Biomarkers in Metastatic Colorectal Cancer

Predicting Prognosis and Therapeutic Response
  • Connie I. Diakos
  • Kellie A. Charles
  • Wei Chua
  • Viive M. Howell
  • Stephen J. ClarkeEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series


Significant advances in chemotherapeutics over the past decade have seen a doubling in the median survival time of patients with metastatic colorectal cancer. However, this comes at the cost of toxicity to the patient and financial burden to the community. Biomarkers to predict disease course and treatment response are therefore of major importance so as to allow for the judicious selection of treatment candidates and agents and doses. This review seeks to summarize the current markers available for the prediction of prognosis and treatment response in metastatic colorectal cancer.


Colorectal cancer Chemotherapy Targeted agents Biomarkers Predictive factor Prognostic factor 

List of Abbreviations




American Society of Clinical Oncology


Body Mass Index


Body Surface Area


C-Reactive Protein




Disease-Free Survival


Deoxyribonucleic Acid


Dihydropyrimidine Dehydrogenase


Epithelial Growth Factor Receptor


Excision Repair Cross-Complementing Group 1


Glasgow Prognosis Score




Hypoxia-Inducible Factor 1α


Kirsten Rat Sarcoma Viral Oncogene


Lactate Dehydrogenase


Monoclonal Antibody


Mitogen-Activated Protein Kinase


Metastatic Colorectal Cancer


Mismatch Repair


Microsatellite Instability


Microsatellite Stability


Methylenetetrahydrofolate Reductase


Nuclear Factor-κβ


Neutrophil to Lymphocyte Ratio


Neuroblastoma Ras


Overall Survival


Platelet-Derived Endothelial Cell Growth Factor


Progression-Free Survival




Platelet to Lymphocyte Ratio


Randomized Controlled Trial


Ribonucleic Acid


Response Rate


Single-Nucleotide Polymorphism


Signal Transducers and Activators of Transcription 3


The Cancer Genome Atlas






Thymidine Phosphorylase


Thymidylate Synthase


Uridine-Diphosphoglucuronosyl Transferase


Vascular Endothelial Growth Factor


Wild Type


Xeroderma Pigmentosum Complementation Group D


X-Ray Repair Cross-Complementing Protein 1



Connie Diakos is supported by a Cancer Institute NSW and Northern Translational Cancer Research Unit (NTCRU) Clinical Research Fellowship. Kellie Charles is supported by a Cancer Institute NSW Career Development Fellowship.


