Although the current study did not find a significant difference in gender distribution or age between BRAF wild-type and mutant patients, the small number of patients in the BRAF mutant group makes it difficult to draw definitive conclusions.

Interestingly, a predominance of BRAF V600E mutation in females has been reported by others14 while we found a non-statistically significant trend towards female predominance. BRAF mutation is also more commonly found in females in colorectal cancer23,24.

Continue Reading

This finding is akin to the female predominance of EGFR mutations and may represent a similar underlying mechanism.

An association betweenEGFR mutation and oestrogen receptor has been found, possibly indicating a hormonally driven phenomenon25. However, a clear mechanism has yet to be substantiated.

The BRAF V600E mutation has been previously reported to be associated with the aggressive micropapillary subtype of lung adenocarcinoma14,26.

This finding is supported by the current study as both patients with a micropapillary component showed BRAF V600E mutation. However, it is difficult to be conclusive due to the small number of patients in the current study precluding statistical analysis.

The most common BRAF mutation in melanoma is the V600E mutation, which accounts for more than 90% of mutations6. However, the current study shows that BRAF V600E mutation only accounts for 58% of mutations in NSCLC.

This finding is supported by others who found the non-V600E mutation rate to be between 50-89%16,27. Although the biological significance of this is unknown, this raises the possibility thatBRAF-related oncogenesis in NSCLC arises from a different mechanism compared to melanomas with V600E mutations.

It has been shown that the V600E mutation confers a much higher kinase activity compared to other mutations within the kinase domain7. The G469V mutation found in the current study occurs in the P-loop which is the ATP binding site.

Mutations within the P-loop have been shown to have a lower activity compared to wild-type BRAF7, therefore whether these mutations drive oncogenesis is uncertain. Similarly, rare mutations at codons 439 and 440 (AKT phosphorylation motif) have been reported in NSCLC and they do not increase the oncogenic properties of BRAF28.

This indicates that the genotype of the BRAF mutation may be an important therapeutic consideration. Unfortunately, there is currently only limited phase I clinical trial data for RAF inhibitors in NSCLC19 and the significance of the different mutation spectrum remains uncertain.

In conclusion, the current study confirmed that a small proportion of NSCLC patients harbour BRAF mutations. Their clinicopathological characteristics appear to differ from patients with EGFR mutations and their genotype differs from that found in melanoma.

Further work needs to be done to determine whether this small subset of patients will benefit from BRAF inhibitors.


The authors would like to thank Thang Tran for performing the statistical analysis. WC and SOT have received funding from National Foundation for Medical Research and Innovation.

Disclosure: The authors declare no conflict of interest.

Peter P. Luk1, Bing Yu2,3, Chiu Chin Ng2, Belinda Mercorella2, Christina Selinger1, Trina Lum1, Steven Kao4, Sandra A. O’Toole1,3,5, Wendy A. Cooper1,3,6

1Department of Tissue Pathology and Diagnostic Oncology, 2Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia; 3Sydney Medical School, University of Sydney, Sydney, Australia; 4Lifehouse Cancer Centre, The Chris O’Brien Lifehouse, Sydney, Australia; 5Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; 6School of Medicine, University of Western Sydney, Sydney, NSW,Australia

Correspondence to: A/Prof. Wendy Cooper. Department of Tissue Pathology and Diagnostic Oncology, The Royal Prince Alfred Hospital, Camperdown NSW 2050, Australia. Email: [email protected]


  1. Tsao AS, Papadimitrakopoulou V. The importance of molecular profiling in predicting response to epidermal growth factor receptor family inhibitors in non-small-cell lung cancer: focus on clinical trial results. Clin Lung Cancer 2013;14:311-21. [PubMed]
  2. Cooper WA, Lam DC, O’Toole SA, et al. Molecular biology of lung cancer. J Thorac Dis 2013;5:S479-90. [PubMed]
  3. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006;441:424-30. [PubMed]
  4. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305-15. [PubMed]
  5. Platz A, Egyhazi S, Ringborg U, et al. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2008;1:395-405. [PubMed]
  6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54. [PubMed]
  7. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004;116:855-67. [PubMed]
  8. Torii S, Yamamoto T, Tsuchiya Y, et al. ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci 2006;97:697-702. [PubMed]
  9. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-65. [PubMed]
  10. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. [PubMed]
  11. Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet 2007;39:347-51. [PubMed]
  12. MacConaill LE, Campbell CD, Kehoe SM, et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009;4:e7887. [PubMed]
  13. R Development Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2011.
  14. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-9. [PubMed]
  15. Schmid K, Oehl N, Wrba F, et al. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res 2009;15:4554-60. [PubMed]
  16. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29:2046-51. [PubMed]
  17. Yip PY, Yu B, Cooper WA, et al. Patterns of DNA mutations and ALK rearrangement in resected node negative lung adenocarcinoma. J Thorac Oncol 2013;8:408-14. [PubMed]
  18. Australian Institute of Health and Welfare. Lung cancer in Australia: an overview. Cancer series no. 64. Australian Institute of Health and Welfare, Canberra, 2011.
  19. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:1893-901. [PubMed]
  20. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009;4:1450-4. [PubMed]
  21. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-44. [PubMed]
  22. Forbes SA, Tang G, Bindal N, et al. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res 2010;38:D652-7. [PubMed]
  23. Roth AD, Tejpar S, Delorenzi M, 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. [PubMed]
  24. Kalady MF, Dejulius KL, Sanchez JA, et al. BRAF mutations in colorectal cancer are associated with distinct clinical characteristics and worse prognosis. Dis Colon Rectum 2012;55:128-33. [PubMed]
  25. Raso MG, Behrens C, Herynk MH, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin Cancer Res 2009;15:5359-68. [PubMed]
  26. De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol 2009;131:694-700. [PubMed]
  27. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002;62:6997-7000. [PubMed]
  28. Ikenoue T, Kanai F, Hikiba Y, et al. Functional consequences of mutations in a putative Akt phosphorylation motif of B-raf in human cancers. Mol Carcinog 2005;43:59-63. [PubMed]

Source: Translational Lung Cancer Research.