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Purpose  To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC) and their outcomes in early-phase trials using pathway-targeting agents.    Patients and Methods  We analyzed characteristics of 238 patients with mCRC referred to the phase 1 trials unit at MD Anderson Cancer Center.  KRAS ,  PIK3CA  and  BRAF  status were tested using PCR-based DNA sequencing.    Results  Fifty-one percent of patients harbored  KRAS  mutations; 15% had  PIK3CA  mutations. In the multivariate regression model for clinical characteristics  KRAS  mutations were associated with an increased incidence of lung and bone metastases and decreased incidence of adrenal metastases;  PIK3CA  mutations were marginally correlated with mucinous tumors (p = 0.05). In the univariate analysis,  KRAS  and  PIK3CA  mutations were strongly associated. Advanced Duke's stage (p<0.0001) and  KRAS  mutations (p = 0.01) were the only significant independent predictors of poor survival (Cox proportional hazards model). Patients with  PIK3CA  mutations had a trend toward shorter progression-free survival when treated with anti-EGFR therapies (p = 0.07). Eighteen of 78 assessable patients (23%) treated with PI3K/Akt/mTOR axis inhibitors achieved stable disease [SD] ≥6 months or complete response/partial response (CR/PR), only one of whom were in the subgroup (N = 15) with  PIK3CA  mutations, perhaps because 10 of these 15 patients (67%) had coexisting  KRAS  mutations. No SD ≥6 months/CR/PR was observed in the 10 patients treated with mitogen-activating protein kinase (MAPK) pathway targeting drugs.    Conclusions    KRAS  and  PIK3CA  mutations frequently coexist in patients with colorectal cancer, and are associated with clinical characteristics and outcome. Overcoming resistance may require targeting both pathways.

KRASness and PIK3CAness in Patients with Advanced Colorectal Cancer: Outcome after Treatment with Early-Phase Trials with Targeted Pathway Inhibitors