BRAF- DERMATOLOGIA

MOLECULARLY TARGETED THERAPY FOR METASTATIC MELANOMA

Author
Jeffrey A Sosman, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD
All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Nov 2014. | This topic last updated: Oct 06, 2014.
INTRODUCTION — Although the incidence of malignant melanoma is increasing, most
cases are diagnosed at an early stage. In that setting, surgical excision is curative in most
cases, and patients at high-risk of developing metastatic disease may benefit from
adjuvant therapy with interferon alpha [1]. (See "Initial surgical management of melanoma
of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)

The management of patients with disseminated disease is a difficult problem. Approaches

that have been shown to provide clinically important benefit for appropriately selected
patients with disseminated melanoma include immunotherapy with high-dose interleukin-
2 (IL-2), immunotherapy with ipilimumab (a monoclonal antibody targeting CTLA-4), and
inhibition of the MAP kinase pathway in patients whose tumors contain a V600 mutation
in the BRAF gene using either a BRAF inhibitor or a MEK inhibitor. There are no
randomized trials that compare targeted therapy with immunotherapy and there are no
prospective data on the appropriate sequencing of these therapies for patients with a
V600 BRAF mutation.

The use of targeted therapies in the treatment of advanced melanoma will be reviewed
here.

APPROACH TO TREATMENT — An understanding of the role of activation of the MAPK

pathway has led to the identification of several drug targets. This is resulting in the
development of important therapeutic approaches for the treatment of advanced
melanoma in various patient subsets (figure 1). These include inhibition of BRAF, MEK,
NRAS, and Kit.

The general approach to the treatment of advanced melanoma, and the integration of
targeted therapy with other treatment modalities is presented separately. (See "Overview
of the management of advanced cutaneous melanoma" and "The molecular biology of
melanoma".)

Mutation status of tumor — All patients with advanced cutaneous melanoma should have
their tumors assayed for the presence or absence of a driver mutation at the V600 site in
BRAF- DERMATOLOGIA

BRAF. Patients with an acral or mucosal primary tumor that does not contain a BRAF
mutation should have their tumor assessed for the presence of a driver mutation in KIT.

BRAF INHIBITION — Activating mutations in BRAF are present in approximately 40 to 60

percent of advanced melanomas [2-4]. In 80 to 90 percent of cases, this activating
mutation consists of the substitution of glutamic acid for valine at amino acid 600 (V600E
mutation) with most of the remainder consisting of an alternate substitution (lysine for
valine) at the V600 locus (V to K).

In one study, advanced melanomas with a mutation in BRAF appear to have some clinical
differences that are associated with a more aggressive clinical course [ 4]. In a consecutive
series of 197 patients at a single institution, the presence of mutant BRAF was significantly
more frequent in patients with a truncal primary, an earlier age of onset, and lack of
chronic skin damage. Furthermore, for patients not treated with a BRAF inhibitor, survival
was shorter overall.

Vemurafenib and dabrafenib, inhibitors of BRAF, have demonstrated dramatic antitumor

activity in phase III trials in patients with advanced disease whose tumors have
characteristic mutations in BRAF. However, virtually every patient treated with an inhibitor
of BRAF eventually has disease progression [ 5]. Additional data will be required to
determine whether different agents have a differential effect depending upon the specific
mutation present.

In an analysis from the large phase II BRIM-2 single arm trial of vemurafenib, tumor
samples were centrally collected and analyzed for mechanisms of resistance through use
of sequenom mutation analysis, Sanger DNA sequencing of MEK1 exons 2,3 and 6,and
immunohistochemistry for activation of MAP kinase pathway [ 6]. Nearly all tumors
demonstrated re-activation of the MAP kinase pathway with elevation of pERK at the time
of resistance. In some patients progression was associated with an
additional NRASQ61 mutation. In a small subset of patients, several MEK1 mutations were
found in association with resistance, which was the first time these mutations were found
in patient tumor samples. These included MEK1 Q56 and E203 mutations. On the other
hand MEK1P124L  was not associated with resistance and was seen de novo. All relapse
tumor specimens continued to demonstrate the BRAFV600mutation.

Vemurafenib — Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF.

Vemurafenib prolongs both progression-free and overall survival in melanoma patients
whose tumors contain a V600 mutation.

In the phase III BRIM-3 trial, 675 patients were randomly assigned to either vemurafenib
(960 mg twice a day) or dacarbazine (1000 mg/m2 intravenously every three weeks) [5].
Treatment was to be continued until disease progression. All patients had either
BRAF- DERMATOLOGIA

metastatic disease or unresectable stage IIIC disease (95 and 5 percent, respectively). The
co-primary endpoints of the trial were overall survival and progression-free survival.

Following a planned interim analysis based upon predetermined criteria, patients assigned
to dacarbazine were allowed to crossover to vemurafenib, and 25 percent of patients
assigned to dacarbazine were crossed over to vemurafenib. Approximately 20 percent of
patients on each treatment arm received treatment with ipilimumab. Patients assigned to
dacarbazine were censored at the time of crossover to vemurafenib.

With a median follow-up of 12.5 months for patients treated with vemurafenib and 9.5
months for those initially receiving dacarbazine, the following results were observed [7]:

●For the entire study population, overall survival was significantly prolonged with
vemurafenib compared with dacarbazine (13.6 versus 9.7 months, hazard ratio [HR] 0.70,
95% CI 0.57-0.87). Progression-free survival was also significantly prolonged (6.9 versus 1.6
months, HR 0.0.38, 95% CI 0.32-0.46)

●For the 598 patients with a V600E mutation, overall survival was significantly prolonged
with vemurafenib (13.3 versus 10.0 months), as was the progression free survival (6.9
versus 1.6 months).

●For the 57 patients with a V600K mutation, overall survival was prolonged with
vemurafenib (14.5 versus 7.6 months) as was the progression free survival (5.9 versus 1.7
months).

The toxicity observed with vemurafenib is discussed below. (See 'Toxicity from BRAF
inhibition' below.)

Dabrafenib — Dabrafenib is another BRAF kinase inhibitor that has demonstrated

significant activity in patients with advanced melanoma compared with dacarbazine
chemotherapy. Dabrafenib was approved by the US Food and Drug Administration in May
2013 for the treatment of patients with advanced melanoma that contains the V600E
mutation of BRAF [8].

In the pivotal phase III trial, 250 patients with unresectable stage III or stage IV melanoma
were randomly assigned in a 3:1 ratio to either dabrafenib (150 mg orally twice a day) or
dacarbazine (1000 mg/m2 IV every three weeks) [8,9]. All patients had the V600E mutation
in BRAF.

The primary endpoint of the trial was progression-free survival (PFS) as ascertained by the
investigators; the PFS was independently reviewed as a secondary trial endpoint. Patients
were allowed to cross over to the alternative treatment upon the development of
progressive disease.
BRAF- DERMATOLOGIA

●Dabrafenib significantly increased PFS compared with dacarbazine (median 5.1 versus 2.7
months, HR 0.33, 95% CI 0.20-0.54). Based upon independent review of the data, the PFS
was similarly increased (6.7 versus 2.9 months, HR 0.35, 95% CI 0.20-0.61).

●Objective responses, as assessed by the independent review committee, were seen in 93

of 187 patients treated with dabrafenib (50 percent), including six cases (3 percent) with a
complete response. Among those treated with dacarbazine there were four partial
responses in 63 cases, for an overall response rate of 6 percent.

●Overall survival was updated at the 2013 ASCO meeting [ 10]. With a median follow-up of
15 and 13 months for the two groups, overall survival favored patients treated with
dabrafenib (HR 0.76, 95% CI 0.48-1.21), but was not statistically significant. However, 36 of
63 patients (57 percent) originally treated with dacarbazine crossed over to dabrafenib,
potentially obscuring an overall survival benefit from initial dabrafenib therapy.

●Treatment with dabrafenib was generally well tolerated. Like vemurafenib, the most
frequent grade 2 or greater toxicities were dermatologic. Other grade 2 or greater
toxicities observed in between 5 and 15 percent of cases included arthralgia, fatigue,
headache, and fever. (See 'Toxicity from BRAF inhibition' below.)

Duration of BRAF inhibition — Most patients treated with BRAF inhibition develop

progressive disease while on therapy. Tumor heterogeneity within an individual patient
provides the rationale for continuing BRAF inhibition, if there is only slowly progressive
disease present [11,12].

A retrospective, single institution analysis of 95 patients who had progressive disease

while on BRAF inhibitor therapy found that 31 percent had progression at a single site, and
that continued treatment beyond the initial progression was associated with prolonged
survival [13].

The optimal approach to managing patients whose tumors have progressed while on
treatment with a BRAF inhibitor (with or without MEK inhibition) remains an area of active
investigation.

Brain metastases — Both vemurafenib and dabrafenib have activity in patients with brain
metastases. The results of clinical studies in this setting and the role of these agents in the
management of brain metastases in patients with melanoma are discussed separately.
(See "Management of brain metastases in melanoma", section on 'Targeted therapy'.)

Toxicity from BRAF inhibition — The most common toxicities associated with BRAF
inhibition include dermatologic complications (rash, photosensitivity reactions,
hyperkeratosis), arthralgia, fatigue, alopecia, nausea, and diarrhea. These have all been
reported in 15 percent or more of patients in extended postmarketing experience [14].
BRAF- DERMATOLOGIA

Toxicities of particular concern and those associated with particular agents are discussed
in this section.

Cutaneous toxicity and secondary tumors — Clinically significant cutaneous side effects

are common with both vemurafenib and dabrafenib [ 15,16]. These include squamous cell
carcinomas, including keratoacanthomas, in 19 to 26 percent of cases [ 17]. These skin
tumors occur within weeks of initiation of treatment with these BRAF inhibitors and are
generally treated with excision. The development of such lesions did not require
discontinuation of therapy. (See "Keratoacanthoma: Management and prognosis".)

In addition, in the BRIM-3 trial comparing vemurafenib with dacarbazine, 8 of 337 (2.4
percent) patients assigned to vemurafenib developed a second primary melanoma [ 5,18].
Similarly, 3 of 187 patients in the phase III dabrafenib trial developed new melanomas [ 8].
Patients with advanced melanoma are at risk for development of further primary
melanomas; whether the incidence rates in patients treated with BRAF inhibitors is higher
than in those not receiving these agents is not clear [19].

Molecular studies indicate that these squamous cell carcinomas and keratoacanthomas
are due to a paradoxical activation of the mitogen activated protein kinase MAPK pathway
that bypasses the inhibition of BRAF [20]. Furthermore, the short latency period until the
development of these skin lesions is consistent with the presence of preexisting RAS
mutations in the skin that enhance their activation of downstream proteins in the MAPK
pathway when subjected to BRAF inhibition.

Data from studies of the combination of a BRAF inhibitor and a MEK inhibitor indicate that
there is a reduced incidence of skin toxicity including the development of skin cancers,
presumably by the MEK inhibitor blocking this paradoxical activation of the MAPK
pathway. (See 'Combined MEK plus BRAF inhibition' below.)

