scholarly journals PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linda Vidarsdottir ◽  
Alireza Azimi ◽  
Ishani Das ◽  
Ingibjorg Sigvaldadottir ◽  
Aldwin Suryo Rahmanto ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Braf Inhibitor ◽  
Stage Iii ◽  
Expression Levels ◽  
Promising Target ◽  
Stage Iii Melanoma ◽  
Inhibitor Resistance ◽  
The Impact ◽  
Resistant Cells

AbstractBRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

scholarly journals PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

2020 ◽  
Author(s):  
Linda Vidarsdottir ◽  
Alireza Azimi ◽  
Ingibjorg Sigvaldadottir ◽  
Aldwin Suryo Rahmanto ◽  
Andreas Petri ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Transcriptional Repression ◽  
Regional Lymph Node ◽  
Braf Inhibitor ◽  
Suppressor Gene ◽  
Stage Iii ◽  
Activating Mutations ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
The Impact

ABSTRACTApproximately 50% of human cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. BRAF inhibitors (BRAFi) selectively target the oncogenic BRAFV600E/K and are effective in approximately 80% of patients carrying the mutation. However, resistance to BRAFi is common and emerges within a median time of 6-7 months of treatment and is prolonged to 11 months when combined with MEK inhibitors. Better characterization of the underlying molecular processes is therefore needed to further improve treatments. Inactivation of the tumor suppressor gene PTEN has been suggested to occur during melanomagenesis and drug resistance development. We recently demonstrated that transcription of PTEN is negatively regulated by an antisense RNA from the PTEN pseudogene (PTENP1-AS) and here set out to investigate the impact of this molecular pathway on the resistance to BRAFi and clinical outcome. We used a panel of BRAFi resistant A375 sublines, and observed increased levels of PTENP1-AS associated with reduced expression of PTEN. Furthermore, this loss of PTEN expression was correlated to increased recruitment of Enhancer of zeste homolog 2 (EZH2) and formation of the transcriptional repression mark H3K27me3 at the PTEN promoter in the resistant cells. We demonstrated that targeting of PTENP1-AS was able to re-activate the expression of PTEN and sensitize resistant melanoma cells to BRAFi. Finally, we showed that PTENP1-AS is a promising prognostic marker for clinical outcome in melanoma patients as high expression of PTENP1-AS in regional lymph node metastases from stage III melanoma patients correlated with poor survival.

scholarly journals Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial

2020 ◽  
Vol 38 (33) ◽  
pp. 3925-3936 ◽  
Author(s):  
Alexander M. M. Eggermont ◽  
Christian U. Blank ◽  
Mario Mandala ◽  
Georgina V. Long ◽  
Victoria G. Atkinson ◽  
...  
Keyword(s):  
Lymph Node ◽  
High Risk ◽  
Phase Iii ◽  
Stage Iii ◽  
Recurrence Free Survival ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Stage Iii Melanoma ◽  
The Impact

PURPOSE We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up. PATIENTS AND METHODS A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)–positive tumors. RESULTS Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1–positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600E/K v wild type). CONCLUSION In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Predicting clinical outcome through gene expression profiling in stage III melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8502-8502
Author(s):  
T. John ◽  
M. A. Black ◽  
T. Toro ◽  
C. A. Gedye ◽  
I. D. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Stage Iiib ◽  
Stage Iii ◽  
Test Set ◽  
Prognostic Groups ◽  
Melanoma Patients ◽  
Stage Iii Melanoma

8502 Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB & IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP<6 months) and 13 good (TTP>28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies. [Table: see text]

Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma

2014 ◽  
Vol 32 (8) ◽  
pp. 816-823 ◽  
Author(s):  
Lisa Zimmer ◽  
Lauren E. Haydu ◽  
Alexander M. Menzies ◽  
Richard A. Scolyer ◽  
Richard F. Kefford ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Incidence Rates ◽  
Stage Iii ◽  
Prior History ◽  
Braf Inhibitors ◽  
History Of ◽  
Stage Iii Melanoma ◽  
Stage Iv Melanoma

Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor. Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials.

scholarly journals Predicting Clinical Outcome through Molecular Profiling in Stage III Melanoma

