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Alexander M. Menzies - One of the best experts on this subject based on the ideXlab platform.
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circulating tumour dna predicts response to anti pd1 antibodies in Metastatic Melanoma
Annals of Oncology, 2017Co-Authors: Georgina V. Long, Alexander M. Menzies, Jenny H Lee, Suzanah C Boyd, Varsha Tembe, Alexander Guminski, V Jakrot, Richard A ScolyerAbstract:Background Programmed death 1 (PD1) inhibitors are now a foundation of medical management of Metastatic Melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. Patients and methods We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in Melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. Results ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09; P Conclusion Longitudinal assessment of ctDNA in Metastatic Melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.
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activity and safety of radiotherapy with anti pd 1 drug therapy in patients with Metastatic Melanoma
OncoImmunology, 2016Co-Authors: Elizabeth Liniker, Richard F. Kefford, Alexander M. Menzies, Alexander Guminski, Benjamin Y Kong, Adam Cooper, S Ramanujam, Gerald B Fogarty, T W Wang, Matteo S CarlinoAbstract:ABSTRACTThe anti-PD-1 antibodies nivolumab and pembrolizumab are active in Metastatic Melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for Metastatic Melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent “salvage” treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one pati...
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increased mapk reactivation in early resistance to dabrafenib trametinib combination therapy of braf mutant Metastatic Melanoma
Nature Communications, 2014Co-Authors: Georgina V. Long, Alexander M. Menzies, Matteo S Carlino, Carina Fung, Gulietta M Pupo, Jessica HymanAbstract:Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant Metastatic Melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant Melanoma metastases and identify mutations that confer resistance to combination therapy.
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correlation of braf and nras mutation status with outcome site of distant metastasis and response to chemotherapy in Metastatic Melanoma
British Journal of Cancer, 2014Co-Authors: Matteo S Carlino, Richard F. Kefford, Alexander M. Menzies, Lauren E Haydu, Anne Hamilton, John F Thompson, Hojabr Kakavand, Wendy A Cooper, Sandra A Otoole, Richard A ScolyerAbstract:Activating mutations in the oncogenes BRAF or NRAS occur in approximately 40 and 20% of Melanomas, respectively, and result in constitutive activation of the mitogen-activated kinase (MAPK) cell signalling pathway (Davies et al, 2002; Platz et al, 2008). Small molecule inhibitors of mutant BRAF and the downstream kinase MEK (MAPK inhibitors) have transformed the management of BRAF-mutant Metastatic Melanoma and improved overall survival (OS) compared with standard chemotherapy in patients with BRAFV600 mutant Metastatic Melanoma (Chapman et al, 2011; Flaherty et al, 2012; Hauschild et al, 2012). Similarly, although to a lesser extent, single agent MEK inhibition has shown activity in NRAS-mutant Metastatic Melanoma (Falchook et al, 2012; Ascierto et al, 2013), with a phase III trial currently underway (NCT01763164). The presence of a BRAF mutation in Metastatic colorectal cancer is associated with a shorter OS compared with KRAS mutant or RAS/RAF wild-type disease (Van Cutsem et al, 2011; Yokota et al, 2011; Toland et al, 2012). Similarly BRAF mutations are associated with an increased risk of recurrence in papillary thyroid cancer (Elisei et al, 2012; Prescott et al, 2012; Fernandez et al, 2013). The prognostic significance of a BRAF mutation in Metastatic Melanoma is less clear. Recent analysis of survival in Metastatic Melanoma patients were performed when BRAF and MEK inhibitors were available and some patients included received these therapies (Long et al, 2011; Jakob et al, 2012), making comparisons between the BRAF-mutant and wild-type populations difficult. One study examining BRAF status only (Long et al, 2011) reported no difference in survival from stage IV diagnosis between patients with BRAF-mutant and wild-type Metastatic Melanoma; however, when the analysis was limited to patients with BRAF-mutant Melanoma who did not receive a MAPK inhibitor, a significantly shorter survival in BRAF-mutant patients was observed. It is unclear if this difference in survival was due to differences in the biology of BRAF-mutant versus wild-type Melanoma or a selection bias due to the non-random selection of BRAF-mutant patients for entry into the early phase clinical trials of MAPK inhibitors. Another study examining BRAF and NRAS status reported that NRAS-mutant Melanoma was associated with the poorest survival (Jakob et al, 2012). However, an earlier study found that NRAS-mutant Melanoma was associated with improved survival compared with BRAF-mutant or BRAF/NRAS wild-type disease (Ugurel et al, 2007). This uncertainty regarding the prognostic significance of BRAF and NRAS mutations in Metastatic Melanoma led us to perform a retrospective analysis in a cohort of patients with advanced Melanoma who were treated before the availability of MAPK inhibitors. We sought to correlate BRAF and NRAS mutation status with clinicopathologic characteristics, response to chemotherapy and survival, as well as to determine the frequency of other oncogenic mutations in Metastatic Melanoma.
