CASE REPORT
A 45-year-old Caucasian female with a history of melanoma,
1.0mm in depth, Sentinel lymph node biopsy negative,
11-years prior, presented for routine skin exam
and was noted to have lymphadenopathy of the right side of
her neck. A subsequent CT scan revealed 10cm lesions in both
the liver and spleen. Biopsies demonstrated metastatic melanoma;
no cutaneous manifestations were present. Interferon
treatment was initially used with no response. Genetic analysis
revealed a positive BRAFV600E mutation, and vemurafenib therapy
was initiated. One month after starting vemurafenib, two
superficial spreading melanomas on the left mid back and left
upper abdomen were discovered, depth 0.25mm and 0.60mm,
respectively. The visceral tumors responded well, each shrinking
to less than 2cm. Over the next 11 months four additional
superficial spreading melanomas emerged, on the left upper
and left superior upper arm, depth 0.32mm and 0.80mm, and
the mid back and mid upper back, 0.27mm and 0.50mm. All six
primary melanomas were confirmed by two dermatopathologists
at separate institutions. Two of the six melanomas occurring
while on vemurafenib were tested and were BRAF mutation
negative. The patient is currently closely monitored. She
continues to be treated with vemurafenib and more recently
taxol, as 3 years after starting vemurafenib therapy, the tumors
have grown back to their original diameters of 10cm. In addition
to the aforementioned melanomas, 2 atypical melanocytic
proliferations, 9 dysplastic nevi some with moderate cytologic
atypia, and 5 compound melanocytic nevi were removed. In
summary, a total of 6 superficial spreading melanomas, each
uniquely located, developed after vemurafenib initiation.
Unresectable or metastatic melanoma has a poor prognosis
with a 1-year survival rate of 25.5%.1 For years, dacarbazine or
interferon was the standard care for these patients. In phase III
clinical trials (BRIM-3), vemurafenib compared to dacarbazine
demonstrated significant reduction in risk of death, clinical superiority
in median overall survival, 13.6 to 9.7 months, and
a significant increase in progression free survival, median of
5.3 to 1.6 months.2 Vemurafenib is an inhibitor for mutated
BRAFV600E, which is a common mutation found in up to 66% of
metastatic melanomas3 and constitutively activates a specific
RAF kinase involved in the MAPK cellular proliferation pathway.
While vermurafenib specifically inhibits proliferation in
BRAF-mutated cells, it can paradoxically activate wild-type
cells with mutated or activated RAS, previously found in
potentially precancerous actinic keratoses.4 Cutaneous squamous
cell carcinomas (cSCCs) or keratoacanthomas (KAs)
may occur in approximately 25% of patients.4 Often, they
occur in the first 2-3 months after starting therapy on sunexposed
areas.4 Oberholzer et al found that squamous cell
tumors treated with a RAF inhibitor had higher rates of HRAS
mutations, despite similar rates of total mutations. Increased
RAS mutation rates in these cutaneous cancers plus its preferential
development in sun-exposed locations on older patients
rapidly following treatment initiation supports the theory of
an underlying mutational predisposition that is unmasked due
to a RAF inhibitor pro-proliferative state.4 RAS-mutated tumors
in BRAF wild type cells allow inhibitor binding to cause
RAF dimerization, permitting transactivation of the drug-free
promoter and activating the MEK substrate.5 Aside from the
risk of cutaneous carcinomas, RAS mutations in BRAF positive
cells may be a mechanism for BRAF inhibitor resistance as
well as potentially increase the risk of extracutaneous cancer,
since RAS mutations are seen in many types including colon,
pancreatic, and lung, although this not been seen.4
