Prognostic vs predictive molecular biomarkers in colorectal cancer: Is KRAS and BRAF wild type status required for anti-EGFR therapy?

Department of Surgical and Oncological Sciences, Section of Medical Oncology, University of Palermo, Via del Vespro 127, Palermo, Italy.
Cancer Treatment Reviews (Impact Factor: 7.59). 11/2010; 36 Suppl 3:S56-61. DOI: 10.1016/S0305-7372(10)70021-9
Source: PubMed


An important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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    • "Finally, this was a post-hoc analysis of multiple biomarkers of the MAX trial, and our findings may be related to a random effect. Bevacizumab efficacy has no clinically useful predictive biomarker, such as KRAS mutation status, which is a definitive negative predictive biomarker for efficacy of epidermal growth factor receptor antibody therapy in advanced colorectal cancer (Lievre et al, 2006; Amado et al, 2008; De Roock et al, 2008; Van Cutsem et al, 2008; Bardelli and Siena, 2010; De Roock et al, 2010; Douillard et al, 2010; Rizzo et al, 2010; Van Cutsem et al, 2011; Bokemeyer et al, 2012). Various studies have examined the associations of potential biomarkers with bevacizumab efficacy. "
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    British Journal of Cancer 06/2015; 113(1). DOI:10.1038/bjc.2015.209 · 4.84 Impact Factor
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    • "PIK3CA (12.4%), and NRAS (7.4%) mutations in a colon cancer tissue collection (N = 121). The prevalence of these mutations also correlate well with those listed in the COSMIC database and other literature [19], [20], [21], [22], [23], [24], [25], . These results show that MUT-MAP is a sensitive and accurate platform to determine the mutational status in FFPE tissues and may be utilized to classify patients in clinical trials who may derive greater benefit with a targeted therapy. "
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    PLoS ONE 03/2014; 9(3):e90761. DOI:10.1371/journal.pone.0090761 · 3.23 Impact Factor
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    • "Biomarkers are anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific disease states. They may be diagnostic, perhaps before the cancer is detectable by conventional methods, prognostic , forecasting how aggressive the disease process will be, or predictive, identifying which patient will respond to which drug [303] [304] [305] [306]. Failure to differentiate these subtypes can be problematic when evaluating clinical outcomes (e.g., mortality, progression , and symptom sets) or when comparing the toxicity profiles of therapy. "
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