<i>BRAF</i> Mutations as Predictive Biomarker for Response to Anti-EGFR Monoclonal Antibodies

Brummelen, Emilie M.J. van; Boer, Anthonius de; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1634/theoncologist.2017-0031

Cited by 55 publications

(36 citation statements)

References 58 publications

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“…These tumors showed cell-line-specific morphological features such as vascularization and an erratic surface ( Figure 4C). The presence of KRAS and BRAF mutations in these cell lines might contribute to insensitivity to erlotinib as studies showed that patients with BRAF mutations do not benefit from anti-EGFR treatment [34]. Furthermore, in SW620, administration of axitinib led to a significant tumor growth inhibition, which might be attributed to its relatively high expression of axitinib targets FGFR1 and TNIK ( Figure 3B).…”

Section: Axitinib Erlotinib and Dasatinib Combination Therapy Inhibmentioning

confidence: 99%

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib

Berndsen

Swier

Beijnum

et al. 2019

Cancers

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Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy. We have previously identified a strongly synergistic drug combination (SDC), consisting of axitinib, erlotinib, and dasatinib that is active in renal cell carcinoma cells. In this study, we investigated the activity of this SDC in different CRC cell lines (SW620, HT29, and DLD-1) in more detail. SDC treatment significantly and synergistically decreased cell metabolic activity and induced apoptosis. The translation of the in-vitro-based results to in vivo conditions revealed significant CRC tumor growth inhibition, as evaluated in the chicken chorioallantoic membrane (CAM) model. Phosphoproteomics analysis of the tested cell lines revealed expression profiles that explained the observed activity. In conclusion, we demonstrate promising activity of an optimized mixture of axitinib, erlotinib, and dasatinib in CRC cells, and suggest further translational development of this drug mixture.

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Section: Axitinib Erlotinib and Dasatinib Combination Therapy Inhibmentioning

confidence: 99%

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib

Berndsen

Swier

Beijnum

et al. 2019

Cancers

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“…KRAS mutation is considered a key point for treatment decisions in oncology as it can predict resistance to monoclonal antibodies against epidermal growth factor receptor (EGFR) [48], restricting the use of these therapies to KRAS wild-type CRC patients [10]. BRAF mutations also confer resistance to anti-EGFR therapies in patients with mCRC [49,50]. Biologic treatment is predominantly administered in combination with standard chemotherapy to mCRC patients.…”

Section: Discussionmentioning

confidence: 99%

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Garcia-Carbonero

Martínez‐Useros

et al. 2020

Cells

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KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

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“…While initial studies concluded that the sensitivity and specificity of BRAFV600E IHC was too low to be useful, 22 subsequent studies have reported high sensitivity (96-100%) and specificity (98-100%) [23][24][25][26][27] using automated Ventana stainers, which were used in this study. Furthermore, BRAF testing has additional predictive and prognostic utility, [28][29][30] playing a role in predicting response to both anti-epidermal growth factor receptor (EGFR) therapies 31,32 and potentially immune checkpoint inhibitors. 33 The role of MLH1 promoter methylation analysis is less clear, having not been well studied until recent years.…”

Section: Discussionmentioning

confidence: 99%

Impact of universal immunohistochemistry on Lynch syndrome diagnosis in an Australian colorectal cancer cohort

Loh

Williams

Salmon

et al. 2019

Internal Medicine Journal

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Background Current guidelines recommend a step‐wise screening algorithm for all colorectal carcinomas (CRC) to identify patients with Lynch syndrome (LS). Aim To describe the frequencies of mismatch repair deficiency (dMMR), BRAFV600E mutations and MLH1 methylation in resected CRC, and evaluate the impact of universal screening on LS detection. Methods Retrospectively, 1171 consecutive cases of resected CRC were identified between 2010 and 2017 from a large multi‐centre pathology service. Testing for dMMR by immunohistochemistry (IHC) was initiated by the reporting pathologist from 2010, until universal testing was introduced in 2015. Patients with dMMR were referred to the Family Cancer Clinic (FCC) for consideration of germline mutation analysis. Results IHC was performed on 680 tumours, with abnormal expression in 124 (18%). Referral to FCC was made for 44 of the 88 patients with abnormal IHC (excluding those with BRAFV600E mutations). Of the 29 who attended, 16 underwent germline genetic testing, and LS was diagnosed in 7 with a germline mutation. After implementation of universal testing, there was a greater incidence of dMMR (17% vs 10%, P = 0.02), rate of BRAFV600E testing (79% vs 25%, P < 0.0001), and referral to FCC (61% vs 33%, P < 0.0001), but no difference in FCC attendance rate (65% vs 67%, P = 0.59) or new LS diagnoses (1.6% vs 0%, P = 0.06). Conclusion Universal IHC testing may increase the detection of LS, and should be implemented where possible. However, the full benefit was limited by low referral to and uptake of genetic testing, and further strategies are needed to overcome these barriers.

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BRAF Mutations as Predictive Biomarker for Response to Anti-EGFR Monoclonal Antibodies

Cited by 55 publications

References 58 publications

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Impact of universal immunohistochemistry on Lynch syndrome diagnosis in an Australian colorectal cancer cohort

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