  1. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15:425–30.PubMedCrossRefGoogle Scholar
  2. Agrelo R, Cheng W-H, Setien F, et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci U S A. 2006;103:8822–7.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 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;26:1626–34.PubMedCrossRefGoogle Scholar
  4. Ando Y, Saka H, Ando M, et al. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 2000;60:6921–6.PubMedGoogle Scholar
  5. Andreyev HJN, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–6.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Aparicio T, Jouve J-L, Teillet L, et al. Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001–02 Phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol. 2013;31:1464–70.PubMedCrossRefGoogle Scholar
  7. Baar J, Silverman P, Lyons J, et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res. 2009;15:3583–90.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28:1254–61.PubMedCrossRefGoogle Scholar
  9. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22:1535–46.PubMedCrossRefGoogle Scholar
  10. Braun MS, Richman SD, Quirke P, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol. 2008;26:2690–8.PubMedCrossRefGoogle Scholar
  11. Braun MS, Richman SD, Thompson L, et al. Association of molecular markers with toxicity outcomes in a randomised trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol. 2009;27:5519–28.PubMedCrossRefGoogle Scholar
  12. Capitain O, Boisdron-Celle M, Poirier A-L, et al. The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogenomics J. 2008;8:256–67.PubMedCrossRefGoogle Scholar
  13. Cecchin E, Innocenti F, D’Andrea M, et al. Predictive role of the UGT1A1, UGT1A7, and UGT1a9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol. 2009;27:2457–65.PubMedCrossRefGoogle Scholar
  14. Chambers P, Daniels SH, Thompson LC, et al. Chemotherapy dose reductions in obese patients with colorectal cancer. Ann Oncol. 2011;23:748–53.PubMedCrossRefGoogle Scholar
  15. Charles KA, Rivory LP, Brown SL, et al. Transcriptional repression of hepatic cytochrome P450 3A4 gene in the presence of cancer. Clin Cancer Res. 2006;12:7492–7.PubMedCrossRefGoogle Scholar
  16. Cheng H, Zhang L, Cogdell DE, et al. Circulating plasma miR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS One. 2011;6:e17745.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chibaudel B, Bonnetain F, Tournigand C, et al. Simplified prognostic model in patients with oxaliplatin-based or irinotecan-based first-line chemotherapy for metastatic colorectal cancer: a GERCOR study. Oncologist. 2011;16:1228–38.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chua W, Goldstein D, Lee CK, et al. Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer. Br J Cancer. 2009;101:998–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chua W, Charles KA, Baracos VE, et al. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer. 2011;104:1288–95.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Clarke SJ, Chua W, Moore MM, et al. Use of inflammatory markers to guide cancer treatment. Clin Pharmacol Ther. 2011;90:475–8.PubMedCrossRefGoogle Scholar
  21. Cohen SJ, Punt CJA, Iannotti N, et al. Relationship of circulating tumour cells to tumour response, progress-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213–21.PubMedCrossRefGoogle Scholar
  22. Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–81.PubMedCrossRefGoogle Scholar
  23. De Mattos-Arruda L, Dienstmann R, Tabernero J. Development of molecular biomarkers in individualised treatment of colorectal cancer. Clin Colorectal Cancer. 2011;10:279–89.PubMedCrossRefGoogle Scholar
  24. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.PubMedCrossRefGoogle Scholar
  25. Des Guetz G, Schischmanoff O, Nicolas P, et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890–6.PubMedCrossRefGoogle Scholar
  26. Dignam JJ, Polite BN, Yothers G, et al. Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst. 2006;98:1647–54.PubMedCrossRefGoogle Scholar
  27. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11–22.PubMedCrossRefGoogle Scholar
  28. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score. Cancer. 2012;118:3377–86.PubMedCrossRefGoogle Scholar
