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 Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

2008 ◽  
Vol 26 (35) ◽  
pp. 5705-5712 ◽  
Author(s):  
Federica Di Nicolantonio ◽  
Miriam Martini ◽  
Francesca Molinari ◽  
Andrea Sartore-Bianchi ◽  
Sabrina Arena ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Braf Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Cellular Models ◽  
Mutational Status

Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

Molecular biology from bench-to-bedside: Which colorectal cancer patients to refer for genetic counseling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4113-4113
Author(s):  
L. H. Jensen ◽  
L. Dysager ◽  
J. Lindebjerg ◽  
S. Kølvraa ◽  
L. Byriel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Wild Type ◽  
Mlh1 Promoter ◽  
Dna Quality ◽  
Colorectal Cancer Patients

4113 Background: The single most common cause of hereditary colorectal cancer is the Lynch syndrome, which is associated with deficiency of the mismatch repair genes MLH1, MSH2, or MSH6. Most MLH1 negative tumors are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 promoter. If Lynch syndrome is detected in a patient and its family, screening can prevent death from new colorectal cancer. A family history should always be obtained, but in small families or patients with de-novo mutations and mutations with late or low penetrance, this is not sufficient. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. Methods: The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumors was tested for MLH1, MSH2, and MSH6 with immunohistochemistry. DNA from MLH1 negative tumors was sequenced for BRAF mutations. If wild-type, MLH1 promoter was analyzed with methylation specific multiplex ligation-dependent probe amplification (MLPA). MLH1 negative tumors were considered sporadic if BRAF V600E mutation or MLH1 promoter hypermethylation was found. A follow up was done on patients with MSH2 or MSH6 negative tumors and MLH1 negative cases not shown to be sporadic. Results: Most tumors, 251 (88%), stained positive for all three proteins. Six (2%) had negative MSH2 and one (<1%) isolated loss of MSH6. MLH1 was negative in 29 cases (10%). DNA quality allowed BRAF analysis in 27 of these with 14 mutations and 13 wild-type. DNA quality allowed MLPA in four of the 13 BRAF wild-type, and all four were methylated. Subsequently, Lynch syndrome could not be ruled out in 18 patients. A follow-up at 8–10 years revealed four definite Lynch syndrome and four highly suspicious. Conclusions: An easy and clinically applicable step-wise approach with immunohistochemistry (100%), BRAF sequencing (10%), and methylation analysis (5%) identified several patients with hereditary cancer. The family history should be supplemented with a molecular screening for whom to send for genetic counselling. No significant financial relationships to disclose.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Jing Chen ◽  
Fang Guo ◽  
Xin Shi ◽  
Lihua Zhang ◽  
Aifeng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Poor Survival ◽  
Colorectal Cancer Patients ◽  
Kras Codon

scholarly journals Clinicopathological Significance of BRAF V600E Mutation in Egyptian Colorectal Cancer Patients

2020 ◽  
Vol 88 (6) ◽  
pp. 991-997
Author(s):  
MONA A. KORA, M.Sc.; NANSY Y. ASAAD, M.D. ◽  
HALA S. EL-REBEY, M.D.; RANIA A. HASSANIN, M.D. ◽  
ALSHIMAA M. ALHANAFY, M.D.
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Clinicopathological Significance ◽  
Colorectal Cancer Patients

scholarly journals Detection of the BRAF V600E Mutation in Colorectal Cancer by NIR Spectroscopy in Conjunction with Counter Propagation Artificial Neural Network

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2238 ◽  
Author(s):  
Xue Zhang ◽  
Yang Yang ◽  
Yalan Wang ◽  
Qi Fan
Keyword(s):  
Neural Network ◽  
Colorectal Cancer ◽  
Artificial Neural Network ◽  
Nir Spectroscopy ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Ann Model ◽  
Wild Type ◽  
Tissue Samples ◽  
Cp Ann