At least one case report has observed rapid progression of a chronic myelomonocytic
leukemia that was associated with a RAS mutation concurrent with the initiation of
vemurafenib therapy [21]. As experience with BRAF inhibitors increases, it is possible that
progression of other malignancies associated with RAS may also be observed. It is
hypothesized that the combination of a BRAF inhibitor and a MEK inhibitor could reduce
the incidence of such cancers similar to that seen with skin cancers, although this remains
to be determined.

A spectrum of other cutaneous toxicities (rash, photosensitivity reactions, alopecia, etc)

are common with both vemurafenib and dabrafenib, and may be somewhat more
common with vemurafenib [8,17]. (See "Cutaneous complications of molecularly targeted
therapy and other biologic agents used for cancer therapy", section on 'Vemurafenib and
dabrafenib'.)
BRAF- DERMATOLOGIA

Other toxicities — Other toxicities frequently reported with both BRAF inhibitors include
arthralgias, headache, and weakness or fatigue [5,8,9]. Ocular toxicity (including uveitis,
conjunctivitis, dry eyes) has been reported with both vemurafenib and dabrafenib [8,22].

There are other clinically significant toxicities that appear to be specific to each agent
rather than being a class effect. A full understanding of the frequency and mechanism of
less common toxicities will require additional clinical experience.

Vemurafenib — Areas of specific concern associated with vemurafenib include:

●Prolongation of the QT interval can occur with vemurafenib administration. Vemurafenib

is a CYP3A4 substrate, and it should be used with caution in patients with congenital long
QT syndrome and those who are receiving other drugs that prolong the QT interval (table
1) or inhibit CYP3A4 (table 2). The FDA-approved manufacturers’ labeling recommends
that ECG and electrolytes be monitored before treatment and after dose modification.
(See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on
'Vemurafenib'.)

●Peripheral facial palsy has been reported and may be bilateral [23].

●Severe radiation dermatitis has been reported in patients who receive radiation therapy
for a localized symptomatic area while being treated with a BRAF inhibitor [24].

●A decrease in creatinine clearance has been reported in patients treated with

vemurafenib, generally occurring in the first two months of therapy [25-27]. Recovery
after treatment has been variable.

Dabrafenib — Areas of specific concern associated with dabrafenib include:

●Febrile reactions are relatively common and were reported in 28 percent of patients in
the phase III trial. In approximately 4 percent of cases, these were severe and required
drug discontinuation or dose modification.

●Hyperglycemia severe enough to require treatment was observed in 6 percent of cases.

MEK INHIBITION — The MEK inhibitor trametinib has significant clinical activity in

melanoma patients whose tumor contains a V600 BRAF mutation; several other BRAF
inhibitors are under development.

Trametinib — Trametinib is a potent, highly specific inhibitor of MEK1/MEK2.

●Trametinib was originally approved for the treatment of patients who had previously
been treated with a BRAF inhibitor for advanced melanoma that contained a BRAF V600E
BRAF- DERMATOLOGIA

or V600K mutation [28]. This approval was based upon prolongation of overall survival
using trametinib as a single agent in patients who had not received prior treatment with a
BRAF inhibitor.

●Subsequently, trametinib was approved by the US Food and Drug Administration for use
in combination with dabrafenib as the initial targeted therapy for patients whose
melanoma contained a BRAF V600E or V600K mutation [ 29]. (See 'Combined MEK plus
BRAF inhibition' below.)

Efficacy as a single agent — The efficacy of trametinib as a single agent was demonstrated

in the phase III METRIC trial, in which 322 patients with advanced melanoma were
randomly assigned in a 2:1 ratio to either trametinib (2 mg/day orally) or chemotherapy
(dacarbazine or paclitaxel) [28,30]. All patients had either the V600E or V600K mutation in
their melanoma (87 and 13 percent, respectively). One third of patients had received prior
chemotherapy and 30 percent had received prior immunotherapy, but prior BRAF inhibitor
therapy was not allowed. Crossover to trametinib was permitted in patients who
progressed on chemotherapy.

Key results included the following:

●Progression-free survival, the primary endpoint of the trial, was significantly increased
with trametinib compared with chemotherapy (median 4.8 versus 1.5 months, HR 0.47,
95% CI 0.34-0.65).

●Overall survival was significantly improved with trametinib (6 month survival rate 81
versus 67 percent, HR for death 0.54, 95% CI 0.32-0.92), even though 47 percent of
patients who progressed on chemotherapy received secondary treatment with trametinib.

●The improvements in progression-free survival (PFS) and overall survival were present in
all patient subsets, including those with brain metastases or other visceral metastases
(M1c).

In a separate study, 40 patients who had received prior treatment with a BRAF inhibitor
were treated with trametinib [28]. No partial responses were observed.

Trametinib plus dabrafenib — Trametinib has been combined with dabrafenib, a BRAF

inhibitor, in an effort to delay the development of resistance to treatment and to minimize
the toxicity associated with BRAF inhibition. (See 'Dabrafenib plus trametinib' below.)

Toxicity — Cutaneous toxicity was reported by 87 percent of patients in the phase III trial.
This was severe in 12 percent of cases and required hospitalization in 6 percent of
patients. Other common side effects included diarrhea and edema in 43 and 26 percent of
cases, respectively.
BRAF- DERMATOLOGIA

Less common toxicities of particularly concern identified during the phase III trial or in the
expanded clinical trials experience with trametinib included [28]:

●A decreased cardiac ejection fraction was seen in 7 percent of patients treated with
trametinib in the phase III trial, and this led to discontinuation of trametinib in four cases
(2 percent) and dose reduction in seven cases (3 percent).

●Interstitial lung disease was reported in approximately 2 percent of cases.

●Visual problems, due to retinal detachment and retinal vein occlusion (0.5 and 0.2
percent of cases).

Other MEK inhibitors

Cobimetinib — Cobimetinib is a highly selective inhibitor of MEK. It has been evaluated

extensively in combination with vemurafenib. (See 'Vemurafenib plus cobimetinib' below.)

Binimetinib — Binimetinib is a specific inhibitor of MEK that has demonstrated activity in

patients with advanced melanoma and a mutation of NRAS.

Binimetinib was studied in a phase II study in 71 patients with advanced melanoma and
either a V600 BRAF mutation or an NRAS mutation (41 and 30 cases, respectively) [ 31]. At
a median follow-up of three months, partial responses were observed in 8 of 41 cases with
BRAF mutation (20 percent) and 6 of 30 patients with NRAS mutation (20 percent). The
rates of objective response plus stable disease were 52 and 63 percent, respectively, for
those with BRAF and NRAS mutations [32].

The combination of binimetinib plus a BRAF inhibitor is being compared in a phase III trial
with BRAF inhibition alone. (See 'Encorafenib plus binimetinib' below.)

A phase III trial comparing binimetinib versus dacarbazine in patients with advanced NRAS
mutation positive melanoma is planned (NCT01763164). Binimetinib is also being studied
in combination with a CDK4/6 inhibitor as a way to enhance its activity in patients with
NRAS mutant [33]. Significant antitumor responses were noted in one-third of patients,
stimulating further interest in this combination.

Selumetinib — Selumetinib is another MEK inhibitor that was compared with

temozolomide in a randomized, phase II trial that included 200 patients with previously
untreated, unresectable stage III or IV melanoma [ 34]. Patients were not selected based
upon their BRAF mutation status. There was no significant difference in progression-free
survival, the primary endpoint of the trial. In a retrospective analysis, 5 of 45 (11 percent)
patients with a BRAF mutation had an objective tumor response.
BRAF- DERMATOLOGIA

In addition, selumetinib has been combined with chemotherapy in two randomized phase
II studies. In one, selumetinib plus dacarbazine was compared with dacarbazine alone in
91 patients who were selected based upon the presence of a BRAF mutation [ 35]. The
combination significantly improved progression-free survival but did not improve overall
survival. In the other, the combination of selumetinib plus docetaxel was compared with
docetaxel alone in 83 patients [36]. There was a trend toward an increased objective
response rate, but there was no significant difference in the progression-free survival or
overall survival.

COMBINED MEK PLUS BRAF INHIBITION — Two different combinations of BRAF inhibitors

plus MEK inhibitors have been shown to yield a higher response rate, longer progression-
free survival (PFS), and possibly longer overall survival compared with BRAF inhibition
alone.

Dabrafenib plus trametinib — Trametinib has been combined with dabrafenib, a BRAF

inhibitor, in an effort to delay the development of resistance to treatment and to reduce
some toxicities directly associated with BRAF inhibition.

Based upon phase I and phase II results [37,38], the phase III COMBI-d trial randomly
assigned 423 patients to either dabrafenib plus trametinib or to dabrafenib plus placebo
[39]. All patients had advanced melanoma with a V600E or V600K mutation, and all were
previously untreated. The primary objective of the study was investigator determined
progression-free survival, and secondary objectives included overall survival, objective
response rate, and toxicity.

●At a median follow-up of nine months, progression-free survival was significantly

prolonged with the combination compared with dabrafenib alone (median 9.3 versus 8.8
months, hazard ratio [HR] 0.75, 95% CI 0.57-0.99). More patients (18 versus 6) treated
with dabrafenib plus placebo were censored early, largely due to symptomatic disease
progression prior to formal imaging, and therefore excluded from the PFS calculation,
perhaps explaining the greater than anticipated median PFS on this arm.

●The objective response rate (complete plus partial) was significantly improved (67 versus
51 percent) with the combination.

●Overall survival was improved with the combination (HR 0.63, 95% CI 0.42-0.94).
However, this was not sufficient to terminate the study due to the low number of deaths,
and additional follow-up for overall survival will be required.

●There were substantial differences in toxicity. Toxicities that were decreased with the
combination of dabrafenib plus trametinib include the incidence of cutaneous squamous
cell carcinoma and keratoacanthoma (2 versus 9 percent), hyperkeratosis (3 versus 32
percent), skin papilloma (1 versus 21 percent), hand-foot syndrome (5 versus 27 percent),
BRAF- DERMATOLOGIA

and alopecia (7 versus 26 percent). Toxicities more frequently associated with the
combination included diarrhea (24 versus 14 percent) and hypertension (22 versus 14
percent).

●Dose interruptions were significantly more frequent with the combination. This was due
to the increased incidence of pyrexia and chills associated with the combination, relative
to dabrafenib alone (51 versus 28 percent, and 30 versus 16 percent, respectively).

A second phase III is comparing the combination of dabrafenib plus trametinib with
vemurafenib plus placebo (NCT01597908).

Vemurafenib plus cobimetinib — Based upon the results of a phase I trial [ 40], the
combination of vemurafenib plus cobimetinib was evaluated in a phase III in which 495
patients with previously untreated advanced melanoma were randomly assigned to
vemurafenib plus cobimetinib or vemurafenib plus placebo [41]. All patients’ tumors
contained a V600 mutation.

