IMPORTANCE Recent advances in targeting BRAF(V600E) mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes

Atkinson, Victoria

Flewell-Smith, Ross

Jagirdar, Kasturee

Lambie, Duncan

Lin, Lynlee L.

McClenahan, Phil

Prow, Tarl W.

Schaider, Helmut

Soyer, Peter

Sturm, Richard A.

Tan, Jean-Marie

University of Queensland eSpace

Copyright 2014 American Medical Association. All rights reserved.
BRAFV600EMutation Status of Involuting and Stable Nevi
in Dabrafenib TherapyWith orWithout Trametinib
Phil McClenahan, BSc; Lynlee L. Lin, BSc; Jean-Marie Tan, MB, BCh, BAO (hons); Ross Flewell-Smith, BCom, BEng;
Helmut Schaider, MD; Kasturee Jagirdar, MSc; Victoria Atkinson, MBBS, FRACP;
Duncan Lambie, BDSc, MBBS, FRCPA; Tarl W. Prow, BS, MSc, PhD; Richard A. Sturm, PhD;
H. Peter Soyer, MD, FACD
M elanocytes, like many other human cells, expressthe BRAF gene. However, mutation of BRAF inmelanocytes occurs at high frequency in melano-
cytic proliferations such as nevi (70%-82%) and melanomas
(50%-60%).1,2 Mutation of BRAF results in a defect of the
mitogen-activated protein kinase (MAPK) pathway causing
oncogenic proliferation and avoidance of apoptosis.3 Most
frequently, BRAF mutations occur at the V600E position
(74%-90%), and the next most common mutation occurs at
V600K (16%-29%)4; together, these sites account for 95% of
all BRAFmutations.
Initial breakthrough treatments were made with vemu-
rafenib, a selective inhibitorofBRAFV600E-mutatedkinase.The
inhibition of BRAFV600E initially induces tumor growth arrest
and partial or complete tumor regression in metastatic
melanoma.5GiventhefrequencyofBRAFV600Emutations inbe-
nign nevi,2 it is also not surprising that changes have been ob-
served in existing melanocytic nevi and that new nevi appear
during BRAFV600E inhibitor therapy.6,7 Recently, a study of 42
patients treated with vemurafenib for a mean duration of 6.7
months described a high level of dermoscopic change in pre-
existing lesions such as color changes, appearance and disap-
pearanceofglobules,dermoscopic islandpigmentation,and in-
creases insizeofnevi.8Newprimarymelanomashavealsobeen
reportedduring theearlystagesofvemurafenib treatment,aris-
ing from new erupting melanocytic proliferations or rapidly
changing existing nevi.9 Zimmer et al,9 Dalle et al,7 and Perier-
Muzet et al8 report that these newprimarymelanomas arising
during vemurafenib therapy are BRAFwild type.
Hereinwedescribeanexampleofnevusvolatility andpro-
pose the molecular involvement in a patient undergoing
BRAFV600E inhibition therapy and who participated in a ne-
vus surveillance study. All patients in the surveillance study
provided written consent, and the study followed the Decla-
ration ofHelsinki protocols andwas approvedby thePrincess
Alexandra Hospital human research ethics committee.
IMPORTANCE Recent advances in targeting BRAFV600E mutations, which occur in roughly
50% of melanomas and 70% of benign nevi, have improved response rates and survival in
patients with melanoma. With increased survival, the importance of other comorbidities
increases and requires consideration in long-termmanagement. This case report discusses
dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some
conclusions regarding BRAFmutations and the changes.
OBSERVATIONS Aman in his 30s had beenmonitored with whole-body dermoscopy at
roughly 7-month intervals as part of a nevus surveillance study. Fourteenmonths after his
initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with
or without trametinib therapy. Continued dermoscopic monitoring for the next 12 months
revealed that approximately 50% of the existing acquiredmelanocytic nevi involuted, while
the remaining nevi did not change. Biopsy findings from 1 unchanged and 1 involuted nevus
showed BRAFwild type in the unchanged nevus, BRAFV600E mutation in the involuting
nevus, and nomalignant histopathologic characteristics in either one.
CONCLUSIONS AND RELEVANCE Our observations indicate that a previously suggested
hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute
while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E
mutation, while others that grow or remain unchanged are wild type. However larger-scale
trials are required to gather conclusive data and create a more complete clinical picture.
JAMA Dermatol. 2014;150(10):1079-1082. doi:10.1001/jamadermatol.2014.436
Published online April 2, 2014.
Author Affiliations:Dermatology
Research Centre, The University of
Queensland, School of Medicine,
Translational Research Institute,
Brisbane, Queensland, Australia
(McClenahan, Lin, Tan, Flewell-Smith,
Schaider, Jagirdar, Prow, Sturm,
Soyer); The University of Queensland,
Institute for Molecular Biosciences,
Brisbane, Queensland, Australia
(Jagirdar, Sturm); Medical Oncology,
Princess Alexandra Hospital,
Wooloongabba, Queensland,
Australia (Atkinson); The University
of Queensland, Translational
Research Institute, Brisbane,
Queensland, Australia (Lambie);
IQ Pathology, Brisbane, Queensland,
Australia (Lambie).
Corresponding Author:H. Peter
Soyer, MD, FACD, Level 5,
Translational Research Institute (TRI),
37 Kent St, Woolloongabba QLD
4102, Australia (p.soyer@uq.edu.au).
Research
Case Report/Case Series
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Report of a Case
While participating in a nevus surveillance study, 1 of the pa-
tients, a man in his 30s who had been diagnosed 5 years ear-
lier as having a superficial melanoma (Clark level 3, Breslow
index 0.64mm), developedmetastases in the pancreas, liver,
and mesenteric lymph nodes. Two months later, he was en-
rolled in a clinical trial of dabrafenib with or without tra-
metinib therapy. Dabrafenib is a BRAF inhibitor similar to ve-
murafenib, and it was being tested with trametinib, a MEK
(MAPK kinase) inhibitor that targets the same MAPK path-
way. The trial was blinded and still ongoing at the time of the
present report, and so it is unknown whether this patient’s
treatment regimen included trametinib.
The patient presented with Fitzpatrick skin type III, dark
brown hair, and green eyes. He underwent imaging with a
FotoFinder system (FotoFinder Systems GmbH) of all nevi
larger than 2mmon the back and larger than 5mmon the rest
of thebody.Nosignificant changeswereobserveddermoscopi-
cally throughout.Tennevi larger than5mmwere identifiedon
thebody,while 25nevi larger than2mmwere identifiedon the
back, for a total of 31 nevi included in our analysis. Therewere
2 globular, 15 reticular, and 14nonspecific/homogeneousnevi.
Full-bodyanddermoscopic imagingwasconducted5times
over the next 27months at roughly 7-month intervals, and no
significant dermoscopic changes were identified by assess-
ment of imaged nevi at the 7- or 14-month visits. However, at
the 21-month visit, 6 months after he commenced participa-
tion in the BRAF inhibitor trial, assessment revealed signifi-
cantdermoscopic changes 16nevi (51%of total) (Figure 1). The
nevi changes predominantly involved involution and a de-
crease in pigmentation and size. In addition, in concurrence
with other reports,6 flattening of raised nevi was also ob-
served. By dermoscopic pattern, 4 reticular, 10 homoge-
neous, and 2 globular nevi showed signs of involution. There-
fore, 71%of theunspecificand26%of the reticularnevi showed
signs of involution, while both raised globular nevi de-
creased in pigmentation and flattened.
By the time of final imaging at 27 months’ surveillance
(12 months into the BRAF inhibitor trial), the nevi had gen-
erally not further changed, but 5 nevi had continued to
involute: 3 reticular and 2 homogeneous nevi. Again, no
increase in pigmentation was observed in any lesions, and
no new nevi were observed. The patient had an otherwise
excellent systemic response to the targeted therapy and an
excellent partial response to the point of almost a complete
response, with the exception of a small unchanged node
near the pancreas that was seen on computed tomographic
imaging.
There are a number of external and endogenous factors
influencing changes and appearance of nevi over time. These
Figure 1. Surveillance of Involuting Nevi During BRAFV600E Inhibitor Therapy and Clinical Image of Back
A F
B
C
D
E
Baseline 7 Months 14 Months 21 Months 27 Months
A-C, Three nevi have undergone involution 7months after initiation of
BRAFV600E inhibitor therapy. D and E, The other 2 nevi remain unchanged.
Excisional shave biopsies and numerous ex vivomicrobiopsies were performed
on nevi C and E. Images to the left of the vertical red line were obtained before
the patient commenced participation in the BRAF inhibitor trial; images to the
right of the line were obtained after he entered the trial. F, Clinical image of the
back shows nevi locations: white arrow indicates biopsied involuting nevus;
white circles indicate involuting nevi; black arrow indicates biopsied unchanged
nevus; black circles indicate unchanged nevi.
Research Case Report/Case Series BRAFV600E Nevi Status in BRAF-Inhibitor Treatment
1080 JAMADermatology October 2014 Volume 150, Number 10 jamadermatology.com
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Copyright 2014 American Medical Association. All rights reserved.
Figure 2. Histopathologic Images andMolecular Sequencing Charts for BRAFV600E Status of 1 Involuting
Nevus and 1 Noninvoluting Nevus
A C
D
G
H
B
E
F
1
23
4
5
6
1
2 3
4
5
6
M
icr
ob
io
ps
y 1
M
icr
ob
io
ps
y 2
M
icr
ob
io
ps
y 3
M
icr
ob
io
ps
y 4
M
icr
ob
io
ps
y 6
M
icr
ob
io
ps
y 5
M
icr
ob
io
ps
y 1
M
icr
ob
io
ps
y 2
M
icr
ob
io
ps
y 3
M
icr
ob
io
ps
y 4
M
icr
ob
io
ps
y 6
M
icr
ob
io
ps
y 5
A/T
A/T
AAA A AC G G
AAA A AC G GT
AAA A AC G GT
AAA A AC G
A A A AA C G
A A A AA C G G
G
GT
T
A A A AA C G GT
A A A AA C G GT
A A A AA C G GT
A A A AA C G GT
A A A AA C G GT
A A A AA C G GT
A-D, Workup of an involuting nevus.
E-H, Workup of a noninvoluting
nevus. C and G, Dermoscopic images
showmicrobiopsy sites 1 through 5
(scale bar = 1 mm); site 6 in each
panel is a control biopsy site adjacent
to the nevus. D and H, Molecular
analysis charts for microbiopsy sites
shown in panels C and G,
respectively. A and E, Histopathologic
images of the nevi, neither of which
shows any histopathological criteria
for melanoma (scale bars = 200 μm;
boxes enclose areas shown at higher
magnification in panels B and F).
The involuted nevus in panel A is a
benign, predominantly junctional
nevus with few discrete nests of
nonpigmented nevus cells at the
dermal-epidermal junction; subtle
lymphatic infiltration around
suprapapillary vascular plexus; and
no obvious signs of fibrosis or
regression; sequencing (D) reveals
that the nevus is heterogeneous for
BRAFV600E mutation at sites 1 and 5.
The noninvoluted nevus in panel E is
a benign lentiginous melanocytic
nevus with elongated pigmented rete
ridges and slightly increased numbers
of melanocytes at the
dermal-epidermal junction; small
junctional nests of melanocytes are
also present; and sequencing (H)
reveals no presence of BRAFV600E
mutation. B and F, Greater
magnifications of the boxed areas of
panels A and E, respectively (scale
bars = 200 μm).
BRAFV600E Nevi Status in BRAF-Inhibitor Treatment Case Report/Case Series Research
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Copyright 2014 American Medical Association. All rights reserved.
includeUV radiation exposure, hormonal changes associated
with pregnancy,10 and targeted melanoma therapies such as
selective BRAFV600E inhibitors.6 As unchanged and changed
nevi were at times adjacent at the same body site, UV expo-
sure was not considered to be amajor influencing factor, and
pregnancy cannot be considered in our male patient. There-
fore to sample molecular markers, specifically BRAF muta-
tion status of changed and unchanged nevi, we used a newly
described microbiopsy device.11-13
Diagnostic shave excisions were performed on 1 invo-
lutednevusand1unchangednevus (Figure 1). Thehistopatho-
logic diagnosis for the involuted lesion was a predominantly
junctional compound nevus without significant inflamma-
tion or fibrosis, and the unchanged lesion was characterized
