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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)

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Abstract

This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and the Spanish Society of Medical Oncology, makes diagnostic and treatment recommendations for the management of patients with hereditary, localised and advanced CRC based on the current scientific evidence on biomarker use. This consensus statement thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the currently available data on this subject, this expert group recommends testing for microsatellite instability (MSI) in patients with localised CRC, as this is a strong predictive factor for deciding on adjuvant treatment. However, although the ColoPrint® and Oncotype Dx® gene expression signatures have been shown to have prognostic value, no consensus yet exists concerning their use in clinical practice. For advanced CRC, it is essential to test for KRAS mutation status before administering an anti-EGFR treatment, such as cetuximab or panitumumab. However, testing for other biomarkers, such as BRAF, EGFR, PI3K and PTEN mutations, should not be done routinely, because this does not influence treatment planning at the present time. Other important issues addressed include organisational requirements and the quality controls needed for proper testing of these biomarkers as well as the legal implications to be borne in mind when testing some biomarkers.

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References

  1. American Gastroenterological Association (2001) American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology 121:195–197

    Google Scholar 

  2. Vasen HF, Watson P, Mecklin JP et al (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456

    Article  PubMed  CAS  Google Scholar 

  3. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932

    Article  PubMed  CAS  Google Scholar 

  4. Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  PubMed  CAS  Google Scholar 

  5. Balmana J, Stockwell DH, Steyerberg EW et al (2006) Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296:1469–1478

    Article  PubMed  CAS  Google Scholar 

  6. Popat S, Houlston RS (2005) A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 41:2060–2070

    Article  PubMed  CAS  Google Scholar 

  7. Shibata D, Reale MA, Lavin P et al (1996) The DCC protein and prognosis in colorectal cancer. N Engl J Med 335:1727–1732

    Article  PubMed  CAS  Google Scholar 

  8. Alazzouzi H, Alhopuro P, Salovaara R et al (2005) SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res 11:2606–2611

    Article  PubMed  CAS  Google Scholar 

  9. Roth AD, Tejpar S, Yan P et al (2009) Stage-specific prognostic value of molecular markers in colon cancer: results of the translational study on the PETACC 3–EORTC 40993–SAKK 60-00 trial. ASCO Meeting Abstracts 27:4002

    Google Scholar 

  10. Ogino S, Nosho K, Kirkner GJ et al (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27:1477–1484

    Article  PubMed  CAS  Google Scholar 

  11. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618

    Article  PubMed  CAS  Google Scholar 

  12. Sargent DJ, Marsoni S, Monges G et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219–3226

    Article  PubMed  CAS  Google Scholar 

  13. Hutchins G, Southward K, Handley K et al (2011) Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29:1261–1270

    Article  PubMed  Google Scholar 

  14. Sinicrope FA, Foster NR, Thibodeau SN et al (2011) DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 103:863–875

    Article  PubMed  CAS  Google Scholar 

  15. Tejpar S, Saridaki Z, Delorenzi M et al (2011) Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. J Natl Cancer Inst 103:841–844

    Article  PubMed  Google Scholar 

  16. Bertucci F, Salas S, Eysteries S et al (2004) Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters. Oncogene 23:1377–1391

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Komuro K, Tada M, Tamoto E et al (2005) Right- and left-sided colorectal cancers display distinct expression profiles and the anatomical stratification allows a high accuracy prediction of lymph node metastasis. J Surg Res 124:216–224

    Article  PubMed  Google Scholar 

  19. Eschrich S, Yang I, Bloom G et al (2005) Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 23:3526–3535

    Article  PubMed  CAS  Google Scholar 

  20. Croner RS, Peters A, Brueckl WM et al (2005) Microarray versus conventional prediction of lymph node metastasis in colorectal carcinoma. Cancer 104:395–404

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Barrier A, Roser F, Boelle PY et al (2007) Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling. Oncogene 26:2642–2648

    Article  PubMed  CAS  Google Scholar 

  23. Lin YH, Friederichs J, Black MA et al (2007) Multiple gene expression classifiers from different array platforms predict poor prognosis of colorectal cancer. Clin Cancer Res 13:498–507

    Article  PubMed  CAS  Google Scholar 

  24. Vendrell E, Ribas M, Valls J et al (2007) Genomic and transcriptomic prognostic factors in R0 Dukes B and C colorectal cancer patients. Int J Oncol 30:1099–1107

    PubMed  CAS  Google Scholar 

  25. O’Connell MJ, Lavery I, Yothers G et al (2010) Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 28:3937–3944

    Article  PubMed  Google Scholar 

  26. Gray RG, Quirke P, Handley K et al (2011) 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 29:4611–4619

    Article  PubMed  Google Scholar 

  27. Glas AM, Roepman P, Salazar R et al (2009) Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients. ASCO Meet Abstr 27:4036

