scholarly journals Application of Circulating Cell-Free Tumor DNA Profiles for Therapeutic Monitoring and Outcome Prediction in Genetically Heterogeneous Metastatic Melanoma

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Renáta Váraljai ◽  
Kilian Wistuba-Hamprecht ◽  
Teofila Seremet ◽  
Joey Mark S. Diaz ◽  
Jérémie Nsengimana ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Quantitative Detection ◽  
Early Assessment ◽  
Free Survival ◽  
Mitogen Activated Protein ◽  
Tumor Dna

PURPOSE Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma. MATERIALS and METHODS We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAFV600E and NRASQ61 driver mutations as well as TERTC250T and TERTC228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase–targeted or immune checkpoint therapies. RESULTS Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAFV600E ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans ( P < .05), with a mean lead time of 3.5 months. NRAS-mutant ctDNA was detected in a significant proportion of patients with BRAF-mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRASQ61 ctDNA in baseline samples of patients with BRAFV600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P = .01). CONCLUSION Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma.

scholarly journals P.022 Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma

2019 ◽  
Vol 46 (s1) ◽  
pp. S19 ◽  
Author(s):  
A Zaloum ◽  
JR Falet ◽  
A Elkrief ◽  
C Chalk
Keyword(s):  
Protein Kinase ◽  
Myasthenia Gravis ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Mitogen Activated Protein

Background: Inhibitors of BRAF and MEK, enzymes in the mitogen-activated protein kinase (MAPK) pathway, are now widely used in the treatment of metastatic melanoma. We report a case of acetylcholine receptor (AChR) antibody-positive myasthenia gravis developing after exposure to dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Methods: A 68-year-old man presented with dysarthria, dysphagia, cough, dyspnea, and fever. Examination revealed fatigable ptosis and proximal muscle weakness. He had started dabrafenib and trametinib for metastatic melanoma two weeks prior. He was diagnosed with myasthenia gravis and superimposed aspiration pneumonia. AChR antibodies were positive. Dabrafenib and trametinib were stopped. He improved rapidly with pyridostigmine alone, and remained free of myasthenic symptoms for the next two months. Another course of dabrafenib and trametinib was given, and seven weeks later, his myasthenic symptoms recurred. Pyridostigmine produced only partial improvement, and treatment with intravenous immunoglobulin and prednisone was initiated. Results: We are unaware of prior reports of an association between BRAF/MEK inhibitors and seropositive myasthenia gravis. The development of myasthenic symptoms twice after BRAF/MEK inhibitor exposure suggests that the association is more than coincidental. Conclusions: Myasthenia gravis may be a complication of treatment of melanoma with dabrafenib and trametinib. The mechanism by which this occurs is unknown.

scholarly journals Single Center Experience Study with Pembrolizumab in Patients with BRAF Mutant Negative Metastatic Melanoma

2018 ◽  
Vol 35 (4) ◽  
pp. 267-272
Author(s):  
Ivica Pejčić ◽  
Ivan Petković ◽  
Ana Cvetanović ◽  
Irena Conić
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Performance Status ◽  
Progression Free Survival ◽  
Complete Response ◽  
Wild Type ◽  
Free Survival ◽  
Good Performance Status ◽  
Melanoma Patients ◽  
Braf Mutant

Abstract The aim of the paper was to determine the efficacy, toxicity and progression free survival with anti-PD-1 immunotherapy pembrolizumab in BRAF wild type metastatic melanoma patients with good performance status (ECOG PS 0-1). From February 2017 to April 2018, 17 patients with BRAF mutant wild type metastatic melanoma were enrolled in the study. Only 3/17 patient had received chemotherapy previously. The aim of the study was to confirm the efficacy of pembrolizumab immunotherapy in patients with good performance status (ECOG 0-1). Treatment consisted of pembrolizumab 2 mg/kg Q3 weeks continued until disease progression or intolerable toxicity. Secondary end points included toxicity and progression-free survival (defined as the time from randomization to documented disease progression according to RECIST). The overall response rate (ORR) was 11/17 (53.0 %), with complete response (CR) 0, partial response (PR) 3 (18 %), stable disease (SD) 8 (47%), and progressive disease (PD) 6 (35%). A total number of 97 consecutive cycles were administered. Adverse effects were mild. The most common toxicity was pneumonitis grade 1. None of the patients in the study demonstrated grade 2, 3 and 4 toxicity. No treatment-related deaths occurred. The median time to disease progression was 5.8 months. Anti-PD-1 pembrolizumab immunotherapy appeared to be a beneficial therapeutic approach with less toxicity for metastatic BRAF wild type melanoma patients with good PS.