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Dabrafenib and Trametinib, alone and in combination for BRAF-mutant Metastatic Melanoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014Co-Authors: Alexander M. Menzies, Georgina V. LongAbstract:Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant Metastatic Melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) Metastatic Melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naive patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant Melanoma.
Matteo S Carlino - One of the best experts on this subject based on the ideXlab platform.
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miller fisher syndrome associated with immunotherapy for Metastatic Melanoma
The Neurohospitalist, 2018Co-Authors: Jonathan Bairdgunning, Dinushi Weerasinghe, Matthew Silsby, Yash Gawarikar, Matteo S Carlino, Jessica Smith, Steve VucicAbstract:Immunotherapy is a treatment strategy that has demonstrated survival benefit for Metastatic Melanoma. Ipilimumab and nivolumab are examples of immunotherapy, in which monoclonal antibodies antagoni...
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activity and safety of radiotherapy with anti pd 1 drug therapy in patients with Metastatic Melanoma
OncoImmunology, 2016Co-Authors: Elizabeth Liniker, Richard F. Kefford, Alexander M. Menzies, Alexander Guminski, Benjamin Y Kong, Adam Cooper, S Ramanujam, Gerald B Fogarty, T W Wang, Matteo S CarlinoAbstract:ABSTRACTThe anti-PD-1 antibodies nivolumab and pembrolizumab are active in Metastatic Melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for Metastatic Melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent “salvage” treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one pati...
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increased mapk reactivation in early resistance to dabrafenib trametinib combination therapy of braf mutant Metastatic Melanoma
Nature Communications, 2014Co-Authors: Georgina V. Long, Alexander M. Menzies, Matteo S Carlino, Carina Fung, Gulietta M Pupo, Jessica HymanAbstract:Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant Metastatic Melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant Melanoma metastases and identify mutations that confer resistance to combination therapy.
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correlation of braf and nras mutation status with outcome site of distant metastasis and response to chemotherapy in Metastatic Melanoma
British Journal of Cancer, 2014Co-Authors: Matteo S Carlino, Richard F. Kefford, Alexander M. Menzies, Lauren E Haydu, Anne Hamilton, John F Thompson, Hojabr Kakavand, Wendy A Cooper, Sandra A Otoole, Richard A ScolyerAbstract:Activating mutations in the oncogenes BRAF or NRAS occur in approximately 40 and 20% of Melanomas, respectively, and result in constitutive activation of the mitogen-activated kinase (MAPK) cell signalling pathway (Davies et al, 2002; Platz et al, 2008). Small molecule inhibitors of mutant BRAF and the downstream kinase MEK (MAPK inhibitors) have transformed the management of BRAF-mutant Metastatic Melanoma and improved overall survival (OS) compared with standard chemotherapy in patients with BRAFV600 mutant Metastatic Melanoma (Chapman et al, 2011; Flaherty et al, 2012; Hauschild et al, 2012). Similarly, although to a lesser extent, single agent MEK inhibition has shown activity in NRAS-mutant Metastatic Melanoma (Falchook et al, 2012; Ascierto et al, 2013), with a phase III trial currently underway (NCT01763164). The presence of a BRAF mutation in Metastatic colorectal cancer is associated with a shorter OS compared with KRAS mutant or RAS/RAF wild-type disease (Van Cutsem et al, 2011; Yokota et al, 2011; Toland et al, 2012). Similarly BRAF mutations are associated with an increased risk of recurrence in papillary thyroid cancer (Elisei et al, 2012; Prescott et al, 2012; Fernandez et al, 2013). The prognostic significance of a BRAF mutation in Metastatic Melanoma is less clear. Recent analysis of survival in Metastatic Melanoma patients were performed when BRAF and MEK inhibitors were available and some patients included received these therapies (Long et al, 2011; Jakob et al, 2012), making comparisons between the