Analysis of plasma-based BRAF and NRAS mutation detection in patients with stage III and IV melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9023-9023
Author(s):  
David Polsky ◽  
Jyothirmayee S. Tadepalli ◽  
Shria Hafner ◽  
Gregory Chang ◽  
Nathaniel H. Fleming ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Stage Iv ◽  
Inhibitor Therapy ◽  
Braf V600e ◽  
Stage Iii ◽  
Plasma Dna ◽  
Nras Mutation ◽  
Blood Draw ◽  
Tumor Specimen ◽  
Active Disease

9023 Background: Patients with metastatic melanoma are eligible for BRAF inhibitor therapy if the BRAF V600E mutation can be identified in their tumor specimen. Patients lacking an available specimen for genotyping are unable to receive inhibitor therapy. We developed two mutation-specific genotyping platforms and tested their ability to detect BRAF and NRAS mutations in archived plasma and tumor samples to determine the potential utility of blood-based tumor genotyping in melanoma. Methods: We analyzed a group of 96 patients with stage III or IV melanoma, prospectively enrolled and followed in the NYU Melanoma Biorepository program. Each patient had a plasma sample and one or more tumor samples available for analysis. We used a combination of allele-specific PCR (Taqman) and SNaPshot assays to identify BRAF V600 and NRAS Q61 mutations in the tumor and plasma samples. Results: Among the 96 patients, 51 had stage III disease at the time of analysis; 45 had stage IV disease. Seventy-two patients had 2 or more tumor samples available for analysis, for a total of 204 tumors analyzed. In total, 52/96 (54%) patients had one or more BRAF or NRAS mutant tumors, including one patient with separate BRAF and NRAS mutant tumors (BRAF, n=35 (36%); NRAS, n=18 (19%)). We successfully amplified plasma DNA from 39/52 (75%) patients with tumor-associated mutations. Among those patients with amplifiable plasma DNA we detected mutations in 7 (18%) patients including 3 BRAF V600E, one V600K, 2 NRAS Q61K and one Q61L. Plasma-based mutations matched tumor-associated mutations in all 7 patients. All 7 patients had active disease at the time of blood draw. There were 32 patients with tumor-associated mutations in which a mutation could not be detected in the plasma. Only 15 of those 32 (47%) had active disease at the time of blood draw. There were no mutations detected in the plasma of the 44 patients whose tumors lacked BRAF or NRAS mutations. Conclusions: These data suggest that plasma-based detection of BRAF and NRAS mutations has a high specificity for tumor-associated mutations. It may prove to be a useful adjunct to tumor-based genotyping in patients with active disease, especially those lacking an available tumor specimen.

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 Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9025-9025 ◽  
Author(s):  
Joanna Mangana ◽  
Simone M. Goldinger ◽  
Katja Schindler ◽  
Sima Rozati ◽  
Anna L. Frauchiger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Wild Type ◽  
Nras Mutation ◽  
Mutation Status ◽  
Mutational Status ◽  
Melanoma Patients

9025 Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/NRAS mutant patients (n=44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n=27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.

Patient characteristics and survival outcomes in gastrointestinal cancers harboring RNF43 mutations or RSPO3 fusions: a retrospective analysis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 473-473
Author(s):  
Paul Sackstein ◽  
Garrett Buechner ◽  
Benjamin Adam Weinberg
Keyword(s):  
Clinical Outcomes ◽  
Gene Mutations ◽  
Stage Iv ◽  
Stage Ii ◽  
Braf V600e ◽  
Stage Iii ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Gastrointestinal Cancers ◽  
Stage Iv Disease

