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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4528-4535 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.4752 Pharmacogenetic Assessment of Toxicity and Outcome After Platinum Plus Taxane Chemotherapy in Ovarian Cancer: The Scottish Randomised Trial in Ovarian Cancer
From the Washington University School of Medicine, Division of Oncology, St Louis, MO; UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC; University of Glasgow, Centre for Oncology and Applied Pharmacology; and Cancer Research UK Beatson Laboratories, University of Glasgow, Glasgow, United Kingdom Address for reprint requests to Sharon Marsh, PhD, Washington University School of Medicine, Campus Box 8069, 660 S Euclid Ave, St. Louis, MO 63110; e-mail: smarsh{at}im.wustl.edu
Purpose Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane, which has a 5-year survival rate of approximately 45%. The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect. Patients and Methods We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery. Results No reproducible significant associations between genotype and outcome or toxicity were found for any of the genes analyzed. Previously reported genotype associations could not be replicated in this large study of a well-defined patient population within one specific clinical trial. Conclusion There are no clear candidates for taxane/platinum pharmacogenetic markers. This study highlights the need for validation of putative genetic markers in large, well-defined clinical sample sets.
Ovarian cancer is the eighth most common cancer among women.1 It accounts for approximately 3% of all female cancers and is the fifth most common cause of cancer death in women (accounting for 6% of cancer deaths). Standard treatment for ovarian cancer involves chemotherapy with a platinum agent (cisplatin or carboplatin) and a taxane (paclitaxel).2,3 In recent years docetaxel has also been assessed as an alternate taxane to paclitaxel for ovarian cancer treatment.4-6 Despite modern chemotherapy, the 5-year survival rate is approximately 45%. A comparison of docetaxel-carboplatin versus paclitaxel-carboplatin in 1,077 ovarian cancer patients on the Scottish Randomised Trial in Ovarian Cancer (SCOTROC1) phase III trial showed similar progression-free survival and overall survival rates for both treatment groups.5 However, the toxicity profiles between the two groups differed significantly. Docetaxel-containing therapy had significantly higher incidence of grade 3 to 4 neutropenia, whereas paclitaxel-containing therapy had significantly more grade 2 or higher neurotoxicity.5 The interindividual variability of response within treatment arms and toxicity both within and between treatment arms for ovarian cancer highlights the need for the identification of pharmacogenetic markers to enable individualized therapy selection.7 The cellular toxicity of taxanes and platinum agents are likely controlled by the actions of multiple genes.8-10 Genes involved in transport (eg, ABCB1, ABCC1, and ABCC2), metabolism (cytochrome P450s), and pharmacodynamics (eg, TP53, CDKN1A) all appear to play a role in taxane efficacy.9 Similarly, platinum agents such as carboplatin are regulated by genes involved in DNA detoxification (GSTP1, MPO) and repair (ERCC1, ERCC2, XRCC1). There are varying levels of in vitro and in vivo evidence to suggest that DNA polymorphisms in genes involved in taxane and platinum drug pathways may be associated with treatment outcome and toxicity (reviewed by Marsh8,9 and Watters et al10). This study assessed polymorphisms selected on the basis of previously described associations11-28 or putative functional effects29,30 in 16 key genes from the taxane and platinum pathways in 914 patients from the SCOTROC1 ovarian cancer trial (Fig 1A and 1B). This represents the largest ovarian cancer and taxane-platinum pharmacogenetic study to date, with the goals to determine any associations with toxicity and outcome both within and between the docetaxel and paclitaxel treatment arms.
