Role of BRAF mutations in melanoma, lung cancer, and more

By Lynne Eldridge, MD 

 Medically reviewed by Oliver Eng, MD

BRAF mutations are DNA changes in some cancer cells that can be treated with newer targeted therapies.

BRAF mutations are found in roughly half of melanomas. Medications that target these mutations have significantly improved the survival rates of metastatic melanoma. BRAF mutations are also present in some non-small cell lung cancers, colon cancers, and other tumor types.

Genomic testing of tumors can look for DNA alterations and determine if the cancer will respond to drugs targeting mutations.

This article looks at what a BRAF mutation is and its frequency in different types of cancer. It also looks at testing, treatment options, and recent advances.

How BRAF Mutations Work

Cancer begins when a series of gene mutations or other genomic alterations transforms a normal cell into a cancer cell. Some of these mutations, referred to as "driver mutations," code for proteins that drive the growth of the tumor.

You may hear the term "targetable mutation" or "actionable mutation." What this means is that a mutation or other alteration in the cancer cells can be "targeted" by an available drug that may slow or halt the growth of the tumor.

Oncogenes and Tumor Suppressor Genes

Most often, cancer develops after a series of mutations in both oncogenes and tumor suppressor genes occurs.

Proto-oncogenes are normal genes that code for proteins important in stimulating cell growth and division. These genes are primarily active during fetal development in the uterus, and for short periods of time in adults to aid in tissue repair.

When mutated, proto-oncogenes become oncogenes. These genes can be thought of as an accelerator on a car that is stuck in the on position. BRAF is a proto-oncogene that becomes an oncogene when mutated—resulting in the continuous production of proteins that stimulate cell proliferation.

Tumor suppressor genes are genes that code for proteins that function to repair damaged DNA or eliminate cells that can't be repaired. When these genes are damaged, they allow abnormal cells to continue to grow and reproduce. The BRCA genes linked to breast cancer are examples of tumor suppressor genes.

The BRAF Gene

The BRAF gene is a proto-oncogene found on chromosome 7, and becomes an oncogene when mutated. The gene codes for a protein (a serine-threonine kinase) that sends signals from outside of the cell to the nucleus that in turn drives the growth of a cell. Discovered in 2002, the oncogene is now known to be an important driver in more than one type of cancer.

While BRAF is an important "driver" of melanoma, a BRAF mutation alone is not responsible for the development of cancer. (At least one other mutation is needed for cancer to develop.) Alone, the mutation can lead to the development of benign moles.

Hereditary vs. Acquired Gene Mutations

It's important to briefly discuss the difference between acquired (somatic) gene mutations (mutations that are acquired after birth in the process of a cell becoming a cancer cell), and hereditary (germline) mutations, mutations that are inherited from one's parents.

BRAF mutations associated with cancer are almost always acquired mutations. Unlike the BRCA mutations that have received a lot of attention in recent years, these mutations are not inherited from a person's parents and cannot be passed down to children. They are present only in the cancer cells and not all of the cells in the body. Acquired mutations are much more common in oncology.

Types

There are more than 30 different types of mutations that may occur in the BRAF gene, and the most common types of mutations can vary with the type of cancer.

BRAF V600E and BRAF V600K

With melanoma, BRAF V600 E and BRAF V600K account for roughly 90% of BRAF mutations (with BRAF V600E by far the most common).

Non-V600 BRAF Mutations

With lung adenocarcinoma, around 50% to 80% of BRAF mutations are non-V600 variants. In colorectal cancer, 22% to 30% are non-V600 variants.1

BRAF Mutations Classes

The science is in its infancy with regard to evaluating the different types of BRAF mutations with respect to treatment and prognosis.

A 2019 study looked at BRAF mutations in non-small cell lung cancer, separating these into three classes with different clinical characteristics. It could be that in the future, specific therapies will be designed to treat subsets of BRAF mutations rather than BRAF mutations in general.2

How BRAF Mutations Drive the Growth of Cancer

The BRAF gene codes for (is a blueprint for) a protein called B-Raf. Mutations in the BRAF gene are referred to as "activating mutations" as the mutation results in continuous production of the protein. The continued presence of the B-Raf proteins, in turn, results in continuous signaling for the cell to divide and grow.

B-Raf proteins are part of a signaling pathway (RAF-MEK-ERK) that affects cell growth in several ways. This pathway:

• Promotes cell proliferation (growth)

• Promotes cell survival

• Aids in differentiation (differentiation is the process by which cells mature such that they have specific functions)

• Aids in migration (movement of cells)

• Inhibits apoptosis (cell death or self-destruction)

This pathway is very important in the womb as the embryo develops. When continuously activated in an adult, it can result in uncontrolled growth of cells (cancer).