473 Background: The growth of intestinal epithelium is dependent on the Wnt/β-catenin signaling pathway. The R-Spondin (RSPO) family of proteins form complexes with Wnt ligand and RNF43 protein, which promote ubiquitination and degradation of Wnt receptors. Patients with gastrointestinal cancers harboring RSPO3 gene fusions or RNF43 gene mutations may benefit from Wnt pathway inhibitors. Methods: We retrospectively studied 51 patients at our institution diagnosed with gastrointestinal cancers with RSPO3 gene fusions or RNF43 gene mutations identified using Caris Life Sciences next-generation sequencing (NGS). Microsatellite-instability (MSI) was evaluated using NGS. Tumor mutational burden (TMB) was estimated from 592 genes by counting all nonsynonymous missense mutations not previously defined as germline mutations, expressed as mutations per megabase. First-line median progression-free survival (PFS) and median overall survival (mOS) were estimated using the Kaplan-Meier method. Results: Of the 51 patients in our study, 44 (86.3%) had RNF43 mutations and 7 (13.7%) had RSPO3 fusions, 6 of whom had colorectal cancer (CRC) and had PTPRK as the fusion partner, 1 case of small bowel cancer had a RSPO3: IFNGR1 fusion. Median age at diagnosis was 64.0 ± 12.0 years. The most common primary tumors were CRC in 23 patients (45.1%) and pancreas in 12 patients (23.5%). Co-occurring mutations in CRC patients with RSPO3 fusions included KRAS (50%, Q61H, G12C, and G12V), BRAF V600E (50%), and TP53 (100%), none were MSI-H, median TMB (mTMB) was 9.5 (range 7-11). Sixty-seven percent of RNF43-mutated CRC patients had the G659fs mutation. Co-occurring findings in RNF43-mutated CRC patients included 67% MSI-H, median TMB 27 (range 6-123), KRAS (28%), BRAF V600E (28%), and TP53 mutations (33%). Twenty-two patients (43.1%) had stage IV disease, 18 (35.3%) had stage III disease and 11 (21.6%) had stage II disease. Thirty RNF43-mutated patients (58.8%) underwent definitive surgical resection, with a mean time to recurrence of 22.2 months and mOS of 43.0 months (95% CI, 15.6-70.4). Among RNF43-mutated stage IV CRC (mCRC) patients, median PFS was 8.0 months (95% CI, 5.9-10.1). Stratified by stage, mOS was 111.0 months for stage II disease, 72.0 months for stage III disease, and 37.0 months for stage IV disease (95% CI, 14.7-59.3). Conclusions: RNF43 correlates with overall favorable mOS in patients with mCRC. mOS in RNF43-mutated mCRC is similar to those of RAS and BRAF wild-type subgroups as reported in the TRIBE study (Cremolini et al. 2015). Therefore, RNF43 mutational status appears to be useful in predicting clinical outcomes for patients with stage IV CRC and overlaps significantly with MSI-H. RSPO3 fusions are rare events and the clinical outcomes of this subset of patients with tumors with RSPO3 fusions remains largely unknown.

Bilateral Panuveitis in a Patient on Vemurafenib BRAF Inhibitor Therapy for Stage IV Melanoma

2014 ◽  
Vol 24 (4) ◽  
pp. 629-632 ◽  
Author(s):  
Steven A. Agemy ◽  
Ankur N. Mehta ◽  
Sophia I. Pachydaki ◽  
Asheesh Tewari
Keyword(s):  
Braf Inhibitor ◽  
Stage Iv ◽  
Inhibitor Therapy ◽  
Stage Iv Melanoma

Updated 5-y landmark analyses of phase 2 (BREAK-2) and phase 3 (BREAK-3) studies evaluating dabrafenib monotherapy in patients with BRAF V600–mutant melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9526-9526 ◽  
Author(s):  
Paul B. Chapman ◽  
Paolo Antonio Ascierto ◽  
Dirk Schadendorf ◽  
Jean Jacques Grob ◽  
Antoni Ribas ◽  
...  
Keyword(s):  
Single Agent ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Braf V600e ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Study Results ◽  
Landmark Analyses

9526 Background: Prior analyses of phase 2 (BREAK-2; NCT01153763) and phase 3 (BREAK-3; NCT01227889) trials showed that durable clinical benefit and tolerability lasting ≥ 3 y are achievable with the BRAF inhibitor dabrafenib in some patients (pts) with BRAFV600–mutant metastatic melanoma. Here, we report 5-y landmark analyses for BREAK-2 and BREAK-3. Methods: BREAK-2, a single-arm, phase 2 study, evaluated dabrafenib 150 mg twice daily in pts with stage IV BRAF V600E/K–mutant MM. BREAK-3, an open-label, randomized (3:1), phase 3 study, assessed dabrafenib 150 mg twice daily vs dacarbazine 1000 mg/m2 every 3 weeks in pts with previously untreated BRAFV600E–mutant unresectable stage III or stage IV MM. Updated analyses were performed to describe ≥ 5-y outcomes in each study. Results: BREAK-2 enrolled 92 pts (V600E, n = 76; V600K, n = 16), of whom most (90%) had prior systemic anticancer therapy. At data cutoff (17 Jun 2016), all pts had discontinued, mostly due to progression (84%). In V600E pts, 5-y progression-free survival (PFS) was 11%, and 5-y overall survival (OS) was 20%. Postprogression immunotherapy was received by 22% of enrolled pts. In BREAK-3 (data cutoff, 16 Sep 2016), median follow-up was 18.6 mo for the dabrafenib arm (n = 187) and 12.8 mo for the dacarbazine arm (n = 63). Follow-up for the 37 dacarbazine-arm pts (59%) who crossed over to receive dabrafenib was based on the initial assignment of dacarbazine. The 5-y PFS was 12% vs 3% and 5-y OS was 24% vs 22% for the dabrafenib and dacarbazine arms, respectively. A subset of pts in each respective arm received postprogression anti–CTLA-4 (24% vs 24%) and/or anti–PD-1 (8% vs 2%) therapy, whereas 31% vs 17% did not receive any further therapy following study treatment. No new safety signals were observed in either study with long-term follow-up. Additional characterization of pts using cfDNA analysis will be presented. Conclusions: These data provide the longest reported PFS and OS follow-up for BRAF inhibitor monotherapy in BRAF V600–mutant MM. Both BREAK-2 and BREAK-3 showed that 11%-12% of pts initially treated with single-agent dabrafenib remained progression free at 5 y. Clinical trial information: NCT01153763; NCT01227889.

