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.

Download full-text


Available from: Federica Di Nicolantonio
  • Source
    • "wild-type (wt) patients with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Atreya et al, 2015). Although RAS status ascertainment is recommended by all major guidelines (Van Cutsem et al, 2014; Clinical Practice Guidelines in Oncology (NCCN Guidelines), 2015), the predictive role towards anti-EGFRs of V600E activating mutation of BRAF is still debated (Di Nicolantonio et al, 2008;Laurent-Puig et al, 2009;Loupakis et al, 2009;Souglakos et al, 2009;De Roock et al, 2010) To this extent, studies have not been conclusive maybe due to the low incidence of BRAFV600E mutation (o10% of mCRC;Davies et al, 2002) and to the intrinsic limitations of retrospective subgroup analyses. Nevertheless, all the published series recognised that BRAFV600E mutation is a strong negative prognostic determinant in mCRC and BRAF-mutated metastatic patients have an extremely poor lifeexpectancy of around 12 months (Richman et al, 2009;Souglakos et al, 2009;Saridaki et al, 2010;Tie et al, 2011;Tran et al, 2011;Yokota et al, 2011;Saridaki et al, 2013;Yaeger et al, 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05-19.92), female gender (OR: 2.90, 95% CI 1.14-7.37) and mucinous histology (OR: 4.95, 95% CI 1.90-12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2%; specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.British Journal of Cancer advance online publication, 17 november 2015; doi:10.1038/bjc.2015.399
    Full-text · Article · Nov 2015 · British Journal of Cancer
    • "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). "
    [Show abstract] [Hide abstract]
    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
    No preview · Article · May 2015 · British Journal of Cancer
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Sep 2014 · Oncology letters
Show more