Despite this genetic profile represents a small percentage of the human primary CRCs, the constitutive and simultaneous activation of KRAS and PIK3CA pathways, associated with β-Catenin stabilization, confers maximal resistance to Cetuximab41 and the mesenchymal phenotype reduces the sensitivity to Erlotinib42, features accounting for a significant number of metastatic cancers unresponsive to therapies. The gene discussed is PIK3CA; the disease is metastatic malignant neoplasm.