BRAF inhibitor therapy–associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression

2016 ◽  
Vol 50 ◽  
pp. 79-89 ◽  
Author(s):  
Kumaran Mudaliar ◽  
Michael T. Tetzlaff ◽  
Madeleine Duvic ◽  
Ana Ciurea ◽  
Sharon Hymes ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Inhibitor Therapy ◽  
Braf V600e ◽  
Melanocytic Lesions

scholarly journals Efficacy of BRAF‐Inhibitor Therapy in BRAF V600E ‐Mutated Adult Langerhans Cell Histiocytosis

2020 ◽  
Vol 25 (12) ◽  
pp. 1001-1004
Author(s):  
Antonious Z. Hazim ◽  
Gordon J. Ruan ◽  
Aishwarya Ravindran ◽  
Jithma P. Abeykoon ◽  
Caleb Scheckel ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Braf Inhibitor ◽  
Langerhans Cell ◽  
Inhibitor Therapy ◽  
Braf V600e

Differential clinical associations of BRAF and NRAS mutations among histologic types of cutaneous melanomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20034-e20034
Author(s):  
David Stockman ◽  
Michael T. Tetzlaff ◽  
Tariq Al-Zaid ◽  
Carlos A. Torres-Cabala ◽  
Amanda Dawn Bucheit ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Stage Iv ◽  
Braf V600e ◽  
Nras Mutation ◽  
Braf Mutations ◽  
Mutation Status ◽  
Mutational Status ◽  
Significant Difference ◽  
Clinical Associations ◽  
Histologic Types

e20034 Background: Previous studies have investigated whether BRAF and NRAS mutation status in melanoma correlate with histologic parameters and overall survival (OS), but evaluation of mutation groups irrespective of specific mutation among histologic types of melanoma has led to variability in the reproducibility of results. We tested the hypothesis that different histologic types of melanoma (nodular [NM] and superficial spreading [SSM]) have distinct clinical associations with specific BRAF and NRAS mutations. Methods: Primary tumor histology, BRAF/NRAS mutation status, and clinical outcomes were collected for 195 patients (pts) with stage III or IV disease. Clinical associations with specific mutations were determined separately for patients with NM (n=105) and SSM (n=90) histologic types of primary cutaneous melanomas. Results: Mutational status in NM: 69 BRAF (66%), 19 NRAS (18%), & 17 wild-type (WT;16%). Specific BRAF mutations in NM: V600E 50 (75%), V600K 13 (19%), V600R 4 (6%). Specific NRAS mutations in NM: Q61K 6 (32%), Q61L 2 (11%), Q61R 8 (42%); other 3 (16%). Mutation status in SSM: 45 BRAF (50%), 24 NRAS (27%), 21 WT (23%). Specific BRAF mutations in SSM: V600E 32 (71%), V600K 12 (24%), V600R 0. Specific NRAS mutations in SSM: Q61K 2 (8%), Q61L 5 (21%), Q61R 12 (50%). The distribution of specific BRAF (p=0.21) and NRAS (p=0.29) mutations between NM and SSM was not significantly different. Among NM pts, pts with activating NRAS mutations had shorter OS from the diagnosis of Stage IV melanoma than WT (HR 3.42, p=0.02) and BRAF (HR 2.40, p=0.009). There was no significant difference for BRAF pts vs WT (HR 1.43, p=0.47). Among SSM patients, neither NRAS (HR 1.3, p=0.53) nor BRAF(HR 0.54, p=0.16) were significantly associated with OS compared to WT. Comparison of patients with BRAF V600E vs V600K showed significant association for OS from stage 4 in SSM pts (HR 0.24, p=0.01), but not in NM pts (HR 0.64, p=0.36). Conclusions: The prognostic significance of BRAF and NRAS mutations on OS from stage IV differed for pts with NM and SSM primaries. Further investigation of the histologic types of melanoma with specific BRAF and NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.

Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9564-9564 ◽  
Author(s):  
Jan Braune ◽  
Dagmar von Bubnoff ◽  
Marie Follo ◽  
Erika Graf ◽  
Ulrike Philipp ◽  
...  
Keyword(s):  
Treatment Response ◽  
Locally Advanced ◽  
Prospective Trial ◽  
Stage Iv ◽  
Hazard Ratio ◽  
Braf V600e ◽  
Locked Nucleic Acid ◽  
Stage Iii ◽  
Response To Treatment ◽  
Negative Slope

9564 Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS (hazard ratio [HR] 1.487, 95% CI 0.34-6.45). A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS (hazard ratio [HR] 0.230, 95% CI 0.04-1.20) with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS (hazard ratio [HR] 2.02, 95% CI 0.39-10.53). Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. Clinical trial information: DRKS00009507.

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