  29. Field KM, Kosnider S, Jefford M, et al. Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. J Oncol Practice. 2008;4:108–13.CrossRefGoogle Scholar
  30. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006;24:4085–91.PubMedCrossRefGoogle Scholar
  31. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Society Clinical Practice Guideline. J Clin Oncol. 2012;30:1553–61.PubMedCrossRefGoogle Scholar
  32. Grothey AAG, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled phase III trial. Lancet. 2013;381:303–12.PubMedCrossRefGoogle Scholar
  33. Gusella M, Frigo AC, Bolzonella C, et al. Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer. Br J Cancer. 2009;100:1549–57.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  35. Hecht JR, Trarbach T, Hainsworth JD, et al. Randomised, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29:1997–2003.PubMedCrossRefGoogle Scholar
  36. Hoskins JM, Goldberg RM, Qu P, et al. UGT1A1*28 genotype and irinotecan-induced neutropaenia: dose matters. J Natl Cancer Inst. 2007;99:1290–5.PubMedCrossRefGoogle Scholar
  37. Hurwitz HI, Yi J, Ince W, et al. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. J Clin Oncol. 2009;14:22–8.Google Scholar
  38. Hurwitz HI, Douglas PS, Middleton JP, et al. Analysis of early hypertension and clinical outcome with bevacizumab: results from seven Phase III studies. Oncologist. 2013;18:273–80.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Ince WL, Jubb AM, Holden SN, et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 2005;97:981–9.PubMedCrossRefGoogle Scholar
  40. 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;22:1382–8.PubMedCrossRefGoogle Scholar
  41. Iyer L, King CDW, Peter F, Green MD, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). J Clin Invest. 1998;101:847–54.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2002;2:43–7.PubMedCrossRefGoogle Scholar
  43. Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11:1172–83.PubMedCrossRefGoogle Scholar
  44. Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol. 2006;24:217–27.PubMedCrossRefGoogle Scholar
  45. Kacevska M, Robertson GR, Clarke SJ, et al. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008;4:137–46.PubMedCrossRefGoogle Scholar
  46. 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;359:1757–65.PubMedCrossRefGoogle Scholar
  47. Kawahara H, Watanabe K, Toyama Y, et al. Determination of circulating tumour cells for prediction of recurrent colorectal cancer progression. Hepatogastroenterology. 2012;59:2115–8.PubMedCrossRefGoogle Scholar
  48. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230–7.PubMedCrossRefGoogle Scholar
  49. Kheirelseid EAH, Miller N, Chang KH, et al. Clinical applications of gene expression in colorectal cancer. J Gastroint Oncol. 2013;4:144–57.Google Scholar
  50. Khorana AA, Ryan CK, Cox C, et al. Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with stage II and stage III colon carcinoma. Cancer. 2003;97:960–8.PubMedCrossRefGoogle Scholar
  51. Kim S-H, Kwon H-C, Oh SY, et al. Prognostic value of ERCC1, thymidylate synthase and glutathione S-transferase [pi] for 5-FU/oxaliplatin chemotherapy in advanced colorectal cancer. Am J Clin Oncol. 2009;32:38–43.PubMedCrossRefGoogle Scholar
  52. Koopman M, Krijin N, Richman SD, et al. Abstract 6003: The correlation between Topoisomerase-I (Topo1) expression and outcome of treatment with capecitabine and irinotecan in advanced colorectal cancer (ACC) patients (pts) treated in the CAIRO study of the Dutch Colorectal Cancer Group (DCCG). Eur J Cancer Suppl. 2009a;7:321.CrossRefGoogle Scholar
  53. Koopman M, Venderbosch S, Nagtegaal ID, et al. A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned? Eur J Cancer. 2009b;45:1935–49.PubMedCrossRefGoogle Scholar
  54. Koopman M, Venderbosch S, van Tinteren H, et al. Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study. Eur J Cancer. 2009c;45:1999–2006.PubMedCrossRefGoogle Scholar
  55. Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28:453–9.PubMedCrossRefGoogle Scholar
  56. Kweekel DM, Gelderblom H, Guchelaar H-J. Pharmacology of oxaliplatin and the use of pharmacogenomics to individualise therapy. Cancer Treat Rev. 2005;31:90–105.PubMedCrossRefGoogle Scholar
  57. Kweekel DM, Gelderblom H, Antonini NF, et al. Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients. Eur J Cancer. 2009;45:572–8.PubMedCrossRefGoogle Scholar
