Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

Azienda Ospedaliera Niguarda Ca' Granda, Milano, Lombardy, Italy
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2008; 26(35):5705-12. DOI: 10.1200/JCO.2008.18.0786
Source: PubMed


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.

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Available from: Federica Di Nicolantonio,
    • "They often arise from serrated adenomas, occur in the right side of the colon more commonly in women, are high grade in nature, and are strongly associated with defective mismatch repair (Lochhead et al, 2013; Gonsalves et al, 2014). As with RAS mutations, mutation of codon 600 in the activation segment of the BRAF gene (BRAF MT) causes constitutive activation of the MAPK pathway, and is implicated as a source of impaired response to anti-EGFR mAbs in patients with mCRC (Benvenuti et al, 2007; Cappuzzo et al, 2008; Di Nicolantonio et al, 2008; Freeman et al, 2008; Laurent-Puig et al, 2009; Loupakis et al, 2009; Molinari et al, 2009; Perrone et al, 2009; Sartore-Bianchi et al, 2009; Tol et al, 2009). Notably, a metaanalysis of data from observational studies has provided evidence that BRAF MT is associated with a poor prognosis (i.e., negative prognostic biomarker) in mCRC (Yuan et al, 2013). "
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    ABSTRACT: Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.British Journal of Cancer advance online publication, 19 May 2015; doi:10.1038/bjc.2015.173 www.bjcancer.com.
    British Journal of Cancer 05/2015; 112(12). DOI:10.1038/bjc.2015.173 · 4.84 Impact Factor
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    • "BRAF mutations can abnormally activate downstream signaling pathways in HCC and act as indicator of cetuximab resistance in patients with colon cancer (34,35). BRAF mutations are believed to be rare in HCCs. "
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    ABSTRACT: The RAS/RAF and PI3K/PTEN signaling pathways play central roles in hepatocarcinogenesis. KRAS, NRAS, HRAS, BRAF, PIK3CA, PIK3R1 and PTEN are key cancer-related genes in the RAS/RAF and PI3K/PTEN signaling pathways. Genetic alterations in these genes often lead to the dysregulation of the two cascades. Little is known regarding the frequency of hotspot mutations in these critical components among Chinese patients with hepatocellular carcinoma (HCC). In the current study, 57 somatic hotspot mutations in 36 HCCs samples collected from Chinese patients using direct DNA sequencing method were examined. Two cases of KRAS somatic mutations (KRAS codon 61; Gln to His) were identified among 36 HCCs (5.6%). However, no mutations were found in the NRAS, HRAS, BRAF, PIK3CA, PIK3R1 and PTEN genes. These findings indicated that point mutations in the KRAS gene, but not mutations in NRAS, HRAS, BRAF, PIK3CA, PIK3R1 and PTEN genes, at a somatic level contribute to the abnormal activation of the RAS/RAF and PI3K/PTEN pathways in HCC.
    Oncology letters 09/2014; 8(3):1249-1254. DOI:10.3892/ol.2014.2253 · 1.55 Impact Factor
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    • "The knowledge of the mutational status of many genes implicated in response to the therapy (KIT, EGFR, BRAF, KRAS, PI3K, etc.) [29–31] is a real fact in the clinical management of the patients. By combining the copious amount of sequencing data over the past year, we find that the PIK3CA gene is one of the two most commonly mutated genes identified in human cancers (the other being KRAS) [2–4,6,8]. "
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    ABSTRACT: Background The PIK3CA gene mutation was found to associate with prognosis and might affect molecular targeted therapy in esophageal carcinoma (EC). The aim of this study is to compare different methods for analyzing the PIK3CA gene mutation in EC.Methods Genomic DNA was extracted from 106 surgically resected EC patient tissues. The PIK3CA mutation status (exons 9 and 20) were screened by mutant-enrich liquid chip (ME-Liquidchip), Sanger sequencing, and pyrosequencing. And all samples with mutations were independently reassessed using amplification refractory mutation system (ARMS) methods again.Results PIK3CA mutation rates were identified as 11.3% (12/106) by ME-Liquidchip. 10 mutations occurred in exon 9 and 2 in exon 20, including G1624A:E542K (n¿=¿4), G1633A:E545K (n¿=¿6) and A3140G:H1047R (n¿=¿2). The results were further verified by ARMS methods. Among these 12 cases characterized for PIK3CA mutation, however, only 7 and 6 cases were identified by Sanger sequencing (6.6%,7/106) and pyrosequencing (5.7%,6/106), respectively.Conclusion Sanger sequencing and pyrosequencing are less sensitive and are not efficiently applicable to the detection of PIK3CA mutation in EC samples. Choosing between ME-Liquidchip and ARMS will depend on laboratory facilities and expertise.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_153.
    Diagnostic Pathology 08/2014; 9(1):153. DOI:10.1186/s13000-014-0153-4 · 2.60 Impact Factor
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