2008 ◽  
Vol 14 (16) ◽  
pp. 5173-5180 ◽  
Author(s):  
Thomas John ◽  
Michael A. Black ◽  
Tumi T. Toro ◽  
Debbie Leader ◽  
Craig A. Gedye ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Molecular Profiling ◽  
Stage Iii ◽  
Stage Iii Melanoma

High expression of glycolytic and pigment proteins is associated with worse clinical outcome in stage III melanoma

2013 ◽  
Vol 23 (6) ◽  
pp. 452-460 ◽  
Author(s):  
Johan Falkenius ◽  
Joakim Lundeberg ◽  
Hemming Johansson ◽  
Rainer Tuominen ◽  
Marianne Frostvik-Stolt ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
High Expression ◽  
Stage Iii ◽  
Stage Iii Melanoma

High BAALC Expression in Cytogenetically Normal Acute Myeloid Leukemia Strongly Correlates with Adverse Markers Such As RUNX1mut, MLL-PTD and FLT3-ITD and Is Useful for Disease Monitoring

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1376-1376
Author(s):  
Simone Weber ◽  
Tamara Alpermann ◽  
Christiane Eder ◽  
Frank Dicker ◽  
Sabine Jeromin ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Clinical Outcome ◽  
Mrna Expression ◽  
Cox Regression ◽  
Disease Monitoring ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Equity Ownership ◽  
The Impact

Abstract Abstract 1376 Introduction: BAALC expression is thoroughly explored in cytogenetically normal AML (CN-AML) and has been shown to be associated with an adverse outcome. Nevertheless, its prognostic importance in relation to other molecular markers and its relevance for detection of minimal residual disease (MRD) remains to be defined. The objective of this study was to evaluate the prognostic impact of BAALC expression on clinical outcome in the context of other relevant molecular prognosticators and to examine its utility as a marker for detection of MRD in CN-AML. Patients: BAALC mRNA expression was analyzed in a cohort of 332 patients with de novo CN-AML. The cohort was composed of 169 females (50.9%) and 163 males (49.1%). Age ranged from 18.3 to 64.8 years (median: 52.9). Data on other molecular markers was available in: FLT3-ITD: n=332, NPM1: n=332, RUNX1: n=330, CEBPA: n=332, MLL-PTD: n=332, ASXL1: n=330, FLT3-TKD: n=331, IDH1G105: n=229, IDH1R132: n=253, IDH2: n=232, NRAS: n=254, WT1 mut: n=247, TET2: n=74 and TP53: n=182. In addition, BAALC expression was assessed in 25 follow-up samples of 8 patients in comparison with an established MRD marker. Methods: To assess BAALC mRNA expression levels RQ-PCR was performed by the use of the Applied Biosystems 7500 Fast Real Time PCR System. BAALC expression was normalized against the expression of the control gene ABL1. The median ratio BAALC/ABL1 was used to separate low from high BAALC expressers. Expression data of diagnostic samples was correlated to clinical outcomes and to the presence of molecular mutations. BAALC expression ratios of follow-up samples were also correlated to the status of other molecular markers available in the same patients. Results: 1) Evaluation of prognostic relevance: Expression ratios of BAALC/ABL1 represented a continuum ranging from 0.001 to 80.199 (median: 0.321). In agreement with previous studies, patients with high BAALC expression had shorter overall survival (OS at 3 years: 51.4% vs 73.0%, p=0.046) and event free survival (EFS at 3 years: 38.5% vs 50.6%, p=0.021) as compared to low BAALC expressers. Though, associations of BAALC expression to other molecular markers were found. In high BAALC expressers, as compared to low BAALC expressers, the following mutations were more frequent: RUNX1 mut (32/164, 19.5% vs 2/166, 1.2%, p<0.001), MLL-PTD (22/166, 13.3% vs 5/166, 3.0%, p=0.001) and FLT3-ITDmut/wt ratio>0.5 (51/166, 30.7% vs 24/166, 14.5%, p=0.001), whereas NPM1 mut were less frequent (72/166, 43.3% vs 138/166, 83.1%, p<0.001). In univariable Cox regression analyses shorter OS and EFS was associated with higher age, higher WBC count, high BAALC expression and the presence of at least one of the established adverse markers RUNX1 mut, MLL-PTD, or FLT3-ITDmut/wt ratio>0.5 grouped together as one parameter (OS, p<0.001, <0.001, 0.0048, <0.001, respectively; EFS, p=0.002, <0.001, 0.022, <0.001, respectively). In multivariable models, BAALC expression had an independent impact on EFS (p=0.042) but not on OS. Further, Kaplan Meier analysis within the subgroup with adverse markers (RUNX1 mut, MLL-PTD, or FLT3-ITDmut/wt ratio>0.5, n=98) revealed no additional impact of BAALC expression on OS or EFS. Also within the prognostically favorable subgroup with NPM1 mut/FLT3-ITDmut/wt ratio<0.5 high BAALC expression had no impact on OS or EFS. 2) Validation as follow-up marker: To evaluate the impact of BAALC expression for disease monitoring during follow-up, the BAALC/ABL1 ratio of high BAALC expressers was compared to the %MLL-PTD/ABL1 or %RUNX1 mut levels in patients who had at least one of these aberrations in parallel. In total, 33 diagnostic and follow-up samples of 8 patients were analyzed. Comparison of BAALC/ABL1 ratios to mutational status of MLL-PTD and/or RUNX1 revealed a significant correlation (r=0.577, p<0.001). Additionally, in one case with paired samples at diagnosis and relapse, BAALC expression levels at diagnosis and at relapse were in the same range (BAALC/ABL1: 10.870 vs 17.600). Conclusion: 1) BAALC expression in CN-AML predicts an adverse clinical outcome, but is associated with other well established prognostic markers. Thus, in our study BAALC expression had no independent prognostic impact on OS when analyzed together with RUNX1, MLL-PTD, FLT3-ITD and NPM1. 2) Correlation of BAALC expression with MLL-PTD and RUNX1 during follow up indicates that BAALC expression is a potential target for MRD monitoring. Disclosures: Weber: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership.