This paper proposes a sensitive, sample preparation-free, rapid, and low-cost method for the detection of the B-rapidly accelerated fibrosarcoma (BRAF) gene mutation involving a substitution of valine to glutamic acid at codon 600 (V600E) in colorectal cancer (CRC) by near-infrared (NIR) spectroscopy in conjunction with counter propagation artificial neural network (CP-ANN). The NIR spectral data from 104 paraffin-embedded CRC tissue samples consisting of an equal number of the BRAF V600E mutant and wild-type ones calibrated and validated the CP-ANN model. As a result, the CP-ANN model had the classification accuracy of calibration (CAC) 98.0%, cross-validation (CACV) 95.0% and validation (CAV) 94.4%. When used to detect the BRAF V600E mutation in CRC, the model showed a diagnostic sensitivity of 100.0%, a diagnostic specificity of 87.5%, and a diagnostic accuracy of 93.8%. Moreover, this method was proven to distinguish the BRAF V600E mutant from the wild type based on intrinsic differences by using a total of 312 CRC tissue samples paraffin-embedded, deparaffinized, and stained. The novel method can be used for the auxiliary diagnosis of the BRAF V600E mutation in CRC. This work can expand the application of NIR spectroscopy in the auxiliary diagnosis of gene mutation in human cancer.

scholarly journals The impact of the Glasgow Prognostic Score on survival in second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation

2019 ◽  
Vol 11 ◽  
pp. 175883591882029 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hiroya Taniguchi ◽  
Keiji Sugiyama ◽  
Toshiki Masuishi ◽  
Kazunori Honda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Prognostic Score ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Second Line ◽  
Second Line Chemotherapy ◽  
Colorectal Cancer Patients ◽  
Line Chemotherapy

Background: BRAF (v-raf murine sarcoma viral oncogene homolog B1) V600E mutant colorectal cancer is associated with short survival. Recently, clinical trials have been conducted to improve outcomes of second or later lines of chemotherapy. However, there is a paucity of reference data pertaining to outcomes of second-line chemotherapy and prognostic factors that are relevant only to BRAF mutant patients. Patients and methods: We retrospectively reviewed metastatic colorectal cancer patients with BRAF V600E mutation who underwent second-line chemotherapy between January 2007 and March 2017. We evaluated treatment outcomes and performed prognostic analyses. Results: A total of 52 patients were included. The median progression-free survival and overall survival (OS) were 2.5 [95% confidence interval (CI) = 1.91–4.11] and 6.5 (95% CI = 4.30–9.63) months, respectively. Overall response and disease control rates were 7% and 48%, respectively. All the regimens which elicited a partial response included BRAF inhibitors in combination with anti-epidermal growth factor receptor (EGFR) antibodies. Therefore, the overall response was 0% after exclusion of patients treated with study drugs. Multivariate analysis for OS revealed that the Glasgow Prognostic Score (GPS), elevated lactate dehydrogenase, and poor performance status were independent prognostic factors. In particular, survival curves according to the GPS stratified the patients into distinct risk groups. The median OSs in patients with GPS of 0, 1, and 2 were 9.9, 5.0, and 1.9 months, respectively. Conclusions: Outcomes of second-line chemotherapy for metastatic colorectal cancer patients with BRAF V600E mutation were extremely poor. GPS may be useful in future clinical trials.

scholarly journals TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectableRASandBRAFwild-type metastatic colorectal cancer

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000403 ◽  
Author(s):  
Beatrice Borelli ◽  
Roberto Moretto ◽  
Sara Lonardi ◽  
Andrea Bonetti ◽  
Carlotta Antoniotti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Initial Therapy ◽  
Phase Iii ◽  
Wild Type ◽  
Open Label ◽  
Multicentre Phase ◽  
Phase Iii Study ◽  
Colorectal Cancer Patients ◽  
To Receive

BackgroundFOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective ofRASandBRAFmolecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity inRASandBRAFwild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients withRASandBRAFwild-type metastatic colorectal cancer.MethodsThis is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreatedRASandBRAFwild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, L-leucovorin 200 mg/m2, 5-fluoruracil 2400 mg/m248-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria.DiscussionThe relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres.Clinical trial informationNCT03231722.

High Frequency of Genes’ Promoter Methylation, but Lack of BRAF V600E Mutation among Iranian Colorectal Cancer Patients

2011 ◽  
Vol 17 (4) ◽  
pp. 819-825 ◽  
Author(s):  
Fakhraddin Naghibalhossaini ◽  
Hamideh Mahmoodzadeh Hosseini ◽  
Pooneh Mokarram ◽  
Mozhdeh Zamani
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Promoter Methylation ◽  
High Frequency ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Colorectal Cancer Patients

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.

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