Results included the following:

●Progression-free survival, the primary endpoint of the trial, was significantly increased
with vemurafenib plus cobimetinib compared with vemurafenib plus placebo (median 9.9
versus 6.2 months, HR 0.51, 95% CI 0.39-0.68).

●The complete plus partial response rate was increased with vemurafenib plus
cobimetinib (68 versus 45 percent, p<0.001).

●There was a trend toward longer overall survival with vemurafenib plus cobimetinib,
although longer follow-up will be required (nine month survival rate 81 versus 73 percent,
HR 0.65, 95% CI 0.42-1.00).

Encorafenib plus binimetinib — Encorafenib (LGX818) plus binimetinib – Phase I results

with the combination of the novel BRAF inhibitor encorafenib plus binimetinib have led to
the initiation of a phase III trial [42], in which this combination is being compared with
vemurafenib alone and LGX818 alone (NCT01909453).

KIT INHIBITION — Mutations in c-kit are seen in approximately 15 to 20 percent of

patients with acral or mucosal melanomas and in a smaller percentage of melanomas
arising in areas of chronic skin damage. Phase II studies using imatinib in unselected
groups of patients with advanced melanoma demonstrated only minimal evidence of
activity [43-45].

However, kit inhibitors have useful clinically activity in some patients with activating
mutations of the c-kit gene. Additional studies using targeted inhibitors are in progress in
BRAF- DERMATOLOGIA

selected patient populations with mutations of c-kit; results are pending. The data
supporting the use of kit inhibitors is discussed in conjunction with their use for patients
with mucosal melanomas. (See "Mucosal melanoma", section on 'Targeted therapy'.)

ANGIOGENESIS  — Numerous angiogenesis-promoting molecules are overexpressed in

melanoma, including VEGF, PDGF, fibroblast growth factor, and interleukin-8. The
expression of these factors has been associated with a poorer prognosis in patients with
melanoma. Inhibition of small molecule tyrosine kinases and the monoclonal antibody
bevacizumab, which binds to VEGF, have been most extensively studied.

Sorafenib — Sorafenib blocks BRAF, as well as tyrosine kinases associated with vascular

endothelial growth factor and platelet derived growth factor. However, sorafenib does not
block the V600E mutated oncogenic BRAF.

Although sorafenib appeared to have antitumor activity when combined with

chemotherapy in phase II studies [46-48], two randomized phase III trials failed to confirm
any benefit from combining sorafenib with cytotoxic chemotherapy [ 49,50]. There is no
rationale at present for the clinical use of sorafenib either as a single agent or in
combination with chemotherapy in patients with advanced melanoma, regardless of their
V600 mutation status.

Axitinib — Axitinib, a potent inhibitor of multiple vascular endothelial growth factor

receptors, was evaluated in a phase II study that included 32 patients with metastatic
melanoma, 25 of whom had received one prior systemic treatment modality [ 51]. The
objective response rate was 19 percent, and the median progression-free and overall
survival durations were 2.9 and 6.6 months. Additional clinical trials will be required to
determine whether axitinib has a role in patients with metastatic melanoma, either alone
or in a combination regimen.

Bevacizumab — Several small phase II studies evaluating bevacizumab, either alone or in

combination with interferon-alfa or chemotherapy (paclitaxel, carboplatin), showed
evidence of activity in patients with advanced melanoma [52-54].

Based upon these results, the randomized Bevacizumab in Advanced Melanoma (BEAM)
phase II trial was conducted, in which 214 patients were treated with carboplatin plus
paclitaxel, with or without bevacizumab [55]. In the planned analysis with a median follow-
up of 13 months, progression-free survival and overall survival were better with
bevacizumab (5.6 versus 4.2 months, p = 0.14 and 12.3 versus 8.6 months, p = 0.04). The
combination with bevacizumab resulted in a higher response rate (25.5 versus 16.4
percent, p = 0.16). Although the overall data only showed a trend toward benefit, in the
subset of patients with M1c disease, particularly those with high LDH, there was significant
overall survival benefit. A randomized phase III trial is being considered in this subset of
patients to prospectively validate this observation.
BRAF- DERMATOLOGIA

APOPTOSIS PATHWAY

Oblimersen — Oblimersen is an antisense oligonucleotide that suppresses expression of

Bcl-2, a key anti-apoptotic protein in malignant cells. Although results from an initial phase
III trial suggested that the agent had promising results in one subset [ 56], these findings
were not confirmed in a second trial [57].

COMENTARIO

● La proteína activada por mitógeno (MAP) quinasa vía se compone de varios objetivos importantes para la terapia
del melanoma. Las mutaciones específicas en BRAF, que están presentes en aproximadamente el 40 a 60 por ciento
de los melanomas cutáneos avanzados, pueden estimular esta vía. Los pacientes con melanoma metastásico
deberían haber evaluado tejido para la presencia o ausencia de la mutación V600 en el gen BRAF.

● La presencia de una mutación V600E o K predice la capacidad de respuesta a los inhibidores de BRAF o la
inhibición de MEK. Tres agentes han demostrado beneficio clínico significativo y han sido aprobados para su uso en
pacientes con mutaciones BRAF: los inhibidores de BRAF vemurafenib y dabrafenib y el trametinib inhibidor de
MEK. No hay ensayos clínicos que comparan estos tres agentes entre sí; Sin embargo, los datos sugieren que los
inhibidores de BRAF, vemurafenib y dabrafenib, son más activos que el trametinib inhibidor de MEK. Dabrafenib y
vemurafenib parecen tener una actividad clínica similar, así que la elección entre estos dos agentes es probable que
se basa en otros factores, incluyendo sus perfiles de toxicidad distintos

● La combinación de dabrafenib y trametinib tiene una supervivencia libre de progresión y una mayor tasa de
respuesta objetiva en comparación con dabrafenib solo. No parece haber una mayor supervivencia global con este
enfoque en el estudio de fase II, pero se requiere mayor tiempo de seguimiento en el ensayo de fase III para una
conclusión definitiva al respecto. La combinación también se asoció significativamente con una menor toxicidad de
la piel, pero mayor pirexia y escalofríos. Para los pacientes que son candidatos para la terapia dirigida, se
recomienda iniciar los pacientes con la combinación de dabrafenib y trametinib en lugar de un único agente (Grado
1B).

● Para los pacientes con una mutación BRAF V600 y un buen estado general, se aconseja la inmunoterapia en lugar
de la terapia dirigida como la terapia sistémica inicial (Grado 2C).

• Para los pacientes con una mutación BRAF V600, que fueron tratados inicialmente con inmunoterapia y cuya
enfermedad ya no puede ser controlada con la terapia de la inmunoterapia utilizando altas dosis de IL-2 o
ipilimumab, recomendamos centramos en lugar de la quimioterapia (Grado 1A).

● Los pacientes con una mutación BRAF V600 y enfermedad voluminosa, las metástasis viscerales, una LDH sérica
elevada (enfermedad M1c (tabla 3A-B)), o un estado funcional pobres tienen más probabilidades de tener la
enfermedad rápidamente progresiva y una menor supervivencia global. En esta situación, se sugiere la terapia en
lugar de la inmunoterapia (Grado 2C) dirigida.

● La terapia dirigida con inhibidores de BRAF no está indicado en pacientes sin mutación BRAF V600 característica.

● Para los pacientes sin una mutación BRAF V600, pero con una mutación KIT, el uso de un inhibidor de KIT (por
ejemplo, imatinib) puede proporcionar una importante opción de tratamiento, de preferencia en el contexto de un
ensayo clínico formal.menor supervivencia global. En esta situación, se sugiere la terapia en lugar de la
inmunoterapia (Grado 2C) dirigida.
BRAF- DERMATOLOGIA

REFERENCES

Cole BF, Gelber RD, Kirkwood JM, et al. Quality-of-life-adjusted survival analysis of
1 interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an
Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14:2666.
Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol
2
2010; 80:561.
Smalley KS, Sondak VK. Melanoma--an unlikely poster child for personalized cancer
3
therapy. N Engl J Med 2010; 363:876.
Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of
4
oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011; 29:1239.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in
5
melanoma with BRAF V600E mutation. N Engl J Med 2011; 364:2507.

THE MOLECULAR BIOLOGY OF MELANOMA

Authors
Ryan J Sullivan, MD
David E Fisher, MD, PhD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: Nov 2014. | This topic last updated: Mar 24, 2014.
INTRODUCTION — Melanoma is currently the fifth and seventh most common cancer in
American men and women, respectively, and its incidence has risen dramatically [ 1].
(See "Risk factors for the development of melanoma", section on 'Epidemiology'.)

Although patients with localized disease can be treated successfully with surgical
resection in the majority of cases, some individuals present with or subsequently
develop disseminated disease. The prognosis for patients with distant metastases from
melanoma is poor, and the vast majority of those with stage IV melanoma will die from
their disease.

An increasing understanding of melanocyte biology and melanoma pathogenesis is

leading to the development of targeted therapies and the potential for major
improvements in the care of patients with advanced melanoma. The most important
breakthroughs have been the discovery that the mitogen activated protein kinase
(MAPK) pathway is the key signaling pathway and the elucidation of the critical role of
microphthalmia-associated transcription factor (MITF).

This topic provides an overview of melanocyte biology and the important molecular
alterations of genes and signaling pathways that are critical to thedevelopment and
BRAF- DERMATOLOGIA

pathogenesis of melanoma. The clinical results with targeted agents that are being
developed based upon this information are discussed separately. (See "Molecularly
targeted therapy for metastatic melanoma".)

MELANOCYTE BIOLOGY — Melanocytes are the pigment-containing cells of the skin that

produce melanin in response to stimuli such as ultraviolet (UV) radiation. Melanocytes
also make the pigment that determines skin and hair color.

Melanocytes are derived from pluripotent neural crest stem cells. Melanocyte
development is modulated by the KIT and microphthalmia-associated transcription
factor (MITF), factors that are mutated or amplified oncogenes in a fraction of
melanomas [2].

Alpha-melanocyte stimulating hormone (MSH) is a pro-pigmentation peptide that

stimulates the melanocortin 1 receptor (MC1R) on the surface of melanocytes [ 3]. The
MC1R gene exists in numerous variant (polymorphic) forms; non-signaling variants
produce the red-hair/fair-skin phenotype, which is associated with an increased risk of
melanoma and non-melanoma skin cancers [4].

Intracellular cAMP induction downstream of MC1R activates the expression of

microphthalmia-associated transcription factor (MITF), which stimulates transcription of
numerous genes that participate in the conversion of tyrosine into melanin pigments.
Stimulation of cutaneous pigmentation following UV exposure (tanning) is thought to
occur via keratinocyte DNA damage, p53-mediated induction of POMC/MSH expression,
followed by secretion of MSH and stimulation of MC1R in epidermal melanocytes [5].