An analysis of the National Cancer Database (NCDB): Immunotherapy and survival in stage III melanoma.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 159-159 ◽  
Author(s):  
Mridula Krishnan ◽  
Aabra Ahmed ◽  
Nabin Khanal ◽  
Peter T. Silberstein
Keyword(s):  
Statistical Significance ◽  
Private Insurance ◽  
Stage Iii ◽  
High Dose ◽  
Chi Square ◽  
Modest Improvement ◽  
Kaplan Meier ◽  
Stage Iii Melanoma ◽  
Chi Square Analysis ◽  
The Impact

159 Background: High dose Interferon (IFN) was the standard adjuvant treatment used for stage III melanoma between 2004-2010. To our knowledge, this is the largest study using the NCDB to determine the impact of immunotherapy used prior to 2011 in stage III melanoma. Methods: We identified 19,864 patients with stage III melanoma between 2004-2010. Among these, 5,406 of them received immunotherapy. Chi-square analysis was used to determine demographic differences between those with versus without immunotherapy. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < 0.05 indicated statistical significance. Results: Patients who received immunotherapy had a mean survival of 89.8 months while those who did not had a mean survival of 71 months. The percentage of patients alive at 5 and 10 years was 62% and 52% (among those who received immunotherapy) compared to 46% and 32% (among those who did not receive immunotherapy) respectively. A much higher percentage of these patients were privately insured (73% vs. 47.1%, p<0.001). Those who received immunotherapy were more likely to be younger, have a higher income (36.2% vs. 34.8%, p<0.001), and a greater percentage of females received immunotherapy compared to males. (See Table 1.) Conclusions: Previously, Kirkwood et al. demonstrated a modest improvement in overall survival with IFN by 12 months (2.8 to 3.8 years). In our study, patients who received immunotherapy had a significant improvement in mean survival by 19 months. It was observed that patients who received immunotherapy were substantially younger, had private insurance and fewer comorbidities. [Table: see text]

Toxicities with combination BRAF and MEK inhibition in resected stage III melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22086-e22086
Author(s):  
Govind Warrier ◽  
Morgan Homan ◽  
Christopher D. Lao ◽  
Sarah Elizabeth Yentz ◽  
Shawna Kraft ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Reduction ◽  
Real World ◽  
Case Series ◽  
Braf Inhibitor ◽  
Stage Iii ◽  
World Population ◽  
Mek Inhibition ◽  
Stage Iii Melanoma ◽  
Resected Stage

e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

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