Patient Samples Germline DNA was available from whole blood of 914 of the 1,077 patients enrolled onto the SCOTROC1 phase III trial. Patients had been randomly assigned to carboplatin (to area under the plasma concentration-time curve of 5) and either paclitaxel 175 mg/m2 (n = 456) or docetaxel 75 mg/m2 (n = 458).5 Pharmacogenetic analysis was performed with appropriate ethics approval from both institutions. Data on patient characteristics, treatment outcome, and toxicity for each treatment arm have been presented elsewhere and are summarized in Table 1. 5
Genotyping Genotyping for 27 polymorphisms from 16 genes involved in the taxane (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) drug pathways (Figs 1A and 1B) was performed using polymerase chain reaction and Pyrosequencing, as described previously,31 with primers and conditions listed in Appendix Table A1 (online only). Data were analyzed on a PSQ hs96A system using PSQ HS96 SNP software version 1.1 (Biotage, Uppsala, Sweden). Genotyping was carried out by researchers blinded to treatment arm, clinical outcome, and toxicity data. Genotypes were assessed for Hardy-Weinberg equilibrium using hwsim.32 ABCB1 2677G>T/A genotype data in the SCOTROC1 study has been published previously.33
Statistics
Techniques for controlling the false discovery rate at less than 10%34 were then used to select genotypes from the univariate testing stage as candidates for inclusion in multivariate models. These multivariate models of significant genotypes were built using conventional stepwise techniques, and cross-validated likelihood methods were used to select the final model size. These models also encompassed other possible risk factors (age, performance status, stage, and so on). The performance of the final model was assessed in the validation set. Neurotoxicity and GI toxicity were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. Serious hematologic toxicity was defined as any of the following: grade 4 neutropenia for longer than 1 week, grade 4 neutropenia with fever (> 38.5°C) lasting more than 2 days, grade 4 neutropenia with fever (single oral temperature > 38°C), grade 4 thrombocytopenia with hemorrhage, or grade 4 thrombocytopenia with platelet transfusion. Clinical response was measured using modified Southwest Oncology Group response criteria and CA-125 response was assessed using an approach developed by Rustin et al.35 Progression-free survival was measured at the time from entry onto the trials until progression or death as a result of any cause.
Wherever possible for this study, we aimed to comply with the recently published Reporting Recommendations for Tumour Marker Prognostic Studies Criteria (Fig 2).36 Genotype data was available for between 841 and 905 of the 914 samples (Table 2). All genotypes were in Hardy-Weinberg equilibrium and no genotype frequencies deviated from those previously reported for white populations.
The only associations identified in the development set between genotype and toxicity were between CYP1B1*3 and CDKN1A 10971C and grade 3/4 GI toxicity in docetaxel patients (Table 3). A multiple logistic regression model was built on the development set, including both CYP1B1*3 and CDKN1A 10971C>T; both were independently prognostic in the model (P = .005 and P = .007, respectively). None of the patient or tumor characteristics (Table 1) added any prognostic value for toxicity to the model. A linear predictive score for grade 3/4 GI toxicity was derived from the model. When this score was examined in the validation set, no statistically significant association with grade 3/4 GI toxicity was found (P = .617).
Additional examination of the individual single nucleotide polymorphisms revealed that the association for CDKN1A 10971C>T did not approach statistical significance in the validation set (P = .623); moreover, the direction of the association was reversed, indicating that this was a false-positive result. For CYP1B1*3, the association also was not found to be statistically significant in the validation set (P = .189), although in both the development and validation sets the homozygous wild-type patients had the lowest percentage of grade 3/4 toxicity: 14% (11 of 80) v 26% (48 of 186) in the development set and 11% (four of 36) v 24% (27 of 111) in the validation set. There was no association between genotype and outcome (Table 4). Previously published pharmacogenetic associations for either platinum or taxane therapies were not observed in this study.11-28
