Influence of Pharmacogenomic Profiling Prior to Pharmaceutical Treatment in Metastatic Colorectal Cancer on Cost Effectiveness
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Metastatic colorectal cancer (mCRC) imposes a substantial health burden on individual patients and society. Furthermore, rising costs in oncology cause a growing concern about reimbursement for innovations in this sector. The promise of pharmacogenomic profiling and related stratified therapies in mCRC is to improve treatment efficacy and potentially save costs. Among other examples, the commonly used epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are only effective in patients with kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type cancers. Hence, the adaptation of predictive biomarker testing might be a valid strategy for healthcare systems worldwide.
This study aims to review the clinical and economic evidence supporting pharmacogenomic profiling prior to the administration of pharmaceutical treatment in mCRC. Moreover, key drivers and areas of uncertainty in cost-effectiveness evaluations are analysed.
A systematic literature review was conducted to identify studies evaluating the cost effectiveness of predictive biomarkers and the result dependent usage of pharmaceutical agents in mCRC.
The application of predictive biomarkers to detect KRAS mutations prior to the administration of EGFR antibodies saved treatment costs and was cost effective in all identified evaluations. However, because of the lack of data regarding cost-effectiveness analyses for predictive biomarker testing, e.g. for first-line treatment, definitive conclusions cannot be stated. Key drivers and areas of uncertainty in current cost-effectiveness analyses are, among others, the consideration of predictive biomarker costs, the characteristics of single predictive biomarkers and the availability of clinical data for the respective pharmaceutical intervention. Especially the cost effectiveness of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mutation analysis prior to irinotecan-based chemotherapy remains unclear.
Pharmacogenomic profiling has the potential to improve the cost effectiveness of pharmaceutical treatment in mCRC. Hence, quantification of the economic impact of stratified medicine as well as cost-effectiveness analyses of pharmacogenomic profiling are becoming more important. Nevertheless, the methods applied in cost-effectiveness evaluations for the usage of predictive biomarkers for patient selection as well as the level of evidence required to determine clinical effectiveness are areas for further research. However, mCRC is one of the first indications in which stratified therapies are used in clinical practice. Thus, clinical and economic experiences could be helpful when adopting pharmacogenomic profiling into clinical practice for other indications.
- Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917. CrossRef
- Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46(4):765–81. CrossRef
- Van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol. 2010;21(Suppl. 5):v93–7. CrossRef
- Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov. 2007;6(4):287–93. CrossRef
- Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. CrossRef
- Schilsky RL. Personalized medicine in oncology: the future is now. Nat Rev Drug Discov. 2010;9(5):363–6. CrossRef
- Ferraldeschi R, Newman WG. Pharmacogenetics and pharmacogenomics: a clinical reality. Ann Clin Biochem. 2011;48(5):410–7. CrossRef
- Adelstein BA, Dobbins TA, Harris CA, et al. A systematic review and meta-analysis of KRAS status as the determinant of response to anti-EGFR antibodies and the impact of partner chemotherapy in metastatic colorectal cancer. Eur J Cancer. 2011;47(9):1343–54. CrossRef
- Jackson DB, Sood AK. Personalized cancer medicine: advances and socio-economic challenges. Nat Rev Clin Oncol. 2011;8(12):735–41. CrossRef
- Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16(8):1311–9. CrossRef
- Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47. CrossRef
- Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240(4):644–57.
- Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80. CrossRef
- Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–83. CrossRef
- Köhne CH, Lenz HJ. Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist. 2009;14(5):478–88. CrossRef
- Edwards MS, Chadda SD, Zhao Z, et al. A systematic review of treatment guidelines for metastatic colorectal cancer. Colorectal Dis. 2012;14(2):31–47. CrossRef
- Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672–80. CrossRef
- Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72. CrossRef
- Jubb AM, Miller KD, Rugo HS, et al. Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res. 2011;17(2):372–81. CrossRef
- Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5. CrossRef
- Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96(8):1166–9. CrossRef
- Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34. CrossRef
- Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65. CrossRef
- Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54. CrossRef
- Jarry A, Masson D, Cassagnau E, et al. Real-time allele-specific amplification for sensitive detection of the BRAF mutation V600E. Mol Cell Probes. 2004;18(5):349–52. CrossRef
- Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–12. CrossRef
- Blank PR, Moch H, Szucs TD, et al. KRAS and BRAF mutation analysis in metastatic colorectal cancer: a cost-effectiveness analysis from a Swiss perspective. Clin Cancer Res. 2011;17(19):6338–46. CrossRef
- 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. 2004;22(8):1382–8. CrossRef
- Hoskins JM, Goldberg RM, Qu P, et al. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99(17):1290–5. CrossRef
- Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32. CrossRef
- Van Kuilenburg AB, Meinsma R, van Gennip AH. Pyrimidine degradation defects and severe 5-fluorouracil toxicity. Nucleosides Nucleotides Nucleic Acids. 2004;23(8–9):1371–5. CrossRef
- Yong WP, Innocenti F, Ratain MJ. The role of pharmacogenetics in cancer therapeutics. Br J Clin Pharmacol. 2006;62(1):35–46. CrossRef
- Soh TI, Yong WP, Innocenti F. Recent progress and clinical importance on pharmacogenetics in cancer therapy. Clin Chem Lab Med. 2011;49(10):1621–32.
- Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924–30. CrossRef
- Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69(5):1851–7. CrossRef
- Etienne MC, Chazal M, Laurent-Puig P, et al. Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses. J Clin Oncol. 2002;20(12):2832–43. CrossRef
- Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 2001;19(23):4298–304.
