BRAF Mutations in Colorectal Cancer Are Associated With Distinct Clinical Characteristics and Worse Prognosis

2012 ◽  
Vol 55 (2) ◽  
pp. 128-133 ◽  
Author(s):  
Matthew F. Kalady ◽  
Kathryn L. DeJulius ◽  
Julian A. Sanchez ◽  
Awad Jarrar ◽  
Xiuli Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Characteristics ◽  
Braf Mutations ◽  
Worse Prognosis

CLINICAL CHARACTERISTICS OF COLORECTAL CANCER IN PATIENTS WITH EGFR-SIGNALING PATHWAY GENE MUTATIONS

2019 ◽  
pp. 60-67
Author(s):  
I.A. Bogomolova ◽  
I.I. Antoneeva ◽  
D.R. Dolgova
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Clinical Characteristics ◽  
Gene Mutations ◽  
Egfr Signaling ◽  
Braf Gene ◽  
Braf Mutations ◽  
Kras Gene ◽  
Egfr Signaling Pathway ◽  
Gene Exon

KRAS, NRAS, BRAF mutations are associated with an unfavorable prognosis for colorectal cancer (CRC). At the same time, there is no single point of view on disease development during adjuvant chemotherapy (ACT). Objective. The authors aimed at studying KRAS, NRAS and BRAF mutations in the tumor and their influence on the clinical characteristics of colorectal cancer development. Materials and Methods. Paraffin blocks of the primary CRC tumor (n=37) were used as the material for the study. Using genomic DNA, isolated from the primary tumor, real-time PCR was used to determine the most common mutations in CRC: KRAS gene (exon 2, codon region 12–13), NRAS gene (exon 3, codon region 61), B6F V600E gene. Results. The results of genotyping of DNA samples isolated from the primary CRC tumor paraffin blocks showed that BRAF gene mutations were detected in 8.2 % of cases, NRAS gene mutations were detected in 5.4 % of cases, and KRAS gene mutations were detected in 37.8 % of cases. The authors didn’t reveal any dependencies of the mutation distribution on patients’ gender and age. The examined mutations were more common in adenocarcinomas of high and moderate degrees of differentiation. The relapse-free period after ACT in patients with identified KRAS, NRAS, BRAF gene mutations is significantly less than in those without mutations. Conclusion. The findings suggest that EGFR signaling pathway mutations (KRAS, NRAS and BRAF) increase the risk of disease recurrence and are an unfavorable prognostic factor. Keywords: colorectal cancer, NRAS, KRAS, BRAF mutations, adjuvant chemotherapy.

scholarly journals Clinicopathological and prognostic significance of Fusobacterium nucleatum infection in colorectal cancer: a meta-analysis

2020 ◽  
Author(s):  
Shuchen Huangfu ◽  
Wen-bin Zhang ◽  
haoran Zhang ◽  
Yang Li ◽  
Yiran Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Characteristics ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Fusobacterium Nucleatum ◽  
High Abundance ◽  
Cancer Specific Survival ◽  
Relationship Of ◽  
Worse Prognosis

Abstract Background: Accumulating evidences about the association between Fusobacterium nucleatum (F. nucleatum) and colorectal cancer (CRC) has been reported in various studies. However, the definite relationship between abundance of F. nucleatum with clinical characteristics and prognosis of CRC is still controversial. Methods: PubMed, Embase and Web of Science were searched for relevant articles up to April 7, 2020. Outcomes of interest included clinical characteristics, molecular characteristic and survival analysis. HR (OR), odds ratios (OR) and 95% confidence interval (CI) were calculated to explore the prognostic value and relationship of clinical characteristics of Fusobacterium nucleatum in CRC.Results: A total of 3626 patients with CRC from 13 eligible studies were included. High abundance of F. nucleatum was associated with worse prognosis on overall survival (OS) (HR= 1.40, P < 0.0001), disease-free survival (DFS) (HR = 1.71, P = 0.0002) and cancer-specific survival (OR= 1.93, P <0.0001). In addition, F. nucleatum abundance was related with T (T3-T4) stage(OR = 2.20, P < 0.00001), M (M1) stage (OR = 2.11, P = 0.005), poor tumor differentation(OR = 1.83, P =0.02), microsatellite instability (MSI) -high (OR = 2.53, P = 0.0003) and KRAS mutation (OR =1.27, P=0.05).Conclusion: The present evidences revealed that high abundance of F. nucleatum is inclined to indicate worse prognosis and is associated with tumor growth, distant Impact: This study highlights the risk factor of F. nucleatum for worse prognosis of CRC.