This study assessed 27 polymorphisms from 16 key genes involved in taxane and platinum pathways in 914 patients from the SCOTROC1 phase III trial. This is the most comprehensive taxane-platinum pharmacogenetic study in ovarian cancer to date. There are multiple potential reasons for the discrepancies between this study and previously published data. Most previous studies of taxane-platinum pharmacogenetics have been small (many in < 100 patients), in different tumor types (non–small-cell lung cancer [NSCLC], breast cancer), and with a variety of treatment regimens (single-agent taxane, different doses, different platinum agent, or additional chemotherapy agents). In addition, population differences in allele frequencies may be a factor. Only four previous studies have assessed paclitaxel pharmacogenetics in ovarian cancer, and sample sizes were between 23 and 114 patients.13-15,17 Docetaxel pharmacogenetics has not been assessed previously in ovarian cancer. Although there is little overlap between platinum and taxane gene pathways (Figs 1A and 1A), it is possible that the combination of taxane-carboplatin alters the pharmacogenetic effects of polymorphisms that were previously determined to be functional in studies involving single-agent therapy or different drug combinations. The relative contribution of transporters ABCC2 and ABCG2 to both carboplatin and taxane efflux when used in combination is unclear, but may mask any polymorphism/outcome associations. Previously, polymorphisms in CYP2C8, CYP3A4, CYP3A5, and ABCB1 have been studied in 97 cancer patients receiving paclitaxel, and were not associated with paclitaxel pharmacokinetics.37 In 93 breast cancer patients receiving high-dose paclitaxel, polymorphisms in ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5, and CYP2C8 were not associated with paclitaxel pharmacokinetics.11 Additional studies of 26 patients with solid tumors receiving paclitaxel26 and 58 patients with solid tumors receiving docetaxel27 found no association between ABCB1 polymorphisms and pharmacokinetics. However, in a study of 23 Japanese ovarian cancer patients, ABCB1 3435C>T was significantly associated with paclitaxel clearance (P < .05),13 and in 97 patients with solid tumors receiving docetaxel, the ABCB1 1236C>T homozygous variant genotype was associated significantly with reduced docetaxel clearance (P = .0039).25 Recent studies have also identified an association between ABCB1 2677G>T/A and response to paclitaxel in 53 Swedish ovarian cancer patients (P < .05),15 neutropenia and ABCB1 3435C>T homozygous variants in 58 solid tumor patients receiving docetaxel (P = .046),27 and a trend toward risk of developing neuropathy in ABCB1 3435C>T homozygous variant patients receiving paclitaxel (n = 22; P = .09),26 but these findings could not be replicated in the SCOTROC1 study. Likewise, ABCG2 Q141K was putatively significantly associated with survival in 51 prostate cancer patients receiving docetaxel (P = .05)12 but this was not seen in the ovarian cancer patients in the SCOTROC1 study, although this could be related to the limited expression of ABCG2 protein in ovarian tissue.38 In addition, CYP3A4*1B has also been associated with higher docetaxel clearance in 58 solid tumor patients receiving docetaxel (P = .005).27 In the SCOTROC1 study, pharmacokinetic data were not available; however, polymorphisms in these genes were not associated with outcome or toxicity. Polymorphisms previously associated with taxane pharmacokinetics may not predict treatment outcome when taxanes are administered in combination with platinum agents. Despite in vitro evidence demonstrating that CYP2C8*3 affects CYP2C8 metabolism of paclitaxel,21 this polymorphism has not been identified as clinically relevant in any in vivo study to date. The CYP1B1*3 leucine allele was significantly associated with paclitaxel outcome in the breast cancer study (P = .037),11 but this was not replicated in the SCOTROC1 study. CYP1B1 is the predominant cytochrome in breast tissue39 and is overexpressed in breast tumor40; consequently, the functional effect of the CYP1B1*3 allele may be tissue specific. In this study, the development set indicated a possible association between CYP1B1*3 and docetaxel GI activity, however, as this association was not replicated in the validation set, there was no strong evidence that this was a real effect. TP53 R72P has been identified in two conflicting studies as a prognostic marker for paclitaxel/platinum therapy.14,17 In 46 patients with advanced poorly differentiated serous epithelial ovarian cancer, patients homozygous for the TP53 codon 72 proline allele showed a trend toward longer progression-free survival and overall survival.14 Conversely, in 114 Portuguese ovarian cancer patients, those individuals homozygous for the TP53 codon 72 arginine