PIK 3 CAMutations Are Not aMajor Determinant of Resistance to the Epidermal Growth Factor Receptor Inhibitor Cetuximab in Metastatic Colorectal Cancer

Purpose: It has been reported that activating KRAS mutations negatively affect response to anti ^ epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer.The mutation status of signalingmolecules downstream of the EGFR target is thus crucial to predict clinical benefit to EGFR-targeted therapies. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the PI3K/PTEN/AKT pathway. Experimental Design:We analyzed the PIK3CA and KRAS mutation status in a large group (n = 200) of chemorefractory metastatic colorectal cancers treated with cetuximab (Erbitux) in monotherapy or in combinationwith irinotecan, and correlated themutation status with outcome. Results:Twenty-three (12%) of the 200 samples carried1of the PIK3CA mutations included in our assay.We found no correlation between the presence of a PIK3CA mutation and impaired response to cetuximab. Conclusions:Our findings do not provide any evidence for a strong role ofPIK3CA mutations as a single marker in determining response to cetuximab in chemorefractory metastatic colorectal cancer. The identification of patients with colorectal cancer that respond to the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab remains a major challenge. It is well-established that activation of the EGFR pathway triggers a complex program of intracellular signals. The two major pathways activated by the EGFR are the KRAS/RAF/MEK/ ERK 1/2 pathway, which controls gene transcription, cell-cycle progression, and cell proliferation, and the PI3K/PTEN/AKT pathway, which activates a cascade of antiapoptotic and prosurvival signals. It has been shown recently that KRAS, a small G-protein downstream of EGFR, can acquire activating mutations, which isolate the KRAS/RAF/MEK/ERK1/2 pathway from its receptor and thereby render EGFR inhibitors ineffective. As a result, activating KRAS mutations negatively affect response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (1–3). The mutation status of signaling molecules downstream of the EGFR target is thus crucial to predict clinical benefit to EGFR-targeted therapies. Although patients without a KRAS mutation exhibit a much better response to EGFR inhibitors, not all of them respond to treatment. For instance, the response rate to cetuximab in advanced colorectal cancer patients with wild-type (WT) KRAS tumors was still limited to only 40% (3). Other mechanisms of resistance to EGFR inhibitors thus exist, and could for instance involve activating mutations of the other main EGFR effector pathway, i.e., the PI3K/PTEN/AKT pathway. Indeed, a recent report by Perrone et al. (4) investigated a cohort of 54 colorectal cancer tumors treated with cetuximab, and identified 4 mutations in the PIK3CA gene, which is the p110a catalytic subunit of PI3K, in patients not responding to cetuximab, thereby suggesting that mutations in PIK3CA cause resistance to cetuximab. In the current study, we further investigated the PIK3CA and KRAS mutation status in a much larger group (n = 200) of chemorefractory metastatic colorectal cancers treated with cetuximab (Erbitux) in monotherapy or in combination with irinotecan, and correlated the mutation status with outcome. Our aim was to investigate a possible role of PIK3CA mutations in resistance to cetuximab in KRAS WT patients.