Objective: Immunotherapy with chemotherapy significantly improves progression-free survival in advanced endometrial cancer (EC) especially in microsatellite-instability high (MSI-H) cases. Despite this, for recurrent EC in the post-immunotherapy setting, new treatment options are urgently awaited. The PI3K pathway is frequently altered in gynecological cancers in EC representing a potential treatment target. Patients and methods: In a pre-planned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 pts with samples eligible for Next Generation Sequencing (NGS) analysis (FoundationOne CDx®) focusing on PIK3CA mutational status. Results: In our analysis, the 4 most frequently mutated genes were TP53, PIK3CA, ARID1A, PTEN. PIK3CA mutations were detected in 51.4% (55/107 pts) of tissue samples. A total of 68 different PIK3CA mutations were observe, of which 64 were considered pathogenic and 4 variants of uncertain significance, with the co-expression of 2 different pathogenic mutations in 2 pts. The most frequent PIK3CA mutations were found in the kinase domain most commonly H1047R, (11/68), H1047Y (3/68), and in the helical domain such as E545K with a frequency of 4/68, and E542K with a frequency of 3/68. Notable, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered as predictive of response to PI3K inhibition with alpelisib by the current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all the TCGA categories. Conclusion: In this post-hoc analysis from the MITO END 3 trial, we confirmed the high frequency of PIK3CA mutations in EC establishing this tumor as an ideal candidate for testing of PI3K inhibitors in clinical trials.
pignata et al. (Mon,) studied this question.