allele had a significantly longer progression-free survival (P = .011).17 No association of either TP53 codon 72 allele and progression-free survival was seen in the SCOTROC1 patients. This study was biased toward pharmacogenetic markers for taxane therapy, given that published data for carboplatin-genotype associations are limited. Previous platinum pharmacogenetics studies have focused mainly on the platinum agents oxaliplatin and cisplatin. These associations were tested in the current study because markers for one platinum agent may have similar effects on related drugs. One recent study in 60 ovarian cancer patients treated with paclitaxel/carboplatin identified a trend toward increased platinum resistance in patients with wild-type ERCC1 N118N (P = .064).28 In a study of 62 docetaxel/cisplatin treated NSCLC patients, ERCC1 N118N was associated significantly with median survival (P = .04) and time to progression (P = .03).24 In another NSCLC study, in 109 patients treated with cisplatin combination therapy, the ERCC1 N118N polymorphism was significantly associated with overall survival (P = .0001).23 These findings are also seen for oxaliplatin combination therapy.20,22 Studies on oxaliplatin/fluorouracil therapy in colorectal cancer patients also show significant associations between outcome and GSTP1,19,20 ERCC2,20,41 and XRCC118 polymorphisms, and neurotoxicity and GSTP1 I105V.16 However, no association between outcome or toxicity and ERCC1, ERCC2, GSTP1, or XRCC1 was seen for carboplatin in the SCOTROC1 ovarian cancer study. The absence of a clear relationship with any of the candidate genes for taxane/platinum pharmacogenetic markers likely reflects a lack of true understanding of the regulation of chemotherapy action. This study focused on candidate polymorphisms from previously published taxane and/or platinum pharmacogenetics studies. Other genes known to be involved in taxane and platinum metabolism, efflux, and pharmacodynamics could also play a role (eg, ABCC10, SLC22A7, SLCO1B3 [taxanes], SLC22A1, SLC22A2 [platinum drugs]). However, to date these genes do not have known functional polymorphisms. When pharmacogenetics studies have been performed for these genes, the results did not indicate any relationship between polymorphism and taxane or platinum efficacy or toxicity. For example, polymorphisms in SLCO1B3 were not associated with taxane pharmacokinetics.42 In addition to identifying functional polymorphisms in known candidate genes, ongoing genome-wide strategies may provide novel candidate genes/chromosome regions for future pharmacogenetics studies.43 Recent studies also suggest that combinations of genotypes may provide a better prediction for docetaxel pharmacokinetics27 and toxicity.26,27 However, epigenetic regulation, physiologic factors, concurrent medications, herbal remedies, and environmental factors are also likely to play a large role in interindividual variability to taxane response.44-52 The pharmacogenetic basis for variability in response and toxicity to taxane-platinum therapy in ovarian cancer is still unknown. This study assessed 27 polymorphisms from 16 candidate genes in 914 patients and could not identify any significant associations. No previously published associations could be replicated in this study. This study highlights the need for validation of putative pharmacogenetic markers from small studies in large, well-defined samples sets (such as the SCOTROC1 study) to confirm associations before they are developed into routine clinical tests.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Robert Brown, Scottish Gynaecological Clinical Trials Group, Cancer Research UK Testimony: N/A Other: N/A
Conception and design: Sharon Marsh, Howard L. McLeod, Robert Brown Financial support: Howard L. McLeod, Robert Brown Administrative support: Jim Paul, Howard L. McLeod, Robert Brown Provision of study materials or patients: Gillian Gifford, Robert Brown Collection and assembly of data: Sharon Marsh, Jim Paul, Cristi R. King, Robert Brown Data analysis and interpretation: Sharon Marsh, Jim Paul, Howard L. McLeod, Robert Brown Manuscript writing: Sharon Marsh, Jim Paul, Howard L. McLeod, Robert Brown Final approval of manuscript: Sharon Marsh, Jim Paul, Cristi R. King, Gillian Gifford, Howard L. McLeod, Robert Brown
We thank Tiffany Scott-Horton, Ranjeet Ahluwalia, and Derek Van Booven; and all patients and Scottish Gynaecological Clinical Trials Group investigators who participated in the Scottish Randomised Trial in Ovarian Cancer (SCOTROC1) trial, and the SCOTROC1 data management team at the Beatson Oncology Centre, Glasgow, for all their work supporting this study.
