Review

Cytochrome P-450 Polymorphisms and Clinical Outcome in Patients with Non-Small Cell Lung Cancer

10.4274/tjps.28291

  • Mümtaz İŞCAN
  • Ahmet Oğuz ADA

Received Date: 09.12.2016 Accepted Date: 19.01.2017 Turk J Pharm Sci 2017;14(3):319-323

Lung cancer is an increasing worldwide public health problem. Most patients with lung cancer have non-small cell lung cancer (NSCLC). These patients are mainly treated with standard platinum-based chemotherapy. Poor response and great inter-individual variety in treatment response occurs among these patients. There is accumulating evidence to support the hypothesis that genetic polymorphisms alter the drug response and survival. Cytochrome P450 (CYP) enzymes metabolize antineoplastic drugs and are involved in drug resistance. Polymorphic CYPs have altered enzyme activities and thus they may influence the response to chemotherapy and survival in patients with lung cancer. In the current review, recent findings with respect to the role of mainly CYP1A1, CYP1B1, CYP2D6, CYP2E1 and CYP3A4 gene polymorphisms in response to chemotherapy and survival in patients with NSCLC have been provided, which could be useful for clinicians in the prognosis of these patients who are mainly treated with platinum-based chemotherapy.

Keywords: CYP,polymorphisms,response to chemotherapy,survival,lung cancer

INTRODUCTION

Lung cancer is an increasing worldwide public health problem, particularly in men.1 It is responsible for the majority of the deaths arising from cancer.2 However, non-small cell lung cancer (NSCLC) is the most common type among patients with lung cancer and standard platinum chemotherapy has poor efficiency in these patients.3,4 Thus, the investigation of the reasons behind this failure of chemotherapy and thus possibly poorer survival in these patients is very important. There are various mechanisms involved in the resistance of tumors against antineoplastic agents.5 There is accumulating evidence to support the hypothesis that genetic polymorphisms alter drug response and survival.6-11

Cytochrome P450 (CYP) is a superfamily of phase I oxidation enzymes, the first 3 families of which metabolize xenobiotics such as environmental carcinogens and various drugs (Table 1) including antineoplastic drugs (Table 2).12-16 They are also involved in drug resistance.14,15 These CYP genes are polymorphic, and the most common alleles of these CYP polymorphisms have been shown to alter enzyme activities (Table 3).17

The therapeutic efficiency and survival period may vary among patients with lung cancer because CYPs metabolize several chemotherapeutic agents depending on CYP activity.16,18,19 Therefore, the relationship between CYP gene polymorphisms and response to chemotherapy and survival in patients with cancer is currently a major area of research. All these kinds of information obtained from studies are necessary and important to lead physicians toward the new era of precision medicine in lung cancer therapy.

Several previous reviews described the potential of CYP polymorphisms in cancer therapy.16,20,21 The research area is rapidly developing, with many studies and insights being published, bringing the possibility of individualized cancer therapy closer. However, this review provides a different aspect of CYP polymorphisms compared with previous ones, particularly focusing on recent findings with respect to the role of CYP1A1, CYP1B1, CYP2E1, CYP2D6, and CYP3A4 gene polymorphisms in response to chemotherapy and survival in patients with NSCLC.

The associations between CYP polymorphisms and response to chemotherapy and survival in patients with lung cancer

Studies investigating the relationship between CYP gene polymorphisms and response to platinum-based chemotherapy and survival in patients with lung cancer have mainly focused on CYP1A1, CYP1B1, CYP2E1, CYP2D6, and CYP3A4 (Table 4).

As seen in Table 4, a couple of studies exist with respect to the CYP1A1 polymorphism and survival in lung cancer, and their results are contradictory.7,18,22,23 Goto et al.22 found that the CYP1A1*2A mutant allele significantly shortened survival compared with those of wild-type genotypes in patients with NSCLC. However, Li et al.18 found no such association in this regard for the CYP1A1*2A polymorphism. Pryzgodzki et al.23 observed no association between the CYP1A1*2C polymorphism and survival in patients with NSCLC. Likewise, a recent study also demonstrated the lack of association between the CYP1A1*2C polymorphism and survival in patients with NSCLC.7

There are only two studies in regard to the influences of CYP1B1 polymorphisms on survival in lung cancer (Table 4). Recently, Vasile et al.19 demonstrated that CYP1B1*3 mutant allele carriers had shorter survival compared with wild-type allele carriers. These investigators, however, observed no association between CYP1B1*4 polymorphisms and survival in patients with NSCLC. In line with Vasile et al.19, Ada et al.7 previously showed that the CYP1B1*4 polymorphism was not associated with survival in patients with NSCLC, although a notable trend towards worsening of survival in CYP1B1*4 mutant allele carriers was determined (Table 4).

