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

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 219 ◽  
Author(s):  
Nuria Garcia-Carbonero ◽  
Javier Martinez-Useros ◽  
Weiyao Li ◽  
Alberto Orta ◽  
Nuria Perez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Predictive Biomarkers ◽  
Braf V600e ◽  
Chemotherapy Response ◽  
First Line ◽  
Standard Chemotherapy ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Line Standard

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.

Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study

2012 ◽  
Vol 30 (15) ◽  
pp. 1755-1762 ◽  
Author(s):  
Kjell Magne Tveit ◽  
Tormod Guren ◽  
Bengt Glimelius ◽  
Per Pfeiffer ◽  
Halfdan Sorbye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
First Line Treatment

Purpose The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. Patients and Methods Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. Results Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. Conclusion Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

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.

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.

Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3570-3570
Author(s):  
Josep Tabernero ◽  
Axel Grothey ◽  
Dirk Arnold ◽  
Michel Ducreux ◽  
Peter J. O'Dwyer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maintenance Treatment ◽  
Predictive Biomarkers ◽  
Experimental Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
First Line ◽  
Tissue Samples ◽  
First Line Therapy

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC > 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

Survival outcome in HER2-amplified metastatic colorectal cancer (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 642-642
Author(s):  
Kentaro Sawada ◽  
Wataru Okamoto ◽  
Yoshiaki Nakamura ◽  
Takeharu Yamanaka ◽  
Satoshi Yuki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Survival Outcome ◽  
Braf V600e ◽  
Her2 Status ◽  
Her2 Amplification ◽  
Braf Mutations ◽  
Signal Ratio ◽  
Group B

642 Background: HER2 amplifications have been observed in approximately 3% of patients (pts) with metastatic colorectal cancer (mCRC). Early clinical trials with combined HER2-targeted therapies showed promising activities. However, it remains unclear whether HER2 amplification in mCRC is as prognostic as RAS or BRAF V600E mutant (mt). We aimed to evaluate survival outcome for mCRC pts with HER2 amplification compared to those with RAS or BRAF mt. Methods: mCRC pts who received a palliative resection of the primary tumor with metastatic diseases at presentation, or recurred after curative resection of the primary tumor between 2005 and 2015, were analyzed. HER2 immunohistochemistry (IHC) was performed using formalin-fixed and paraffin-embedded (FFPE) sections obtained from the primary tumor, and HER2 amplification was confirmed by fluorescence in situ hybridization (FISH) in case of IHC 2+ or 3+. Criteria for HER2 amplification were a HER2- to CEP17- signal ratio of 2.0 or higher. RAS / BRAF status was centrally assessed by a PCR-based method. The pts were classified into four subgroups based on RAS, BRAF and HER2 status: Group R , RAS mt; Group B, BRAF V600E mt; Group H, HER2 amplification with RAS / BRAF wild-type (wt); and Group W, RAS / BRAF wt. Results: Among 370 pts, 359 pts (97%) were successfully analyzed. A total of 15 pts (4%) had HER2 amplifications, out of which four pts had overlapped RAS mt (subclassified as Group R). RAS or BRAF mutations are mutually exclusive. The number in Group R, B, H and W was 204 (57%), 13 (4%), 11 (3%) and 131 (36%), respectively. There was no remarkable difference in baseline characteristics among groups. With a median follow-up time of 63 months (mos), the median overall survival of the 359 pts was 27 mos (95%CI 24 - 29 mos); Group R, 24 mos; Group B, 14 mos; Group H, 20 mos; and Group W, 39 mos. The HR of R vs. H is 0.83 (95%CI 0.41-1.70, p= 0.618), B vs. H is 1.16 (95%CI 0.47-2.84, p= 0.748), and W vs. H is 0.52 (95%CI 0.25-1.08, p= 0.080), respectively. Conclusions: This study suggests that the prognosis of mCRC pts with HER2 amplification tends to be worse as compared to those with RAS / BRAF wt, similar to those with RAS mt, and better than those with BRAF mt, although these comparisons were not statistical significant.

cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3542-3542 ◽  
Author(s):  
Alexandre Harle ◽  
Celine Gavoille ◽  
Olivier Bouche ◽  
Meher Ben Abdelghani ◽  
Jérôme Edouard Plaza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Accurate Determination ◽  
Braf V600e ◽  
Molecular Testing ◽  
Braf Mutations ◽  
Blood Samples

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.

What is the role of the anti-angiogenic therapy in BRAF (V600E) mutant metastatic colorectal cancer patients in a real-world setting?

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 620-620 ◽  
Author(s):  
Nieves Martinez Lago ◽  
Marta Covela Rúa ◽  
Elena Brozos Vazquez ◽  
Ana Fernandez Fernandez Montes ◽  
Juan Cruz De La Camara Gomez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Real World ◽  
Strong Predictor ◽  
Tumor Resection ◽  
Braf V600e ◽  
Prognostic Impact ◽  
First Line ◽  
Multicentric Study ◽  
Real World Setting

620 Background: Activating B-type Raf kinase (BRAF) mutations, mostly missense V600E, occur in approximately 8% to 12% of patients with metastatic colorectal cancer (mCRC). BRAF (V600E)mt is a strong predictor of a poor prognosis, with distinct clinical and pathological features. However, it is unknown whether this mutation is predictive of any treatment benefit in a real world setting. Methods: We conducted an observational, retrospective, multicentric study of patients with BRAF V600E-mt mCRC treated at nine university Spanish hospitals in NW Spain, belonging to GITuD (Galician Research Group on Digestive Tumors). Demographic, clinic and pathological characteristics, overall survival (OS) and first-line progression free survival (PFS) were retrospectively collected and analyzed. Results: Data from 65 patients treated between November 2010 to June 2018 were recorded in this study. Median age was 62.8 years (range 30-83 years), 55.4 % female, 75.4% ECOG PS0-1, 49.2% right-sided, 35.2% high grade, 69.2% synchronous presentation, 66.2% primary tumor resection and median metastatic locations was 2 (range 1-5). With a median follow up of 64.6 months, median OS was 12.9 months (95% CI, 9.8-16.0 months) and first line PFS was 4.1 months (95% CI, 2.7-5.5 months). First line PFS according treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 6.2 vs 4.8 vs 2.9 vs 2.1 months (p = 0.020). Bevacizumab based chemotherapy was associated with a prolonged first line PFS (median 5.0 vs. 2.1 months, HR, 0.406; 95% CI, 0.20-0.81; p = 0.005). Nevertheless, no statistical differences between bevacizumab based regimes, (Triplet-CT vs Doublet-CT (HR 0.830; 95% CI 0.4-1.9; p = 0.666)) or between Doublet-CT with or without a antiEGFR were found (HR 0.511; 95% CI 0.2-1.6; p = 0.223). Conclusions: Our study confirms the negative prognostic impact of BRAF V600Emt in mCRC and encourage the use of anti-angiogenic based chemotherapy in this subgroup of patients.

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