Part of the difficulty in treating cancer lies in the fact that cancer cells are not just a clone of cells that grows continuously. They have other characteristics, such as the ability to break free and spread, avoid cell death, and more. They are also continuously changing, developing new mutations that may allow them to escape our current treatments.

Cancers That May Involve BRAF Mutations

At the current time, several different types of cancer have been found to harbor BRAF mutations. However, the frequency, as well as the response to BRAF inhibitors, varies.

BRAF mutations are an example of how cancer treatment is changing. In the past, cancers were usually treated according to type (such as breast cancer or colon cancer treatments). BRAF inhibitors, in contrast, are what are now considered "tumor agnostic" medications.

This means that the drugs may work for different types of cancer (for example, melanoma, lung cancer, and colon cancer). However, the cancer cells must have the same type of mutation responsible for driving the growth of the tumor.

Melanoma

BRAF mutations are present in a large number of melanomas, and their discovery has led to treatments that have changed the outlook for some people with metastatic or locally advanced melanoma (stage IIIB or stage IIIC). Present in roughly 40% to 60% of melanomas, around 90% are BRAF V600E mutations, with most of the remaining being BRAF V600K.

BRAF mutations appear to be more common in some people and with some tumors, including:

• Young people with melanoma

• Tumors found in areas of the body that do not have chronic sun damage (mucosal tumors, such as anal melanoma, have a high incidence of BRAF mutations)

• Tumors classified as superficial spreading or nodular

Tumors that are BRAF mutated also appear to be more likely to spread to the brain.3

Non-Small Cell Lung Cancer (Lung Adenocarcinoma)

BRAF mutations are present in a small number (roughly 3%) of people with the type of non-small cell lung cancer called lung adenocarcinoma. This is the type of lung cancer that is most common in never smokers, women, and young people who develop the disease.

With lung adenocarcinoma, BRAF mutations may be present when the tumor is diagnosed, but are more often found as a resistance mutation. This is a mutation that develops in a cancer that has already been treated with another targeted therapy (such as an EGFR inhibitor).

Resistance mutations allow a tumor that had been previously kept in check with a targeted therapy to bypass the pathway targeted by the drug and begin to grow again.

Colorectal Cancer

BRAF mutations are common in colon cancer, but occur primarily in cancers that are "sporadic" (non-genetic). It is very uncommon for BRAF mutations to be present in hereditary colon cancers, such as those in people who have Lynch syndrome. In this way, the presence of the mutation may provide some information on whether the cancer has a genetic basis or not.

Colon tumors with BRAF mutations are more common:4

• In women

• In people who are diagnosed at an older age

• In people who do not have a family history of colon cancer

• In people with right-sided colon cancer

While treatment addressing BRAF mutations in colon tumors was relatively ineffective in the past, newer triple therapy offers much more promise.

Hairy Cell Leukemia

BRAF mutations are relatively common with hairy cell leukemia. The presence of a BRAF mutation can help distinguish hairy cell leukemia from other B cell lymphomas or leukemias.

Thyroid Cancer

BRAF mutations are present in a large number of anaplastic thyroid cancers (a very aggressive tumor that has been challenging to treat), and up to half of papillary thyroid cancers. BRAF mutations are not found in follicular thyroid cancer, medullary carcinomas, or benign tumors, so the presence of the mutation can help distinguish different types of thyroid cancer.

With papillary thyroid cancer, the presence of a BRAF mutation is associated with a higher risk of recurrence and spread to lymph nodes.

Serous Ovarian Cancer

BRAF mutations are relatively common in people who have serous ovarian cancer. The fact that BRAF inhibitors may be effective for treatment is yet another reason why all women who have ovarian cancer should be tested for mutations in addition to BRCA mutations.

Others

BRAF mutations have been found in a number of other cancers, although infrequently (usually less than 3%). It's not yet known what the significance of the mutation might be with respect to treatment. Some of these include:

• Non-Hodgkin's lymphoma

• Acute lymphoblastic leukemia

• Biliary tract cancer

• Stomach cancer, GI stromal tumors

• Esophageal cancer

• Ependymoma

• Glioma

• Cholangiocarcinoma

• Langerhans cell histiocytosis

• Ganglioneuroma

Other Conditions Related to BRAF Mutations

While BRAF mutations associated with cancer are almost always somatic (acquired mutations), both acquired and inherited mutations may be responsible for some non-cancer related conditions, such as cardiofaciocutaneous syndrome, Noonan syndrome, Erdheim Chester disease, and giant melanocytic nevus.

BRAF Mutation Testing

Testing for BRAF mutations is critical both for those who are found to have a BRAF mutation and those who are not. Those who have the mutation may be eligible for a treatment that has a significant chance of controlling the cancer for a period of time.

