 0.029). There was no significant association between rs1800566 polymorphism and treatment response.

Conclusion: Polymorphisms in ALDH1A1 (rs13959) and NQO1 (rs1800566) may be useful in predicting the probability of treatment response and adverse effects from CEF or CAF-based chemotherapy in breast cancer patients.

Citing Articles

Identification of the optimal candidates to benefit from surgery and chemotherapy among elderly female breast cancer patients with bone metastases.

Hu Y, Tang J, Liu X, Sun Y, Gong B, Gao Q Sci Rep. 2025; 15(1):4678.

PMID: 39920239 PMC: 11806091. DOI: 10.1038/s41598-025-89222-7.

References

Benson J, Jatoi I . The global breast cancer burden. Future Oncol. 2012; 8(6):697-702. DOI: 10.2217/fon.12.61. View

Moo T, Sanford R, Dang C, Morrow M . Overview of Breast Cancer Therapy. PET Clin. 2018; 13(3):339-354. PMC: 6092031. DOI: 10.1016/j.cpet.2018.02.006. View

Miteva-Marcheva N, Ivanov H, Dimitrov D, Stoyanova V . Application of pharmacogenetics in oncology. Biomark Res. 2020; 8:32. PMC: 7429778. DOI: 10.1186/s40364-020-00213-4. View

Stearns V, Davidson N, Flockhart D . Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J. 2004; 4(3):143-53. DOI: 10.1038/sj.tpj.6500242. View

Weinshilboum R . Inheritance and drug response. N Engl J Med. 2003; 348(6):529-37. DOI: 10.1056/NEJMra020021. View

Wiechec E, Hansen L . The effect of genetic variability on drug response in conventional breast cancer treatment. Eur J Pharmacol. 2009; 625(1-3):122-30. DOI: 10.1016/j.ejphar.2009.08.045. View

Balkhi B, Alqahtani S, Altayyar W, Ghawaa Y, Alqahtani Z, Alsaleh K . Drug utilization and expenditure of anticancer drugs for breast cancer. Saudi Pharm J. 2020; 28(6):669-674. PMC: 7292878. DOI: 10.1016/j.jsps.2020.04.007. View

Nebert D, Roe A, Vandale S, Bingham E, Oakley G . NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genet Med. 2002; 4(2):62-70. DOI: 10.1097/00125817-200203000-00003. View

Islam M, Islam M, Parvin S, Ahmed M, Sayeed M, Uddin M . Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients. Tumour Biol. 2015; 36(7):5451-7. DOI: 10.1007/s13277-015-3211-y. View

10.

Glorieux C, Buc Calderon P . Cancer Cell Sensitivity to Redox-Cycling Quinones is Influenced by NAD(P)H: Quinone Oxidoreductase 1 Polymorphism. Antioxidants (Basel). 2019; 8(9). PMC: 6770057. DOI: 10.3390/antiox8090369. View

11.

Akhtari F, Green A, Small G, Havener T, House J, Roell K . High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs. PLoS Genet. 2021; 17(8):e1009732. PMC: 8439493. DOI: 10.1371/journal.pgen.1009732. View

12.

Shortall K, Djeghader A, Magner E, Soulimane T . Insights into Aldehyde Dehydrogenase Enzymes: A Structural Perspective. Front Mol Biosci. 2021; 8:659550. PMC: 8160307. DOI: 10.3389/fmolb.2021.659550. View

13.

Townsend A, Leone-Kabler S, Haynes R, Wu Y, Szweda L, Bunting K . Selective protection by stably transfected human ALDH3A1 (but not human ALDH1A1) against toxicity of aliphatic aldehydes in V79 cells. Chem Biol Interact. 2001; 130-132(1-3):261-73. DOI: 10.1016/s0009-2797(00)00270-2. View

14.

Yang L, Ren Y, Yu X, Qian F, Bian B, Xiao H . ALDH1A1 defines invasive cancer stem-like cells and predicts poor prognosis in patients with esophageal squamous cell carcinoma. Mod Pathol. 2013; 27(5):775-83. DOI: 10.1038/modpathol.2013.189. View

15.

Kalra S, Kaur R, Ludhiadch A, Shafi G, Vashista R, Kumar R . Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array. Eur J Clin Pharmacol. 2018; 74(10):1291-1298. DOI: 10.1007/s00228-018-2505-6. View

16.

Helsby N, Yong M, van Kan M, de Zoysa J, Burns K . The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. Br J Clin Pharmacol. 2019; 85(9):1925-1934. PMC: 6710526. DOI: 10.1111/bcp.14031. View

17.

Ekhart C, Rodenhuis S, Smits P, Beijnen J, Huitema A . Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet Genomics. 2008; 18(11):1009-15. DOI: 10.1097/FPC.0b013e328313aaa4. View

18.

Yao S, Sucheston L, Zhao H, Barlow W, Zirpoli G, Liu S . Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer. Pharmacogenomics J. 2013; 14(3):241-7. PMC: 3940691. DOI: 10.1038/tpj.2013.32. View

19.

Islam M, Ahmed M, Sayeed M, Maruf A, Mostofa A, Hussain S . Lung cancer risk in relation to nicotinic acetylcholine receptor, CYP2A6 and CYP1A1 genotypes in the Bangladeshi population. Clin Chim Acta. 2012; 416:11-9. DOI: 10.1016/j.cca.2012.11.011. View

20.

Parvin M, Aziz M, Rabbi S, Al-Mamun M, Hanif M, Islam M . Assessment of the Link of and gene polymorphisms with the prednisolone resistance in pediatric nephrotic syndrome patients of Bangladesh: A genotype and haplotype approach. J Adv Res. 2021; 33:141-151. PMC: 8463901. DOI: 10.1016/j.jare.2021.02.001. View