Skip to main content

Advertisement

Log in

Predicting benefit from adjuvant therapy in colon cancer

  • Published:
Current Colorectal Cancer Reports

Abstract

Colorectal cancer is a significant cause of morbidity and mortality despite recent advances in therapy. Given the variety of options that exist for treatment of metastatic colorectal cancer and the fact that resistance to any single approach is common, the need to identify predictors of response to specific therapies is urgent. This need is particularly critical in the adjuvant setting where the stakes are highest in terms of both cure and treatment-associated toxicities. In this manuscript, we review some of the putative markers of prognosis and the effects of treatment that ultimately may play a role in the selection of patients and treatments for the adjuvant therapy of colorectal cancer, with a focus on recent developments and ongoing clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43–66.

    Article  PubMed  Google Scholar 

  2. De Gramont A, Boni C, Navarro M, et al.: Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. J Clin Oncol 2005, 23(16S):3501.

    Google Scholar 

  3. Benson AB, Schrag D, Somerfield MR, et al.: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004, 22:3408–3419.

    Article  PubMed  Google Scholar 

  4. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342.

    Article  PubMed  CAS  Google Scholar 

  5. Giantonio BJ, Catalano PJ, Meropol NJ, et al.: Bevacizumab in combination with oxaliplatin, fluorouracil and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol, In press.

  6. Cunningham D, Humblet Y, Siena S, et al.: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004, 351:337–345.

    Article  PubMed  CAS  Google Scholar 

  7. Peeters M, Van Cutsem E, Siena S, et al.: A phase 3, multicenter, randomized controlled trial (RCT) of panitumumab plus best supportive care (BSC) vs BSC alone in patients (pts) with metastatic colorectal cancer (mCRC) [abstract CP-1]. Presented at the 97th Annual Meeting of the American Association of Cancer Research. Washington, DC; April 1–5, 2006.

  8. Sargent DJ, Conley BA, Allegra C, et al.: Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 2005, 23:2020–2027.

    Article  PubMed  Google Scholar 

  9. Peltomaki P: Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003, 21:1174–1179.

    Article  PubMed  CAS  Google Scholar 

  10. Cortellino S, Turner D, Masciullo V, et al.: The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity. Proc Natl Acad Sci U S A 2003, 100:15071–15076.

    Article  PubMed  CAS  Google Scholar 

  11. Watanabe T, Wu T, Catalano P, et al.: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001, 344:1196–1206.

    Article  PubMed  CAS  Google Scholar 

  12. Ribic CV, Sargent DJ, Moore MJ, et al.: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003, 349:247–257.

    Article  PubMed  CAS  Google Scholar 

  13. Jover R, Zapater P, Castells A, et al.: Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 2006, 55:848–855.

    Article  PubMed  CAS  Google Scholar 

  14. Kim GP, Colangelo LH, Weiand HS, et al.: Prognostic and predictive roles of high-degree microsatellite-instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel project collaborative study. J Clin Oncol 2007, 25:1–6.

    Article  Google Scholar 

  15. Sarli L, Bottarelli L, Bader G, et al.: Association between recurrence of sporadic colorectal cancer, high level of microsatellite instability, and loss of heterozygosity at chromosome 18q. Dis Colon Rectum 2004, 47:1467–1482.

    PubMed  Google Scholar 

  16. Barratt PL, Seymour MT, Stenning SP, et al.: DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002, 360:1381–1391.

    Article  PubMed  CAS  Google Scholar 

  17. Salonga D, Danenberg KD, Johnson M, et al.: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000, 6:1322–1327.

    PubMed  CAS  Google Scholar 

  18. 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, 19:4298–4304.

    PubMed  CAS  Google Scholar 

  19. Popat S, Matakidou A, Houlston RS: Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004, 22:529–536.

    Article  PubMed  CAS  Google Scholar 

  20. Aguiar S, Lopes A, Soares FA, et al.: Prognostic and predictive value of the thymidylate synthase expression in patients with non-metastatic colorectal cancer. Eur J Surg Oncol 2005, 31:863–868.

    Article  PubMed  Google Scholar 

  21. Kornmann M, Schwabe W, Sanders S, et al.: Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: predictors of survival in colorectal cancer patients receiving adjuvant 5-fluorouracil. Clin Canc Res 2003, 9:4116–4124.

    CAS  Google Scholar 

  22. Sinicrope FA, Rego RL, Halling KC, et al.: Thymidylate synthase expression in colon carcinomas with microsatellite instability. Clin Cancer Res 2006, 12:2738–2744.

