Elisabeth Livingstone

Atypical Melanocytic Proliferations and New Primary Melanomas in Patients With Advanced Melanoma Undergoing Selective BRAF Inhibition

PURPOSE Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. PATIENTS AND METHODS In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment. RESULTS Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. CONCLUSION Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.

TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma

BACKGROUND Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. METHODS 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. RESULTS TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). CONCLUSIONS UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas. Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples. Results: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma. Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents. Clin Cancer Res; 19(12); 3143–52. ©2013 AACR.

Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management.

BACKGROUND Painful lobular panniculitis appears to be a novel cutaneous adverse effect of selective BRAF inhibitors. OBSERVATION We report the clinical course and management in 2 women with metastatic melanomas harboring the BRAF(V600E) mutation, who developed panniculitis with arthralgia during therapy with selective oral BRAF inhibitors. Panniculitis with arthralgia was the acute presenting adverse effect in both patients. Painful, red, nodular lesions were located on the upper and lower extremities. Biopsy specimens of the nodules showed a mild, predominantly lobular neutrophilic panniculitis. Analgesic and anti-inflammatory treatment improved panniculitis and arthralgia in both cases. It was also necessary to reduce the BRAF inhibitor dose in 1 patient. CONCLUSIONS During therapy with selective BRAF inhibitors, panniculitis with arthralgia represents a new adverse effect that can require dose reduction. In case of this adverse effect, treatment with nonsteroidal anti-inflammatory drugs, such as etoricoxib, should be initiated early to keep patients on treatment and to avoid drug discontinuation and tumor progression.

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

Purpose Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. Patients and Methods We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed. Conclusions Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. Trial Registration ClinicalTrials.gov NCT01355120

Immunotherapy in melanoma: Recent advances and future directions

Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma. Ipilimumab, a monoclonal antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as nivolumab and pembrolizumab which target the programmed cell death protein 1 (PD-1) have been shown to prolong overall survival in patients with advanced melanoma. The latter substances seem to have an increased response rate and more tolerable safety profile compared to ipilimumab. The combination of a CTLA-4 and a PD-1 inhibitor seems to be superior to the monotherapies, especially in patients with PD-L1 negative tumours. Checkpoint inhibitors are currently being tested in the adjuvant setting with initial data for ipilimumab suggesting efficacy in this context. Talimogene laherparepvec (TVEC) is the first oncolytic virus approved in the therapy of metastatic melanoma offering a treatment option especially for patients with limited disease. In this review, data on these recently developed and approved immunotherapies are presented. However, further studies are necessary to determine the optimal duration, sequencing and combinations of immunotherapies to further improve the outcome of patients with advanced melanoma.

A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up

AIM OF THE STUDY To describe the current management of patients diagnosed with cutaneous melanoma and melanoma in situ in Germany and assess for adherence with the existing German guideline in a first prospective population-based analysis. METHODS Prospective and longitudinal population-based study using online questionnaires. Registration by practitioners and hospitals was open for all patients diagnosed with melanoma between April and June 2008 in Germany. For data analysis, patients with melanoma stages 0-III (AJCC 2002) were included. RESULTS Data from 1081 patients registered by 106 different centres were available for analysis. Male patients were significantly older than female patients (61.4 years versus 55.8years, p<0.0001) and presented with thicker primary tumours (1.62 mm [median 0.9 mm] versus 1.48 mm [median 0.8 mm], p=0.01). Excessive safety margin excisions were most often applied in melanoma in situ and in small centres. Insufficient excision margins (6.9%) were associated with head and neck localisation, geographical region and implementation of further staging procedures. Decision on sentinel lymph node biopsy complied with the German guideline in >85% of cases and was dependent on age and tumour localisation. Only 60% of patients received a complete lymph node dissection (CLND) after a positive SLNB, the rate of CLND was lowest in older patients. Adjuvant treatments were initiated in only 34% of patients formally qualifying for adjuvant treatment based on guideline recommendations. Approximately half of all staging procedures were done in no-risk/low-risk tumour patients. CONCLUSIONS Management of melanoma in Germany did not show great dependency on centre size, geographical area or treating physician but rather on patient and tumour characteristics. The low rate of adjuvant treatment initiations reflects the need of treatment options in this patient group. Excessive initial staging procedures generate significant costs.

Prospective Randomized Multicenter Adjuvant Dermatologic Cooperative Oncology Group Trial of Low-Dose Interferon Alfa-2b With or Without a Modified High-Dose Interferon Alfa-2b Induction Phase in Patients With Lymph Node–Negative Melanoma

PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

Combination of BRAF Inhibitors and Brain Radiotherapy in Patients With Metastatic Melanoma Shows Minimal Acute Toxicity

ACKNOWLEDGMENT Supported by the National Health and Medical Research Council of Australia, The Cancer Council of New South Wales, Cancer Institute New South Wales, Royal Australasian College of Surgeons, St Vincent’s Clinic Foundation, R.T. Hall Trust, and the Avner Nahmani Pancreatic Cancer Foundation (Australia); the Chief Scientist’s Office of the Scottish Government (UK); and the Italian Association for Cancer Research, Fondazione Cariverona, and Miriam Cherubini Loro (Italy).

Metastatic Melanoma: Scientific Rationale for Sorafenib Treatment and Clinical Results

In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.