Skip to main content
Log in

BRAF Mutation Testing and Metastatic Colorectal Cancer in the Community Setting: Is There an Urgent Need for More Education?

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Background

Patients with metastatic colorectal cancer (mCRC) with BRAF mutation (BRAF MT) generally have a poorer prognosis. BRAF MT may also have implications for treatment strategy. Despite this, inclusion of BRAF in routine molecular testing varies. Here we report the frequency of BRAF reporting in the South Australian (SA) mCRC registry reflecting community practice, together with the survival outcomes based on mutation status.

Methods

The SA population-based mCRC registry was analysed to assess the number of patients where a BRAF MT result was available. The patient characteristics are reported and overall survival was analysed using the Kaplan–Meier method.

Results

Of the 3639 patients who have been entered in the registry, only 6.2 % (227) have BRAF MT results available. Of the patients tested, the BRAF MT rate is 12.7 %. The mutation rate was highest in rightsided primary; right colon 23 versus left colon 8.9 % and rectum 7 %. There was no significant difference in median age or male/female proportion. The median overall survival (mOS) for BRAF MT versus wild-type (WT) patients is 14.0 versus 32.9 months (p = 0.003). For patients who have chemotherapy (plus or minus surgery) the mOS is 14.6 months BRAF MT versus 36.1 months (p ≤ 0.001) WT. Liver or lung resection was performed on only 8 % of the BRAF MT group versus 26.5 % of the WT group.

Conclusion

Results in a population setting confirm our understanding that BRAF MT is more frequently right sided and of lower frequency in rectal cancer. Survival is lower for patients with mCRC that have BRAF MT, regardless of the therapy. BRAF testing is currently performed infrequently in an Australian setting despite its importance as a significant prognostic factor, and the implications for alternate therapeutic approaches.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Price TJ, Segelov E, Burge M, Haller DG, Tebbutt NC, Karapetis CS, et al. Current opinion on optimal systemic treatment for metastatic colorectal cancer: outcome of the ACTG/AGITG expert meeting ECCO 2013. Expert Rev Anticancer Ther. 2014;14(12):1477–93 (PubMed PMID: 25138900, Epub 2014/08/21. eng).

  2. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, Group EGW. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncology. 2014;25(Suppl 3):iii1–9 (PubMed PMID: 25190710).

  3. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65 (PubMed PMID: 18946061. Epub 2008/10/24. eng).

  4. 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(11):1023–34 (PubMed PMID: 24024839. Epub 2013/09/13. eng).

  5. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–9 (PubMed PMID: 19571295).

    Article  PubMed  CAS  Google Scholar 

  6. Rozek LS, Herron CM, Greenson JK, Moreno V, Capella G, Rennert G, et al. Smoking, gender, and ethnicity predict somatic BRAF mutations in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2010;19(3):838–43 (PubMed PMID: 20200438. Pubmed Central PMCID: PMC2872124).

  7. Shaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? Dig Dis Sci. 2010;55(8):2352–6 (PubMed PMID: 20300843).

    Article  PubMed  CAS  Google Scholar 

  8. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–94 (PubMed PMID: 25673558).

    Article  PubMed  CAS  Google Scholar 

  9. Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015;112(12):1888–94 (PubMed PMID: 25989278).

    Article  PubMed  CAS  Google Scholar 

  10. Price TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol. 2011;29(19):2675–82 (PubMed PMID: 21646616. Epub 2011/06/08. eng).

  11. 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(15):2011–9 (PubMed PMID: 21502544. Epub 2011/04/20. eng).

  12. Loupakis F, Cremolini C, Antoniotti C, Lonardi S, Ronzoni M, Zaniboni A, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as initial treatment for metastatic colorectal cancer (TRIBE study): Updated survival results and final molecular subgroups analyses. J Clin Oncol. 2015.

  13. 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 (PubMed PMID: 24687833. Epub 2014/04/02. Eng).

  14. 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(10):1065–75 (PubMed PMID: 25088940. Epub 2014/08/05. eng).

  15. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O’Neil B, Shaw JE, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:55(Suppl):LBA3

  16. Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B. BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer. 2006;5:2 (PubMed PMID: 16403224. Pubmed Central PMCID: PMC1360090).

  17. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–32 (PubMed PMID: 21456008. Pubmed Central PMCID: PMC4257471).

  18. Arnold D. ESMO colorectal guidelines draft presentation. WGIC. Ann Oncol. 2015;26(Suppl 4).

  19. Price T. BRAF mutation testing. Personal communication. Colorectal Cancer symposium, World Gastrointestinal Conference; 2015.

  20. Neo EL, Beeke C, Price T, Maddern G, Karapetis C, Luke C, et al. South Australian clinical registry for metastatic colorectal cancer. ANZ J Surg. 2011;81(5):352–7 (PubMed PMID: 21518185. Epub 2011/04/27. eng).

