Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients

Abstract

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.

Pathologist initiated reflex BRAF mutation testing in metastatic melanoma: experience at a specialist melanoma treatment centre

“…19,29 Recently, Zhou et al proposed that mutation testing be considered in patients with high risk (>4 mm, or >2 mm with ulceration) stage II primary melanomas, to pre-empt management options on anticipated disease progression. 8 Furthermore, recent Phase 3 trials of adjuvant systemic therapy in stage II melanoma have shown positive results. 30,31 Therefore, the BRAF mutation status will be increasingly important in earlier stages of disease.…”

“…7 Access to BRAF targeted therapy (dabrafenib + trametinib, vemurafenib + cobimetinib or encorafenib + binimetinib) is currently only available through the Australian Pharmaceutical Benefits Scheme in patients with a known BRAF mutation. 1,8,9 BRAF mutations can be identified through a range of molecular techniques, with varying degrees of specificity, tissue requirements, turn-around time and financial cost. 10 When internally validated and performed with appropriate positive and negative controls, immunohistochemistry (IHC) using a highly specific antibody for BRAF V600E (which accounts for approximately 80% of BRAF V600 mutations in melanomas) when strong 3+ and diffuse staining is present is robust evidence of the presence of a BRAF mutation and is sufficient to commence targeted therapy.…”

Reflex Molecular Testing in Melanoma Diagnosis: When Should BRAF Mutation Testing Be Ordered and Who Should Order It?

“…Zhou et al 3 propose that reflex testing criteria implemented by clinicians and pathologists can streamline treatment initiation. Optimally, the BRAF mutation status of melanoma patients will be known upon arrival to their first medical oncology appointment.…”

“…4 In this study, pathologists reflexively ordered biomarker tests (EGFR, ALK) upon pathological confirmation of NSCLC diagnosis. 4 This review article synthesizes evidence of reflex testing reducing time to treatment initiation in breast, colon, lung, and ovarian cancer 3 .…”

“…2 A review of the pathophysiology, clinical presentation, and current guidelines surrounding BRAF-mutated melanoma was recently published in Cancers. 3 Importantly, the Canadian authors address the current barriers to the timely and effective use of personalized treatment for advanced melanoma. The treatment of advanced melanoma often involves a multidisciplinary approach, including dermatologists, pathologists, medical oncologists, and surgeons.…”