    Google Scholar 

  28. Salazar R, Roepman P, Capella G et al (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29:17–24

    Article  PubMed  Google Scholar 

  29. Rosenberg R, Maak M, Simon I et al Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients. ASCO Meeting Abstracts 29:358

  30. Kennedy RD, Bylesjo M, Kerr P et al (2011) Development and independent validation of a prognostic assay for stage ii colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol 29:4620–4626

    Article  PubMed  Google Scholar 

  31. Roth AD, Tejpar S, Delorenzi M et al (2010) 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 28:466–474

    Article  PubMed  CAS  Google Scholar 

  32. Van Cutsem E, Kohne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417

    Article  PubMed  Google Scholar 

  33. Van Cutsem E, Kohne CH, Lang I et al (2011) 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 29:2011–2019

    Article  PubMed  Google Scholar 

  34. Bokemeyer C, Bondarenko I, Hartmann JT et al (2011) Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 22:1535–1546

    Article  PubMed  CAS  Google Scholar 

  35. Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671

    Article  PubMed  CAS  Google Scholar 

  36. Folprecht G, Gruenberger T, Bechstein WO et al (2010) Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 11:38–47

    Article  PubMed  CAS  Google Scholar 

  37. Maughan TS, Adams RA, Smith CG et al (2011) Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377:2103–2114

    Article  PubMed  CAS  Google Scholar 

  38. De Roock W, Claes B, Bernasconi D et al (2010) 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 11:753–762

    Article  PubMed  Google Scholar 

  39. De Roock W, Jonker DJ, Di Nicolantonio F et al (2010) Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812–1820

    Article  PubMed  Google Scholar 

  40. Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705

    Article  PubMed  CAS  Google Scholar 

  41. Douillard J, Siena S, Cassidy J et al (2011) Final results from PRIME: Randomized phase III study of panitumumab (pmab) with FOLFOX4 for first line metastatic colorectal cancer (mCRC). ASCO Meet Abstr 29:3510

    Google Scholar 

  42. Knijn N, Mekenkamp LJ, Klomp M et al (2011) KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer 104:1020–1026

    Article  PubMed  CAS  Google Scholar 

  43. Richman SD, Seymour MT, Chambers P et al (2009) 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 27:5931–5937

    Article  PubMed  CAS  Google Scholar 

  44. Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237

    Article  PubMed  CAS  Google Scholar 

  45. Spindler KL, Andersen RF, Jensen LH et al (2010) EGF61A>G polymorphism as predictive marker of clinical outcome to first-line capecitabine and oxaliplatin in metastatic colorectal cancer. Ann Oncol 21:535–539

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Laurent-Puig P, Cayre A, Manceau G et al (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930

    Article  PubMed  CAS  Google Scholar 

  48. Negri FV, Bozzetti C, Lagrasta CA et al (2010) PTEN status in advanced colorectal cancer treated with cetuximab. Br J Cancer 102:162–164

    Article  PubMed  CAS  Google Scholar 

  49. (2009) Libro Blanco de la Anatomía Patológica en España. Recursos, calidad e impacto de la Patología en España., 2nd edn. ISBN 13:978-84-692-1562-3

  50. Bosman FT, Organization WH, Cancer IAfRo (2010) WHO classification of tumours of the digestive system. In: Fred T, Bosman et al. (eds) 4th edn. IARC Press, Lyon

  51. Balschun K, Haag J, Wenke AK et al (2011) KRAS, NRAS, PIK3CA exon 20, and BRAF genotypes in synchronous and metachronous primary colorectal cancers diagnostic and therapeutic implications. J Mol Diagn 13:436–445

    Article  PubMed  CAS  Google Scholar 

  52. Bouchahda M, Karaboue A, Saffroy R et al (2010) Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis. Cancer Chemother Pharmacol 66:605–609

    Article  PubMed  CAS  Google Scholar 

  53. Italiano A, Hostein I, Soubeyran I et al (2010) KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications. Ann Surg Oncol 17:1429–1434

    Article  PubMed  Google Scholar 

  54. Mariani P, Lae M, Degeorges A et al (2010) Concordant analysis of KRAS status in primary colon carcinoma and matched metastasis. Anticancer Res 30:4229–4235

    PubMed  CAS  Google Scholar 

  55. Hernández-Losa J, Sanz J, Landolfi S et al (2012) Recomendaciones para la determinación de mutaciones de K-RAS en cáncer de colon. Rev Esp Patol (In press)