On the other hand, in recent years, data about the associations between the CYP1A1*2A, CYP1A1*2C, CYP1B1*3, and CYP1B1*4 polymorphisms and responses to mainly platinum-based chemotherapy have been provided by researchers (Table 4).7,18,19 Li et al.18 found that wild-type allele carriers of the CYP1A1 gene had a better response to non-platinum drug therapy only, but not to platinum-based chemotherapy, than those of variant allele carriers of the gene. There was no influence of the CYP1A1*2C polymorphism on the response to platinum-based chemotherapy in patients with NSCLC.7 The response to chemotherapy of CYP1B1*3 variant allele carriers was worse than wild-type allele carriers of the CYP1B1 gene in patients with NSCLC who were treated with docetaxel after platinum-based chemotherapy.19 However, no association was found between the CYP1B1*4 polymorphism and response to chemotherapy.7,19

A study investigating the association between the CYP2D6*10A polymorphism and therapeutic response or survival in patients with NSCLC has recently been reported (Table 4).18 These investigators observed no influence of this polymorphism on response to either platinum-based chemotherapy or non-platinum-based chemotherapy and survival in patients with advanced NSCLC.

Studies concerning the relationship between the CYP2E1 polymorphism and survival in patients with lung cancer are also rather limited and the results are not conclusive (Table 4). For example, studies on the CYP2E1*5B polymorphism are rather conflicting. Oyama et al.24 found an increase in survival in mutant allele carriers, whereas Haque et al.25 observed shorter survival in mutant carriers, and Li et al.18 found no association between this CYP gene polymorphism and survival in patients with NSCLC. Przygodzki et al.23 reported no significant association between the CYP2E1*6 polymorphism and survival in patients with NSCLC. Moreover, almost no information is available with respect to the relationship between these polymorphisms and response to chemotherapy in patients with NSCLC. The first data in this regard were provided by Li et al.18 who observed no significant association between the CYP2E1*5B polymorphism and response to chemotherapy in NSCLC. Likewise, the recent results of Karacaoğlan et al.9 on the CYP2E1*5B polymorphism are also in line with the findings of Li et al.18, both in regard to response to chemotherapy and survival. However, their findings are in contrast to those of Oyama et al.24 and Haque et al.25 in respect to survival. The findings of Karacaoğlan et al.9 in regard to the effect of CYP2E1*6 polymorphism on survival also coincided with the results of Przygodzki et al.23 The only study for the CYP2E1*7B polymorphism on this issue was reported by Karacaoğlan et al.9 who observed no association between the CYP2E1*7B polymorphism and response to chemotherapy and survival in patients with NSCLC.

Choi et al.26 investigated the influences of CYP3A4 polymorphisms on response to chemotherapy in patients who had various type of cancer, including lung cancer (Table 4). The authors genotyped CYP3A4 polymorphisms, namely CYP3A4*1B, CYP3A4*3, and CYP3A4*18, but could find no association between these polymorphisms and response to chemotherapy in patients with lung cancer treated with docetaxel concomitantly with cisplatin, doxorubicin, capecitabine, cisplatin-cetuximab, and ifosfamide.

Multigene polymorphisms in response to chemotherapy and survival in lung cancer

Recent studies have demonstrated that the simultaneous analysis of gene polymorphisms may correlate well with the clinical outcome better than the single polymorphism studies. This seems to be valid for CYPs as well. For example, the combined CYP1A1*2A mutant allele and GSTM1 null genotype were associated with better response to chemotherapy in NSCLC patients.18 The study of Ada et al.7 in NSCLC patients also revealed that the combined CYP1A1*2C and GSTP1 (Ile105Val) mutant alleles or CYP1B1*4 and GSTP1 (Ile105Val) mutant alleles had notable trends toward worsening of survival. Recently, Karacaoğlan et al.9 demonstrated that combined CYP1A1*2C and TP53 (Arg72Pro) mutant genotypes were associated with the worsening of the survival in NSCLC patients. In addition, they observed that the combined CYP2E1*7B and TP53 (Arg72Pro) mutant alleles had notable trends toward worsening survival. Hence, the analysis of more than one gene polymorphisms of CYPs with other gene polymorphisms as shown with other xenobiotic/drug metabolizing enzymes and TP53 gene polymorphisms could provide more important information of their involvement in the clinical outcome in NSCLC.


