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.

Systemic Therapy for Colorectal Cancer

2019 ◽  
Author(s):  
Anna M. Varghese
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Targeted Therapies ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Ongoing Research ◽  
Medical Oncologists ◽  
Epidermal Growth ◽  
Cytotoxic Therapies

Colorectal cancer remains the second most common cause of cancer-related deaths in this country. Although colorectal cancer is best managed by a multidisciplinary team of surgical, radiation, and medical oncologists, cytotoxic therapy remains the backbone of treatment in the metastatic disease setting. In addition to cytotoxic therapies, vascular-targeted therapies and epidermal growth factor receptor (EGFR)–targeted therapies for selected patients with metastatic colorectal cancer improve outcomes for patients with metastatic colorectal cancer. Growing understanding of various biological subsets of colorectal cancer, including BRAF V600E mutant and mismatch repair–deficient colorectal cancers, is expanding treatment opportunities for patients and is the focus of ongoing research. This review contains 4 tables and 57 references. Key Words: chemotherapy, colorectal cancer, fluoropyrimidines, immunotherapy, metastatic, mismatch repair–deficient colorectal cancer, targeted therapy, topoisomerase inhibitors

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).

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 Molecular targeted therapy of BRAF-mutant colorectal cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591985649 ◽  
Author(s):  
Michel Ducreux ◽  
Ali Chamseddine ◽  
Pierre Laurent-Puig ◽  
Cristina Smolenschi ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Line Treatment ◽  
Second Line ◽  
Braf Inhibitors ◽  
First Line ◽  
Braf Mutations

Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.

Analysis of BRAF and KRAS mutations in colorectal cancer and rectal carcinogenesis via fluorescent allele-specific PCR.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 436-436
Author(s):  
D. G. Stover ◽  
A. M. Cushman-Vokoun ◽  
C. L. Vnencak-Jones ◽  
J. Berlin
Keyword(s):  
Colorectal Cancer ◽  
Mapk Signaling ◽  
Braf V600e Mutation ◽  
Response To Therapy ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Specific Pcr ◽  
Allele Specific ◽  
Allele Specific Pcr

436 Background: Molecular analysis has become increasingly relevant in the evaluation of colorectal carcinomas. Mutations in Ras-MAPK pathway proteins KRAS (present in 30-40% of colorectal cancer) and BRAF (10-14% of colorectal cancer) or mismatch repair (MMR) enzymes can impact response to therapy and/or can assist in defining hereditary predisposition. High frequency microsatellite instability (MSI) in colorectal cancer is associated with improved outcomes. Targeted therapies against BRAF and other components of the Ras-MAPK signaling pathway are becoming important aspects of treatment in colorectal and other cancers. Methods: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted between 1/07 and 3/09 for MSI testing based on family history and/or histologic features. DNA samples were screened for the BRAF V600E mutation and 7 KRAS mutations in codons 12 and 13 using fluorescent allele specific PCR with capillary electrophoresis. Clinical data was collected via chart review. Results: 58 males and 53 females were studied. The incidence of KRAS and BRAF mutations among the 111 samples was 49.5% and 6.3%, respectively. KRAS G12D and G12V were the most common mutations, representing 57% of total KRAS mutations. Dually positive KRAS and MSI tumors exclusively demonstrated G12D and G13D mutations. KRAS and BRAF mutations were mutually exclusive. Rectal cancers did not show evidence of BRAF V600E mutation (p=0.04). KRAS, BRAF, and MSI status did not correlate with survival, however pre-operative and post-operative carcinoembryonic antigen (CEA) levels were significantly associated with survival both in univariate and multivariate analyses. Conclusions: We demonstrate that BRAF V600E mutation is significantly associated with colon cancer and not rectal cancer, suggesting that BRAF mutations are not relevant in rectal carcinogenesis. Correlation between specific KRAS mutation and outcome may require larger populations. 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.

Systemic Therapy for Colorectal Cancer

2019 ◽  
Author(s):  
Anna M. Varghese
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Targeted Therapies ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Ongoing Research ◽  
Medical Oncologists ◽  
Epidermal Growth ◽  
Cytotoxic Therapies

Colorectal cancer remains the second most common cause of cancer-related deaths in this country. Although colorectal cancer is best managed by a multidisciplinary team of surgical, radiation, and medical oncologists, cytotoxic therapy remains the backbone of treatment in the metastatic disease setting. In addition to cytotoxic therapies, vascular-targeted therapies and epidermal growth factor receptor (EGFR)–targeted therapies for selected patients with metastatic colorectal cancer improve outcomes for patients with metastatic colorectal cancer. Growing understanding of various biological subsets of colorectal cancer, including BRAF V600E mutant and mismatch repair–deficient colorectal cancers, is expanding treatment opportunities for patients and is the focus of ongoing research. This review contains 4 tables and 57 references. Key Words: chemotherapy, colorectal cancer, fluoropyrimidines, immunotherapy, metastatic, mismatch repair–deficient colorectal cancer, targeted therapy, topoisomerase inhibitors

scholarly journals Hereditary non-polyposis colorectal cancer is predicted to contribute towards colorectal cancer in young South African blacks

2009 ◽  
Vol 105 (1/2) ◽  
Author(s):  
L. Cronjé ◽  
P.J. Becker ◽  
A.C. Paterson ◽  
M. Ramsay
Keyword(s):  
Colorectal Cancer ◽  
South Africa ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf V600e ◽  
Cancer Tissue ◽  
Braf Mutations ◽  
Tissue Samples ◽  
Molecular Features ◽  
Black Patients

A disproportionately large number of young (less than 50 years) black patients present with colorectal cancer (CRC) in South Africa. Although a phenomenon previously described elsewhere in Africa, its specific molecular basis, whether sporadic or hereditary, has not been established. Molecular analysis of these tumours could link them to the features known to be associated with specific types of hereditary colorectal cancer, specifically through examination of levels of microsatellite instability, promoter methylation and the presence or absence of KRAS and BRAF mutations. The molecular features of cancer tissue samples from 44 CRC cases of black and white patients in South Africa were accordingly retrospectively analysed without knowledge of family history. Compared with samples from older blacks (>50 years), those from young black patients presented more often with a low methylation phenotype (CIMP-L) and high levels of microsatellite instability (MSI-H). Furthermore, as determined by real-time PCR using probe technology, the tissues from 35% of young blacks showed mutations within exon 1 of the KRAS gene. The BRAF-V600E mutation was only evident in the case of a single young black patient. Based on these results it seems likely that a proportion of CRC cases in young black patients from South Africa develop through the accumulation of mutations resulting in a mismatch repair deficiency linked to MSI-H and, possibly, germline mutations in the mismatch repair genes. The features in these patients are consistent with a diagnosis of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome. This finding has important implications for patient management and suggests that family members may be at high risk for CRC.

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