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The pathogenesis of colorectal adenocarcinoma is driven by the accumulation of multiple genetic and epigenetic aberrations, and is influenced by various endogenous and exogenous factors [1] [Kudryavtseva AV, et al. Oncotarget. 2016;7:53959-53983]. Phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) serves as a major signaling hub downstream of epidermal growth factor receptor (EGFR). The PI3K signaling pathway plays a key role in the pathogenesis of many cancer types, including colorectal cancer. Gain-of-function mutations in PIK3CA (the phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha gene) upregulate the downstream AKT-MTOR signaling pathway, thereby promoting cancer cell growth and proliferation. Mutations in PIK3CA exons 9 and/or 20 are present in 1020% of colorectal cancers and are associated with other molecular alterations, including KRAS mutations and high-degree CpG island methylator phenotype [2] [Rosty C, et al. PLoS One. 2013;8:e65479]. Interestingly, the proportion of PIK3CA-mutant colorectal cancer appears to increase gradually from the rectum to the cecum rather than showing an abrupt change at the splenic flexure, supporting the “colorectal continuum theory” [3] and the role of the gut microbiota in carcinogenesis [4] [Ericsson AC, et al. Oncotarget. 2015:6:33689-33704; Wei Z, et al. Oncotarget. 2016:7:46158-46172]. Understanding the pathogenic heterogeneity between PIK3CA-mutant and PIK3CA-wild-type tumors may explain differences in treatment response between individual colorectal cancers. In this issue of Oncotarget, Ziv and colleagues report a retrospective study of yttrium-90 radioembolization for colorectal cancer liver metastases that suggested differential treatment response according to PI3K pathway gene mutation status (i.e., PIK3CA, AKT1) [5]. Among 40 patients with metastatic disease, PIK3CA and AKT1 mutations were observed in nine (23%) and one (2.5%) patients, respectively. Patients with mutations in either PIK3CA or AKT1 had a lower cumulative incidence of local progression after radioembolization compared with wild-type patients (55% vs. 92% at 1-year postembolization). This result could not be solely attributed to differences in tumor aggressiveness by PIK3CA mutation status [2]; therefore, the findings suggested that mutational activation of the PI3K pathway may enhance radio-sensitivity of colorectal tumors. Although small, this study has potential therapeutic implications. First, only a fraction of patients incur survival benefit from radioembolization, yet they are all subjected to an invasive procedure. Therefore, it would be clinically beneficial to identify the target population that might respond best to radioembolization. PI3K pathway mutation status may serve as such a biomarker to predict benefit from radioembolization. Furthermore, tumors harboring mutations in the PI3K pathway may be less susceptible to treatment using anti-EGFR antibodies, including cetuximab and panitumumab, which is the current mainstay for targeted therapy of metastatic colorectal cancer [Zhao B, et al. Oncotarget. 2016]. This suggests that PI3K pathway mutation status should be considered in the choice of anti-EGFR therapy, as is currently done for KRAS mutation status. The findings of the current study suggest that radioembolization may be an effective treatment modality for this specific subgroup that is already more likely to be resistant to anti-EGFR therapy. The PI3K pathway interacts with other key signaling pathways in colorectal cancer. Therefore, survival benefits associated with inhibition of other pathways may differ by PIK3CA mutation status. Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), inhibits PTGS1 News

PIK3CA mutation and colorectal cancer precision medicine