CONCLUSION

Based on current data, the role of polymorphisms of genes that encode CYP enzymes in response to chemotherapy and survival in patients with NSCLC seems to depend on the individual CYP gene and to a certain extent, the treatment regimen.

The altered enzyme activities due to gene mutations appear to have no significant impact in patients with NSCLC treated with distinct chemotherapy regimens, namely platinum-based chemotherapy, non-platinum-based chemotherapy or docetaxel-based chemotherapy because there is a lack of associations between CYP1A1*2C, CYP1B1*4, CYP2D6*10A, CYP2E1*6, CYP2E1*7B, CYP3A4*1B, CYP3A4*3, and CYP3A4*18 polymorphisms and response to chemotherapy. These findings are also likely to show that these CYP polymorphisms are not functioning as a predictor of response to the distinct chemotherapy regimens mentioned above. However, wild-type allele carriers of CYP1A1 gene seems to benefit more from non-platinum-based treatment than platinum-based chemotherapy. On the other hand, CYP1B1*3 mutant allele carriers had a poor response, mainly to docetaxel-based chemotherapy. However, further studies are required to confirm these findings.

Conflicting results are also noted with respect to the influence of CYP1A1*2A and CYP2E1*5B polymorphisms in particular on the survival of patients with NSCLC. These inconsistencies need to be clarified through further studies. On the other hand, the lack of association between the CYP1A1*2C, CYP1B1*4, and CYP2E1*6 polymorphisms and survival in patients with NSCLC appears to be conclusive. The CYP2D6*10A and CYP2E1*7B polymorphisms are also likely to have no influence on survival in patients with NSCLC. However, these findings need to be verified in further studies.

It is noteworthy that other important factors should also be considered when evaluating the role of these genes in the clinical outcome of cancer therapy. For example, besides single gene polymorphisms, multiple function CYP gene polymorphisms with other gene polymorphism analyses have also shown to provide important information about their involvement in clinical outcomes in NSCLC.

Overall, current studies have shown that the effects of each individual CYP gene polymorphism on clinical outcomes in patients with NSCLC are likely to be modest, which suggests that more comprehensive information is necessary to predict more accurately the role of CYP polymorphisms in selecting the most appropriate chemotherapy regimen. Recent efforts in this regard are promising.27

Thus, future studies that incorporate multigene polymorphisms, and phenotypic, epigenetic, and clinical variables will hopefully provide a better understanding of the role of CYP polymorphisms in precision medicine for patients with NSCLC.


ACKNOWLEDGEMENT

The authors’ research was supported by the Research Fund of Ankara University; grants: 20060803002HPD, 20070803005HPD and 10A3336002.

Conflict of Interest: No conflict of interest was declared by the authors.


