Malignant melanoma is the deadliest form of skin cancer. Fast-growing, melanoma is best beaten with an early and accurate diagnosis followed by the right treatment tailored to the patient based on the identification of a specific biomarker. Biomarkers can predict therapeutic response to treatment. An example of a biomarker is a genetic mutation in a tumor. One of the biomarkers commonly found in melanoma is the BRAF gene mutation, in which V600E is the most common mutation.1
Recent advances in the biomarker-based treatment of melanoma include the targeted treatments vemurafenib and dabrafenib, which target tumors with the BRAF mutation. When combined with mitogen-activated protein kinase (MEK) inhibitors, vemurafenib and dabrafenib have prolonged progression-free survival and overall survival rates in patients with the BRAF mutation.2-7
Melanoma deriving from a BRAF mutation is more aggressive than other forms of melanoma. It typically affects younger patients, is more likely to metastasize to the brain, and is associated with shorter overall survival in patients with advanced-stage melanoma.8-10 Therefore, once a diagnosis has been made, it is imperative that biomarker testing immediately ensue to confirm the presence of the BRAF mutation in order to initiate targeted treatment, which will yield a therapeutic response far superior to standard care.
Diagnostic tests play a crucial role in identifying patients and, ultimately, predicting a therapeutic response and optimizing treatment selection. Tests for determining BRAF mutation status include pharma-produced DNA-based companion diagnostics (CDx kits) and DNA- and protein-based tests developed by laboratories, called laboratory developed tests (LDTs).11 However, just because a test exists does not mean it will be used, run on the optimal platform, or interpreted correctly—all of which may lead to inaccurate results, missed patients, and suboptimal treatment.
The setting of melanoma presents additional challenges to understanding tumor mutational status because of the common occurrence of tumor heterogeneity and discordance in BRAF mutational status.11 When a tumor is heterogenous, not all the cells within the tumor will express the BRAF mutation. This means patients with BRAF mutations could possibly be missed because the tissue sample biopsied did not contain cells expressing the BRAF mutation, whereas a second sample or a larger sample may. Alternatively, the biomarker test used may not have been sensitive enough to detect the low frequency of the BRAF mutations in the tissue sample. For example, traditional Sanger sequencing is a form of genetic testing that is limited to detecting substitutions and small deletions and insertions of DNA, and provides only 20% sensitivity.12 This may lead to sample rejection or patients being missed, as revealed in a poster recently presented at the European Congress of Pathology.13 In contrast, Next Generation Sequencing (NGS) offers complete mutational coverage and excellent sensitivity, and, if used, is much more likely to pick up on the BRAF mutation even when expressed with low frequency on a particular tumor tissue sample.
Additionally, BRAF mutational status may change within the same patient, so biomarker testing should not stop at diagnosis. For example, patients who initially presented negative for the BRAF mutation may develop it once the melanoma has metastasized.11 Patients may develop primary or acquired resistance to both immune and molecularly targeted agents, which necessitates on-treatment biomarker monitoring that may predict the likelihood of treatment failure and disease relapse.14