BRAF-mutant and wild-type populations difficult. One study examining BRAF status only (Long et al, 2011) reported no difference in survival from stage IV diagnosis between patients with BRAF-mutant and wild-type Metastatic Melanoma; however, when the analysis was limited to patients with BRAF-mutant Melanoma who did not receive a MAPK inhibitor, a significantly shorter survival in BRAF-mutant patients was observed. It is unclear if this difference in survival was due to differences in the biology of BRAF-mutant versus wild-type Melanoma or a selection bias due to the non-random selection of BRAF-mutant patients for entry into the early phase clinical trials of MAPK inhibitors. Another study examining BRAF and NRAS status reported that NRAS-mutant Melanoma was associated with the poorest survival (Jakob et al, 2012). However, an earlier study found that NRAS-mutant Melanoma was associated with improved survival compared with BRAF-mutant or BRAF/NRAS wild-type disease (Ugurel et al, 2007). This uncertainty regarding the prognostic significance of BRAF and NRAS mutations in Metastatic Melanoma led us to perform a retrospective analysis in a cohort of patients with advanced Melanoma who were treated before the availability of MAPK inhibitors. We sought to correlate BRAF and NRAS mutation status with clinicopathologic characteristics, response to chemotherapy and survival, as well as to determine the frequency of other oncogenic mutations in Metastatic Melanoma.
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distinguishing clinicopathologic features of patients with v600e and v600k braf mutant Metastatic Melanoma
Clinical Cancer Research, 2012Co-Authors: Alexander M. Menzies, Lauren E Haydu, Matteo S Carlino, Lydia Visintin, Julie R Howle, John F ThompsonAbstract:Purpose: Certain clinicopathologic features correlate with BRAF mutation status in Melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF -mutant genotypes correlated with clinicopathologic features and outcome in patients with Metastatic Melanoma. Methods: A prospectively assembled cohort of Australian patients were followed from diagnosis of Metastatic Melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival. Results: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade ( P 40% in those ≥70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E Melanoma ( P = 0.002). The disease-free interval from diagnosis of primary Melanoma to first distant metastasis was shorter for patients with V600K compared with V600E Melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of Metastatic Melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF -mutant Melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type Melanoma (37%, P < 0.001). Conclusion: Different genotypes exist within BRAF -mutant Metastatic Melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. Clin Cancer Res; 18(12); 3242–9. ©2012 AACR .
Georgina V. Long - One of the best experts on this subject based on the ideXlab platform.
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circulating tumour dna predicts response to anti pd1 antibodies in Metastatic Melanoma
Annals of Oncology, 2017Co-Authors: Georgina V. Long, Alexander M. Menzies, Jenny H Lee, Suzanah C Boyd, Varsha Tembe, Alexander Guminski, V Jakrot, Richard A ScolyerAbstract:Background Programmed death 1 (PD1) inhibitors are now a foundation of medical management of Metastatic Melanoma. This study sought to determine whether circulating tumour DNA (ctDNA) provides useful early response and prognostic information. Patients and methods We evaluated the relationship between pre-treatment and early on treatment ctDNA and outcome in Melanoma patients treated with PD1 inhibitors alone or in combination with ipilimumab. Results ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with stage, LDH levels, disease volume and ECOG performance. RECIST response was 72% (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6% (1/18) in group C (elevated ctDNA at baseline and remained elevated during treatment). The median PFS was not reached in groups A and B and was 2.7 months for group C [hazard ratio (HR) 0.09; P Conclusion Longitudinal assessment of ctDNA in Metastatic Melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.