Cutaneous UV exposure may induce behavioral effects, perhaps related to endorphin

components of the POMC/MSH complex, which may produce an addiction to sun
bathing and therefore contribute to the increase in melanoma incidence observed over
recent decades [6]. “Rescue” of this cAMP-MITF-pigment cascade has been achieved via
topical drug delivery in mouse models and confers protection against UV-induced
carcinogenesis [7,8].

MAPK PATHWAY — The mitogen activated protein kinase (MAPK) pathway is activated

in almost all melanomas (figure 1) [ 9]. In nonmalignant cells, the interaction between a
growth factor receptor and its ligand is required to activate this pathway. This leads to a
series of events that promote cellular growth and survival. The RAS family members are
G-proteins, which serve as critical mediators in the transduction of such signals.

NRAS mutations have been identified in 10 to 15 percent of melanomas and are thought
to be an important driver of oncogenesis [ 10-13]. A somatic mutation in the NRAS gene
can cause constitutive activity of the NRAS protein, which is thus incapable of being
“turned off”. This leads to the serial activation of serine/threonine kinases, which
BRAF- DERMATOLOGIA

promotes cell cycle progression, cellular transformation, and increased cell survival. In
addition, this cascade of events may be mediated through the
overexpression and/or hyperactivation of various growth factor receptors, such as c-
Met, epidermal growth factor receptor (EGFR), and KIT, as well as through the loss of
function of the neurofibromatosis 1 (NF1) tumor suppressor gene that acts to suppress
NRAS signaling [14-17].

The most important downstream mediators of activated RAS are

the serine/threonine kinases BRAF and CRAF, which are activated following RAS binding
(figure 1) [18,19]. In contrast to BRAF, activation of the pathway by CRAF requires
additional steps, whereas activation of BRAF alone is sufficient. This may explain why an
activating mutation in the BRAF kinase domain is present in 40 to 50 percent of patients
with melanoma, but there are no descriptions of activating mutations of CRAF [20-22].

Following activation, RAF, typically in the form of either a homo- or heterodimer,

interacts with the MAPK/Extracellular signal-regulated kinase (ERK) Kinase MEK thereby
initiating MEK phosphorylation, which in turn leads to an activating phosphorylation of
ERK, its only known substrate [18,23,24]. The activation of ERK leads to a pro-growth
and transforming signal, through its interaction with a number of molecules, which
appears to be critical to the pathogenesis of many malignancies.

Molecular characterization of melanocytic lesions — BRAF mutations appear to be an

acquired event that occurs in early invasive melanoma and leads to clonal expansion
and tumor progression. The BRAF mutation thus is not a founder event but rather
facilitates malignant transformation with the acquisition of subsequent oncogenic
stimuli. Evidence supporting this interpretation includes the following:

●BRAF mutations are common in melanocytic nevi, vertical growth phase melanomas,
and metastatic melanoma (70 to 80, 40 to 50, and 40 to 50 percent, respectively).
However, BRAF mutations are rarely detected in radial growth phase melanomas or in
situ melanoma (10 and 6 percent, respectively), which are thought to be the initial
malignant lesions prior to development of frankly invasive lesions [22,25-27].

●Polyclonality (ie, BRAF mutated cells mixed with BRAF wild type cells) has been
observed in both atypical nevi and primary melanomas, though such polyclonality has
not been seen in individual metastatic tumors nor in tumors from distinct sites in an
individual patient [9,28,29].

These findings can be viewed as contradicting the popularly held belief that BRAF
mutation precedes all other oncogenic events in BRAF mutant melanoma, based
primarily on the fact that BRAF mutations are present in 70 to 80 percent of dysplastic
nevi [25]. However the precise relationship between nevi and melanomagenesis
remains incompletely understood. Further elucidation of the mechanisms of
BRAF- DERMATOLOGIA

transformation in BRAF mutant melanoma is needed. Irrespective of the mechanism,

however, when these BRAF mutations occur in invasive melanoma, the resultant
constitutive activation of MEK (and subsequently ERK) leads to oncogenesis through the
promotion of cellular growth and opposition of apoptosis, as well as to the strict
reliance of these cells upon the signaling cascade [30].

Genetic abnormalities in melanoma — Genomic mutations and/or aberrations are

present in the majority of melanomas [9,31]. These can lead to activation of the MAPK
pathway and create an oncogenic addiction to the mutated or hyperactivated protein.
Within this pathway, the patterns of mutation frequencies for each subtype differ
significantly [31-39].

Cutaneous melanoma — In cutaneous melanoma, BRAF and NRAS mutations are the
most frequently observed (40 to 50 and 15 to 20 percent of cases, respectively) [ 10-
13,22]. BRAF and NRAS mutations are more common in cutaneous melanomas without
chronic sun damage (CSD) compared with those associated with CSD (60 versus 6 to 22
percent and 20 to 22 versus 0 to 15 percent, respectively), whereas mutations in c-kit
are more common in CSD skin than in non-CSD skin (15 to30 percent versus <1 percent
in Caucasians and up to 11 percent in Asians populations) [ 31,40,41]. Except in rare
cases and in the setting of BRAF inhibitor therapy resistance, activating BRAF, NRAS, and
c-kit mutations are mutually exclusive [ 42]. Additionally, BRAF V600E mutations are
more common in females, younger patients, and in non-CSD skin than the second most
common BRAF mutations, BRAF V600K [43,44].

Inhibitors of both BRAF (vemurafenib, dabrafenib) and MEK (trametinib) have been
shown to prolong overall survival and in patients with cutaneous derived advanced
melanoma containing the mutations in V600. (See "Molecularly targeted therapy for
metastatic melanoma", section on 'BRAF inhibition' and "Molecularly targeted therapy
for metastatic melanoma", section on 'MEK inhibition'.)

Uveal melanomas — In uveal melanoma, the MAPK pathway is upregulated by an

activating mutation in either of the g-proteins GNAQ or GNA11, which together are
observed in over 80 percent of cases. Mutations in BRAF, NRAS, and KIT are rarely, if
ever, seen in uveal melanoma [32,33].

GNAQ and GNA11 — In patients with uveal melanoma, somatic mutations in either of
the homologous GNAQ or GNA11 genes can activate the MAP kinase pathway [ 33].
These mutations are either at the Q209 position of exon 5 or less frequently at the R183
position in exon 4. The oncogenic potential of these mutations and their ability to
activate the MAP kinase pathway through the upregulation of protein kinase C (PKC) has
been confirmed in murine models.

The potential importance of this pathway in patients with uveal melanoma was
BRAF- DERMATOLOGIA

illustrated by a series of 187 patients with uveal melanocytic tumors [ 33]. Somatic
mutations were identified in about 80 percent of cases. In 139 blue nevi, a cutaneous
lesion associated with uveal melanoma, mutations were present in over 60 percent of
cases. Of potential importance, GNAQ mutations were proportionally more common in
blue nevi and primary uveal melanomas while GNA11 mutations predominated in
metastatic uveal melanoma deposits. Due to the reliance of ocular melanoma
on GNAQ/GNA11mutations driving MAPK signaling, it is not surprising that as a proof of
concept, the MEK inhibitor selumetinib was shown to improve progression-free survival
in patients with uveal melanoma in a randomized study compared with dacarbazine
[45]. Additional studies exploring the combinations of MEK plus AKT and MEK plus PKC
therapy are underway. (NCT01941927, NCT01801358) (See "Uveal and conjunctival
melanomas", section on 'Molecularly targeted agents'.)

In contrast, these somatic mutations in GNAQ and GNA11 were absent in all nine cases
of conjunctival melanoma, and a somatic mutation in these genes was identified in only
1 of 273 cases of extraocular melanoma (0.4 percent).

BRCA1-associated protein 1 (BAP1) — Monosomy of chromosome 3 has been

associated with the development of metastatic disease in patients with uveal melanoma
but is rare in patients with cutaneous melanoma [ 46-51]. As an example, genetic
analysis of fine needle aspirates found that partial or complete monosomy of
chromosome 3 was present in 27 and 25 percent of cases in a series of 500 uveal
melanomas [51]. The presence of complete monosomy was associated with significantly
poorer survival at three years.

Somatic mutations in the gene encoding BRCA1-associated protein 1 (BAP1) on

chromosome 3 have been identified in 26 of 31 uveal melanomas (84 percent) with a
gene expression profile consistent with a high metastatic risk (greater than 80 percent at
five years) [34]. In contrast, mutations in BAP1 were present in only 1 of 26 patients (4
percent) classified as being at low risk for metastases. Loss of function of this tumor
suppressor gene is thought to result from the combination of a somatic mutation in one
allele and the loss of one chromosome 3 allele.

Conjunctival melanoma — Unlike uveal melanoma, conjunctival melanoma is associated

with activation of the MAPK pathway with mutations present in either BRAF or NRAS in
approximately one-half of cases [52].

Acral and mucosal melanoma — In mucosal and acral melanomas, KIT is the most
frequently mutated gene (15 to 40 percent of cases). BRAF and NRAS mutations are
much less common, occurring in less that 10 percent of cases overall. Imatinib, an
inhibitor of kit, a cell surface receptor that can activate ras, has demonstrated activity in
this population. (See "Mucosal melanoma", section on 'Targeted therapy'.)
BRAF- DERMATOLOGIA

Mutation status and prognosis — The prognosis of patients with advanced melanoma is

influenced by the specific mutations present in a specific tumor.

●Melanomas with somatic mutations of either NRAS or BRAF are associated with a
poorer prognosis. However, patients whose tumors contain BRAF mutations have
improved response rates and survival when treated with BRAF-inhibitors. (See
"Molecularly targeted therapy for metastatic melanoma", section on 'BRAF inhibition'.)

●Patients with acral or mucosal melanoma that contain KIT mutations have a poorer
prognosis compared with similar patients whose tumors do not contain identifiable KIT
mutations, although they have improved response rates and survival when treated with
imatinib or other kit inhibitors. (See "Mucosal melanoma".)

●In patients with ocular melanoma, somatic mutations in either GNAQ or GNA11
mutation do not appear to be associated with poor prognosis (at least relative to the
small group of patients with tumors lacking either mutation). Mutation in the BAP1
gene, which is thought to regulate cellular growth control via as yet incompletely
understood mechanisms, does appear to be associated with increased risk of metastasis
and worsened prognosis. (See 'Uveal melanomas' above.)

ROLE OF MITF — Microphthalmia-associated transcription factor (MITF) is crucial to

melanin production. (See 'Melanocyte biology' above.)

MITF also has important roles in cell cycling during melanocyte differentiation,
melanocyte invasion during physiologic migration, and the promotion of melanocyte
survival [53]. While these functions are critical to normal melanocyte biology, MITF
dysregulation can contribute to the pathogenesis of melanoma [54].

MITF amplification occurs in approximately 20 percent of melanomas and appears to be

associated with poorer survival [ 54,55]. Additionally, a specific germline mutation in
MITF has been associated with increased nevus count, non-blue eye color, and elevated
melanoma risk [56,57].