  21. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88 (PubMed PMID: 2240880. Epub 1990/11/15. eng).

  22. Sahin IH, Kazmi SM, Yorio JT, Bhadkamkar NA, Kee BK, Garrett CR. Rare though not mutually exclusive: a report of three cases of concomitant KRAS and BRAF mutation and a review of the literature. J Cancer. 2013;4(4):320–2 (PubMed PMID: 23569465. Pubmed Central PMCID: PMC3619093).

  23. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17 (PubMed PMID: 19339720. Epub 2009/04/03. eng).

  24. 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(7):1535–46 (PubMed PMID: 21228335. Epub 2011/01/14. eng).

  25. Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013;14(8):749–59.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Cremolini C, Di Maio M, Petrelli F, Berenato R, Loupakis F, Pietrantonio F. BRAF-mutated metastatic colorectal cancer between past and future. Br J Cancer. 2015;113(11):1634–5 (PubMed PMID: 26355234).

  27. Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, et al. Reply: comment on ‘meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal-antibody therapy for RAS wild-type metastatic colorectal cancer’. Br J Cancer. 2015;113(11):1635 (PubMed PMID: 26355231).

  28. Yuki S YT, Tsuchihara K, Shinozaki E, Muro K, Nishina T, Yamaguchi K, Akagi K, et al. Clinical impact of expanded BRAF mutational status on the outcome for metastatic colorectal cancer patients with anti-EGFR antibody: An analysis of the BREAC trial (Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics). J Clin Oncol. 2015;33(Suppl, #11038).

  29. Cremolini C, Di Bartolomeo M, Amatu A, Antoniotti C, Moretto R, Berenato R, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015;26(10):2092–7 (PubMed PMID: 26153495).

    Article  PubMed  CAS  Google Scholar 

  30. Loupakis F, Cremolini C, Salvatore L, Masi G, Sensi E, Schirripa M, et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014;50(1):57–63 (PubMed PMID: 24138831. Epub 2013/10/22. eng).

  31. Morris V, Overman MJ, Jiang ZQ, Garrett C, Agarwal S, Eng C, et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clinical colorectal cancer. 2014;13(3):164–71 (PubMed PMID: 25069797. Pubmed Central PMCID: PMC4266576).

  32. Stintzing S JA, Rossius L, Modest DP, Fischer von Weikersthal L, Decker LT, Möhler M, et al. Analysis of KRAS/NRAS and BRAF mutations 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. EJC; 2013;49(Suppl 3):abstract 17.

  33. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5 (PubMed PMID: 20130576. Epub 2010/02/05. eng).

  34. Belden S, Flaherty KT. MEK and RAF inhibitors for BRAF-mutated cancers. Expert Rev Mol Med. 2012;14:e17 (PubMed PMID: 23058743. Epub 2012/10/13. eng).

  35. 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(3):227–35 (PubMed PMID: 22448344. Pubmed Central PMCID: PMC3308191).

  36. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36 (PubMed PMID: 26287849).

    Article  PubMed  CAS  Google Scholar 

  37. Van Cutsem E, Atreya C, André T, Bendell J, Schellens J, Gordon M, et al. Updated Results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC) 2015. Ann Oncol. 2015;26(Suppl 4:LBA07).

  38. Jensen LH, Lindebjerg J, Byriel L, Kolvraa S, Cruger DG. Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. Colorectal Dis. 2008;10(5):490–7 (PubMed PMID: 17868408).

    Article  PubMed  CAS  Google Scholar 

  39. Seppala TT, Bohm JP, Friman M, Lahtinen L, Vayrynen VM, Liipo TK, et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br J Cancer. 2015;112(12):1966–75 (PubMed PMID: 25973534).

    Article  PubMed  CAS  Google Scholar 

  40. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20 (PubMed PMID: 26028255. Pubmed Central PMCID: PMC4481136).

  41. Lee B, Lee M, Tie J, Tran B, Turner N, Nott L, et al. BRAF mutations in metastatic colorectal cancer in routine clinical practice. AGITG Annual Scientic Meeting; 2015 September 2nd to 4th; Sydney.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Timothy J. Price.

Ethics declarations

Conflict of interest

TP, CB, AT, LL, AR, RP, DR, GM, JM and CK all indicate there is no conflict of interest for this manuscript.

Funding

TP, CB, AT, LL, AR, RP, DR, GM, JM and CK declare there was no external funding for this project.

Ethical approval and informed consent

The SA mCRC Registry is covered by statewide ethics through state legislation. The registry was also assessed and approved by individual institutions within SA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Price, T.J., Beeke, C., Townsend, A.R. et al. BRAF Mutation Testing and Metastatic Colorectal Cancer in the Community Setting: Is There an Urgent Need for More Education?. Mol Diagn Ther 20, 75–82 (2016). https://doi.org/10.1007/s40291-015-0179-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-015-0179-7

Keywords

Navigation