as a junctional nevuswith a lentiginousmelanocytic pattern.
Microbiopsy specimens were taken from 6 locations on both
of theexcisednevi (Figure 2).DNAsamples extracted frommi-
crobiopsy specimens were subjected to polymerase chain re-
action amplificationusing selected forward and reverseprim-
ers to flank the BRAF exon 15 and NRAS exon 2 mutation
hotspots.14Molecular sequencingof the samples forBRAFand
NRAS mutations were performed after extraction of ampli-
fied products from the DNA gel. Sequencing revealed hetero-
geneousBRAFV600Emutation inthe involutingnevusandBRAF
wild type in the unchanged nevus, while both lesions were
NRASwild type.
Discussion
The involutionofnevi inBRAFV600E inhibitor therapyhasbeen
reported, but herein we report findings that support the
hypothesis6 that thesenevi areBRAFV600E positive. This is re-
lated to decreased MAPK activity due to BRAF inhibition. In
contrast to reports in vemurafenib-treated patients of in-
creased size and pigmentation in some nevi and the appear-
ance of new BRAFwild-type melanoma through paradoxical
BRAF activation,15 we observed no increase in pigmentation
of nevi or suspect changes in our patient. Because we could
not knowwhether our dabrafenib-treatedpatientwas also re-
ceivingtrametinib,conclusionsregardingthecombinationregi-
men cannot be drawn. However, our long-term monitoring
prior to andduring therapy combinedwith confirmationof in-
voluting nevi possessing BRAFV600E mutation adds another
component to the dermoscopic changes in long-term therapy
withBRAFV600E inhibitors. Larger-scale and longer-term trials
will give a broader and more accurate description of specific
medication effects required for dermatologic follow-up.
ARTICLE INFORMATION
Accepted for Publication: February 26, 2014.
Published Online: April 2, 2014.
doi:10.1001/jamadermatol.2014.436.
Author Contributions:MrMcClenahan had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design:McClenahan,
Flewell-Smith, Soyer.
Acquisition of data:McClenahan, Lin, Tan, Jagirdar,
Atkinson, Lambie, Prow, Sturm, Soyer.
Analysis and interpretation of data:McClenahan,
Lin, Schaider, Jagirdar, Prow, Sturm, Soyer.
Drafting of the manuscript:McClenahan, Lin,
Flewell-Smith, Schaider, Prow, Soyer.
Critical revision of the manuscript for important
intellectual content:McClenahan, Tan, Jagirdar,
Atkinson, Lambie, Sturm, Soyer.
Statistical analysis:McClenahan, Sturm, Soyer.
Obtained funding: Soyer.
Administrative, technical, or material support: Lin,
Tan, Flewell-Smith, Jagirdar, Lambie, Prow, Sturm,
Soyer.
Study supervision: Schaider, Sturm, Soyer.
Conflict of Interest Disclosures:None reported.
Funding/Support: This study was supported in
part by research grant APP1004999 from the
National Health andMedical Research Council,
Canberra, Australian Capital Territory, Australia.
Role of the Sponsor: The National Health and
Medical Research Concil had no role in the design
and conduct of the study; collection, management,
analysis, and interpretation of the data;
preparation, review, or approval of themanuscript;
and decision to submit themanuscript for
publication.
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Research Case Report/Case Series BRAFV600E Nevi Status in BRAF-Inhibitor Treatment
1082 JAMADermatology October 2014 Volume 150, Number 10 jamadermatology.com
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BRAFV600E Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy with or without Trametinib

Phil McClenahan

Lynlee L. Lin

Jean-Marie Tan

Ross Flewell-Smith

Helmut Schaider

Kasturee Jagirdar

Victoria Atkinson

Duncan Lambie

Tarl W. Prow

Richard A. Sturm

H. Peter Soyer

Crossref

JAMA Dermatology

<i>BRAF</i><sup>V600E</sup>Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy With or Without Trametinib

http://espace.library.uq.edu.au/view/UQ:330852/UQ330852_OA.pdf

BRAFV600E Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy with or without Trametinib

Abstract

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