  58. 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;27:5924–30.PubMedCrossRefGoogle Scholar
  59. Le Morvan V, Smith D, Laurand A, et al. Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome. Pharmacogenomics. 2007;8:1693–703.PubMedCrossRefGoogle Scholar
  60. Lecomte T, Landi B, Beaune P, et al. Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res. 2006;12:3050–6.PubMedCrossRefGoogle Scholar
  61. Lecomte T, Ceze N, Dorval E, et al. Circulating free tumour DNA and colorectal cancer. Gastroenterol Clin Biol. 2010;34:662–81.PubMedCrossRefGoogle Scholar
  62. Limsui D, Vierkant RA, Tillmans LS, et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst. 2010;102:1012–22.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008;9:962–72.PubMedCrossRefGoogle Scholar
  64. Liu C-Y, Chen P-M, Chiou T-J, et al. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer. 2008;112:1932–40.PubMedCrossRefGoogle Scholar
  65. Manley PW, Martiny-Brown G, Schlaeppi J-M, et al. Therapies directed at vascular endothelial growth factor. Expert Opin Investig Drugs. 2002;11:1715–36.PubMedCrossRefGoogle Scholar
  66. Mao C, Huang Y-F, Yang Z-Y, et al. KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer. A systematic review and meta-analysis. Cancer. 2013;119:714–21.PubMedCrossRefGoogle Scholar
  67. Markman B, Ramos FJ, Capdevila J, et al. EGFR and KRAS in colorectal cancer. Adv Clin Chem. 2010;51:71–119.PubMedCrossRefGoogle Scholar
  68. Martinez ME. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. In: Tumour prevention and genetics III. Springer, Berlin Heidelberg; 2005. pp. 177–211.Google Scholar
  69. Matsumura M, Chiba Y, Lu C, et al. Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression correlated with tumour angiogenesis and macrophage infiltration in colorectal cancer. Cancer Lett. 1998;128:55–63.PubMedCrossRefGoogle Scholar
  70. Matsuura T, Kuratate I, Teramachi K, et al. Thymidylate phosphorylase expression is associated with both increase of intratumoural microvessels and decrease of apoptosis in human colorectal carcinomas. Cancer Res. 1999;59:5037–40.PubMedGoogle Scholar
  71. McCleary NJ, Niedzwiecki D, Hollis D, et al. Impact of smoking on patients with stage III colon cancer. Cancer. 2010;116:957–66.PubMedPubMedCentralCrossRefGoogle Scholar
  72. McHugh SM, O’Donnell J, Gillen P. Genomic and oncoproteomic advances in detection and treatment of colorectal cancer. World J Surg Oncol. 2009;7:36–44.PubMedPubMedCentralCrossRefGoogle Scholar
  73. McMillan DC. The systemic inflammation-based Glasgow Prognosis Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39:534–40.PubMedCrossRefGoogle Scholar
  74. Meropol NJ, Gold PJ, Diasio RB, et al. Thymidylate phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol. 2006;24:4069–77.PubMedCrossRefGoogle Scholar
  75. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24:3527–34.PubMedCrossRefGoogle Scholar
  76. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol. 2008;26:4109–15.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Mitry E, Venat-Bouvet L, Phelip J, et al. Randomised phase III in elderly patients comparing LV5FU2 with or without irinotecan for 1st-line treatment of metastatic colorectal cancer (FFCD 2001–02). Ann Oncol. 2012; 23: ix181. Abstract 529PD.Google Scholar
  78. Moehler M, Frings C, Mueller A, et al. VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab. World J Gastroenterol. 2008;14:4156–67.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Moore MM, Chua W, Charles KA, et al. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther. 2010;87:504–8.PubMedCrossRefGoogle Scholar
  80. Moreno V, Gemignani F, Landi S, et al. Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin Cancer Res. 2006;12:2101–8.PubMedCrossRefGoogle Scholar
  81. Nakajima G, Hayashi K, Xi Y, et al. Non-coding microRNAs hsa-let-7 g and hsa-miR-181b are associated with chemoresponse to S-1 in colon cancer. Cancer Genomics Proteomics. 2006;3:317–24.PubMedPubMedCentralGoogle Scholar
  82. Neki K, Kawahara H, Watanabe K, et al. Usefulness of circulating tumour cells after preliminary chemotherapy for prediction of response to further anticancer therapy in patients with initially unresectable metastatic colorectal cancer. Anticancer Res. 2013;33:1769–72.PubMedGoogle Scholar
