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Mutations of the phosphoinositide-3-kinase (PI3K) catalytic subunit alpha gene ( PIK3CA ) are frequent in endometrial cancer. We sequenced exon9 and exon20 of  PIK3CA  in 280 primary endometrial cancers to assess the relationship with clinicopathologic variables, patient survival and associations with  PIK3CA  mRNA and phospho-AKT1 by gene expression and protein data, respectively. While  PIK3CA  mutations generally had no impact on survival, and were not associated with clinicopathological variables, patients with exon9 charge-changing mutations, providing a positive charge at the substituted amino acid residue, were associated with poor survival (p = 0.018). Furthermore, we characterized  PIK3CA  mutations in the metastatic setting, including 32 patients with matched primary tumors and metastases, and found a high level of concordance (85.7%; 6 out of 7 patients), suggesting limited heterogeneity.  PIK3CA  mRNA levels were increased in metastases compared to the primary tumors (p = 0.031), independent of  PIK3CA  mutation status, which rather associated with reduced  PIK3CA  mRNA expression.  PIK3CA  mutated tumors expressed higher p-AKT/AKT protein levels, both within primary (p < 0.001) and metastatic lesion (p = 0.010). Our results support the notion that the PI3K signaling pathway might be activated, both dependent- and independently of  PIK3CA  mutations, an aspect that should be considered when designing PIK3 pathway targeting strategies in endometrial cancer.

PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer