News & Views
Research Highlights Highlights from the latest articles in pharmacogenomics of irinotecan/cisplatin toxicity
First genome-wide association study to identify novel genes related to irinotecan toxicity Evaluation of: Han JY, Shin ES, Lee YS et al. A genome-wide association study for irinotecanrelated severe toxicities in patients with advanced non-small-cell lung cancer. Pharmacogenomics J. doi:10.1038/tpj.2012.24 (2012) (Epub ahead of print). Irinotecan is commonly used for treatment of colorectal cancer in the 5‑fluorouracil– leucovorin–irinotecan (FOLFIRI) sched‑ ule, but it has also demonstrated activity in non-small-cell lung cancer, either alone or in combination with cisplatin. Irinotecan is an inhibitor of topoisomerase-I, and is metabolized by carboxylesterases to SN-38, which is 100–1000-fold more effective. The impact of specific genotypes in the metabolism of irinotecan represents one of the first-described associations of pharma‑ cokinetics with pharmacogenetics. The effi‑ cacy of SN-38 may be limited by its uptake by SLCO and efflux by ABC-transporters. Irinotecan is inactivated by the CYP450 variants CYP3A4/3A5, while SN-38 is inactivated by glucuronidation catalyzed by UGT1A1. Topoisomerase-I, transport‑ ers and metabolizing enzymes have been associated with efficacy and toxicity. Several polymorphisms such as UGT1A1*28 lead to reduced SN-38 glucuronidation, causing severe diarrhea and neutropenia. Patients with this UGT1A1 variant need a dose reduction; therefore, irinotecan is one of the first drugs dosed according to the recip‑ ient’s genotype, as indicated by a US FDA pharmacogenetics labeling [1] . Han et al. earlier showed that UGT1A1, SLCO and ABC variant genotypes in Koreans were predictive for increased 10.2217/PGS.12.134 © 2012 Future Medicine Ltd
neutropenia and diarrhea [2–4] , similar to non-Asian populations [5–7] . A more recent genome-wide association study in 103 patients treated with irinotecan–cis‑ platin identified 49 SNPs associated with diarrhea and 32 SNPs with neutropenia [8] . A subsequent verification focussing on specific gene variants was performed on 73 patients on irinotecan–cisplatin, and 73 on irinotecan–capecitabine treat‑ ment. The initial genome-wide association study revealed SNPs in Cborf34, FLJ4 and PLCB1 associated with diarrhea and SNPs in PDZRN3 and SEMA3C with neutro penia; this was confirmed in the replication study. The authors hypothesize that these enzymes may affect irinotecan’s metabo‑ lism and hence its toxicity. The authors also investigated the role of SNPs previously cor‑ related with irinotecan’s toxicity and verified that UGT1A1*6 was associated with neutro penia, ABCC2 397C>T with diarrhea and SLCO1B1 521T>C with neutropenia in the replication stage. However, whether these associations were still present in a multivariate analysis was not reported. The present study has other limitations such as the small sample size in the initial and verification studies, as well as the com‑ bination with cisplatin. Some toxicities may indeed be related to cisplatin and/or to the irinotecan–cisplatin combination. Although the replication study includes a cohort without cisplatin, this appears too small to exclude a cisplatin effect. Since these stud‑ ies were performed in Korean non-smallcell lung cancer patients, similar verifica‑ tion studies should be performed in other ethnic populations and diseases, such as in colorectal cancer patients. In order to verify a causative relationship, one should inves‑ tigate the role of these enzymes in suitable
Godefridus J Peters*1 & Elisa Giovannetti1 Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands *Author for correspondence: Tel.: +31 204 442 633 Fax: +31 204 443 844
[email protected] 1
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Pharmacogenomics (2012) 13(13), 1445–1447
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News & Views – Research Highlights 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J. Clin. Oncol. 24, 4534–4538 (2006). 2
model systems, in which the metabolism of irinotecan is being investigated in rela‑ tion to the expression of candidate genes, for example, by using specific inhibitors or genetic variants, and measuring the different metabolites [9] . In summary, this study represents the first genome-wide study using an unbiased noncandidate gene-driven approach to identify novel SNPs associated with irinotecan tox‑ icities. However, these findings need a func‑ tional verification as well as a clinical vali‑ dation in larger and homogeneously-treated cohorts, with appropriate statistical analysis.
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References 1
O’Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT)
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Han JY, Lim HS, Shin ES et al. Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J. Clin. Oncol. 24, 2237–2244 (2006). Han JY, Lim HS, Yoo YK et al. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 110, 138–147 (2007). Han JY, Lim HS, Lee SY, Kim HT, Lee JS. Influence of the organic anion transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer 59, 69–75 (2008). Innocenti F, Undevia SD, Iyer L et al. Genetic variants in the UDP-glucuronosyltransferase
1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol. 22, 1382–1388 (2004). 6
de Jong FA, Scott-Horton TJ, Kroetz DL et al. Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein. Clin. Pharmacol. Ther. 81, 42–49 (2007).
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Schellens JH, Maliepaard M, Scheper RJ et al. Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications. Ann. NY Acad. Sci. 922, 188–194 (2000).
