BRAF, PIK3CA, and KRAS mutations and loss of PTEN expression impair response to EGFR-targeted therapies in mCRC
Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select patients eligible for anti-EGFR therapies
Mutations in KRAS can only explain 30-40% of resistantance in patients with metastatic colorectal cancer (mCRC) to the EGFR-targeted monoclonal antibodies (MoAbs) cetuximab or panitumumab. 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.
To clarify the relative contribution of these molecular alterations to response to anti-EGFR MoAbs, a group of researchers led by Federica Di Nicolantonio from the University of Turin Medical School, Turin, Italy 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. They presented results as a late-breaking abstract during the Plenary session of the American Association for Cancer Research (AACR) Annual Meeting (Denver, 18-22 April 2009).
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 also displayed 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 for 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), and negatively impacted 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.
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.
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