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Article Type : Correspondence

Concerns regarding BRAF testing algorithm Authors: R.R. Clark, J.J. Garioch, M.D.S. Moncrieff Institution: Skin Tumour Unit, Norfolk & Norwich University Hospital, Colney Lane Norwich NR4 7UY Correspondence: Richard Clark, Plastic Surgery, Norfolk & Norwich University Hospital, Colney Lane Norwich NR4 7UY richardclark@nhs.net 01603287287 Dear Editor, We commend the recent work by Gonzalez et al(1) for their efforts in attempting to provide a nationalised framework and guidance for the testing of BRAF mutation in melanoma. However, we feel that these recommendations are somewhat premature, given the lack of evidence and experience to draw from in the international published literature. We have serious concerns that there is significant potential for misdiagnosis, deleterious harm to patients and wastage of resources were all of these ambitious recommendations to be adopted as a UK national standard. We outline our concerns below

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The authors recommend that primary melanoma specimens should be tested for all high-risk, AJCC IIB & IIC, (pT3b-pT4b) tumours. We are unaware of any evidence to suggest that this provides any prognostic information for the patients at this stage of the disease. Accordingly, the only potential benefit that remains is for providing early intervention for patients. Since there is no adjuvant treatment modality for patients at this stage and no major adjuvant clinical trials, BRAF testing cannot be justified on these grounds either. The only possible justification remaining is testing for early intervention following inoperable relapse. We have very grave concerns for testing of the primary for this eventuality. To date there is no good evidence to suggest a consistent correlation between the BRAF status in the primary melanoma and the ensuing metastases. While it is likely that BRAF mutations are transmitted from the primary melanoma to the metastasis on many occasions, it remains unknown if the mutation is uniformly represented across the primary tumour or appears in only a select group of cell lines that then progress to metastatic disease. Accepting that the cells lines in the primary melanoma are likely to be polyclonal, testing only a small subsection of the tumour from a histology slide runs the risk of a false negative test result. Patients may be denied a potentially life prolonging therapy after being falsely labelled as being BRAF negative (wild type) at initial diagnosis. There is also the potential for misdiagnosing patients as carrying the BRAF mutation by adopting this approach. Up to 80% of benign naevus cells may also demonstrate BRAF mutations and we have found from our own sentinel node database that 16% of metastatic melanomas were from primaries arising in pre-existing naevi(2). A polyclonal primary melanoma may also have a co-existent BRAF mutation +ve radial growth phase, with no metastatic potential, with a BRAF -ve vertical growth phase colony with a highly aggressive metastatic potential in the same tumour. Furthermore, the theoretical risk of primary tumours developing resistance to BRAF inhibitors prior to the development of stage III or IV disease has yet to be thoroughly explored. There is now evidence to suggest that administering BRAF inhibitors to patients with BRAF wild type metastases activates the MAP Kinase pathway in the these tumours and accelerates growth and disease progression(3). Therefore, a false positive misdiagnosis could prove costly to the patient in terms of reduced survival and costly to the treating hospital in terms of potential litigation. The authors argue that the delay involved in retrospective examination of specimens using the current, highly centralised molecular testing services in the UK justifies this pro-active stance. This argument is weak, particularly when effective immunochemistry is available to perform the same task(4). In our unit, our colleagues in pathology can provide us with a result in 48 hours at a cost of approximately £60 per patient using this approach. We accept some limitations of

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this immunostain as, at present, only a V600E mutation can be detected by this method, but this still allows us to rapidly initiate therapy in about 80% of cases likely to benefit from BRAF inhibitor therapy. Until such time as there is high quality evidence to support the position that there is correlation between primary and metastatic BRAF status in clinical practice, molecular testing for BRAF V600 mutations in high-risk primary melanoma outside of a clinical trial is not justified, is a waste of resources and is potentially harmful. We suggest, therefore, that BRAF testing is restricted to metastatic tumour only. This is, after all, the disease that we are attempting to treat. References 1. Gonzalez D, Fearfield L, Nathan P, Taniere P, Wallace A, Brown E, et al. BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel. Br J Dermatol. 2013 Apr;168(4):700-7. 2. Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006 Aug;16(4):267-73. 3. van Akkooi AC, Nijsten T. A costly revolution for a subgroup of patients with metastatic melanoma. Br J Dermatol. 2013 Mar;168(3):467-70; discussion 70-1. 4. Long GV, Wilmott JS, Capper D, Preusser M, Zhang YE, Thompson JF, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol. 2013 Jan;37(1):61-5.