Testing is also important for those who do not have the mutation. For example, using BRAF inhibitors in melanomas without a BRAF mutation may actually lead to progression of a tumor.

Testing is recommended per guidelines for melanoma, non-small cell lung cancer, colon cancer, serous ovarian cancer, and others.

Methods

Several different methods of testing for BRAF are currently available. DNA sequencing (eg. next-generation sequencing) takes time but is the gold standard. It can detect different types of BRAF mutations, as well as many other alterations that may be treatable. A faster test (PCR) can be done, but only detects V600E mutations.

Tumor Testing vs. Liquid Biopsy

Historically, testing done on a sample of tissue obtained via a biopsy has been the gold standard. Unfortunately, tissue biopsies are invasive and may not always be possible.

In recent years, a simple blood test that looks for fragments of tumor DNA (cell-free DNA) in the blood has offered an additional option for genomic testing. Liquid biopsies have been found to be comparable to tissue biopsies in some cases, though many oncologists believe that the ideal is to do genomic testing on both tissue and blood samples.

Discordance

The concept of discordance is an important one for people living with advanced cancer. Some people may be aware that breast cancer can change. For example, a tumor that was once estrogen receptor positive may become negative (and vice versa) when it progresses or spreads. The same is true with genomic alterations such as BRAF mutations.

For this reason, many oncologists recommend re-testing a tumor if it progresses or spreads (even if next-generation sequencing was done before). There can be discordance within a tumor as well, such that some parts of the tumor have a BRAF mutation and others do not.

A potential advantage of liquid biopsies is that they may detect mutations present in a tumor, but not seen in a specific area that is biopsied.

A common scenario is with lung adenocarcinoma that progresses. Since BRAF commonly develops as a resistance mutation, it may not be present on initial testing but may be present when a tumor progresses.

Cancers continually change and develop new mutations. With melanoma, metastases are more likely to be BRAF positive than a primary tumor.

How Cancer With BRAF Mutation Is Treated

There are several important treatment implications associated with the presence of BRAF mutations. This stresses the importance of testing.

For instance, BRAF-positive tumors are not only treated with targeted therapies, but those tumors may respond differently to other forms of treatment, such as chemotherapy or immunotherapy. The presence of BRAF mutations may also provide information about the prognosis of a tumor. Tumors that harbor BRAF mutations can behave differently clinically.

BRAF Inhibitors

BRAF inhibitors are medications that target the pathways cancer cells use to grow in tumors that harbor BRAF mutations.

Unlike chemotherapy drugs, these medications do not "kill" cancer cells, but rather control the growth of a tumor by interrupting the signaling pathway that leads to cell growth and division. As such, they do not (usually) "cure" a cancer, but can sometimes control the growth of a cancer for a significant period of time.

Combined Therapy

BRAF inhibitors are most often used along with medications that inhibit the growth of a tumor at other points in the signaling pathway (such as MEK inhibitors). Interestingly, adding a MEK inhibitor to a BRAF inhibitor is actually associated with fewer side effects than using a BRAF inhibitor alone. The combination also appears to work for a longer period of time.

Triple Therapy

With both melanoma and colon cancer, combining a BRAF inhibitor and a MEK inhibitor with another medication has shown promise in clinical trials.

BRAF Inhibitors

There are now three BRAF inhibitors that have been approved. These drugs directly attack the protein coded for by the mutated BRAF gene.

• Zelboraf (vemurafenib): This was the first drug approved in 2011 for BRAF V600E mutations

• Taflinar (dabrafenib): Taflinar was approved (in combination with Mekinist) in 2013 for both V600 E and V600K mutations

• Braftovi (encorafenib)

MEK Inhibitors

• Mekinist (trametinib)

• Cotellic (cobimetinib)

• Mektovi (binimetinib)

Metastatic Melanoma

With metastatic melanoma, using a combination of a BRAF inhibitor and MEK inhibitor has been a "game changer" for many people.

Among those treated, almost two-thirds of people with tumors found to be BRAF positive will respond. Newer combinations (such as the combination of Braftovi and Mektovi) may work even better or result in longer control.

Compared with the previous gold standard (the chemotherapy drug dacarbazine), these targeted therapies can increase both progression-free and overall survival.

Unfortunately, cancers almost always become resistant to these medications after a period of time; usually within a year.

Quandary

There is currently a quandary when it comes to choosing the best treatment for people with metastatic melanoma with BRAF mutations. Targeted therapy has a high chance of working, but only controls the disease for a while.

In contrast, immunotherapy is less likely to work, but in some cases can control the disease for a lengthy period of time. This is something referred to not as a cure, but a "durable response."

Targeted therapy (BRAF plus MEK inhibitors) for metastatic melanoma has a high response rate but lasts, on average, only around a year. Immunotherapy has a lower response rate, but sometimes a much longer duration of action.

