Skip to main content

Advertisement

Log in

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.

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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Garcia-Alfonso P, Salazar R, Garcia-Foncillas J, Musulen E, Garcia-Carbonero R, Paya A, et al. Guidelines for biomarker testing in colorectal carcinoma (CRC): a national consensus of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM). Clin Transl Oncol. 2012;14:726–39.

    Article  CAS  PubMed  Google Scholar 

  2. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.

    Article  CAS  PubMed  Google Scholar 

  3. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1986;89:2S–3S.

    Article  CAS  PubMed  Google Scholar 

  4. Gray RG, Barnwell J, Hills R, McConkey C, Williams N, Kerr D. QUASAR: a randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. ASCO Meeting Abstracts. 2004;22:3501.

  5. Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner FL, et al. Validation study of a quantitative multigene reverse transcriptase polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29:4611–9.

    Article  PubMed  Google Scholar 

  6. Venook AP, Niedzwiecki D, Lopatin M, Ye X, Lee M, Friedman PN, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775–81.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Yothers G, O’Connell MJ, Lee M, Lopatin M, Clark-Langone KM, Millward C, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31:4512–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Tabernero J, Moreno V, Rosenberg R, Nitsche U, Bachleitner-Hofmann T, Lanza G, et al. Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of patients with stage II colon cancer. ASCO Meeting Abstracts. 2012;30:384.

  9. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds). AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

  10. Washington MK, Berlin J, Branton P, Burgart LJ, Carter DK, Fitzgibbons PL, et al. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Based on AJCC/UICC TNM. 7th edn; 2013.

  11. Lo DS, Pollett A, Siu LL, Gallinger S, Burkes RL. Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer. Cancer. 2008;112:50–4.

    Article  PubMed  Google Scholar 

  12. Puppa G, Maisonneuve P, Sonzogni A, Masullo M, Capelli P, Chilosi M, et al. Pathological assessment of pericolonic tumor deposits in advanced colonic carcinoma: relevance to prognosis and tumor staging. Mod Pathol. 2007;20:843–55.

    Article  PubMed  Google Scholar 

  13. Fitzgibbons PL, Bradley LA, Fatheree LA, Alsabeh R, Fulton RS, Goldsmith JD, et al. Principles of analytic validation of immunohistochemical assays: guideline from the college of american pathologists pathology and laboratory quality center. Arch Pathol Lab Med. 2014;138:1432–43.

  14. Schrijver I, Aziz N, Jennings LJ, Richards CS, Voelkerding KV, Weck KE. Methods-based proficiency testing in molecular genetic pathology. J Mol Diagn. 2014;16:283–7.

    Article  PubMed  Google Scholar 

  15. Bartley AN, Hamilton SR, Alsabeh R, Ambinder EP, Berman M, Collins E, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. Arch Pathol Lab Med. 2014;138:166–70.

    Article  PubMed  Google Scholar 

  16. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Greenson JK, Bonner JD, Ben-Yzhak O, Cohen HI, Miselevich I, Resnick MB, et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563–70.

    Article  PubMed  Google Scholar 

  18. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240–7.

  19. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.

    Article  CAS  PubMed  Google Scholar 

  20. Tejpar S, Lenz H-J, Kohne C-H, Heinemann V, Ciardiello F, Esser R, et al. Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: New results from the OPUS study. ASCO Meeting Abstracts. 2014;32:LBA444.

  21. Ciardiello F, Lenz H-J, Kohne C-H, Heinemann V, Tejpar S, Melezinek I, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. ASCO Meeting Abstracts. 2014;32:3506.

  22. Hernández-Losa J, Sanz J, Landolfi S, López-Ríos F, Palacios J, Bautista MD, et al. Recomendaciones para la determinación de mutaciones de K-RAS en cáncer de colon. Rev Esp Patol. 2012;45:76–85.

    Google Scholar 

  23. Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 2012;72:4875–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328–37.

    Article  CAS  PubMed  Google Scholar 

  25. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.

    Article  CAS  PubMed  Google Scholar 

  26. Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, et al. Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat. 2014;35:329–40.

    Article  CAS  PubMed  Google Scholar 

  27. Bossard C, Kury S, Jamet P, Senellart H, Airaud F, Ramee JF, et al. Delineation of the infrequent mosaicism of KRAS mutational status in metastatic colorectal adenocarcinomas. J Clin Pathol. 2012;65:466–9.

    Article  CAS  PubMed  Google Scholar 

  28. Perez K, Walsh R, Brilliant K, Noble L, Yakirevich E, Breese V, et al. Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing WAVE technology. Exp Mol Pathol. 2013;95:74–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Baas JM, Krens LL, Guchelaar HJ, Morreau H, Gelderblom H. Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review. Oncologist. 2011;16:1239–49.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Lamy A, Blanchard F, Le Pessot F, Sesboue R, Di Fiore F, Bossut J, et al. Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls. Mod Pathol. 2011;24:1090–100.

