Melanoma is a heterogenous disease that can be difficult to diagnose and treat.⁴ In its early stages, melanoma can be successfully treated with surgery alone.⁴ However, survival rates fall significantly once melanoma has metastasised. Early and accurate diagnosis is therefore crucial for giving patients their best chance of survival.⁴

Improvements in the understanding of the mutational causes of melanoma have led to the development of treatments, including targeted therapies and immunotherapies. Offering a more personalised approach to treatment may not only contribute to improved prognosis for patients with melanoma, but help with cost savings and improved sustainability of healthcare systems.⁴

ABCDEs of melanoma⁵

A patient will usually consult their general practitioner (GP) if they have concerns about a suspect mole or skin lesion. The GP will use the simple visual ABCDE method to determine if the patient should be referred to a dermatologist or an oncologist for further tests.

Representation of a melanoma – ABCDE identification⁵

A. Asymmetry: the two halves of the area may differ in shape.
B. Border: the edges of the area may be irregular or blurred, and sometimes show notches.
C. Colour: this may be uneven. Different shades of black, brown and pink may be seen.
D. Diameter: change in size, usually an increase. Melanomas can be tiny, but most are larger than the size of a pea (>6 mm).
E. Evolution: change in size, shape, colour or other traits.

Staging melanoma^6–8

Staging has an impact on prognostic assessment and treatment decision making.⁴ There are several different staging systems in current use. The system most commonly used is the American Joint Committee on Cancer (AJCC) TNM system, which is based on tumour size (T), lymph node involvement (N) and metastasis (M).^6–8

Other staging systems used at biopsy include the Breslow Depth,⁹ that measures depth or thickness of the primary tumour, and the Clark Level,⁸ that examines the anatomical depth into subcutaneous tissue. These systems are not interchangeable, but offer useful measures when staging melanoma.⁷ These three systems are described below.

AJCC staging uses three pieces of information^7,8

TNM pathological staging overview^7,8

Breslow classification system⁹

Breslow Depth details the prognostic significance of the thickness of a melanoma. It is based on the depth of invasion in millimeters (mm) rather than the depth by anatomic compartments. Patients with thinner melanomas (Stages I and II) have a much better chance of survival and a lower risk of regional and distant metastasis than those with thicker melanomas (Stages III to V).⁷

Tumours are classified into four categories based on depth:⁷

Clark Level¹⁰

The Clark method looks at the invasion of melanoma cells into the dermis and subcutaneous fat, and the risk of spread to lymph nodes and distant organs.^6–8 There are five levels in the Clark staging system.

AJCC staging uses three pieces of information^7,8

Stage	Melanoma stage description	Prognosis (as of 2018)*10
Image	The tumour is only in the epidermis, the outer layer of the skin, and hasn’t spread deeper.	Highly curable, with very little risk for recurrence or metastasis. 5-year survival rate: 98.4%.
Image	The tumour is thicker than in Stage 0 and may have grown into the dermis, the dense inner layer of the skin, but is still relatively thin.	With appropriate treatment it is highly curable. Low risk for recurrence or metastasis. 5-year survival rate: 98.4%.
Image	The tumour is thicker than in Stage I and has grown past the epidermis into the dermis. At this stage, the melanoma has a higher chance of spreading.	With appropriate treatment it is considered intermediate to high risk for recurrence or metastasis. 5-year survival rate: 98.4%.
Image	The cancer has spread to one or more lymph nodes. There may also be ulceration. Stage III melanoma, which cannot be removed by surgery (resection), is classed as unresectable Stage III melanoma.	With appropriate treatment it is considered intermediate to high risk for recurrence or metastasis. 5-year survival rate: 63.6%.
Image	The cancer has spread to distant lymph nodes and/or other places in the skin or parts of the body, such as the lungs, liver, bones and brain. This stage is also known as metastatic melanoma.	The cancer has already metastasised and is therefore very difficult to cure. However, some patients respond well to treatment and can survive for many years post-diagnosis. 5-year survival rate: 22.5%.
*Melanoma treatments have improved significantly with the addition of immunotherapy and targeted therapies. These survival rates only partially reflect these advancements.10

Genetic mutations in many melanomas cause the tumour to grow out of control. The three most common mutations in melanoma are in BRAF, NRAS and c-KIT genes.¹² By identifying the mutations that have caused a particular patient’s cancer, a more personalised approach to treatment can be offered. The only mutation for which targeted therapy is available is for the BRAF gene.¹²

The efficacy and safety of trametinib have not been evaluated in patients whose melanoma tested negative for the BRAF V600 mutation and should not be used in these patients.^1,2