  83. Network TCGA. Comprehensive molecular characterisation of human colon and rectal cancer. Nature. 2012;487:330–7.CrossRefGoogle Scholar
  84. Ogino S, Meyerhardt JA, Kawasaki T, et al. CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch. 2007;450:529–37.PubMedCrossRefGoogle Scholar
  85. Paradiso A, Xu J, Mangia A, et al. Topoisomerase-1, thymidylate synthase primary tumour expression and clinical efficacy of 5-FU/CPT-11 chemotherapy in advanced colorectal cancer patients. Int J Cancer. 2004;111:252–8.PubMedCrossRefGoogle Scholar
  86. Park DJ, Stoehlmacher J, Zhang W, et al. A Xeroderma Pigmentosum Group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res. 2001;61:8654–8.PubMedGoogle Scholar
  87. Pentheroudakis G, Kotoula V, De Roock W, et al. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer. 2013;13:49.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2004;22:529–36.PubMedCrossRefGoogle Scholar
  89. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRefGoogle Scholar
  90. Popat S, Chen Z, Zhao D, et al. A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer. Ann Oncol. 2006;17:1810–7.PubMedCrossRefGoogle Scholar
  91. Pu X-x, G-l H, H-q G, et al. Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression. J Gastroenterol Hepatol. 2010;25:1674–80.PubMedCrossRefGoogle Scholar
  92. Rizzo S, Bronte G, Fanale D, et al. Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy? Cancer Treat Rev. 2010;36:S56–61.PubMedCrossRefGoogle Scholar
  93. Robertson GR, Liddle C, Clarke SJ. Inflammation and altered drug clearance in cancer: transcriptional repression of a human CYP3A4 transgene in tumour-bearing mice. Clin Pharmacol Ther. 2008;83:804–7.CrossRefGoogle Scholar
  94. Roth AD, Yan P, Dietrich D, et al. Is UGT1A1*28 homozygosity the strongest predictor for severe hematotoxicity in patients treated with 5-fluorouracil (5-FU)-irinotecan (IRI)? Results of the PETACC 3 – EORTC 40993 -SAKK 60/00 trial comparing IRI/5-FU/folinic acid (FA) to 5-FU/FA in stage II- III colon cancer (COC) patients. J Clin Oncol. 2008; 26. Abstract 4036.Google Scholar
  95. Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012;104:1635–46.PubMedCrossRefGoogle Scholar
  96. Roxburgh CSD, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 2010;6:149–63.PubMedCrossRefGoogle Scholar
  97. Roxburgh CS, McMillan DC. The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer. Cancer Treat Rev. 2012;38:451–66.PubMedCrossRefGoogle Scholar
  98. Ruzzo A, Graziano F, Loupakis F, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol. 2007;25:1247–54.PubMedCrossRefGoogle Scholar
  99. Samowitz WS, Sweeney C, Herrick J, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65:6063–9.PubMedCrossRefGoogle Scholar
  100. Sanoff HK, Sargent DJ, Green EM, et al. Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomised controlled clinical trial. J Clin Oncol. 2009;27:4109–15.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345:1091–7.PubMedCrossRefGoogle Scholar
  102. 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;69:1851–7.PubMedCrossRefGoogle Scholar
  103. Sawai H, Yasuda A, Ochi N, et al. Loss of PTEN expression is associated with colorectal cancer liver metastases and poor patient survival. BMC Gastroenterol. 2008;8:56.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Schetter AJ, Leung SY, Sohn JJ, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 2008;299:425–36.PubMedPubMedCentralGoogle Scholar
  105. Schwab M, Zanger UM, Mars C, et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008;26:2131–8.PubMedCrossRefGoogle Scholar
  106. Segalov E, Wilson K, Gebski V, et al. ICE CREAM: irinotecan cetuximab evaluation and the cetuximab response evaluation among patients with G13D mutation. Abstrct TPS3649. J Clin Oncol. 2013; 31.Google Scholar
  107. Seymour MT, Brown SR, Richman S, et al. Addition of panitumumab to irinotecan: results of PICCOLO, a randomised controlled trial in advanced colorectal cancer (aCRC). J Clin Oncol. 2011a;29:a3523.CrossRefGoogle Scholar
  108. Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. Lancet. 2011b;377:1749–59.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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;19:4298–304.PubMedGoogle Scholar
