Melanoma is a skin cancer that develops when melanocytes, the cells that give skin its pigment, begin to grow out of control. The progression of cancers like melanoma is often driven by mutations within the DNA of these cells. A key discovery in melanoma treatment has been the role of a specific genetic mutation in the BRAF gene.
This mutation is found in approximately half of all cutaneous (skin) melanomas. The presence of a BRAF mutation provides a specific target for treatment, changing how doctors approach the disease. Understanding whether a melanoma is “BRAF-positive” has become a standard part of care for individuals with advanced forms of this cancer.
The BRAF Gene and Its Mutation
The BRAF gene provides instructions for making a protein that helps control cell growth and is part of a communication network inside the cell known as the MAPK pathway. Under normal circumstances, this pathway receives signals from outside the cell and relays them inward to regulate cellular functions.
When the BRAF gene mutates, it can become permanently switched on, which is analogous to a car’s gas pedal getting stuck in the down position. The mutated BRAF protein continuously signals the MAPK pathway to promote cell division, leading to the unregulated growth that characterizes cancer. The most common of these mutations is V600E, which accounts for about 90% of all BRAF mutations in melanoma.
The “V600E” designation signifies that at position 600 in the BRAF protein, the amino acid valine (V) has been replaced by glutamic acid (E). This change locks the protein in its active state and drives aggressive growth.
Diagnosis and Testing for BRAF Mutations
Following a melanoma diagnosis from a skin biopsy, the next step for individuals with advanced disease (Stage III or IV) is to determine the tumor’s genetic makeup. This involves molecular testing, where a sample of the tumor tissue is sent to a specialized laboratory to screen for alterations in the BRAF gene.
Pathologists use methods like polymerase chain reaction (PCR) or sequencing to analyze the DNA from the melanoma cells. These tests are designed to detect activating mutations, most commonly the V600E mutation. The results classify the melanoma as either BRAF-positive (if a mutation is found) or BRAF-negative (wild-type), a distinction that is fundamental for treatment planning for melanoma that has spread or cannot be surgically removed.
Targeted Therapy Treatments
The discovery of the BRAF mutation led to the development of drugs known as targeted therapies. These medications are designed to attack cancer cells by interfering with the molecules that fuel their growth, often with fewer effects on healthy cells compared to traditional chemotherapy. For BRAF-mutated melanoma, this approach centers on blocking the overactive signals from the mutated BRAF protein.
The first line of attack involves drugs called BRAF inhibitors. Medications such as dabrafenib (Tafinlar), vemurafenib (Zelboraf), and encorafenib (Braftovi) work by binding to the mutated BRAF protein and blocking its activity, which can lead to the shrinkage or slowed growth of tumors.
To enhance effectiveness, BRAF inhibitors are almost always prescribed in combination with a MEK inhibitor. The MEK protein is the next step after BRAF in the MAPK signaling pathway, and blocking both provides a more complete shutdown of the cancer-driving signals. This combination strategy is more effective and can delay treatment resistance compared to using a BRAF inhibitor alone.
Commonly used MEK inhibitors include trametinib (Mekinist), cobimetinib (Cotellic), and binimetinib (Mektovi). These therapies can cause side effects, including fever, skin rashes, and fatigue, which are managed by the healthcare team.
Additional and Combined Treatment Approaches
While targeted therapies are effective, they are not the only option for treating BRAF-mutated melanoma. Immunotherapy represents another pillar of treatment for advanced melanoma. These therapies, including checkpoint inhibitors like ipilimumab (Yervoy) and nivolumab (Opdivo), work by unleashing the body’s immune system to recognize and destroy cancer cells.
The effectiveness of immunotherapy is not dependent on the tumor’s BRAF status, making it a valuable option for all advanced melanoma patients. For patients with a BRAF mutation, a decision is made whether to start with targeted therapy or immunotherapy. Recent clinical trial data suggest that starting with immunotherapy may lead to better long-term survival, though targeted therapy may be used first when a rapid tumor response is needed.
A challenge with targeted therapy is the development of treatment resistance. When this occurs, switching to immunotherapy is a common strategy. Clinical trials offer access to new drugs and innovative treatment combinations for patients who have exhausted standard options.
Prognosis and Disease Management
The outlook for patients with advanced BRAF-mutated melanoma has improved significantly over the past decade. Before targeted therapies and immunotherapies, the prognosis was often poor. Today, these treatments have improved survival rates and quality of life, turning what was once a rapidly progressing disease into a manageable chronic condition for many.
Research from 2021 found a 5-year survival rate of 60% for people receiving treatment for BRAF-positive melanoma. A prognosis is highly individual and depends on many factors, including the cancer stage at diagnosis, the patient’s overall health, and how the tumor responds to treatment.
Continuous disease management is a part of care. This involves regular follow-up appointments with an oncology team for imaging scans and blood work to monitor treatment effectiveness and check for recurrence. Ongoing management also focuses on controlling treatment side effects to ensure the best possible quality of life.