The role of the BRAF gene in melanoma

The RAS/RAF/MEK/ERK pathway, also known as the MAP kinase pathway (MAPK), is a critical pathway involved in normal cellular functions, but it may be disrupted in many human cancers, including melanoma.¹³ This pathway plays a key role in regulating the growth, proliferation, and survival of normal cells, including melanocytes.^14–16

Mutation of BRAF leads to activation of the MAPK pathway, which stimulates cellular growth and inhibits pro-apoptotic signals. This drives cellular proliferation in tumour cells, migration, survival, angiogenesis and potential metastasis.¹³

Schematic of the BRAF pathway in melanoma¹³

Adapted from Inamdar GS, et al. 2010.¹³

About 50% of melanomas have a BRAF mutation.¹⁴ Among the BRAF mutations in melanoma, >90% are at codon 600 known as BRAF V600 (also known as BRAF V600 mutation-positive or BRAF-positive melanoma).^12,13,17 V600E is a specific mutation in the BRAF gene that results in an amino acid substitution at position 600 in the BRAF protein: valine (V) is replaced by glutamic acid (E).¹³

Several studies showed that patients with a BRAF mutation are diagnosed with metastatic disease at an earlier age than patients with BRAF wild-type.¹⁷

Median age at diagnosis of distant metastases¹⁷

In a prospective study of Australian patients with metastatic melanoma (n=197), a comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.¹⁷

*m+: describes a mutation in the BRAF gene; BRAF WT: describes genes that have no mutations.

Due to the high percentage of melanomas harbouring a BRAF mutation, all melanoma patients should undergo BRAF mutation testing via a biopsy of the tumour to identify if the melanoma is BRAF-positive.¹¹

BRAF mutation testing methods

There are several molecular platforms and methods available to analyse the BRAF mutation status of melanoma tissue, such as first-generation (Sanger) sequencing, polymerase chain reaction (PCR), mass spectrometry base sequencing, next generation sequencing (NGS), high-resolution melting (HRM) analysis, pyrosequencing, and immunohistochemistry.

Each of these methods has different technical and practical advantages and certain limitations, which makes some methods better suited for particular settings and to the workflow in individual laboratories.

One important consideration when selecting the testing methodology is its ability to detect not just the V600E mutation but also other less-common mutations at this location (e.g. V600K and V600D).

Regional biomarker testing centres

In England, BRAF testing can be done as part of the NGS panel. You can find more information in the National Genomic Test Directory for cancer in England.¹⁸

Role of systemic therapies in the treatment of advanced melanoma

A greater understanding of the biology of melanoma has led to the development of drugs targeting underlying mutations, and the development of agents that modulate the immune system.¹³ The availability of these agents has helped improve the prognosis for patients with advanced melanoma (Stage III to Stage IV).¹⁴ 

Targeted therapies block cancer growth through interaction with specific molecules.²⁰ These therapies may switch-off uncontrolled signalling caused by a specific genetic mutation, or block one or more pathways to inhibit cell proliferation in the cancer cells.²⁰ Targeted therapies are usually administered as tablets or capsules, taken orally, a convenient option that allows for self-administration at home.²⁰ Some targeted therapies may be taken alone or in combination with other targeted therapies.^11,21–24

Immunotherapies stimulate the immune system to attack melanoma by recognising and destroying malignant cells. They are used to switch on or block certain aspects of the immune system pathways to improve the body’s natural immune response.¹⁹ These drugs are usually given as an intravenous infusion every few weeks in a healthcare setting, either as a single treatment or in combination with other types of treatment.^21–24

Chemotherapy destroys cells that are in the process of dividing into two cells, thereby stopping or slowing the growth of tumours. Chemotherapy drugs affect specific stages of a cell’s cycle, but they do not differentiate between malignant and healthy cells that have a rapid cell cycle, such as those in the gastrointestinal tract, bone marrow and hair follicles.²⁵

Milestones in melanoma diagnosis and treatment^26–33

Image 1975: Dacarbazine approved for Stage IV melanoma

Image 1984: Rose Ann Padua identifies activating NRAS mutations in melanoma for first time

Image 1992: Immunotherapy, IL-2 gains US approval

Image 2002: Helen Davies shows that activating BRAF mutations are evident in the majority of human cutaneous melanomas

Image 2011: Ipilimumab monotherapy in metastatic setting*28

Image 2012: Vemurafenib in metastatic setting*

Image 2013: TAFINLAR monotherapy in metastatic setting*

Image 2014: TAFINLAR monotherapy in metastatic setting; Dabrafenib + MEKINIST combination in metastatic setting*

Image 2018: TAFINLAR + MEKINIST in adjuvant setting; nivolumab in adjuvant setting;* encorafenib + binimetinib in metastatic setting

Image 2018: Pembrolizumab in adjuvant setting*

Image 2022: Nivolumab and relatlimab*