    Article  PubMed  CAS  Google Scholar 

  23. ClincialTrials.gov: Phase II study of treatment selection based upon tumor thymidylate synthase expression in previously untreated patients with metastatic colorectal cancer (ECOG 4203). ID: NCT00098787. Available at www.clinicaltrials.gov. Accessed February 16, 2007.

  24. Meropol NJ, Gold PJ, Diasio RB, et al.: Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 2006, 25:4069–4077.

    Article  CAS  Google Scholar 

  25. Wang Y, Jatkoe T, Zhang Y, et al.: Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 2004, 22:1564–1571.

    Article  PubMed  CAS  Google Scholar 

  26. Barrier A, Boelle PY, Roser F, et al.: Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol 2006, 24:4685–4691.

    Article  PubMed  CAS  Google Scholar 

  27. Johnston PG, Mulligan K, Kay E, et al.: A genetic signature of relapse in stage II colorectal cancer derived from formalin fixed paraffin embedded tissue (FFPE) using a unique disease specific colorectal array. J Clin Oncol 2006, 24(18S):3519.

    Google Scholar 

  28. Mariadason JM, Arango D, Shi Q, et al.: Gene expression profiling-based prediction of response of colon carcinoma cells to 5-fluorouracil and camptothecin. Cancer Res 2003, 63:8791–8812.

    PubMed  CAS  Google Scholar 

  29. Arango D, Wilson AJ, Shi Q, et al.: Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells. Br J Cancer 2004, 91:1931–1946.

    Article  PubMed  CAS  Google Scholar 

  30. Matsuyama R, Togo S, Shimizu D, et al.: Predicting 5-fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: three-gene expression model predicts clinical response. Int J Cancer 2006, 119:406–413.

    Article  PubMed  CAS  Google Scholar 

  31. Willet CG, Boucher Y, di Tomaso E, et al.: Direct evidence that the VEGF-specific antibody bevacizumab has anti-vascular effects in human rectal cancer. Nat Med 2004, 10:145–147.

    Article  CAS  Google Scholar 

  32. Willet CG, Boucher Y, Duda DG, et al.: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005, 23:8136–8139.

    Article  Google Scholar 

  33. Rugo HS, Dickler MN, Scott JH, et al.: Change in circulating endothelial cells (CEC) and tumor cells (CTC) in patients receiving bevacizumab and erlotinib for metastatic breast cancer predicts stable disease at first evaluation [abstract 525]. J Clin Oncol 2005, 23:525.

    Article  CAS  Google Scholar 

  34. Cristofanilli M, Budd T, Ellis MJ, et al.: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004, 351:781–791.

    Article  PubMed  CAS  Google Scholar 

  35. Cohen SJ, Punt CJ, Iannotti N, et al.: Monitoring patients with metastatic colorectal cancer using circulating tumor cells (CTC) [abstract 342]. Presented at the 2007 Gastrointestinal Cancers Symposium. Orlando, Florida; January 19–21, 2007.

  36. Koopman M, Tissing H, Miller MC, et al.: Changes in circulating tumor cells in advanced colorectal cancer patients undergoing first-line treatment with chemotherapy, bevacizumab and cetuxima [abstract 405]. Presented at the 2007 Gastrointestinal Cancers Symposium. Orlando, Florida; January 19–21, 2007.

  37. Fyfe GA, Hurwitz HI, Fehrenbacher L, et al.: Bevacizumab plus irinotecan/5FU/leucovorin for the treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patient subgroups [abstract 3617]. J Clin Oncol 2004, 22(24S):3617.

    Google Scholar 

  38. 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, 24:217–226.

    Article  PubMed  CAS  Google Scholar 

  39. Tokunga 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, 79:354–359.

    Google Scholar 

  40. Dowlati A, Gray R, Johnson DH, et al.: Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel +/-bevacizumab in advanced non-small cell lung cancer (NSCLC) [abstract 7027]. J Clin Oncol 2006, 24(18S):7027.

    Google Scholar 

  41. Uthoff SM, Duchrow M, Schmidt MH, et al.: VEGF isoforms and mutations in human colorectal cancer. Int J Cancer 2002, 101:32–36.

    Article  PubMed  CAS  Google Scholar 

  42. Motzer RJ, Michaelson MD, Redman BG, et al.: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24:16–24.

    Article  PubMed  CAS  Google Scholar 

  43. Etling J, Bigwood D, Brown-Shimer S, et al.: Biomarkers associated with clinical outcomes in TARGETs, a phase III single-agent, placebo-controlled study of sorafenib in advanced renal cell carcinoma [abstract 2909]. Presented at the 97th Annual Meeting of the American Association of Cancer Research. Washington, DC; April 1–5, 2006.

