BRAF mutation analysis of only one metastatic lesion can restrict the treatment of melanoma: a case report

Abstract

Funding sources: none. Conflicts of interest: J.C.B. is on the ad board and speakers’ bureau for Roche and GlaxoSmithKline. Madam, The RAS‐RAF‐MEK‐ERK‐mitogen activated protein kinase (MAPK) pathway is a crucial signalling pathway for the growth of malignant cells. BRAF (v‐raf murine sarcoma viral oncogene homolog B1) mutations, especially V600E1 and to a lesser extend V600K, are frequently present in melanoma.2, 3 Consequently, therapeutic inhibition of this pathway has become an attractive approach for the treatment of patients with melanoma. Indeed, several investigational drugs have been shown to block this pathway to a more or less significant extent.4 For example, vemurafenib (Zelboraf™; Roche Pharma AG, Grenzach‐Wyhlen, Germany), an orally available selective inhibitor of the oncogenic BRAF V600E kinase, has demonstrated impressive clinical efficacy even in advanced disease.5 As a result, Zelboraf™ received approval from the U.S. Food and Drug Administration for the treatment of the corresponding patients in August 2011.6 In contrast to vemurafenib, MEK 1/2 inhibitors targeting the downstream molecules of BRAF signalling should allow the treatment of patients harbouring activating mutations in any of the upstream molecules of MEK. Notably, the combination of the MEK 1/2 inhibitor GSK 1120212 with the mutation‐specific BRAF inhibitor GSK 2118436 has demonstrated encouraging antitumour activity in patients with mutated V600.7 Currently, clinical trials that are testing inhibitors of the respective MAPK pathways are based on the identification of a mutation in one selected melanoma lesion, either primary or metastasized. Once the respective drugs are approved, clinical practice will likely follow this standard as well. However, the following case report raises concerns associated with this current practice.