Mechanistic data have revealed an intriguing relationship between MITF and the MAPK
pathway, which is relevant to therapies targeting BRAF. MITF serves as a direct substrate
for phosphorylation at serine 73 by MAPK [58]. One of the critical sequelae of this
phosphorylation is the targeting of MITF for ubiquitin-modification, resulting in rapid
degradation of MITF protein [59]. A key consequence of this homeostatic circuitry is that
BRAF antagonists block MITF phosphorylation, ubiquitination, and degradation, resulting
in its stabilization and profound upregulation of certain (if not all) MITF transcriptional
target genes. Some of these target genes are known antigens in immunologic
recognition of melanomas, such as Mart1 or gp100. Thus, BRAF antagonism may
enhance the antigenicity of melanomas via enhanced MITF stability and subsequent
BRAF- DERMATOLOGIA

upregulation of melanocytic antigen expression [60]. Additionally, MITF was shown to

directly control expression of PGC1a, which induces mitochondrial respiration and an
attendant metabolic shift from glycolysis to oxidative phosphorylation [61].

CLINICAL IMPLICATIONS — Small molecule inhibitors have been developed that

effectively target mutated BRAF. In addition, trametinib, an inhibitor of MEK, a
downstream mediator of RAS and RAF activation, also is clinically useful in patients with
a characteristic BRAF mutation and possibly useful in patients with NRAS
and GNAQ/GNA11 mutations, and inhibitors of ERK are under development. The other
protein that can be effectively targeted in patients with melanoma is mutant KIT.

BRAF inhibitors — Potent, selective inhibitors of BRAF, such as vemurafenib and

dabrafenib, have induced tumor regression and prolonged overall survival in patients
with metastatic melanoma that contains the mutated form of BRAF-V600E. (See
"Molecularly targeted therapy for metastatic melanoma", section on 'BRAF inhibition'.)

As would be predicted, treatment with these agents leads to a reduction in levels of

pERK in tumors containing the BRAF-V600E mutation, which is associated with clinical
response [62,63]. However, selective BRAF inhibitors may paradoxically hyperstimulate
RAF kinases within cells in which the RAS pathway is activated upstream of a wild type
BRAF kinase [64-66].

Mechanisms of resistance — Virtually every patient treated with an inhibitor of BRAF

eventually has disease progression [ 67]. No consistent mechanism of resistance has
been identified.

Resistance has not been associated with the development of a second mutation that
impairs the binding of the treatment drug to BRAF, a resistance mechanism observed in
targeted therapy in other malignancies. Several resistance mechanisms have been
described that typically involve tumor cell reactivation via the MAPK pathway through a
variety of alternative means.

Studies using BRAF-V600E mutated cells that were generated to exhibit acquired
resistance to BRAF inhibitors provide insights into how BRAF mutated cells survive BRAF
inhibition. Several mechanisms of resistance have been identified, each of which has
been investigated in at least a small number of tumor cells:

●Bypass mechanisms within the MAPK pathway can restore ERK activation regardless of
ongoing BRAF inhibition. Reestablishment of signaling can be achieved through
upregulation of receptor tyrosine kinases (ie, PDGFRB, ERBB2) [ 68,69], activation of
NRAS via mutation [69-71], upregulation of CRAF [68,72], activating mutations of MEK
[71,73,74], and activation of the serine/threonine MAPK kinases (COT) [68],
BRAF- DERMATOLOGIA

overexpression of mutant BRAF [75] and loss of NF1 [76].

●Shortened forms of the BRAF protein may be produced due to altered RNA processing
[77]. These modified forms of the BRAF protein can activate the MAPK pathway even in
the presence of a BRAF inhibitor. This abnormality was identified in 6 of 19 patients with
acquired resistance to vemurafenib.

●Signaling through the parallel growth and survival PI3K pathway, that can be initiated
by insulin growth factor receptor 1 (IGF-1R) expression or AKT1 mutation is an
alternative mechanism of acquired resistance that has been described and fits the
definition of an outside of pathway bypass mechanism [78,79].

While complete primary resistance to BRAF inhibition (ie, active progression during
initiation of therapy) is seen in less than 10 percent of patients with BRAF mutant
melanoma treated with vemurafenib [80], only a small fraction of patients experience
complete remissions, suggesting the existence of mechanism(s) that acutely limit the
tumor lethality of BRAF inhibition in most patients.

Preclinical studies suggest that elevated pretreatment levels of CRAF, as well as baseline
CCND1 amplification in tumors, leading to downstream overexpression of cyclin D1 and
enhanced CDK4 expression, are pretreatment biomarkers worth further investigation
[72,81]. In evaluation of baseline samples obtained from patients with BRAF-mutant
melanoma prior to treatment with dabrafenib, loss of the cyclin dependent kinase
inhibitor CDKN2A (p16INK4a) and amplification of CCND1 were associated with poorer
outcome to therapy [82]. Additionally, high pretreatment expression of the anti-
apoptotic BCL-2 family member BCL2A1, as well as elevated stromal and plasma
hepatocyte growth factor, and loss of PTEN expression are associated with poorer
outcomes to BRAF inhibitor therapy [ 82-85]. Finally, contemporary studies have
identified a metabolic pathway through which BRAF-inhibition upregulates
mitochondrial respiration via MITF and PGC1a, in a response that limits the ability of
BRAF inhibition to kill melanoma cells [61].

MEK inhibitors — Although the MAP kinase pathway is activated in most melanomas,

the presence of BRAF-V600E mutation correlates strongly with response to MEK
inhibition in murine melanoma xenograft models [86]. Clinically, several agents are
being evaluated and have shown some evidence of activity, particularly in patients with
characteristic BRAF mutations.

Trametinib has been shown to prolong progression-free and overall survival in patients
with tumors harboring BRAF-V600 mutations. Other agents, such as binimetinib are in
development. In additional, binimetinib is associated with responses in a minority of
patients with NRAS mutations and is currently being investigated in a Phase III clinical
trial (NCT01763164) [87]. Lastly, selumetinib has been shown to improve progression
 BRAF- DERMATOLOGIA

free survival in patients with uveal melanoma in combination with temozolomide

compared to temozolomide alone [88]. (See "Molecularly targeted therapy for
metastatic melanoma", section on 'MEK inhibition'.)

KIT inhibitors — Activating mutations of KIT have been demonstrated in only a small

percentage of all melanoma cases. Initial clinical trials with KIT inhibitors did not show
evidence of significant activity, but subsequent studies in highly selected populations
were encouraging. Additional clinical trials are in progress. (See "Molecularly targeted
therapy for metastatic melanoma", section on 'Kit inhibition'.)

COMENTARIO

● La investigación sobre la patogénesis molecular del melanoma se ha identificado la vía MAPK

(figura 1) y el factor de transcripción microftalmia-asociado (MITF) como factores clave en el
desarrollo del melanoma.
● Aunque la vía MAPK se activa en casi todos los melanomas, diferentes anomalías en la vía están
asociados con subtipos específicos de melanoma. Los más comunes incluyen BRAF y ANR en los
melanomas cutáneos y conjuntivales, KIT en acral y melanomas de la mucosa, y GNAQ y GNA11
en melanoma uveal.
● Comprensión de la importancia de la vía MAPK y las mutaciones BRAF ha llevado al desarrollo
de vemurafenib, dabrafenib y trametinib, que se han demostrado prolongar significativamente
libre de progresión y la supervivencia global en pacientes con melanoma que contiene una
mutación V600. Agentes adicionales están en desarrollo para dirigir este y otros componentes de
la vía MAPK.

REFERENCES

1 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9.
Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the
2
genomic era. Genes Dev 2006; 20:2149.
3 Lin JY, Fisher DE. Melanocyte biology and skin pigmentation. Nature 2007; 445:843.
4 Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003; 37:67.
Cui R, Widlund HR, Feige E, et al. Central role of p53 in the suntan response and
5
pathologic hyperpigmentation. Cell 2007; 128:853.
Fisher DE, James WD. Indoor tanning--science, behavior, and policy. N Engl J Med
6
2010; 363:901.

WHAT'S NEW IN ONCOLOGY

BRAF- DERMATOLOGIA

Authors
Don S Dizon, MD, FACP
April F Eichler, MD, MPH
Michael E Ross, MD
Diane MF Savarese, MD
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: Nov 2014. | This topic last updated: Dec 03, 2014.
The following represent additions to UpToDate from the past six months that were
considered by the editors and authors to be of particular interest. The most recent
What's New entries are at the top of each subsection.

MELANOMA AND OTHER SKIN CANCER

Combined BRAF plus MEK inhibition in advanced melanoma with a BRAF mutation (June
2014, MODIFIED October 2014)

Inhibitors both of mutated BRAF and MEK have clinically significant activity in patients
with advanced melanoma whose tumor contains a V600 mutation in BRAF. Two phase III
trials demonstrated that the combinations dabrafenib plus trametinib [38] and
vemurafenib plus cobimetinib [39] both significantly prolonged overall survival
compared with BRAF inhibition alone. These findings support our recommendation to
use a combination of BRAF plus MEK inhibition rather than a single agent alone for the
initial therapy in patients whose tumors contain a V600 mutation in BRAF. (See
"Molecularly targeted therapy for metastatic melanoma", section on 'Combined MEK
plus BRAF inhibition'.)

Pembrolizumab immunotherapy for previously treated metastatic melanoma

(September 2014)

Pembrolizumab is a monoclonal antibody that targets the programmed death 1 protein

(PD-1), a receptor on T lymphocytes. PD-1 binds to its ligand on tumor cells, preventing
the immune system from rejecting the tumor. Pembrolizumab blocks the interaction of
PD-1 with the tumor cell, thereby augmenting the antitumor immune response. In phase
I and phase II clinical studies, pembrolizumab induced tumor regression or stabilized
disease progression, and increased survival in patients who had progressed after
immunotherapy with ipilimumab [40]. In the United States, pembrolizumab
was approved by the Food and Drug Administration in September 2014 based upon
these results. This drug represents a new type of agent and additional trials of similar
agents are currently ongoing. We recommend treatment with pembrolizumab for
patients with advanced melanoma who have progressed on ipilimumab. Immune-
related adverse events are common and regular monitoring for such events (eg,
enterocolitis, hepatitis, dermatitis) is indicated. (See "Immunotherapy of advanced
BRAF- DERMATOLOGIA

melanoma with immune checkpoint inhibition", section on 'Pembrolizumab'.)

Adjuvant ipilimumab for stage III melanoma (June 2014)

Patients with resected stage III melanoma (table 2A-B) are at a substantially increased
risk for the development of metastatic disease. In a large phase III trial, adjuvant therapy
with ipilimumab, an anti-CTLA-4 monoclonal antibody, significantly prolonged relapse-
free survival compared with placebo [41]. Additional follow-up data are required from
this trial to assess the impact on overall survival. In addition, another phase III trial is
comparing ipilimumab to high dose interferon, the current standard of care for adjuvant
therapy. (See "Adjuvant immunotherapy for melanoma", section on 'Ipilimumab'.)