  44. Wedam SB, Low JA, Yang SX, et al.: Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 2006, 24:769–777.

    Article  PubMed  CAS  Google Scholar 

  45. Bibb JL, Lee S, Lu D, et al.: Increase in systolic blood pressure and decrease in diastolic blood pressure may predict clinical benefit of bevacizumab in patients with metastatic colorectal cancer treated with cytotoxic agents [abstract 450]. Presented at the 2007 Gastrointestinal Cancers Symposium. Orlando, Florida; January 19–21, 2007.

  46. Des Guetz G, Mourad J, Debbabi H, et al.: Mechanism of bevacizumab-induced arterial hypertension: relation with skin capillary rarefaction in patients treated for metastatic colorectal cancer [abstract 431]. Presented at the 2007 Gastrointestinal Cancers Symposium. Orlando, Florida; January 19–21, 2007.

  47. Major P, Trarbach T, Lenz H, et al.: A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients with metastatic colorectal cancer receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival in high LDH patients. J Clin Oncol 2006, 24(18S):3529.

    Google Scholar 

  48. Koukourakis MI, Giatromanolaki A, Sivridis E, et al.: Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the Tumour Angiogenesis Research Group. J Clin Oncol 2006, 24:4301–4308.

    Article  PubMed  CAS  Google Scholar 

  49. Galizia G, Lieto E, Ferraraccio F, et al.: Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol 2006, 13:823–835.

    Article  PubMed  Google Scholar 

  50. Meropol NJ: Epidermal growth factor receptor inhibitors in colorectal cancer: It’s time to get back on target. J Clin Oncol 2005, 23:1791–1793.

    Article  PubMed  CAS  Google Scholar 

  51. Vallbohmer D, Zhang W, Gordon M, et al.: Molecular determinants of cetuximab efficacy. J Clin Oncol 2006, 23:3536–3544.

    Article  CAS  Google Scholar 

  52. Moroni M, Veronese S, Benvenuti S, et al.: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal study: a cohort study. Lancet Oncol 2005, 6:279–286.

    Article  PubMed  CAS  Google Scholar 

  53. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al.: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluorouracil. J Clin Oncol 2006, 24:4914–4921.

    Article  PubMed  CAS  Google Scholar 

  54. 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, 66:3992–3995.

    Article  PubMed  CAS  Google Scholar 

  55. Khambata-Ford S, Garret CR, Clark EA, et al.: Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. AACR Meeting Abstracts 2007, In press.

  56. Berlin J, Van Cutsem E, Peeters M, et al.: Predictive value of skin-toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): a pooled analysis of 5 clinical trials. Proc ASCO 2007, In press.

  57. Van Cutsem E, Humblet Y, Gelderblom H, et al.: Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): preliminary PK and efficacy of a randomized study [abstract 237]. Presented at the 2007 Gastrointestinal Cancers Symposium. Orlando, Florida; January 19–21, 2007.

  58. ClinicalTrials.gov: A randomized phase III study comparing 5FU, leucovorin, and oxaliplatin versus 5FU, leucovorin, oxaliplatin, and bevacizumab in patients with stage II colon cancer at high risk for recurrence to determine prospectively the prognostic value of molecular markers (E5205). ID: NCT00217737. http://www.clinicaltrials.gov. Accessed February 16, 2007.

  59. ClinicalTrials.gov: A phase III clinical trial comparing infusional 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every two weeks with bevacizumab to the same regimen without bevacizumab for the treatment of patients with resected stage II and III carcinoma of the colon (NSABP C-08). ID: NCT00096278. Available at http://www.clinicaltrials.gov. Accessed February 16, 2007.

  60. ClinicalTrials.gov: A randomized phase III trial of oxaliplatin plus 5-fluorouracil/leucovorin with or without cetuximab after curative resection for patients with stage III colon cancer ID: NCT00079274. Available at http://www.clinicaltrials.gov. Accessed February 16, 2007.

  61. ClinicalTrials.gov: Adjuvant treatment of fully resected stage III colon cancer with FOLFOX-4 versus FOLFOX-4 plus cetuximab. ID: NCT00265811. Available at http://www.clinicaltrials.gov. Accessed February 16, 2007.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Neal J. Meropol MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Denlinger, C.S., Meropol, N.J. Predicting benefit from adjuvant therapy in colon cancer. Curr colorectal cancer rep 3, 150–157 (2007). https://doi.org/10.1007/s11888-007-0024-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-007-0024-4

Keywords

Navigation