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Han JY, Shin ES, Lee YS et al. A genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-smallcell lung cancer. Pharmacogenomics J. doi:10.1038/tpj.24. (2012) (Epub ahead of print).
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Giovannetti E, Toffalorio F, De Pas T, Peters GJ. Pharmacogenetics of conventional chemotherapy in non-small-cell lung cancer: a changing landscape? Pharmacogenomics 13(9), 1073–1086 (2012).
Cisplatin toxicity: a role for transport? Evaluation of: Xu X, Ren H, Zhou B et al. Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients. Lung Cancer 77, 438–442 (2012). Treatment with platinum analogs is limited by several toxicities [1] . A common toxicity is ototoxicity characterized by hearing loss and ear pain, which is usually not revers‑ ible [2] . Only a few studies have investigated the genetic basis for cisplatin-induced oto‑ toxicity; however, the prevention of this severe toxicity is an important issue in platinum-based therapies. Pharmacogenetics of platinum analogs has focused mostly on prediction of out‑ come. In particular, ERCC1 expression and polymorphisms have been associated with survival in lung cancer patients [3,4] . Conversely, influx and efflux transporters are major candidates to explain cisplatininduced toxicity [2,3,5] . The uptake of cis‑ platin is not yet fully understood; CTR1 appears to be a limiting factor [6] , but uptake 1446
can also be mediated by organic cation transporters [7] or by passive diffusion. In more than 200 non-small-cell lung cancer patients treated with cisplatin therapy for at least two cycles, Xu et al. screened 20 SNPs of CTR1 [8] . CTR1 rs10981694, encoding for an AA>CC translocation in the promoter region, was associated with increased ototoxicity, but did not have any effect on survival. This is the first evidence of an association of oto‑ toxicity with a CTR1 SNP; however, the authors do not discuss potential applica‑ tions or provide evidence for a mechanistic explanation. Genetic models expressing the wildtype and mutant SNP, such as for the ERCC1 C118T polymorphism [9] , should be developed and tested for their CTR1 activity by measuring the uptake of cis‑ platin. Since the CTR1 gene of mouse and man is similar, one might also engineer a mouse model and investigate the role of a specific SNP in hearing. Such mod‑ els would also enable researchers to test whether this SNP would affect uptake of other platinum analogs such as carboplatin and oxaliplatin. Pharmacogenomics (2012) 13(13)
From a clinical point of view, several additional questions remain. The authors performed their research on a Chinese population, which raises the question of whether this SNP has any ethnicity-specific occurrence. Therefore, further studies should be performed in other populations, and should also evaluate other candidate SNPs that have been related to cisplatin ototoxicity or other severe toxicities, such as genetic variants of TPMT and COMT [10] , or common SNPs in ERCC1 [11] . Second, when larger studies in differ‑ ent populations confirm the association of this SNP with ototoxicity, one should consider pretreatment testing, followed by customized therapy, including otoprotec‑ tion with administration of agents such as thiosulphate or amifostine [12,13] . However, these drugs have not been characterized for this application and future studies should demonstrate their potential. This subject is particularly relevant in pediatric oncol‑ ogy, since 60% of children treated with cis‑ platin develop permanent bilateral hearing loss. Therefore, a recent consensus review presented a new International Society of Pediatric Oncology Boston Ototoxicity future science group
Research Highlights – Grading Scale for grading and compar‑ ing ototoxicity, in order to plan adequate prospective trials [12] . In conclusion, the authors are the first to characterize an interesting association between a CTR1 SNP and ototoxicity. The functional implications of this SNP have not yet been elucidated and require further preclinical mechanistic investiga‑ tions, while prospective clinical studies are required to verify the potential role of this SNP in the clinical setting.
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Lord RV, Brabender J, Gandara D et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin. Cancer Res. 8, 2286–2291 (2002).
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Noordhuis P, Laan AC, van de Born K, Losekoot N, Kathmann I, Peters GJ. Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines. Biochem. Pharmacol. 76, 53–61 (2008).
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References 1
Muggia FM. Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin. Oncol. 16(2 Suppl. 5), S7–S13 (1989).
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Mukherjea D, Rybak LP. Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics 12(7), 1039–1050 (2011).
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Jiang J, Liang X, Zhou X, Huang R, Chu Z, Zhan Q. ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis. Mol. Biol. Rep. 39, 6933–6942 (2012).
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Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit. Rev. Oncol. Hematol. 53, 13–23 (2005). Zhang S, Lovejoy KS, Shima JE et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 66, 8847–8857 (2006). Xu X, Ren H, Zhou B et al. Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients. Lung Cancer 77(2), 438–442 (2012). Gao R, Reece K, Sissung T et al. The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or
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platinum sensitivity. Mutat. Res. 708, 21–27 (2011). 10
Ross CJ, Katzov-Eckert H, Dubé MP et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat. Genet. 41, 1345–1349 (2009).
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Suk R, Gurubhagavatula S, Park S et al. Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients. Clin. Cancer Res. 11, 1534–1538 (2005).
12 Brock PR, Knight KR, Freyer DR et al.
Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J. Clin. Oncol. 30, 2408–2417 (2012). 13 van der Vijgh WJ, Peters GJ. Protection of
normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (Ethyol): preclinical aspects. Semin. Oncol. 21(5 Suppl. 11), S2–S7 (1994).
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