Anti-PD-1 monoclonal antibodies in advanced melanoma (March 2014, MODIFIED June

2014)

The programmed cell death 1 (PD-1) protein and its ligand (PD-1 L1) are important
targets that affect the immune response to tumors. New data on nivolumab [ 42-44] and
pembrolizumab [40], two investigational monoclonal antibodies that are directed
against the PD-1 protein, demonstrated clinically important improvements compared
with earlier treatments for advanced melanoma. Furthermore, the combination of
nivolumab plus ipilimumab, an anti-CTLA-4 monoclonal antibody, appears to be feasible
and even more effective than either agent alone [45]. (See "Immunotherapy of
advanced melanoma with immune checkpoint inhibition", section on 'Anti-PD1
monoclonal antibodies' and "Immunotherapy of advanced melanoma with immune
checkpoint inhibition", section on 'Combined anti-CTLA-4 and anti-PD-1
immunotherapy'.)

Tanning beds and risk of melanoma (May 2014)

There is a growing body of evidence supporting the association between indoor tanning
and risk of melanoma. A meta-analysis of 31 observational studies including nearly
250,000 participants found an overall 16 percent increase of melanoma risk for “ever”
versus “never” use of tanning beds [46]. In subgroup analysis, the risk was further
increased with more than one year of use (61 percent increase), more than 10 lifetime
sessions (34 percent increase), and first use before age 25 (35 percent increase). In light
of these findings, children and young adults should avoid the use of tanning beds. (See
"Risk factors for the development of melanoma", section on 'Tanning beds'.)

.
REFERENCES

1 Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla
after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a
randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;
BRAF- DERMATOLOGIA

15:Online 10/16/2014.
Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating Tumor Cells and Response to
2
Chemotherapy in Metastatic Breast Cancer: SWOG S0500. J Clin Oncol 2014; 32:3483.
van de Water W, Bastiaannet E, Egan KM, et al. Management of primary metastatic
3 breast cancer in elderly patients--an international comparison of oncogeriatric versus
standard care. J Geriatr Oncol 2014; 5:252.
Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2
4 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst 2014;
106:dju091.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125427s033lbl.pdf
5
(Accessed on July 24, 2014).
.

INHERITED SUSCEPTIBILITY TO MELANOMA

Authors
Hensin Tsao, MD, PhD
Michele Jacobs Gabree, MS, CGC
Section Editors
Michael B Atkins, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Michael E Ross, MD
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: Nov 2014. | This topic last updated: Oct 23, 2014.
INTRODUCTION — The etiology of all cancers depends upon the interplay between
environmental and genetic factors. The details of these interactions are not clearly
understood for most malignancies.

For melanoma, the most significant environmental risk factor is solar ultraviolet (UV)
radiation exposure [1]. However, this risk is greatly influenced by genetic factors. As an
example, skin type, a heritable trait, modifies the risk presented by a given amount of
solar exposure. Dark-skinned populations have a much lower incidence of melanoma
than fairer-skinned populations exposed to equivalent sunlight. In the United States,
African-Americans have approximately 10 percent the risk of Caucasians.

Significant progress has been made toward understanding the genes that contribute to
inherited susceptibility for melanoma in some patients [ 2]. Uncommon but high-risk
alleles contribute to the hereditary cancer phenotype that includes multiple cases of the
associated cancer or cancers on one side of the family, multiple primary cancers in a
given individual, and early age of onset for a given cancer. With further advances in both
genomic technologies and the conceptual framework to isolate more prevalent, but
lower risk, alleles, the spectrum of genetic lesions that contribute to melanoma risk can
be expected to broaden.
BRAF- DERMATOLOGIA

The genetic risk factors for melanoma are discussed here, along with potential
implications for genetic screening. Other risk factors associated with the development of
melanoma are discussed separately. (See "Risk factors for the development of
melanoma".)

HIGH-RISK LOCI — Melanoma patients who harbor high-risk variant genes for

melanoma will often report a family history of melanoma or a personal history of
multiple primary melanomas (MPMs). Although it is estimated that 8 to 12 percent of
patients with melanoma have a family history of the disease, not all of these individuals
have hereditary melanoma [3,4].

Several factors may contribute to this observation:

●In some cases, the apparent familial inheritance pattern may be due to clustering of
sporadic cases in families with common heavy sun exposure and a susceptible skin type.

●In other situations, coinheritance of modifying genes may enhance or inhibit the
apparent penetrance of a high-risk mutation and thus dictate the strength of the family
history. Thus, hereditary cancer families may in fact select for the highest risk
genotypes, whether these result from a variant in a single locus or a combination of
coinherited variants from multiple loci.

●Some familial cases occur in the setting of the familial atypical multiple mole and
melanoma (FAMMM) syndrome, also called the dysplastic nevus syndrome (DNS). This
syndrome was originally described in two kindreds in which affected subjects had
multiple (over 100) dysplastic (atypical) nevi, and their lifetime cumulative incidence of
melanoma approached 100 percent [5,6]. A family history of melanoma in multiple first
degree relatives and younger age at diagnosis are important components of this
syndrome. The median age at diagnosis in one series of 23 kindreds was 33, well below
that in patients with sporadic melanomas; this difference may be due in part to
increased surveillance of subjects from affected families [ 7]. (See "Risk factors for the
development of melanoma", section on 'FAMMM syndrome and atypical mole
syndrome'.)

CDKN2A GENE — Initial attempts to study the inheritance of melanoma were

complicated by difficulties in distinguishing clustered sporadic cases with similar
nongenetic risk factors from an inherited single-locus predisposition. The description of
the FAMMM syndrome in 1978 further confounded the search for single genetic
abnormalities because of the clinical and histopathologic variability in the presentation
and diagnosis of this disorder. Estimates of the prevalence of sporadic dysplastic nevi
range from 4.9 to 53 percent (picture 1) [8,9].

Initial clues that chromosome 9p21 contained a melanoma susceptibility locus came
BRAF- DERMATOLOGIA

from cytogenetic investigations and studies of loss of heterozygosity (LOH) [ 10]. Strong
evidence for linkage to this region came from an analysis of 11 melanoma pedigrees in
Texas and Utah [11]. Subsequent studies using positional cloning methods isolated a
candidate locus that was ultimately designated CDKN2A, cyclin-dependent kinase
inhibitor 2A [12,13]. This gene has also been called MTS1 (multiple tumor suppressor 1),
p16INK4A, and CDKN2. The gene encodes two proteins, p16 and p14ARF, that are
transcribed in alternate reading frames through the use of alternative first exons [ 14].
Germline CDKN2A mutations in melanoma families are usually missense or nonsense
changes that impair the function of p16, although rare mutations in p14ARF have also
been reported [15-17].

The p16 protein is a negative regulator of cell cycle progression at the G1/S checkpoint

[18,19]. It interacts with the cyclin-dependent kinases (CDK4 or CDK6), enzymes that
control early events in the cell cycle, to catalyze phosphorylation of the retinoblastoma
family of proteins. A complex of cyclin D and CDK (mutations of CDK4 are also associated
with melanoma; see below) together phosphorylate the retinoblastoma gene (RB1)
protein, thereby releasing the transcription factor E2F-1 from RB1, and allowing E2F-1 to
induce S phase genes. Consequently, the cell proceeds from G1 arrest through S phase.
The p16 protein binds to and inhibits CDK4, and thus serves as a brake on cell cycle
progression. Inactivating mutations of p16 disrupt its inhibitory function on CDK4,
thereby permitting inappropriate progression through the cell cycle [ 20]. Tumorigenesis
may result from an impairment in senescence, cell differentiation, or cell death [21,22].

Prevalence of mutations — There is a variable rate of CDKN2A mutations in patients

with hereditary melanoma [2,23-26]. The most extensive analysis of melanoma families
found that the major features associated with an increased frequency of CDKN2A
mutations were multiple cases of melanoma in a family, early age at diagnosis, and
family members with multiple primary melanomas (MPM) or pancreatic cancer [ 16].
Using these criteria, 385 families with three or more patients with melanoma from the
Melanoma Genetics Consortium (GenoMel) were compared across various geographical
locales. Overall, 39 percent of families had CDKN2A mutations, ranging from 20 percent
(32 of 162) in Australia to 45 percent (29 of 65) in North America and 57 percent (89 of
157) in Europe. An increasing number of cases, earlier age of onset, and multiple lesions
in a given individual all were associated with germline CDKN2A mutations. The presence
of pancreatic cancer in a given family also predicted CDKN2A mutations except for
Australian families.

Germline mutation rates for CDKN2A vary in different studies, probably because of
design and ascertainment bias. The prevalence of germline CDKN2A mutations in the
general population with melanoma appears to be much lower than that suggested by
studies of multiple-case families, which may reflect the presence of other coinherited
risk alleles, increased detection bias, or unknown confounders in these cohorts. This was
illustrated by a study of 3550 patients with melanoma, in which 65 CDKN2A mutation
BRAF- DERMATOLOGIA

carriers were identified (1.8 percent) [ 27]; the rates of CDKN2A mutations among
individuals with a single primary melanoma and multiple primary melanomas were 1.2
and 2.9 percent, respectively [28].

Mutation penetrance — Estimates of the penetrance of CDKN2A mutations among

carriers vary depending upon the methods of population ascertainment [27,29].

●In the multicenter Genes Environment and Melanoma (GEM) study, history was
obtained from 429 first-degree relatives of index cases seeking cases of melanoma [ 27].
Based upon an analysis of these individuals, the incidence of melanoma in CDKN2A in
carriers was estimated to be 14, 24, and 28 percent at 50, 70, and 80 years of age,
respectively. This compared to an incidence of melanoma of1.5, 4.5, and 6.2 percent in
the relatives of non-CDKN2A carriers, and an estimated 0.6, 1.6, and 2.6 percent in the
baseline population.

●In the Melanoma Genetics Consortium (GenoMel) study, which was based upon 80
families with documented CDKN2A mutations and multiple affected family members,
the incidence of melanoma was 30 percent by age 50 and 67 percent by age 80 years
[29]. As alluded to earlier, the higher penetrance observed in this study at least in part
reflects the bias induced by only analyzing families with two or more cases. An
interaction between genetic predisposition and environmental factors was suggested in
this series by geographic variations. In Europe, the United States, and Australia,
mutation penetrance at age 80 years was 58, 76, and 91 percent, respectively.

The same factors that influence the incidence of melanoma in the general population
(eg, total nevus count, presence of dysplastic nevi, sunburn) also affect CDKN2A
penetrance. This was illustrated in a study of 53 melanoma-prone families and 295
families ascertained through probands diagnosed with melanoma but unselected for
family history [30]. The presence of both sunburn and a melanoma-predisposing gene
increased the risk of melanoma 15 times more than in noncarriers. In families with
CDKN2A mutations, total nevus count, dysplastic nevi, and sunburn all significantly
increased the risk of developing melanoma. In addition, the presence of variants in the
melanocortin-1 receptor (MC1R) gene increases the risk of developing melanoma in
CDKN2A carriers. (See 'Melanocortin-1 receptor gene' below and "Risk factors for the
development of melanoma".)