  56. Goldstein NS, Armin M (2001) Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 92:1331–1346

    Article  PubMed  CAS  Google Scholar 

  57. Hemmings C, Broomfield A, Bean E et al (2009) Immunohistochemical expression of EGFR in colorectal carcinoma correlates with high but not low level gene amplification, as demonstrated by CISH. Pathology 41:356–360

    Article  PubMed  CAS  Google Scholar 

  58. Rego RL, Foster NR, Smyrk TC et al (2010) Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status. Br J Cancer 102:165–172

    Article  PubMed  CAS  Google Scholar 

  59. de Castro-Carpeno J, Belda-Iniesta C, Casado Saenz E et al (2008) EGFR and colon cancer: a clinical view. Clin Transl Oncol 10:6–13

    Article  PubMed  Google Scholar 

  60. Frattini M, Saletti P, Romagnani E et al (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145

    Article  PubMed  CAS  Google Scholar 

  61. Jhawer M, Goel S, Wilson AJ et al (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961

    Article  PubMed  CAS  Google Scholar 

  62. Perrone F, Lampis A, Orsenigo M et al (2009) PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 20:84–90

    Article  PubMed  CAS  Google Scholar 

  63. Jang KS, Song YS, Jang SH et al (2010) Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma. Histopathology 56:229–239

    Article  PubMed  Google Scholar 

  64. Hsu CP, Kao TY, Chang WL et al (2011) Clinical significance of tumor suppressor PTEN in colorectal carcinoma. Eur J Surg Oncol 37:140–147

    Article  PubMed  CAS  Google Scholar 

  65. Sangale Z, Prass C, Carlson A et al (2011) A robust immunohistochemical assay for detecting PTEN expression in human tumors. Appl Immunohistochem Mol Morphol 19:173–183

    Article  PubMed  CAS  Google Scholar 

  66. Mao C, Yang ZY, Hu XF et al (2011) PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol 23(6):1518–1525

    Google Scholar 

  67. Shtilbans V, Wu M, Burstein DE (2008) Current overview of the role of Akt in cancer studies via applied immunohistochemistry. Ann Diagn Pathol 12:153–160

    Article  PubMed  Google Scholar 

  68. Washington MK, Berlin J, Branton P et al (2009) Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. Arch Pathol Lab Med 133:1539–1551

    PubMed  Google Scholar 

  69. Sanjuan X, Salas A, Lloreta J et al (2010) Colorectal Cancer OncoGuia: surgical pathology report guidelines. Clin Transl Oncol 12:211–213

    Article  PubMed  Google Scholar 

  70. Sobin LH GMaWC (2009) TNM classification of malignant tumours. 7th edn. Wiley, New York

  71. Ley 14/2007, de 3 de Julio, de Investigación Biomédica. http://www.boe.es/boe/dias/2007/07/04/pdfs/A28826-28848.pdf

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Acknowledgments

Editorial assistance for the development of this manuscript was provided by Dr. Beatriz Gil-Alberdi from HealthCo (Madrid, Spain). The members of the Working Group on Biomarkers SEOM–SEAP are R Colomer, P García-Alfonso, P Garrido, A Ariza, E de Álava and J Palacios.

Conflict of interest

SEOM and SEAP acknowledge the financial support for this project of unrestricted grants from Amgen S.A.; Merck S.L.; Roche Farma of Spain and Sanofi.

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Authors and Affiliations

  1. Medical Oncology Service, Universitary Hospital Gregorio Marañón, Madrid, Spain

    Pilar García-Alfonso

  2. Medical Oncology Service, ICO Hospital Duran i Reynals, Hospitalet de Llobregat, Spain

    Ramón Salazar

  3. Medical Oncology Service and Genetics Clinical Unit, Clínic of Navarra University, Pamplona, Spain

    Jesús García-Foncillas

  4. Anatomic Pathology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    Eva Musulén

  5. Medical Oncology Service, Universitary Hospital Virgen del Rocío, Seville, Spain

    Rocío García-Carbonero

  6. Anatomic Pathology Service, Universitary Hospital of Alicante, Alicante, Spain

    Artemio Payá

  7. Medical Oncology Service, Universitary Clinical Hospital San Carlos, Madrid, Spain

    Pedro Pérez-Segura

  8. Anatomic Pathology Service, Vall d’Hebron University Hospital, Barcelona, Spain

    Santiago Ramón y Cajal

  9. Anatomic Pathology Service, Medical School, University of Valencia, Valencia, Spain

    Samuel Navarro

  10. Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo, 46, 28007, Madrid, Spain

    Pilar García-Alfonso

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  1. Pilar García-Alfonso
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Correspondence to Pilar García-Alfonso.

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García-Alfonso, P., Salazar, R., García-Foncillas, J. 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 14, 726–739 (2012). https://doi.org/10.1007/s12094-012-0856-5

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