  110. Soong R, Shah N, Salto-Tellez M, et al. Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol. 2008;19:915–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Stoehlmacher J, Park DJ, Zhang W, et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphisms and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst. 2002;94:936–42.PubMedCrossRefGoogle Scholar
  112. Stoehlmacher J, Park DJ, Zhang W, et al. A multivariate analysis of genome polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer. 2004;91:344–54.PubMedPubMedCentralGoogle Scholar
  113. Suh KW, Kim JH, Kim DY, et al. Which gene is a dominant predictor of response during FOLFOX chemotherapy for the treatment of metastatic colorectal cancer, the MTHFR or XRCC1 gene? Ann Surg Oncol. 2006;13:1379–85.PubMedCrossRefGoogle Scholar
  114. Syrigos KN, Karapanagiotou E, Boura P, et al. Bevacizumab-induced hypertension. Pathogenesis and management. BioDrugs. 2011;25:159–69.PubMedCrossRefGoogle Scholar
  115. Tabernero J, Cervantes A, Rivera F, et al. Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study. J Clin Oncol. 2010;28:1181–9.PubMedCrossRefGoogle Scholar
  116. Tokunaga T, Nakamura M, Oshika Y, et al. Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer. Br J Cancer. 1999;79:354–9.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–32.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Vallbohmer D, Yang D, Kuramochi H, et al. DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol. 2007;31:413–8.PubMedGoogle Scholar
  119. Van Cutsem E, Kohne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.PubMedCrossRefGoogle Scholar
  120. Van Cutsem E, Bajetta E, Valle J, et al. Randomised, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011a;29:2004–10.PubMedCrossRefGoogle Scholar
  121. Van Cutsem E, Kohne C-H, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumour KRAS and BRAF mutation status. J Clin Oncol. 2011b;29:2011–9.PubMedCrossRefGoogle Scholar
  122. Van Cutsem E, Tabernero J, Lakomy R, et al. Additional of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomised trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506.PubMedCrossRefGoogle Scholar
  123. van Kuilenburg ABP, Haasjes J, Richel DJ, et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000;6:4705–12.PubMedGoogle Scholar
  124. van Rijnsoever M, Elsaleh H, Joseph D, et al. CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res. 2003;9:2898–903.PubMedGoogle Scholar
  125. Van Schaeybroeck S, Allen WL, Turkington RC, et al. Implementing prognostic and predictive biomarkers in CRC clinical trials. Nat Rev Clin Oncol. 2011;8:222–32.PubMedCrossRefGoogle Scholar
  126. Viguier J, Boige V, Miquel C, et al. ERCC1 codon 118 polymorphism is a predictive factor for the tumour response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res. 2005;11:6212–7.PubMedCrossRefGoogle Scholar
  127. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer – the stable evidence. Nat Rev Clin Oncol. 2010;7:153–62.PubMedPubMedCentralCrossRefGoogle Scholar
  128. Wei X, McLeod HL, McMurrough J, et al. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest. 1996;98:610–5.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Weickhardt A, Williams D, Lee C, et al. Vascular endothelial growth factors (VEGF) and VEGF receptor expression as predictive biomarkers for benefit with bevacizumab in metastatic colorectal cancer (mCRC): analysis of the phase III MAX study. J Clin Oncol. 2011; 29. Abstract 3531.Google Scholar
  130. Weikhardt AJ, Tebbutt NC, Mariadason JM. Strategies for overcoming inherent and acquired resistance to EGFR inhibitors by targeting downstream effectors in the RAS/PI3K pathway. Curr Cancer Drug Targets. 2010;10:824–33.CrossRefGoogle Scholar
  131. Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020–6.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Connie I. Diakos
    • 1
  • Kellie A. Charles
    • 2
  • Wei Chua
    • 3
  • Viive M. Howell
    • 1
  • Stephen J. Clarke
    • 1
    Email author
  1. 1.Kolling Institute of Medical ResearchRoyal North Shore Hospital, University of SydneySt LeonardsAustralia
  2. 2.School of Medical Sciences (Pharmacology)Sydney Medical School, University of SydneySt LeonardsAustralia
  3. 3.Department of Medical OncologyLiverpool HospitalLiverpoolAustralia

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