Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma
Einar Birkeland
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Christian Busch
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Elisabet Ognedal Berge
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Ju rgen Geisler
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Go ran Jo nsson
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Johan Richard Lillehaug
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Stian Knappskog
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Per Eystein Lnning
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Present Address: C. Busch Teres Medical Group
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Bergen, Norway
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E. Birkeland C. Busch E. O. Berge J. Geisler S. Knappskog P. E. Lnning Department of Oncology, Haukeland University Hospital
, Jonas Lies vei 26,
5021 Bergen, Norway
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E. Birkeland C. Busch E. O. Berge S. Knappskog P. E. Lnning (&) Section of Oncology, Institute of Medicine, University of Bergen
,
Bergen, Norway
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J. R. Lillehaug Department of Molecular Biology, University of Bergen
,
Bergen, Norway
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G. Jonsson CREATE Health Strategic Center for Translational Cancer, Lund University
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Lund, Sweden
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G. Jonsson Department of Oncology, Clinical Sciences, Lund University
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Lund, Sweden
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J. Geisler Faculty Division, Akershus University Hospital
, 1478 Lrenskog,
Norway
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Present Address: J. Geisler Institute of Medicine, University of Oslo
,
Oslo, Norway
Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p 0.001) compared to patients with tumors wildtype for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and 0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma.
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The incidence of cutaneous malignant melanoma is
increasing among light-skin Caucasians [1]. Although most
patients are cured by surgical excision of the tumor,
approximately 20 % will relapse [2]. Systemic treatment
for metastatic malignant melanomas remains palliative.
Dacarbazine (DTIC) is considered standard chemotherapy
treatment, even though objective response rates as low as
10 % are recorded [3].
Activating mutations in the BRAF (V600E) and NRAS
(Q61K) genes are found at a frequency of 4060 and
1530 % in metastatic melanomas, respectively [410].
In vitro studies have shown that the V600E mutation,
which is located in the proteins activation loop, causes a
500-fold increase in the enzymatic activity of BRAF,
enhancing activation of its downstream target, ERK [11].
Thus, for tumors harboring NRAS or BRAF mutations,
activation of this pathway is thought to play a key role in
driving tumor growth. This is further underlined by recent
studies showing that targeted inhibition of mutated BRAF
may cause tumor regression in metastatic melanomas
harboring BRAF V600E mutations [12, 13], as well as
findings indicating that treatment of BRAF-mutated melanomas
may benefit from inhibition of the downstream effector
MEK [14].
While the effects of the V600E mutation of BRAF
have been extensively studied in experimental systems,
several aspects of BRAF function remain poorly
understood. Interestingly, copy-number gains of the
BRAF gene have been proposed as an alternative
mechanism of activation in both melanoma and glioma
[15, 16], as well as being a cause of resistance towards
BRAF inhibitor treatment of advanced melanoma [17].
Further, BRAF mRNA has been found subject to
alternative splicing, with different transcript variants
identified in colorectal cancer as well as in melanoma [18,
19]. Interestingly, expression of some splice variants has
been related to resistance toward the BRAF inhibitor
vemurafenib [19].
Although overexpression of wild-type BRAF has
been reported to be an underlying mechanism of
pathway activation in experimental systems [15], to the best
of our knowledge the level of BRAF expression in
tumors wild-type for BRAF has not been investigated as
a potential predictive and prognostic factor in
melanoma patients.
The aim of this study was to evaluate the predictive
and prognostic impact of genetic (...truncated)