CDKN2A in early onset melanoma — One common feature of hereditary cancer

syndromes is the early age at diagnosis of cancer in affected individuals. This is true in
other cancers (hereditary nonpolyposis colon cancer, familial adenomatous colon
cancer, familial breast cancer); it has also been described in melanoma [7].

A young age at disease onset is associated with a higher likelihood of a germline

mutation for patients with breast and colon cancer. However, this may not be true in
BRAF- DERMATOLOGIA

melanoma. In one cohort of young patients (median age 32 years) with sporadic
melanoma, there was no increase in the prevalence of germline CDKN2A mutations in
the absence of a positive family history [31].

CDKN2A in multiple primary melanomas — Another feature of inherited cancer

predisposition is the development of multiple cancers, and this appears to be true in
melanoma.

The cumulative probabilities of having a second primary cutaneous melanoma at 1, 5,

10, and 20 years after the initial diagnosis were 1.0, 2.1, 3.2, and 5.3 percent,
respectively, in a study based upon the Surveillance, Epidemiology and End Results
(SEER) database [32]. Data on the incidence of germline CDKN2A mutations in patients
with multiple primary melanomas are variable. In the GEM cohort, 2.9 percent of 1189
patients with multiple primary melanomas had germline CDKN2A mutations [ 27]. In
contrast, in several smaller studies, the incidence of mutations ranged between 8 and 16
percent [33-36]. The role for genetic screening for patients with multiple primary
melanoma is unclear. (See 'Genetic testing' below.)

Familial melanoma and other malignancies — CDKN2A mutations are associated with a

wide variety of other tumor types and may be among the most common mutations in
human cancer. In addition, epidemiologic studies support an association between the
risk of melanoma and other tumors [ 26,37,38]. Other mutations may also play a role in
some cases of familial melanoma.

CDKN2A mutations — The relationship between CDKN2A mutations and other cancer

types is illustrated by a study based upon 330 high-risk melanoma-prone families that
included 236 patients with sporadic multiple primary melanoma and 466 cases with
familial melanoma [26]. Mutations in CKDN2A were identified in 66 families. There was a
statistically significant increased incidence of other solid tumors compared with those
families with wild type CDKN2A (prevalence ratio 3.0). Specific tumor types for which
there was an increased incidence included pancreatic cancer, lung cancer, and breast
cancer (prevalence ratios 3.0, 3.0, and 2.0, respectively). The association with pancreatic
cancer in particular has been described in several other studies [24,38-40].

Brain tumors — Brain tumors have been described in some melanoma-prone kindreds

[41] with germline alterations of the p14ARF component of CDKN2A [ 42]. An exon 1beta
splice junction mutational hotspot in p14ARF has been reported [ 43]; the contribution of
these changes to the full spectrum of hereditary melanoma remains to be clarified.

CYCLIN-DEPENDENT KINASE 4 GENE — As noted above, p16 inhibits both cyclin-

dependent kinase 4 (CDK4) and CDK6, thereby regulating cell cycle progression. Several
melanoma families have been described who lack mutations in CDKN2A, but have
germline mutations in the CDK4 gene [23,39,44]. In these families, the mutations were
BRAF- DERMATOLOGIA

on arginine 24 of CDK4, resulting in a CDK4 protein that is insensitive to inhibition by

p16. There are no apparent differences in the phenotype (eg, age at diagnosis, number
of melanomas) of families carrying either CDKN2A or CDK4 mutations [ 45].

XERODERMA PIGMENTOSUM GENES — Patients with xeroderma pigmentosum (XP)

have an extremely high rate of skin cancers, including cutaneous and conjunctival
melanomas. In one large series from 1994, 22 percent of XP patients under the age of 20
developed melanoma, a rate that is estimated to be at least 1000-fold greater than the
general population [46]. (See "Epidemiology and risk factors for cutaneous squamous
cell carcinoma", section on 'Xeroderma pigmentosum'.)

Clinically, XP has been divided into various complementation groups (XPA to XPG) based
on phenotypic variation. All patients with XP demonstrate a defect in the repair of
ultraviolet (UV) radiation-induced photoproducts, a process known as nucleotide
excision repair (NER). The XPC and XPE genes recognize DNA damage while the XPA
gene verifies the damage. XPB and XPD, both with helicase activity, are then recruited to
unwind the DNA from 3' to 5' and 5' to 3', respectively. XPF and XPG then incise the DNA
at the 5' and 3' ends, respectively. The repair patch is synthesized by proliferating-cell
nuclear antigen (PCNA) and DNA polymerase.

XP is an extremely rare disorder and full-blown disease does not appear to play a
significant role in melanoma burden at the population level. These genetic observations,
however, do provide additional support for the role of UV radiation in melanoma
tumorigenesis.

More common polymorphisms in the XP genes may contribute to the risk for developing
melanoma. This possibility was illustrated by a study in 602 non-Hispanic white
melanoma patients and 603 age- and sex-matched cancer-free controls who were
genotyped for five common, single-nucleotide polymorphisms in the XP genes [ 47].
There was a statistically significant increase in the risk of melanoma with XPD
751 Lys/Gln (adjusted odds ratio [OR] 1.55) and XPD 751 Gln/Gln (OR, 1.66) genotypes
compared with the XPD 751 Lys/Lys genotype. In addition, there was a significant risk
associated withXPD312Asp/Asn (OR, 1.54) and XPD312 Asn/Asn (OR, 1.75) genotypes
compared with the XPD 312 Asp/Asp genotype. No increased risk was observed in the
other three XPC and XPG single-nucleotide polymorphisms.

BAP1 gene — Germline mutations in the BAP1 gene have been identified in families
with cutaneous and ocular melanoma [ 48,49]. The presence of unique nevoid
melanomas and highly atypical nevoid melanoma-like melanocytic proliferations has
also been observed in some of these individuals [ 48]. BAP1 encodes a deubiquitinating
enzyme, which functions as a tumor suppressor. Somatic BAP1 mutations in ocular
melanoma have been associated with an increased risk of metastasis [50,51]. In addition
to cutaneous and ocular melanoma, other cancers, including mesothelioma and renal
BRAF- DERMATOLOGIA

cancer have also been reported in families with germline BAP1 mutations; furthermore,
somatic BAP1 mutations have also been described in RCC [48,49,52].

TERT — There is one report of a German family with a -57T>G variant in the promoter
region of the telomerase (TERT) gene. Analysis of melanoma tumor specimens also
revealed frequent, but distinct, variants in the promoter region. These changes are
thought to increase recognition sites for Ets/Tcftranscription factors and enhance TERT
expression [53].

LOW TO MODERATE RISK LOCI

BRCA2 gene — The BRCA2 (OMIM ID *600185) gene encodes a protein that is important
in DNA repair. Germline BRCA2 mutations are associated with an increased risk of breast
and other cancers. The association between melanoma and germline mutations in the
BRCA1 and BRCA2 genes mutations remains under investigation. (See "BRCA1 and
BRCA2: Prevalence and risks for breast and ovarian cancer".)

In a report from the Breast Cancer Linkage Consortium, BRCA2 carriers have an
increased risk of cutaneous melanoma (relative risk 2.6) [54]. BRCA2 mutations also
appear to occur in families with aggregations of ocular melanoma (7 of 62 such families
in one series) [55].

Other studies have not found an association between melanoma and inherited
mutations in BRCA1 and BRCA2. A study of individuals with cutaneous melanoma and
Ashkenazi Jewish ancestry detected no germline mutations in the 92 individuals
analyzed for the three BRCA Ashkenazi Jewish founder mutations [ 56]. With respect to
ocular melanoma, no germline mutations in BRCA1 or BRCA2 were detected in a cohort
of 25 individuals with a personal history of ocular melanoma and
a personal/family history of breast or ovarian cancers [57].  

Retinoblastoma gene — As mentioned above, the cyclin D/CDK complex phosphorylates

the RB1 protein (OMIM ID +180200), allowing cell cycle progression from G1 to S; p16
binds to and inhibits the activities of these three enzymes, functioning as a brake on cell
cycle progression. In one large cohort study of retinoblastoma survivors, the mortality
from second cancers, including melanoma, was significantly increased [ 58]. Although
germline RB1 mutations have not been reported in patients with melanoma, mutation
or loss of RB1 expression has been described in a limited number of melanoma cell lines
[59].

Melanocortin-1 receptor gene — Variants of the alpha melanocyte stimulating hormone

receptor gene (MC1R) have been associated with the red hair/fairskin phenotype [60],
which is more common in subjects with cutaneous melanoma. In addition, analysis of
the MC1R gene in patients with melanoma has shown an increased prevalence of MC1R
BRAF- DERMATOLOGIA

gene variants compared to healthy controls [61-67].

This was illustrated by a study in which the MC1R gene was sequenced in 267 patients
with melanoma and 382 control subjects [61]. The presence of MC1R variants was
associated with a two- to fourfold increase in the risk of melanoma compared to
individuals carrying the wild-type MC1R gene. The association between MC1R variants
and melanoma was stronger in individuals with fewer additional risk factors (eg, those
with dark skin or few nevi). In addition, patients with a variant MC1R gene were three to
fourfold more likely to have thick melanomas.

There also is evidence that variants of MC1R can interact with other genes involved in
the pathogenesis of melanoma. MC1R variants increase the penetrance of CDKN2A [ 68].
In a GenoMEL study of 815 CDKN2A mutation carriers from 186 families, the presence of
one of the four most common MC1R variants was associated with a statistically
significant increased risk of melanoma; the presence of two or more variants further
increased that risk compared to having just one variant (odds ratios compared to those
without an MC1R variant 5.8 and 2.3, respectively).

The BRAF oncogene is the most common site for somatic mutations in melanoma [ 69].
Such mutations are more common in melanomas arising in skin that has little chronic
sun-induced damage and are less frequent in melanomas associated with severe chronic
solar damage [70]. In patients with melanoma originating in skin with limited sun-
induced damage, somatic mutations of BRAF are strongly associated with the presence
of inherited MC1R variants and are less common in patients with wild type MC1R
[71,72].

MITF (E318K) variant — Several groups identified a low prevalence, moderate

penetrance missense mutation in the microphthalmia (MITF) gene. The gene occurs in
about 1 percent of individuals of European descent and confers about a twofold
increased risk of melanoma development. The E318K alteration abolishes a
SUMOylation site thereby altering the transcriptional function of the MITF protein.
There is also some evidence that MITF E318K variant increases the risk for renal cell
carcinoma [73,74].

1p22 gene locus — A novel melanoma susceptibility locus has been mapped to
chromosome 1p22, but the gene of interest has not yet been identified [75].

Genome-wide association studies — Multiple groups have utilized genome-wide

association studies to identify candidate loci associated with increased melanoma risk
[76-80].