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1. Firat D, Celik I. Cancer Statistics in Turkey and in the World 1993-1995. Turkish Association for the Cancer Re-search and Control. Ankara; 1998.
2. Howe HL, Wingo PA, Thun MJ, Ries LA, Rosenberg HM, Feigal EG, Edwards BK. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst. 2001;93:824-842.
3. Bunn PA Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why? J Clin Oncol. 2002:20(18 Suppl):23S-33S.
4. Goksel T, Akkoclu A; Turkish Thoracic Society, Lung and Pleural Malignancies Study Group. Pattern of lung cancer in Turkey, 1994-1998. Respiration. 2002;69:207-210.
5. Stewart DJ. Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol 2010;75:173-234.
6. Booton R, Ward T, Heighway J, Ashcroft L, Morris J, Thatcher N. Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer. J Thorac Oncol. 2006;1:679-683.
7. Ada AO, C Kunak S, Hancer F, Bilgen S, Suzen SH, Alpar S, Gulhan M, Kurt B, Iscan M. CYP and GST polymorp-hisms and survival in advanced non-small cell lung cancer patients. Neoplasma. 2010;57:512-521.
8. Yin JY, Huang Q, Zhao YC, Zhou HH, Liu ZQ. Meta-analysis on pharmacogenetics of platinum-based chemothe-rapy in non small cell lung cancer (NSCLC) patients. PLoS One. 2012;7:e38150.
9. Karacaoğlan V, Ada AO, Bilgen S, Çetinkaya GT, Soydaş E, Kunak CS, Alpar SM, Gülhan M, Işcan M. Xenobio-tic/drug metabolizing enzyme and TP53 polymorphisms and clinical outcome in advanced nonsmall cell lung cancer patients. Turk J Med Sci. 2017;47:554-562.
10. Chen J, Wang Z, Zou T, Cui J, Yin J, Zheng W, Jiang W, Zhou H, Liu Z. Pharmacogenomics of platinum-based chemotherapy response in NSCLC: a genotyping study and a pooled analysis. Oncotarget. 2016;7:55741-55756.
11. Yin JY, Li X, Zhou HH, Liu ZQ. Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine. Pharmacogenomics. 2016;17:1365-1378.
12. Guengerich FP, Wu ZL, Bartleson CJ. Function of human cytochrome P450s: characterization of the orphans. Biochem Biophys Res Commun. 2005;338:465-469.
13. Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of hu-man cytochrome P450 enzymes: current status. Arch Toxicol. 2008;82:667-715.
14. Michael M, Doherty MM. Drug metabolism by tumours: its nature, relevance and therapeutic implications. Expert Opin Drug Metab Toxicol. 2007;3:783-803.
15. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89-295.
16. van Schaik RH. CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat. 2008;11:77-98.
17. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 29 September 2016. Available: http://cypalleles.ki.se/
18. Li W, Yue W, Zhang L, Zhao X, Ma L, Yang X, Zhang C, Wang Y, Gu M. Polymorphisms in GSTM1, CYP1A1, CYP2E1, and CYP2D6 are associated with susceptibility and chemotherapy response in non-small-cell lung cancer patients. Lung. 2012;190:91-98.
19. Vasile E, Tibaldi C, Leon GL, D’Incecco A, Giovannetti E. Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients. J Cancer Res Clin On-col. 2015;141:1189-1194.
20. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorp-hisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007;116:496-526.
21. Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S. Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PLoS One. 2013;8:e82562.
22. Goto I, Yoneda S, Yamamoto M, Kawajiri K. Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. Cancer Res. 1996;56:3725-3730.
23. Przygodzki RM, Bennett WP, Guinee DG Jr, Khan MA, Freedman A, Shields PG, Travis WD, Jett JR, Tazelaar H, Pairolero P, Trastek V, Liotta LA, Harris CC, Caporaso NE. p53 mutation spectrum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treated patients with non-small cell lung cancer. Pharmacogenetics. 1998;8:503-511.
24. Oyama T, Matsumoto A, Isse T, Kim YD, Ozaki S, Osaki T, Sugio K, Yasumoto K, Kawamoto T. Evidence-based prevention (EBP): approach to lung cancer prevention based on cytochrome 1A1 and cytochrome 2E1 polymorp-hism. Anticancer Res. 2003;23:1731-1737.
25. Haque AK, Au W, Cajas-Salazar N, Khan S, Ginzel AW, Jones DV, Zwischenberger JB, Xie J. CYP2E1 polymorp-hism, cigarette smoking, p53 expression, and survival in non-small cell lung cancer: a long term follow-up study. Appl Immunohistochem Mol Morphol. 2004;12:315-322.
26. Choi JR, Kim JO, Kang DR, Shin JY, Zhang XH, Oh JE, Park JY, Kim KA, Kang JH. Genetic Variations of Drug Transporters Can Influence on Drug Response in Patients Treated with Docetaxel Chemotherapy. Cancer Res Treat. 2015;47:509-517.
27. Yin JY, Li X, Li XP, Xiao L, Zheng W, Chen J, Mao CX, Fang C, Cui JJ, Guo CX, Zhang W, Gao Y, Zhang CF, Chen ZH, Zhou H, Zhou HH, Liu ZQ. Prediction models for platinum-based chemotherapy response and toxicity in advan-ced NSCLC patients. Cancer Lett. 2016;377:65-73.