Introduction: EGFR-mediated signaling involves two main intracellular cascades. On one side, KRAS activates BRAF, which in turn triggers the mitogen-activated protein kinases. On the other side, membrane localization of the lipid kinase PIK3CA counteracts PTEN and promotes AKT1 phosphorylation, thereby activating a parallel intracellular axis. Constitutive activation of KRAS bypasses the corresponding signaling cascade and, accordingly, patients with metastatic colorectal cancer (mCRC) bearing KRAS mutations are clinically resistant to the EGFR-targeted monoclonal antibodies (MoAbs) cetuximab or panitumumab. However, mutations in KRAS can only explain 30-40% of resistant cases. Recent reports indicate that alterations in other members of the EGFR signaling cascade, such as BRAF mutations and deregulation of the PIK3CA/PTEN pathway, could also drive resistance to anti-EGFR therapy. Methods: To clarify the relative contribution of these molecular alterations to response to anti-EGFR MoAbs, we performed a comprehensive analysis of KRAS, BRAF, PIK3CA gene mutations, and loss of PTEN expression in tumor samples from a cohort of 132 mCRC patients treated with regimens containing cetuximab or panitumumab. Results: KRAS, BRAF, and PIK3CA mutations were present in 35, 11, and 17 cases, respectively, while loss of PTEN was found in 41 cases. KRAS and BRAF mutations were mutually exclusive; KRAS and PIK3CA alterations were concomitantly present in 2 samples, while BRAF and PIK3CA mutations co-occurred in 7 cases. In univariate analysis, KRAS mutations were associated with resistance to cetuximab or panitumumab (P=0.026), although 2 patients carrying a KRAS G13D mutated tumor achieved objective response. The presence of BRAF or PIK3CA mutations correlated with lack of clinical response; none of the responders harbored genetic alterations in either of these genes, and only 1/41 patients with PTEN deficient tumors displayed a partial response (P<0.01). BRAF and/or PIK3CA mutated patients displayed also significantly shorter progression-free survival (P<0.005). BRAF mutations were a prognostic factor for decreased overall survival (P<0.01). In multivariate analysis, mutations of KRAS and loss of PTEN were the only independent predictors of lack of objective response (P=0.0014 and 0.0001, respectively). Cox multivariate analysis for survival demonstrated that mutations of BRAF and loss of PTEN are independently associated with decreased overall survival (P=0.011 and 0.012, respectively), with a trend toward statistical significance for KRAS mutations (P=0.054). The presence of mutations in at least one gene among KRAS, BRAF, or PIK3CA was significantly associated with lack of response to EGFR targeted MoAbs (P<0.0001; specificity=0.96; range 0.87-0.99), and negatively impacted on both progression-free and overall survival. When the expression of PTEN and mutations of KRAS, BRAF, or PIK3CA were concomitantly ascertained, over 70% of mCRC patients unlikely to respond to EGFR-targeted MoAbs could be identified. Conclusions: Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients eligible for anti-EGFR MoAbs therapies. Prospective studies are therefore needed to address the potential role of BRAF, PIK3CA, and PTEN to help selection and stratification of mCRC patients treated with anti-EGFR therapies.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-93.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO