scholarly journals Mechanism of resistance to cetuximab therapy in colorectal cancer

mAbs ◽  
2012 ◽  
Vol 4 (5) ◽  
pp. 553-554 ◽  
Author(s):  
Janardan P. Pandey
Keyword(s):  
Colorectal Cancer ◽  
Mechanism Of Resistance ◽  
Cetuximab Therapy

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.

scholarly journals PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in a human colorectal cancer model

2016 ◽  
Vol 27 ◽  
pp. vi5
Author(s):  
S. Napolitano ◽  
B. Valentina ◽  
E. Martinelli ◽  
V. Sforza ◽  
P.P. Vitiello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mek Inhibitor ◽  
Cancer Model ◽  
Human Colorectal Cancer ◽  
Escape Mechanism ◽  
Mechanism Of Resistance ◽  
Pathway Activation ◽  
Inhibitor Treatment

scholarly journals Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer

2018 ◽  
Vol 7 (11) ◽  
pp. 5478-5487 ◽  
Author(s):  
Daniel Shepshelovich ◽  
Amanda R. Townsend ◽  
Osvaldo Espin-Garcia ◽  
Lidija Latifovic ◽  
Chris J. O’Callaghan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Fc Gamma Receptor ◽  
Gamma Receptor ◽  
Cetuximab Therapy

scholarly journals Circulating pEGFR Is a Candidate Response Biomarker of Cetuximab Therapy in Colorectal Cancer

2014 ◽  
Vol 20 (24) ◽  
pp. 6346-6356 ◽  
Author(s):  
Theodora Katsila ◽  
Mercè Juliachs ◽  
Josep Gregori ◽  
Teresa Macarulla ◽  
Laura Villarreal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Response Biomarker ◽  
Cetuximab Therapy

3002 ORAL Comprehensive assessment of molecular markers predicting response to cetuximab therapy in colorectal cancer

2007 ◽  
Vol 5 (4) ◽  
pp. 235
Author(s):  
F. Cappuzzo ◽  
G. Finocchiaro ◽  
P.A. Janne ◽  
W.A. Franklin ◽  
K. Bencardino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Markers ◽  
Comprehensive Assessment ◽  
Cetuximab Therapy

EGFR expression using immunohistochemistry (IHC) testing as a tool for selecting patients (pts) for treatment with cetuximab

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13000-13000 ◽  
Author(s):  
A. L. Ervin-Haynes ◽  
R. M. Schinagl ◽  
M. R. Dalesandro ◽  
J. Roecker ◽  
H. Youssoufian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Routine Practice ◽  
Study Enrollment ◽  
Egfr Expression ◽  
Number Of Patients ◽  
The Us ◽  
Colorectal Cancer Patients ◽  
The Relationship ◽  
Cetuximab Therapy

13000 Background: EGFR expression, as determined by IHC, is currently used to select patients for cetuximab therapy. Based on prior studies in colorectal cancer patients, approximately 60 to 75% of patients express EGFR. There is increasing evidence that EGFR expression is not predictive of response to cetuximab therapy, and does not properly select patients who might benefit from such therapy (Chung et al 2005, Saltz et al 2005, Scartozi et al 2004, NCCN 2005). Such selection limits access to a considerable number of patients who might otherwise benefit. Methods: A clinical trial of cetuximab (Erbitux®) monotherapy is being conducted in 60 EGFR-undetectable patients with metastatic colorectal cancer at 14 sites in the US and Canada to explore the relationship between EGFR expression and cetuximab activity. Results: As of January 5, 2006, 112 patients have been screened. Of these patients, 33 (29%) were EGFR-undetectable and continued screening for study enrollment; 52 (46%) tested positive for EGFR expression; and 2 (2%) did not have enough tissue to evaluate EGFR status and were not enrolled onto the trial. The remaining 25 pts (22%), were initially found to be EGFR-undetectable by IHC testing at local labs, but were subsequently identified as EGFR-positive after reevaluation at a highly experienced, centralized laboratory. Conclusion: The majority of patients tested for EGFR expression are tested using the EGFR pharmDx™ IHC assay. Results of the IHC-based assay for EGFR expression are highly dependent upon sample preparation and the methods used in conducting the assay. Variability in methods among labs may result in poor identification of pts expressing EGFR. This finding, together with the growing evidence that EGFR expression is not predictive of response to cetuximab therapy, indicate that the current routine practice of tumor IHC EGFR testing for the purpose of selecting cetuximab therapy may be inappropriate and pts who could potentially benefit from cetuximab therapy are being excluded from a treatment option. [Table: see text]

KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer

2006 ◽  
Vol 66 (8) ◽  
pp. 3992-3995 ◽  
Author(s):  
Astrid Lièvre ◽  
Jean-Baptiste Bachet ◽  
Delphine Le Corre ◽  
Valérie Boige ◽  
Bruno Landi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Mutation Status ◽  
Cetuximab Therapy ◽  
Kras Mutation Status

scholarly journals Fusobacterium nucleatum facilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways

2020 ◽  
Author(s):  
Hu Han ◽  
Yan Li ◽  
Wan Qin ◽  
Lu Wang ◽  
Han Yin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fusobacterium Nucleatum ◽  
Therapy Resistance ◽  
Tumor Burden ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Functional Studies ◽  
Cetuximab Therapy

AbstractInfectious pathogens contribute to about 20% of the total tumor burden. Fusobacterium nucleatum (Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance of Fn has been observed in patients with right-sided CRC than in those with left-sided CRC. While the KRAS/NRAS/BRAF wild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association of Fn to cetuximab resistance. Our functional studies indicate that Fn facilitates resistance of CRC to cetuximab in vitro and in vivo. Moreover, Fn was found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targeting Fn and the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.

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