Analysis of BRAF, NRAS, cKIT, and EGFR alterations in melanoma lung metastases.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19033-e19033
Author(s):  
Alessandra Ulivieri ◽  
Giuseppe Cardillo ◽  
Liborio Manente ◽  
Andrea Petricca Mancuso ◽  
Leonardo Vigna ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Direct Sequencing ◽  
Primary Melanoma ◽  
High Response Rate ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Fish Analysis ◽  
Braf Mutations ◽  
Curative Intent ◽  
Free Survival

e19033 Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p<0.05), but it had no impact on psPFS (26.9 vs 29.6 months, p=0.6). NRAS mutations were associated with a reduction in both LMFS (3.7 years vs 4.7 years, p = 0.008) and, more significantly, in psPFS (12,5 months vs 41,1 months, p = 0.005; hazard ratio, 2.7). Conclusions: The frequency of mutations in BRAF (51%) and NRAS (18%) observed in lung metastatic melanomas was similar to the rates reported in other metastatic sites. BRAF mutations don't appear to be related with a more aggressive clinical course, while NRAS might be an independent negative prognostic factor after resection of melanoma lung metastases. The presence of BRAF mutations should be tested in melanoma lung metastases to identify the patients eligible for anti BRAF targeted therapy.

Clinical characteristics and treatment outcomes of 65 patients with BRAF-mutated non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21745-e21745
Author(s):  
Yuxin Mu ◽  
Ke Yang ◽  
Xuezhi Hao ◽  
Yan Wang ◽  
Lin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Small Cell Lung ◽  
First Line ◽  
Braf Mutations ◽  
Free Survival ◽  
Stage Disease

e21745 Background: BRAF mutations are infrequently seen in non-small cell lung cancer (NSCLC) in Chinese population. We aimed to investigate the clinicopathologic characteristics and treatment outcomes of Chinese patients with NSCLC harboring BRAF mutations. Methods: We conducted a retrospective multicenter study in China of patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. Results: A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R and T599dup. No significant difference in age or gender was found between BRAF-V600E and non-V600E cases, while the majority of patients with non-V600E mutations were smokers (81.8%). Of the 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2 months, 18.7 months and 10.1 months of stage I, II and IIIA patients (P = 0.07), respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR) and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0% vs. 70.0%, P = 0.027; median PFS, 9.8 months vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, the median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8 months, 5.8 months and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 months vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, DCR and median PFS were 62.5% and 3.0 months (95%CI 2.9, 3.1), respectively. Conclusions: Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.[Table: see text]

scholarly journals Outcome of Radical Surgery for Simultaneous Liver and Lung Metastases Synchronous with Primary Colorectal Cancer

2021 ◽  
Author(s):  
Franz Xaver Singhartinger ◽  
Martin Varga ◽  
Tarkan Jäger ◽  
Adam Dinnewitzer ◽  
Oliver Koch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lung Metastases ◽  
Primary Tumour ◽  
Median Number ◽  
R0 Resection ◽  
Curative Intent ◽  
Median Hospital Stay ◽  
Free Survival ◽  
Colorectal Cancer Patients ◽  
Primary Tumour Site

Abstract Background Colorectal cancer (CRC) leads to metastatic disease in approximately 30% of patients. In patients with newly diagnosed CRC with both liver and lung metastases, curative resection is rarely possible. The aim of this study is to evaluate the overall (OS) and relapse-free survival (RFS) rates of these patients after resection with curative intent. Methods This study is a retrospective analysis of colorectal cancer patients (n=8, median age 54.3 years) with simultaneous liver and lung metastasis undergoing resection with curative intent between May 1st, 2002, to December 31st, 2016, at our institution. Results Colon was the primary tumour site in 2 patients and rectum in 6 patients. The median number of liver and lung metastases was 3 and 2, respectively. Patients received various treatment sequences individualized on tumour disease burden. R0 resection was achieved after all but one procedure. Two severe Clavien-Dindo grade IIIb complications were present. Median hospital stay was 9 (3–24) days per procedure. Tumour relapse was observed in all patients with median RFS of 9 (3–28) months and median OS of 40 (17–52) months. In 4 cases, where repeated resection of recurrent metastases (3 liver and 1 lung) was possible, the median OS was 43 months. Conclusion Our data suggests that patients seem to benefit from resection with curative intent, with tendency to prolonged OS and with acceptable complication rate. Tumour recurrence occurred in all patients. Repeated resection was beneficial and led to further prolonged OS.

Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14708-e14708
Author(s):  
Arturo Quintanilla Guzman ◽  
Arturo Luevano Gonzalez ◽  
Augusto Rojas Martinez ◽  
Juan Pablo Flores Gutierrez ◽  
Juan Francisco Gonzalez Guerrero ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Young Patients ◽  
Gene Promoter ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Mutations ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Msi Analysis

e14708 Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).

BRAF V600E Mutation: A Significant Biomarker for Prediction of Disease Relapse in Pediatric Langerhans Cell Histiocytosis

2019 ◽  
Vol 22 (5) ◽  
pp. 449-455 ◽  
Author(s):  
Erdener Ozer ◽  
Akin Sevinc ◽  
Dilek Ince ◽  
Resmiye Yuzuguldu ◽  
Nur Olgun
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Braf V600e Mutation ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Erk Pathway ◽  
Disease Relapse ◽  
Multisystem Disease ◽  
Mutational Status

Langerhans cell histiocytosis (LCH) is a rare disease presenting with usually a localized disease but sometimes a widespread aggressive disorder especially in children. Among the somatic mutations in RAF-MEK-ERK pathway, especially BRAF mutation has been detected so far in LCH. We aimed in this study to investigate the prognostic significance of the mutations of target genes playing a role in the RAF-MEK-ERK pathway in pediatric LCH. Mutation analyses were performed on tumor DNA extracted from formalin-fixed paraffin-embedded biopsy specimens of 38 pediatric LCH cases using a direct sequencing technique for BRAF, ARAF, MAP2K1, and MAP3K1 genes. The mutational status was correlated statistically with survival, clinical progression (disease relapse), and the established clinical prognostic parameters of LCH such as age, gender, localization, multisystem disease, central nervous system risk lesions, and risk organ or special-site involvement. BRAF V600E mutation was detected in 14 cases (36.8%), whereas ARAF mutation was found in only 1 case. No mutations were identified for MAP2K1 and MAP3K1 genes. The association of BRAF V600E mutation was significant in children with multisystem disease, younger age (<2 years), skin, and special organ involvement. BRAF V600E mutation was an independent predictive parameter for disease relapse. We therefore conclude that BRAF V600E mutation may be a significant marker for predicting disease progression in LCH and a candidate for targeted therapy for children with disease relapse and multisystem disease.

Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9074-9074
Author(s):  
Miguel F. Sanmamed ◽  
Sara Fernandez-Landazuri ◽  
Eduardo Castanon ◽  
Jose Echeveste ◽  
Maria D. Lozano ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Markers ◽  
Direct Sequencing ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Best Response ◽  
Response Table ◽  
S 100 ◽  
Melanoma Patients

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p<0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]

scholarly journals BRAF V600E mutation in papillary thyroid carcinoma: it’s relation to clinical features and oncologic outcomes in a single cancer centre experience

2021 ◽  
Author(s):  
Mahmoud Al-Masri ◽  
Tawfiq Al-Shobaki ◽  
Hani Al-Najjar ◽  
Rafal Iskanderian ◽  
Enas Younis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Disease Free Survival ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Cancer Center ◽  
Papillary Thyroid ◽  
Free Survival ◽  
Disease Free

Purpose: This study focuses on the oncologic influence of BRAF V600E mutations in a cohort of Middle Eastern PTC patients treated at a single centre. We test the association of BRAFV600E mutation with papillary thyroid carcinoma at King Hussein Cancer Center. Methods: Patients with histologically confirmed PTC who underwent surgical treatment between 2006 and 2015 were included in this study. Oncological outcomes, both short and long termed were collected. Results: A total of 128 patients (68% females) were included in this study with a mean age of 38 years (±13.8). The median follow-up period was 50 months. The BRAF V600E mutation was found in 71% of patients. The tumor size for patients with a negative BRAF V600E mutation were significantly larger in comparison to patients who tested positive for the mutation (3.47 cm versus 2.31 cm, respectively, P = 0.009). The two groups showed similar disease-free survival (DFS) rates; positive = 75% (median 43 months (0-168)) compared to 78% for the negative BRAF V600E mutation (median 38 months (3-142)) (P= 0.162, HR=0.731) Furthermore, both groups showed similar overall survival rates: positive = 94.5% (median 56 months (0-228)) compared to 94.6% for the negative BRAF V600E mutation (median 43 months (3-157)) (P = 0.941, HR= 0.940). Conclusion: BRAF V600E mutation had no effect on loco-regional recurrence, distant metastasis, overall survival or disease-free survival. These findings may be attributed to geographic variations or reflect that BRAF V600E may only serve as an indicator of poor prognosis in high risk groups.

scholarly journals BRAF Mutations as Actionable Targets: A Paradigm Shift in the Management of Colorectal Cancer and Novel Avenues

2021 ◽  
pp. OP.21.00160
Author(s):  
Ibrahim Halil Sahin ◽  
Jim Klostergaard
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Growth Factor Receptor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Class I ◽  
Molecular Characteristics ◽  
Braf Mutations ◽  
Therapy Choice ◽  
Checkpoint Inhibitor Therapy

BRAF mutations in colorectal cancer have been studied over the past several decades. BRAF V600E mutation, a class I mutation, is the most common oncogenic BRAF alteration in colorectal cancer. Until recently, the BRAF V600E mutation was not among actionable genes for colorectal cancer. However, recent discoveries have revealed therapeutic opportunities. The BRAF with or without MEK inhibition combined with epidermal growth factor receptor–directed therapy was recently found to be an effective therapy choice for patients with advanced-stage BRAF V600–mutant colorectal cancer. However, it is essential to distinguish patients with BRAF V600E–mutant mismatch repair–deficient colorectal cancer from those with mismatch repair–proficient colorectal cancer, as immune checkpoint inhibitor therapy is more appealing in this subset of patients with colorectal cancer. This review article discusses the molecular characteristics of class I, II, and III BRAF mutants and their impact on the clinical behavior of colorectal cancer. We also review the recent progress in the targetability of BRAF mutations in colorectal cancer, which has led to changes in clinical practice and elaborates on innovative therapeutic approaches to enhance the efficacy of BRAF-targeting therapies, to achieve more durable responses.

scholarly journals BRAF Mutation (V600E) Prevalence in Mexican Patients Diagnosed with Melanoma

2016 ◽  
Vol 9 (1) ◽  
pp. 241-245 ◽  
Author(s):  
Priscilla Denise Zepeda-Lopez ◽  
Julio Cesar Salas-Alanis ◽  
Sonia Toussaint-Caire ◽  
Daniela Gutierrez-Mendoza ◽  
Elisa Vega-Memije ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Statistical Significance ◽  
Primary Melanoma ◽  
Braf V600e ◽  
Molecular Diagnostic ◽  
Braf Mutations ◽  
Diagnostic Laboratory ◽  
Dermatology Department ◽  
Skin Biopsies ◽  
Hospital General

Background: B-Raf is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. It has been shown that 50% of melanomas harbor activating BRAF mutations, with over 90% being the V600E mutation. Objective: The goal of this research was to determine the prevalence of the BRAF V600E mutation in patients from Central Mexico diagnosed with primary melanoma. Methods: Skin biopsies from 47 patients with melanoma were obtained from the dermatology department of the Hospital General ‘Dr. Manuel Gea González' in Mexico City. For BRAF mutation determination, after DNA isolation, the gene region where the mutation occurs was amplified by PCR. Subsequently, the presence or absence of the V600E mutation was detected by Sanger sequencing performed at the private molecular diagnostic laboratory Vitagénesis in Monterrey, Mexico. Results: Of the 47 patients sampled, 6.4% harbored the V600E mutation. No statistical significance was found between mutations and the type of tumor.

Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4058-4058
Author(s):  
A. Ruzzo ◽  
C. Cremolini ◽  
F. Loupakis ◽  
L. Fornaro ◽  
D. Santini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Wild Type ◽  
Braf Mutations ◽  
Allelic Variants ◽  
Mutational Status ◽  
Intron 1 ◽  
Colorectal Cancer Patients ◽  
To Receive

4058 Background: KRAS and BRAF mutations are associated with resistance to anti-EGFR monoclonal antibodies. EGFR Intron-1 (CA)n genotype has been suggested to influence the activity of cetuximab. Methods: We retrospectively assessed KRAS and BRAF mutational status and EGFR Intron-1 (CA)n genotypes in 117 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. We defined short (S) and long (L) allelic variants those presenting < and ≥17 CA repeats respectively. Among KRAS wild-type patients, we investigated the association between BRAF mutational status and EGFR Intron-1 genotype and treatment outcome in terms of RR and PFS. Results: Among 66 (56%) KRAS wild-type patients, BRAF V600E mutation was detected in 9 (14%) patients. BRAF wild-type patients reported improved RR (0/9, 0% vs 19/57, 33%, p = 0.04) and PFS (3.3 vs 5.1 months, p = 0.076; HR = 0.54 [95%CI: 0.18–1.09]) in comparison with BRAF-mutated. EGFR Intron-1 L/L genotype was detected in 13 (20%) KRAS wild-type patients. Objective responses were reported in 1/13 (8%) EGFR Intron-1 L/L patients and in 18/53 (34%) S/L or S/S patients (p = 0.061). Significantly longer PFS was observed among EGFR Intron-1 S/L or S/S patients (5.3 vs 3.3 months, p = 0.0062; HR = 0.45 [95%CI: 0.14–0.72]). Among 57 KRAS and BRAF wild-type patients, 1/11 (9%) EGFR Intron-1 L/L patients and 18/46 (39%) S/L - S/S patients responded to treatment (p = 0.058), achieving median PFS of 3.7 and 5.4 months, respectively (p = 0.022; HR = 0.48 [95%CI: 0.15–0.87]). Conclusions: In KRAS wild-type patients, BRAF mutations are confirmed to predict resistance to cetuximab treatment. EGFR Intron-1 allelic variants are promising markers of benefit in patients with both KRAS and BRAF wild-type and may help to better select mCRC patients candidate to receive cetuximab-containing treatment. No significant financial relationships to disclose.

scholarly journals Frequency of BRAF V600E Mutation in the Mexican Population of Patients With Metastatic Melanoma

2018 ◽  
pp. 1-5
Author(s):  
Erika Ruiz-Garcia ◽  
Juan A. Matus-Santos ◽  
Jorge Alberto Guadarrama-Orozco ◽  
Miguel Angel Alvarez-Avitia ◽  
Jose Luis Aguilar-Ponce ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Large Scale ◽  
Braf V600e Mutation ◽  
Mexican Population ◽  
Braf V600e ◽  
Braf Gene ◽  
Braf Mutations ◽  
Nodular Melanoma ◽  
Pathologic Features

Purpose The BRAF V600E mutation has been described in melanomas occurring in the Caucasian, European, and Asian populations. However, in the Mexican population, the status and clinical significance of BRAF mutation has not been researched on a large scale. Methods Consecutive BRAF-tested Mexican patients with metastatic melanoma (n = 127) were analyzed for mutations in exon 15 of the BRAF gene in genomic DNA by real-time polymerase chain reaction technology for amplification and detection. The results were correlated with the clinical-pathologic features and the prognosis of the patients. Results The frequency of somatic mutation V600E within the BRAF gene was 54.6% (43 of 127 patients). Nodular melanoma was the most prevalent subtype in our population, with BRAF mutations in 37.2% (16 of 55 patients). In contrast, superficial spread had a frequency of 18.6% BRAF mutation (eight of 24). Other clinicopathologic features were assessed to correlate with the mutation status. Conclusion This study searched for the most prevalent BRAF V600E mutation type in melanoma in a heterogeneous population from Mexico. Nodular melanoma was found to be the most prevalent in metastatic presentation and the presence of BRAF V600E mutation, perhaps related to the mixed ancestry; in the north, ancestry is predominantly European and in the south, it is predominantly Asian. The outcomes of the mutation correlations were similar to those found in other populations.

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