A Critical Review of Second-generation anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer

2020 ◽  
Vol 21 ◽  
Author(s):  
Daniel Sur ◽  
Andrei Havasi ◽  
Alecsandra Gorzo ◽  
Claudia Burz
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Metastatic Colorectal Cancer ◽  
Second Generation ◽  
Current Data ◽  
Braf Mutations ◽  
Durable Response ◽  
Ongoing Research

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

scholarly journals Weight loss early after discharge predicts the risk of rehospitalization in non-obese patients with heart failure preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Kamisaka ◽  
K Kamiya ◽  
K Iwatsu ◽  
N Iritani ◽  
Y Iida ◽  
...  
Keyword(s):  
Heart Failure ◽  
Weight Loss ◽  
Regression Analysis ◽  
Ejection Fraction ◽  
Associated Factors ◽  
Clinical Characteristics ◽  
Obese Patients ◽  
Preserved Ejection Fraction ◽  
Kaplan Meier ◽  
Worse Prognosis

Abstract Background Weight loss (WL) has been considered as a prognostic factor in heart failure with reduced ejection fraction (HFrEF). However, the prognosis and associated factors of WL in heart failure with preserved ejection fraction (HFpEF) have remained unclear. Purpose This study aimed to examine the prevalence, prognosis, and clinical characteristics of worse prognosis based on the identified WL after discharge in HFpEF. Methods The study was conducted as a part of a multicenter cohort study (Flagship). The cohort study enrolled ambulatory HF who hospitalized due to acute HF or exacerbation of chronic HF. Patients with severe cognitive, psychological disorders or readmitted within 6-month after discharge were excluded in the study. WL was defined as ≥5% weight loss in 6-month after discharge and HFpEF was defined as left ventricular ejection fraction (LVEF) ≥50% at discharge. Age, gender, etiology, prior HF hospitalization, New York Heart Association (NYHA) class, brain natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), anemia (hemoglobin; male &lt;13g/dL, female &lt;12g/dL), serum albumin, Geriatric Depression Scale, hand grip strength and comorbidities were collected at discharge. Patients were stratified according to their body mass index (BMI) at discharge as non-obese (BMI &lt;25) or obese (BMI ≥25). We analyzed the association between WL and HF rehospitalization from 6 month to 2 years after discharge using Kaplan-Meier curve analysis and Cox regression analysis adjusted for age and gender, and clinical characteristics associated to worse prognosis in WL using logistic regression analysis adjusted for potential confounders in HFpEF. Results A total of 619 patients with HFpEF were included in the analysis. The prevalence of WL was 12.9% in 482 non-obese and 15.3% in 137 obese patients. During 2 years, 72 patients were readmitted for HF (non-obese: 48, obese: 24). WL in non-obese independently associated with poor prognosis (hazard ratio: 2.2: 95% confidence interval: 1.13–4.25) after adjustment for age and sex, while WL in obese patients did not. Logistic regression analysis chose age (odds ratio 1.02 per 1 year; 1.00–1.05), anemia (2.14; 1.32–3.48), and BNP ≥200pg/mL or NT-proBNP ≥900pg/mL (1.83; 1.18–2.86) as independent associated factors for worse prognosis of WL in non-obese patients. Conclusion In HFpEF, WL in early after discharge in non-obese elderly patients may be a prognostic indicator for HF rehospitalization. HF management including WL prevention along with controlling anemia is likely to improve prognosis in this population. Kaplan Meier survival curves Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): A Grant-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science

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 Atypical, Non-V600 BRAF Mutations as a Potential Mechanism of Resistance to EGFR Inhibition in Metastatic Colorectal Cancer

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Benny Johnson ◽  
Jonathan M. Loree ◽  
Alexandre A. Jacome ◽  
Shehara Mendis ◽  
Muddassir Syed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Stable Disease ◽  
Kinase Activity ◽  
Class Ii ◽  
Activity Level ◽  
Class Iii ◽  
Braf Mutations ◽  
Egfr Inhibition ◽  
Mechanism Of Resistance

PURPOSE Atypical, non-V600 BRAF ( aBRAF) mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize aBRAF mutations into class II (intermediate to high levels of kinase activity, RAS independent) and III (low kinase activity level, RAS dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown. PATIENTS AND METHODS Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided. RESULTS BRAF mutations were harbored by 257 patients, including 36 with aBRAF mutations: 22 class III, 10 class II, four unclassified. For patients with aBRAF mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with BRAFV600E mCRC. In contrast to right-sided predominance of tumors with BRAFV600E mutation, 53% of patients with aBRAF mCRC had left-sided primary tumors. Concurrent RAS mutations were noted in 33% of patients with aBRAF mCRC, and 67% of patients had microsatellite stable disease. Among patients with aBRAF RAS wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III aBRAF mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of aBRAF mutations and subclonal aBRAF mutations ( P < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients. CONCLUSION Efficacy of anti-EGFR therapy is limited in class II and III aBRAF mCRC. Detection of aBRAF mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.

Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3577-3577
Author(s):  
Stefano Mariani ◽  
Marco Puzzoni ◽  
Nicole Liscia ◽  
Valentino Impera ◽  
Andrea Pretta ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Selection Criteria ◽  
Wild Type ◽  
Braf Mutations ◽  
Previous Response ◽  
Clinical Variables ◽  
Ct Dna

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

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