MAP2K1/2 and MAP3K14 as a prognostic biomarker on immunotherapy and correlated with immune infiltrates in melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22104-e22104
Author(s):  
Jing Chen ◽  
Ting Ye ◽  
Wenzhuan Xie ◽  
Mengli Huang ◽  
Mengmei Yang
Keyword(s):  
Protein Kinase ◽  
Immune Cells ◽  
Progression Free Survival ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Th2 Cells ◽  
Sequencing Data ◽  
Mait Cells ◽  
Mitogen Activated Protein ◽  
Pre Treatment

e22104 Background: Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) and MAP3K are two subgroup of Mitogen-activated protein kinase cascade. MAP2K1/2 and MAP3K14 are members of two subgroup, respectively. Previous study revealed that MAP2K1/2 and MAP3K14 may be a promising therapeutic target for melanoma. However, the association between MAP2K1/2 and MAP3K14 mutant and melanoma remains elusive. In this study, we aimed to elucidate the efficacy of immunotherapy of MAP2K1/2 and MAP3K14 mutant for melanoma by integrated bioinformatics analysis. Methods: Whole-exome sequencing data for a cohort of 110 patients with metastatic melanoma from whom pre-treatment tumor biopsies were download from cBioPortal. Associations between MAP2K1/2 and MAP3K14 mutations and prognosis and TMB are analyzed, and tumor-infiltrating level (TIL) of 18 T-cell subtypes and 6 other immune cells were used to investigate the underlying mechanism. Results: Results showed that MAP2K1/2 and MAP3K14 mutations were associated with an increased progression-free survival (PFS; HR, 0.42; 95% CI, 0.18-0.96; P = 0.0342) and a superior overall survival (OS; HR, 0.28; 95% CI, 0.09-0.90; P = 0.0227) in melanoma with significance at borderline level. TMB levels in melanoma patients with MAP2K1/2 and MAP3K14 mutations were higher than in wild-type patients (P = 0.007). Moreover, TIL revealed distinct immune cells features in the different groups, where immune cells related to infiltrating levels of Neutrophil cells and natural arising regulatory T (nTreg) cells were more prominently enriched in the mutation group while the wide-type group had higher enrichment of Mucosal associated invariant T (MAIT) cells and T helper 2 (Th2) cells. Conclusions: MAP2K1/2 and MAP3K14 mutations may be a potential predictor for better prognosis in melanoma on immunotherapy. Identification of MAP2K1/2 and MAP3K14 mutations by genomic profiling provides a potentially novel and convenient approach for these patients to predict the prognosis, and refines patient’s management in clinical practice.

Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma

2009 ◽  
Vol 27 (32) ◽  
pp. 5452-5458 ◽  
Author(s):  
Steven O'Day ◽  
Rene Gonzalez ◽  
David Lawson ◽  
Robert Weber ◽  
Laura Hutchins ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Disease Progression ◽  
Evaluation Criteria ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Double Blinded ◽  
Post Hoc

Purpose Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. Patients and Methods We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m2 plus paclitaxel 80 mg/m2 (E + P) or to paclitaxel 80 mg/m2 alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). Results At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. Conclusion E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.

scholarly journals BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer—A Case Series Study Target Therapy of BRAF-Mutated mCRC

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1339
Author(s):  
Jen-Hao Yeh ◽  
Hsiang-Lin Tsai ◽  
Yen-Cheng Chen ◽  
Ching-Chun Li ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Case Series ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Free Survival ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1–26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1–2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.

scholarly journals Rapid Response in a Patient with Relapsed/Refractory Multiple Myeloma Treated with BRAF/MEK Inhibitors

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Steve Biko Otieno ◽  
Syed Nasir ◽  
Alva Weir ◽  
Robert Johnson
Keyword(s):  
Multiple Myeloma ◽  
Mapk Pathway ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Hairy Cell ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Mitogen Activated Protein ◽  
Inhibitor Resistance ◽  
Cancer Côlon

Patients with relapsed and refractory multiple myeloma have a poor prognosis. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathogenesis of multiple myeloma. Several mutations in this pathway can lead to its constitutive activation leading to oncogenesis. One such mutation is BRAFV600E which is a therapeutic target in the treatment of melanoma, lung cancer, colon cancer, thyroid cancer, and hairy cell leukemia. BRAFV600E-directed therapy currently does not have approval in multiple myeloma. It has been proposed that this mutation leads to proteasome inhibitor resistance. About 4–10% of multiple myeloma cases harbor the BRAFV600E mutation. Herein, we report a case of a patient with relapsed and refractory multiple myeloma who had a progression-free survival (PFS) of 8.5 months on BRAF-targeted therapy.

scholarly journals TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2224
Author(s):  
Pauline Blateau ◽  
Etienne Coyaud ◽  
Estelle Laurent ◽  
Benoit Béganton ◽  
Vincent Ducros ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Brain Metastasis ◽  
Poor Prognosis ◽  
Progression Free Survival ◽  
Good Prognosis ◽  
Mitogen Activated Protein Kinase ◽  
Tert Promoter ◽  
Significant Difference ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAFV600 cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to BRAF genotyping. Among co-occurring mutations, TERT promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to BRAFV600, there was a trend of longer PFS for patients harboring TERT c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and TERT c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of BRAFV600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors.

Sign in / Sign up

Export Citation Format

Share Document