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increased mapk reactivation in early resistance to dabrafenib trametinib combination therapy of braf mutant Metastatic Melanoma
Nature Communications, 2014Co-Authors: Georgina V. Long, Alexander M. Menzies, Matteo S Carlino, Carina Fung, Gulietta M Pupo, Jessica HymanAbstract:Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant Metastatic Melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant Melanoma metastases and identify mutations that confer resistance to combination therapy.
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activity of trametinib in k601e and l597q braf mutation positive Metastatic Melanoma
Melanoma Research, 2014Co-Authors: Samantha Bowyer, Georgina V. Long, Aparna D Rao, Megan Lyle, Shahneen Sandhu, Grant A Mcarthur, Jeanette Raleigh, Rodney J Hicks, Michael MillwardAbstract:BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive Metastatic Melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive Metastatic Melanoma treated with the MEK inhibitor t
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Dabrafenib and Trametinib, alone and in combination for BRAF-mutant Metastatic Melanoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014Co-Authors: Alexander M. Menzies, Georgina V. LongAbstract:Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant Metastatic Melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) Metastatic Melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naive patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant Melanoma.
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prognostic and clinicopathologic associations of oncogenic braf in Metastatic Melanoma
Journal of Clinical Oncology, 2011Co-Authors: Georgina V. Long, Alexander M. Menzies, Adnan Nagrial, Lauren E Haydu, Anne Hamilton, Graham J Mann, Michael T Hughes, John F Thompson, Richard A Scolyer, Richard F. KeffordAbstract:Purpose To assess the frequency and type of oncogenic BRAF mutations in Metastatic Melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with Metastatic Melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with Metastatic Melanoma by mutation status. Features of the antecedent primary Melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary Melanoma, trun...
Richard F. Kefford - One of the best experts on this subject based on the ideXlab platform.
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activity and safety of radiotherapy with anti pd 1 drug therapy in patients with Metastatic Melanoma
OncoImmunology, 2016Co-Authors: Elizabeth Liniker, Richard F. Kefford, Alexander M. Menzies, Alexander Guminski, Benjamin Y Kong, Adam Cooper, S Ramanujam, Gerald B Fogarty, T W Wang, Matteo S CarlinoAbstract:ABSTRACTThe anti-PD-1 antibodies nivolumab and pembrolizumab are active in Metastatic Melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for Metastatic Melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent “salvage” treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one pati...
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acneiform eruption in a patient with Metastatic Melanoma after ceasing combination dabrafenib trametinib therapy
Melanoma Research, 2014Co-Authors: Pablo Uribe, Rachael Anforth, Richard F. Kefford, Pablo FernandezpenasAbstract:BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant Metastatic Melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant Metastatic Melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed.
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correlation of braf and nras mutation status with outcome site of distant metastasis and response to chemotherapy in Metastatic Melanoma
British Journal of Cancer, 2014Co-Authors: Matteo S Carlino, Richard F. Kefford, Alexander M. Menzies, Lauren E Haydu, Anne Hamilton, John F Thompson, Hojabr Kakavand, Wendy A Cooper, Sandra A Otoole, Richard A ScolyerAbstract:Activating mutations in the oncogenes BRAF or NRAS occur in approximately 40 and 20% of Melanomas, respectively, and result in constitutive activation of the mitogen-activated kinase (MAPK) cell signalling pathway (Davies et al, 2002; Platz et al, 2008). Small molecule inhibitors of mutant BRAF and the downstream kinase MEK (MAPK inhibitors) have transformed the management of BRAF-mutant Metastatic Melanoma and improved overall survival (OS) compared with standard chemotherapy in patients with BRAFV600 mutant Metastatic Melanoma (Chapman et al, 2011; Flaherty et al, 2012; Hauschild et al, 2012). Similarly, although to a lesser extent, single agent MEK inhibition has shown activity in NRAS-mutant Metastatic Melanoma (Falchook et al, 2012; Ascierto et al, 2013), with a phase III trial currently underway (NCT01763164). The presence of a BRAF mutation in Metastatic colorectal cancer is associated with a shorter OS compared with KRAS mutant or RAS/RAF wild-type disease (Van Cutsem et al, 2011; Yokota et al, 2011; Toland et al, 2012). Similarly BRAF mutations are associated with an increased risk of recurrence in papillary thyroid cancer (Elisei et al, 2012; Prescott et al, 2012; Fernandez et al, 2013). The prognostic significance of a BRAF mutation in Metastatic Melanoma is less clear. Recent analysis of survival in Metastatic Melanoma patients were performed when BRAF and MEK inhibitors were available and some patients included received these therapies (Long et al, 2011; Jakob et al, 2012), making comparisons between the BRAF-mutant and wild-type populations difficult. One study examining BRAF status only (Long et al, 2011) reported no difference in survival from stage IV diagnosis between patients with BRAF-mutant and wild-type Metastatic Melanoma; however, when the analysis was limited to patients with BRAF-mutant Melanoma who did not receive a MAPK inhibitor, a significantly shorter survival in BRAF-mutant patients was observed. It is unclear if this difference in survival was due to differences in the biology of BRAF-mutant versus wild-type Melanoma or a selection bias due to the non-random selection of BRAF-mutant patients for entry into the early phase clinical trials of MAPK inhibitors. Another study examining BRAF and NRAS status reported that NRAS-mutant Melanoma was associated with the poorest survival (Jakob et al, 2012). However, an earlier study found that NRAS-mutant Melanoma was associated with improved survival compared with BRAF-mutant or BRAF/NRAS wild-type disease (Ugurel et al, 2007). This uncertainty regarding the prognostic significance of BRAF and NRAS mutations in Metastatic Melanoma led us to perform a retrospective analysis in a cohort of patients with advanced Melanoma who were treated before the availability of MAPK inhibitors. We sought to correlate BRAF and NRAS mutation status with clinicopathologic characteristics, response to chemotherapy and survival, as well as to determine the frequency of other oncogenic mutations in Metastatic Melanoma.
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prognostic and clinicopathologic associations of oncogenic braf in Metastatic Melanoma
Journal of Clinical Oncology, 2011Co-Authors: Georgina V. Long, Alexander M. Menzies, Adnan Nagrial, Lauren E Haydu, Anne Hamilton, Graham J Mann, Michael T Hughes, John F Thompson, Richard A Scolyer, Richard F. KeffordAbstract:Purpose To assess the frequency and type of oncogenic BRAF mutations in Metastatic Melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with Metastatic Melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with Metastatic Melanoma by mutation status. Features of the antecedent primary Melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary Melanoma, trun...
Pablo Fernandezpenas - One of the best experts on this subject based on the ideXlab platform.
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ipilimumab induced acute generalized exanthematous pustulosis in a patient with Metastatic Melanoma
Melanoma Research, 2016Co-Authors: Shelley Ji Eun Hwang, Giuliana Carlos, Deepal Wakade, Raghwa Sharma, Pablo FernandezpenasAbstract:Ipilimumab is a new anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that stimulates the immune response against Melanoma. A 50-year-old man received ipilimumab for Metastatic Melanoma as part of a clinical trial. Two weeks after drug initiation, he developed a widespread oedematous erythema with sterile pustules. The histological examination showed subcorneal pustulosis formation with eosinophils. The clinical-pathological correlation was consistent with acute generalized exanthematous pustulosis. The symptoms resolved within 25 days after discontinuation of ipilimumab. We suspect that neutrophilic accumulation under the epidermis in this patient is a phenomenon similar to intraepithelial neutrophils aggregating on the surface epithelium over laminar propria in ipilimumab-induced colitis. To our knowledge, this is the first reported case of acute generalized exanthematous pustulosis associated with ipilimumab use in Metastatic Melanoma patients.
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acneiform eruption in a patient with Metastatic Melanoma after ceasing combination dabrafenib trametinib therapy
Melanoma Research, 2014Co-Authors: Pablo Uribe, Rachael Anforth, Richard F. Kefford, Pablo FernandezpenasAbstract:BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant Metastatic Melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant Metastatic Melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed.