    Article  CAS  PubMed  Google Scholar 

  31. Improta G, Zupa A, Possidente L, Tartarone A, Pedicini P, Nappi A, et al. Coexistence of two different mutations in codon 12 of the Kras gene in colorectal cancer: Report of a case supporting the concept of tumoral heterogeneity. Oncol Lett. 2013;5:1741–3.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Engel KB, Moore HM. Effects of preanalytical variables on the detection of proteins by immunohistochemistry in formalin-fixed, paraffin-embedded tissue. Arch Pathol Lab Med. 2011;135:537–43.

    PubMed  Google Scholar 

  33. Wester K, Wahlund E, Sundstrom C, Ranefall P, Bengtsson E, Russell PJ, et al. Paraffin section storage and immunohistochemistry. Effects of time, temperature, fixation, and retrieval protocol with emphasis on p53 protein and MIB1 antigen. Appl Immunohistochem Mol Morphol. 2000;8:61–70.

    CAS  PubMed  Google Scholar 

  34. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3:658–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:221–3.

    Article  CAS  PubMed  Google Scholar 

  38. Vilar E, Tabernero J. Cancer: pinprick diagnostics. Nature. 2012;486:482–3.

    Article  CAS  PubMed  Google Scholar 

  39. Santini D, Vincenzi B, Addeo R, Garufi C, Masi G, Scartozzi M, et al. Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Ann Oncol. 2012;23:2313–8.

    Article  CAS  PubMed  Google Scholar 

  40. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.

  41. Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20:430–5.

    Article  CAS  PubMed  Google Scholar 

  42. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3.

    Article  CAS  PubMed  Google Scholar 

  44. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 2012;72:3228–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, 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.

    Article  PubMed  Google Scholar 

  46. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261–70.

    Article  PubMed  Google Scholar 

  47. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466–74.

    Article  CAS  PubMed  Google Scholar 

  48. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, 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.

    Article  CAS  PubMed  Google Scholar 

  49. Knijn N, Mekenkamp LJ, Klomp M, Vink-Borger ME, Tol J, Teerenstra S, et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer. 2011;104:1020–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, 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;27:5931–7.

    Article  CAS  PubMed  Google Scholar 

  51. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.

    Article  PubMed  Google Scholar 

  52. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.

    Article  CAS  PubMed  Google Scholar 

  53. Peeters M, Oliner KS, Parker A, Siena S, Van Cutsem E, Huang J, et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res. 2013;19:1902–12.

    Article  CAS  PubMed  Google Scholar 

  54. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, 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.

    Article  CAS  PubMed  Google Scholar 

  55. Spindler KL, Andersen RF, Jensen LH, Ploen J, Jakobsen A. EGF61A>G polymorphism as predictive marker of clinical outcome to first-line capecitabine and oxaliplatin in metastatic colorectal cancer. Ann Oncol. 2010;21:535–9.

    Article  PubMed  Google Scholar 

  56. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005;6:279–86.

    Article  CAS  PubMed  Google Scholar 

  57. Rodriguez J, Zarate R, Bandres E, Boni V, Hernandez A, Sola JJ, et al. Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur J Cancer. 2012;48:1774–80.

    Article  CAS  PubMed  Google Scholar 

  58. Stintzing S, Jung A, Rossius L, Modest DP, Fischer von Weikersthal L, Decker T, et al. Mutations within the EGFR signaling pathway: influence on efficacy in FIRE-3—a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. J Clin Oncol. 2014;32:abstract 445.

  59. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, 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.

    Article  CAS  PubMed  Google Scholar 

  60. Negri FV, Bozzetti C, Lagrasta CA, Crafa P, Bonasoni MP, Camisa R, et al. PTEN status in advanced colorectal cancer treated with cetuximab. Br J Cancer. 2010;102:162–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Diehl F, Li M, He Y, Kinzler KW, Vogelstein B, Dressman D. BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions. Nat Methods. 2006;3:551–9.

    Article  CAS  PubMed  Google Scholar 

  62. Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci USA. 1999;96:9236–9241.

  63. Li J, Wang L, Mamon H, Kulke MH, Berbeco R, Makrigiorgos GM. Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing. Nat Med. 2008;14:579–84.

    Article  CAS  PubMed  Google Scholar 

  64. Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007;39:347–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful for the editorial assistance of Ana Martín of HealthCo (Madrid, Spain) in the production of this manuscript. SEOM and SEAP are grateful for financial support for this project in the form of unrestricted grants from Merck, Sanofi and Roche.

Conflict of interest

The authors declare that, when writing and revising the text, they did not know the names of the pharmaceutical companies that provided financial support for this project, so this support has not influenced the content of this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. García-Alfonso.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

García-Alfonso, P., García-Foncillas, J., Salazar, R. et al. Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. Clin Transl Oncol 17, 264–273 (2015). https://doi.org/10.1007/s12094-014-1252-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-014-1252-0

Keywords

Navigation