Supported by Grant No. R21 CA113491 (St Louis and Glasgow), Cancer Research UK programme Grant No. C536/A2662 (Glasgow), the Pharmacogenetics Research Network Grant No. U01 GM63340 (St Louis), and the National Cancer Institute/National Institutes of Health. S.M. and J.P. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. American Cancer Society: Statistics for 2007. http://www.cancer.org/docroot/STT/stt_0.asp 2. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003 3. du Bois A, Luck HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320-1329, 2003 4. Vasey PA: Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer. J Clin Oncol 21:136S-144S, 2003 (10 suppl)[CrossRef][Medline] 5. Vasey PA, Jayson GC, Gordon A, et al: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96:1682-1691, 2004 6. Pfisterer J, du Bois A, Wagner U, et al: Docetaxel and carboplatin as first-line chemotherapy in patients with advanced gynecological tumors: A phase I/II trial of the Arbeitsgemeinschaft Gynakologische Onkologie (AGO-OVAR) Ovarian Cancer Study Group. Gynecol Oncol 92:949-956, 2004[CrossRef][Medline] 7. Evans WE, McLeod HL: Pharmacogenomics: Drug disposition, drug targets, and side effects. N Engl J Med 348:538-549, 2003 8. Marsh S: Pharmacogenetics of colorectal cancer. Expert Opin Pharmacother 6:2607-2616, 2005[CrossRef][Medline] 9. Marsh S: Taxane pharmacogenetics. Personalized Med 3:33-43, 2006[CrossRef] 10. Watters JW, McLeod HL: Cancer pharmacogenomics: Current and future applications. Biochim Biophys Acta 1603:99-111, 2003[Medline] 11. Marsh S, Somlo G, Li X, et al: Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. Pharmacogenomics J [epub ahead of print on January 16, 2007] 12. Hahn NM, Marsh S, Fisher W, et al: Hoosier Oncology Group randomized phase II study of docetaxel, vinorelbine, and estramustine in combination in hormone-refractory prostate cancer with pharmacogenetic survival analysis. Clin Cancer Res 12:6094-6099, 2006 13. Nakajima M, Fujiki Y, Kyo S, et al: Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1. J Clin Pharmacol 45:674-682, 2005 14. Gadducci A, Di Cristofano C, Zavaglia M, et al: P53 gene status in patients with advanced serous epithelial ovarian cancer in relation to response to paclitaxel- plus platinum-based chemotherapy and long-term clinical outcome. Anticancer Res 26:687-693, 2006 15. Gréen H, Söderkvist P, Rosenberg P, et al: Mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res 12:854-859, 2006 16. 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Stoehlmacher J, Park DJ, Zhang W, et al: A multivariate analysis of genomic polymorphisms: Prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91:344-354, 2004[Medline] 21. Soyama A, Saito Y, Hanioka N, et al: Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull 24:1427-1430, 2001[CrossRef][Medline] 22. Viguier J, Boige V, Miquel C, et al: ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res 11:6212-6217, 2005 23. Ryu JS, Hong YC, Han HS, et al: Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 44:311-316, 2004[CrossRef][Medline] 24. Isla D, Sarries C, Rosell R, et al: Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 15:1194-1203, 2004 25. Bosch TM, Huitema ADR, Doodeman VD, et al: Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res 12:5786-5793, 2006 26. Sissung TM, Mross K, Steinberg SM, et al: Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893-2896, 2006[CrossRef][Medline] 27. Tran A, Jullien V, Alexandre J, et al: Pharmacokinetics and toxicity of docetaxel: Role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther 79:570-580, 2006[CrossRef][Medline] 28. Kang S, Ju W, Kim JW, et al: Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp Mol Med 38:320-324, 2006[Medline] 29. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The univariate association between genotype and progression-free survival was assessed using the log-rank test. 