- Chua W, Kho PS, Moore MM, et al. Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. Crit Rev Oncol Hematol. 2011;79(3):224–50. CrossRef
- Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst. 2009;101(19):1308–24. CrossRef
- Tappenden P, Jones R, Paisley S, et al. The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales. Eur J Cancer. 2007;43(17):2487–94. CrossRef
- Tappenden P, Jones R, Paisley S, et al. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess 2007;11(12):1–iv.
- Starling N, Tilden D, White J, et al. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment. Br J Cancer. 2007;96(2):206–12. CrossRef
- Annemans L, Van Cutsem E, Humblet Y, et al. Cost-effectiveness of cetuximab in combination with irinotecan compared with current care in metastatic colorectal cancer after failure on irinotecan: a Belgian analysis. Acta Clin Belg. 2007;62(6):419–25.
- Shiroiwa T, Fukuda T, Tsutani K. Cost-effectiveness analysis of bevacizumab combined with chemotherapy for the treatment of metastatic colorectal cancer in Japan. Clin Ther. 2007;29(10):2256–67. CrossRef
- Chiang A, Million RP. Personalized medicine in oncology: next generation. Nat Rev Drug Discov. 2011;10(12):895–6. CrossRef
- Fojo T, Grady C. How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst. 2009;101(15):1044–8. CrossRef
- Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12. CrossRef
- Asseburg C, Frank M, Kohne CH, et al. Cost-effectiveness of targeted therapy with cetuximab in patients with K-ras wild-type colorectal cancer presenting with initially unresectable metastases limited to the liver in a German setting. Clin Ther. 2011;33(4):482–97. CrossRef
- Mittmann N, Au HJ, Tu D, et al. Prospective cost-effectiveness analysis of cetuximab in metastatic colorectal cancer: evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 trial. J Natl Cancer Inst. 2009;101(17):1182–92. CrossRef
- Shiroiwa T, Motoo Y, Tsutani K. Cost-effectiveness analysis of KRAS testing and cetuximab as last-line therapy for colorectal cancer. Mol Diagn Ther. 2010;14(6):375–84. CrossRef
- Vijayaraghavan A, Efrusy MB, Goke B, et al. Cost-effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany. Int J Cancer. 2011;131(2):438–45. CrossRef
- Gold HT, Hall MJ, Blinder V, et al. Cost effectiveness of pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 before irinotecan administration for metastatic colorectal cancer. Cancer. 2009;115(17):3858–67. CrossRef
- Obradovic M, Mrhar A, Kos M. Cost-effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer. Pharmacogenomics. 2008;9(5):539–49. CrossRef
- Pichereau S, Le Louran A, Lecomte T, et al. Cost-effectiveness of UGT1A1*28 genotyping in preventing severe neutropenia following FOLFIRI therapy in colorectal cancer. J Pharm Pharm Sci. 2010;13(4):615–25.
- Tol J, Dijkstra JR, Vink-Borger ME, et al. High sensitivity of both sequencing and real-time PCR analysis of KRAS mutations in colorectal cancer tissue. J Cell Mol Med. 2010;14(8):2122–31. CrossRef
- Jimeno A, Messersmith WA, Hirsch FR, et al. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol. 2009;27(7):1130–6. CrossRef
- De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19(3):508–15. CrossRef
- Maughan TS, Adams R, Smith G, et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial. J Clin Oncol. 2010; 28 (15s): abstr 3502.
- Tveit K, Guren B, Glimelius B. Randomized phase III study of 5–fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the Nordic VII study (NCT00145314), by the Nordic colorectal cancer biomodulation group. Ann Oncol. 2010;21(8):vii9.
- Garcia-Saenz JA, Sastre J. Díaz-Rubio García E. Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer. Clin Transl Oncol. 2009;11(11):737–47. CrossRef
- De Roock W, Jonker DJ, Di Nicolantonio F. S et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304(16):1812–20. CrossRef
- Smart A, Martin P, Parker M. Tailored medicine: whom will it fit? The ethics of patient and disease stratification. Bioethics. 2004;18(4):322–42. CrossRef
- Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931–7. CrossRef
- Dahabreh IJ, Terasawa T, Castaldi PJ, et al. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154(1):37–49. CrossRef
- Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–9. CrossRef
- Sculpher M. Subgroups and heterogeneity in cost-effectiveness analysis. Pharmacoeconomics. 2008;26(9):799–806. CrossRef
- Brookes ST, Whitely E, Egger M, et al. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol. 2004;57(3):229–36. CrossRef
- Wang R, Lagakos SW, Ware JH, et al. Statistics in medicine-reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357(21):2189–94. CrossRef
- Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005;365(9454):176–86. CrossRef
- Ortega J, Vigil CE, Chodkiewicz C. Current progress in targeted therapy for colorectal cancer. Cancer Control. 2010;17(1):7–15.
- Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11(1):1–13. CrossRef
- Davis JC, Furstenthal L, Desai AA, et al. The microeconomics of personalized medicine: today’s challenge and tomorrow’s promise. Nat Rev Drug Discov. 2009;8(4):279–86. CrossRef
- Deverka PA. Pharmacogenomics, evidence, and the role of payers. Public Health Genomics. 2009;12(3):149–57. CrossRef
- Cook J, Hunter G, Vernon JA. The future costs, risks and rewards of drug development: the economics of pharmacogenomics. Pharmacoeconomics. 2009;27(5):355–63. CrossRef
- Million RP. Impact of genetic diagnostics on drug development strategy. Nat Rev Drug Discov. 2006;5(6):459–62. CrossRef
- Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375(9725):1525–35. CrossRef
- Influence of Pharmacogenomic Profiling Prior to Pharmaceutical Treatment in Metastatic Colorectal Cancer on Cost Effectiveness
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