●A study conducted by the GenoMel consortium included cases and controls from
Sweden, Australia, Italy, UK/Leiden, France and Spain. Cases were selected based on
BRAF- DERMATOLOGIA

family history of melanoma and/or a history of multiple primaries prior to age 40 [76].

Variants in the MC1R, TYR, and MTAP genes were associated with an increased risk of
melanoma.

●Other studies have found evidence for melanoma risk associated with variants in the
ASIP, TYRP1, SLC45A2, TYR, and PLA2G6 genes [77-79,81]. These findings should be
interpreted cautiously, since a biologic mechanism has not yet been elucidated for
melanoma risk associated with these loci [80].

GENETIC TESTING — The question of whether or not to screen for germline CDKN2A

mutations as a cause of a hereditary predisposition to melanoma is a common source of
concern for the practicing clinician.

This issue is likely to arise in one of four settings:

●Family history — Multiple cases of melanoma in a family may suggest that a mutation
in the family is playing a role in the cancer development. However, even in a family in
which three first-degree relatives are affected with melanoma, the likelihood that this is
due to a mutation in the CDKN2A gene is only about 20 to 40 percent [ 82]. (See
'Prevalence of mutations' above.)

●Early onset melanoma − Although early onset cancer is typical of other hereditary
cancer predisposition syndromes, no clear association has been found between the
onset of melanoma prior to age 40 and CDKN2A or CDK4 mutations [ 31]. The lack of
utility of screening was illustrated by a study in which a deleterious CDKN2A mutation
was identified in only one of 51 patients (2 percent) diagnosed with melanoma prior to
age 20 years [83]. (See 'CDKN2A in early onset melanoma' above.)

●Multiple primary melanomas − The best estimate of the incidence of the CDKN2A
mutation rate in patients with multiple primary melanomas is approximately 3 percent
[27], although some studies have shown a higher rate [ 33-36]. (See 'CDKN2A in multiple
primary melanomas' above.)

●The occurrence of other associated tumors (eg, pancreatic cancer, breast cancer, brain
tumors), either in the patient's personal history or family history, should be taken into
account when considering possible hereditary predisposition syndromes. Melanoma and
pancreatic cancer have both been associated with mutations in the CDKN2A gene
[24,39,84,85]. Melanoma and breast cancer may be associated with mutations in the
BRCA2 gene [55]. In patients with a known CDKN2A germline mutation and a relative
with pancreatic cancer who is known or suspected to harbor the familial CDKN2A
mutation, it is appropriate to refer the carrier to a gastroenterologist for discussion of
pancreatic cancer screening. (See 'Familial melanoma and other malignancies' above
BRAF- DERMATOLOGIA

and "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer".)

Genetic testing for CDKN2A is commercially available through several CLIA (Clinical
Laboratory Improvement Amendments) approved laboratories. However, both the
American Society of Clinical Oncology (ASCO) and the Melanoma Genetics Consortium
have recommended that genetic testing for CDKN2A mutations should be carried out in
a research setting rather than a clinical setting [86-88]. These recommendations are
based upon the limited data on the efficacy of prevention and surveillance methods for
melanoma, in addition to the difficulty of interpreting such test results. Of note,
although the efficacy of pancreatic surveillance remains under investigation, the
International Cancer of the Pancreas Screening (CAPS) Consortium summit on the
management of patients with increased risk for familial pancreatic cancer recommends
consideration of pancreatic cancer surveillance for individuals with CDKN2A mutations
and a first degree relative with pancreatic cancer [89].

The clinical availability of next-generation sequencing technology has led to the

development of cancer gene panel testing, which simultaneously analyzes multiple
cancer susceptibility genes. The genes included on these panels vary depending on the
testing laboratory, and some gene panel tests include melanoma susceptibility genes
such as CDKN2A, CDK4, BRCA2, and BAP1. Because many of these tests are not specific
to one type of cancer, gene panel testing could lead to the detection of a melanoma
susceptibility gene mutation in an individual or family not otherwise phenotypically
suggestive of having a hereditary melanoma risk. Such testing should only be performed
once patients are counseled appropriately and made aware of the possibility of
incidental findings, the psychological consequences, and the potential need for
additional testing.

Genetic testing for CDKN2A mutations could potentially increase the motivation for risk-
reducing behaviors and frequent surveillance as well as lowered biopsy threshold for
suspicious lesions, which might improve survival if a melanoma occurs [ 86,90]. On the
other hand, genetic testing could potentially cause psychological distress, lead to
unnecessary biopsies in carriers, and reduce motivation for preventive behaviors in
those without CDKN2A mutations [91].

Genetic counseling, with or without genetic testing, may promote awareness in

individuals at increased risk for melanoma. A study involving two CDKN2A families
concluded that educating patients about genetic testing as well as photoprotection
increased reported photoprotective behaviors regardless of mutation status [ 92]. In
addition, knowledge of familial melanoma risks in families who decline genetic testing
has been suggested to encourage melanoma risk reducing and early detection behaviors
[93].

The most appropriate recommendations for individuals with a CDKN2A mutation are
BRAF- DERMATOLOGIA

close clinical surveillance and education regarding skin cancer risk-reducing behaviors
(eg, sunscreen use, sun avoidance). In families with a CDKN2A mutation suspected or
known to be associated with a family history of pancreatic cancer, mutation carriers
should also be referred to a gastroenterology specialist to discuss the option of
pancreatic cancer surveillance. There are no chemoprevention regimens or other
prophylactic interventions that are known to benefit CDKN2A mutation carriers. (See
"Screening and early detection of melanoma", section on 'High-risk individuals'.)

Familial clustering may be due to an inherited genetic risk or common environmental

exposure with sporadic clustering. In either case, all family members are at risk and
should obtain dermatologic screening and follow-up.

COMENTARIO

● El principal factor de riesgo ambiental asociado con el melanoma cutáneo es la

exposición a la radiación ultravioleta. Este riesgo es modificado por los factores
genéticos de alto riesgo, la más frecuente de las cuales son las mutaciones en el gen
supresor de tumor CDKN2A. También se han identificado otros factores genéticos
(CDK4, xeroderma pigmentoso, las mutaciones del gen BRCA2) asociados con un mayor
riesgo de melanoma.

● familias con mutaciones de línea germinal CDKN2A conocidas se caracterizan por

tener múltiples miembros de la familia con melanoma, una edad temprana de
aparición, los individuos con múltiples melanomas primarios, y la coexistencia con otros
tumores primarios, especialmente el cáncer de páncreas. Incluso en la presencia de
estos criterios, las mutaciones de la línea germinal de CDKN2A son poco frecuentes
fuera del contexto de las familias con mutaciones conocidas

● Para los pacientes que se consideren en mayor riesgo de tener una susceptibilidad
heredada para el melanoma debido a una mutación CDKN2A, sugerimos asesoramiento
genético con un proveedor médico calificado para recibir educación sobre los riesgos y
beneficios de las pruebas genéticas y para discutir expresión de la enfermedad y la
necesidad para las pruebas formalizado. (Grado 2C).

● Para las personas con una mutación CDKN2A conocido, se recomienda una estrecha
monitorización clínica y educación con respecto a los comportamientos de melanoma
de reducción del riesgo (por ejemplo, el uso de protección solar, de evitación del sol)
(Grado 1C). También se recomienda la consideración de una derivación a un
especialista en gastroenterología para discutir la opción de vigilancia del cáncer de
páncreas para portadores de la mutación CDKN2A que tienen antecedentes familiares

COMENTARIO

El descubrimiento de las mutaciones de BRAF en el melanoma y el surgimiento inhibidores de

altamente selectivos que han producido evidencia del beneficio clínico sin precedentes han
energizado el melanoma campo. Al mismo tiempo, las limitaciones clínicas de esta terapia son ya es
evidente y la atención debe centrarse en la comprensión los otros mediadores moleculares de la
BRAF- DERMATOLOGIA

CONTENIDO

 MOLECULARLY TARGETED THERAPY FOR METASTATIC MELANOMA

 THE MOLECULAR BIOLOGY OF MELANOMA

 WHAT'S NEW IN ONCOLOGY

 INHERITED SUSCEPTIBILITY TO MELANOMA

 BIOLOGICAL CHALLENGES OF BRAF INHIBITOR THERAPY

 COMPARING BRAF MUTATION STATUS IN MATCHED PRIMARY AND

METASTATIC CUTANEOUS MELANOMAS: IMPLICATIONS ON OPTIMIZED
TARGETED THERAPY.

 COMPARATIVE PROFILE OF CUTANEOUS ADVERSE EVENTS: BRAF/MEK

BRAF- DERMATOLOGIA

INHIBITOR COMBINATION THERAPY VERSUS BRAF MONOTHERAPY IN

MELANOMA

COMENTARIO

Antecedentes: los inhibidores de BRAF selectivos han demostrado resultados espectaculares

en cuanto a la mejora de los resultados en pacientes con melanoma. Prueba del estado de
BRAF en melanomas primarios y metastásicos coincidentes para optimizar individuo terapia
dirigida no está bien investigado.

Métodos: pruebas BRAF extendido utilizando PCR para 9 mutaciones y VE1

inmunohistoquímica para la detección de BRAF V600E en 95 lesiones, incluyendo 40
melanomas primarios con sus metástasis emparejados (n = 42), recurrencias (n = 9) y segundo
primarias (n = 4) se realizó. Nueve pacientes tenían múltiples metástasis.

Resultados: V600E era el único tipo de mutación identificada; 35,4% de primaria vs. 18,9% de
los melanomas metastásicos. La tasa global discordancia estado BRAF-primaria metastático
era 32,3% mediante PCR y el 27,5% con la inmunohistoquímica, y fue significativamente más
BRAF- DERMATOLOGIA

COMENTARIO

El evento adverso más común previamente informó durante la monoterapia trametinib

es acneiforme dermatitis.5,10,15,23 El mecanismo de activación esta reacción es aún
desconocido, pero un papel fundamental de la vía PI3K / AKT ha planteado la hipótesis.

De hecho, Meki alivia un bucle de retroalimentación negativa en la vía PI3K / AKT que
conduce a un aumento de AKT signaling24 que se sabe que juega un papel central en
acné pathogenesis.25,26 Otra hipótesis previamente reportado es que estas erupciones
acneiformes podría ser un resultado de la apoptosis inducida por fármacos de
queratinocitos epidérmicos homeostasis.15 inquietante En nuestro estudio, trametinib
sólo se administró en combinación con un Brafi, y como se informó anteriormente,
erupciones acneiformes parecían ser menos frecuente con esta combinación en
comparación con el histórico datos relativos a Meki alone.10,15

Ocho pacientes tratados con Brafi y sólo 2 tratados con el régimen de combinación tuvo
que reducir la dosis inhibidor o interrumpir el tratamiento debido a eventos adversos
cutáneos. en el Grupo Brafi, reducción de la dosis o la interrupción del tratamiento
BRAF- DERMATOLOGIA