Triple Therapy

Clinical trials are in progress evaluating the combination of targeted therapy (BRAF and MEK inhibitors) with immunotherapy drugs known as checkpoint inhibitors (PD-1 and PD-L1 inhibitors).

These include a few promising studies published in June of 2019 that suggest that, for at least some people, the combination may result in a longer response:

• A combination of Taflinar and Mekinist plus Keytruda (pembrolizumab)5

• A combination of Zelboraf and Cotellic plus Tecentriq (atezolizumab)6

Stage III Melanoma

A combination of a BRAF inhibitor and MEK inhibitor may also be used in people with locally advanced melanoma (such as stage IIIB and stage IIIC) to reduce the risk of recurrence (adjuvant therapy).

Lung Cancer

A combination of the BRAF inhibitor Taflinar and the MEK inhibitor Mekinist is approved for treating non-small cell lung cancer with a BRAF V600E mutation, with a response rate of 64% in studies.

Guidelines also recommend avoiding immunotherapy (Keytruda) first-line in people with BRAF mutations, even if PD-L1 levels are high since people with BRAF mutations appear less likely to respond.7

Colorectal Cancer

A large number of non-hereditary colon cancers have BRAF mutations, but studies using a combination of BRAF and MEK inhibitors showed a low response rate (roughly 5% with BRAF inhibition alone and 12% with the combination).

In the past, it was thought that the presence of a BRAF mutation might make a colon cancer unlikely to respond to an EGFR inhibitor, but this appears to depend on other genetic changes in the tumor. With colon cancer, tumors that have a BRAF mutation but not a KRAS mutation may not respond well to EGFR inhibitors such as cetuximab or panitumumab.

BRAF + MEK + EGFR Inhibitors

A 2019 study found that using triple therapy with the BRAF inhibitor Mektovi, the MEK inhibitor Braftovi, and the EGFR inhibitor Erbitux (cetuximab) resulted in a higher response rate and significantly longer survival among people with a BRAF V600E mutation.8

Resistance

Unfortunately, most tumors become resistant to these targeted therapies in time. Research is in place evaluating the resistance mutations that develop with hope that further targets can be identified and treated when resistance occurs.

 Sources

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Dagogo-Jack I, Martinez P, Yeap BY, et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res. 2019;25(1):158-165. doi:10.1158/1078-0432.CCR-18-2062

Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31:24-28. doi:10.1038.modpathol.2017.104

Lee HM, Morris V, Napolitano S, Kopetz S. Evolving Strategies for the Management of BRAF-Mutant Metastatic Colorectal Cancer. Oncology (Williston Park). 2019. 33(6):206-11.

Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nature Medicine. 2019. 25(6):941-946. doi:10.1038/s41591-019-0448-9

Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25(6):929-935. doi:10.1038/s41591-019-0474-7

Tan I, Stinchcombe TE, Ready NE, et al. Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study. Translational Lung Cancer Research. 2019;8(3):258-267. doi:10.21037/tlcr.2019.04.03

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632-1643. doi:10.1056/NEJMoa1908075

Takeda H, Sunakawa Y. Management of BRAF gene alterations in metastatic colorectal cancer: From current therapeutic strategies to future perspectives. Frontiers in Oncology. 2021;11. doi:10.3389/fonc.2021.602194

National Library of Medicine. MedlinePlus. BRAF genetic test.

Johns Hopkins Medicine. BRAF mutation and cancer.

Additional Reading

Dagogo-Jack I, Martinez P, Yeap BY, et al. Impact of BRAF mutation class on disease characteristics and clinical outcomes in BRAF-mutant lung cancer. Clin Cancer Res. 2019;25(1):158-165. doi:10.1158/1078-0432.CCR-18-2062

Dankner M, Rose AAN, Raijkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183-3199. doi:10.1038/s41388-018-0171-x

Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018; 36(35):3441-3449. doi:10.1200/jco.18.01219

Kwak M, Farrow N, Salama A, et al. Updates in adjuvant systemic therapy for melanoma. J Surg Oncol. 2019;119(2):222-231. doi:10.1002/jso.25298

Moujaber T, Etemadmoghadam D, Kennedy CJ, et al. BRAF Mutations in low-grade serous ovarian cancer and response to BRAF inhibition. JCO Precision Oncology. 2018;(2):1-14. doi:10.1200/PO.17.00221 

My Cancer Genome. BRAF V600E.

Ribas A, Lawrence D, Atkinson V, et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med. 2019;25(6):936-940. doi:10.1038/s41591-019-0476-5

U.S. National Library of Medicine. Genetics Home Reference. BRAF gene. Updated May 28, 2021

By Lynne Eldridge, MD
 Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time."