PIK3CA Mutations in Advanced or Recurrent Endometrial Cancer: An Exploratory Molecular Profiling From the Phase II MITO END-3 Study.
16 affiliations
- 1Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
- 2Bioinformatics Unit, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy.
- 3Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
- 4Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
- 5Division of Gynecologic Oncology, Humanitas San Pio X, Milan, Italy.
- 6Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- 7Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
- 8Medical Oncology, Breast & GYN Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
- 9Department of Medical Oncology, "S. Maria della Misericordia" University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy.
- 10Clinical Trial Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
- 11U.O.C. Oncologia Medica-Ospedale Senatore Antonio Perrino, Brindisi, Italy.
- 12Department of Experimental Medicine, University of Salento, Fazzi Hospital, Lecce, Italy.
- 13Romagna Cancer Registry IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST), Meldola, Italy.
- 14Department of Oncology, Hospital of Prato Azienda USL Toscana Centro, Prato, Italy.
- 15AOM Liguria, Azienda Ospedaliera Metropolitana di Genova, Genoa, Italy.
- 16Division of Anatomic Pathology and Cytopathology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy.
Abstract
Purpose
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 postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target.Patients and methods
In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on PIK3CA mutational status.Results
In our analysis, the four most frequently mutated genes were TP53, PIK3CA, ARID1A, and PTEN. PIK3CA mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different PIK3CA mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent PIK3CA mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all The Cancer Genome Atlas 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.
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BibTeX
@article{passarelli2026pik3ca,
title = {{PIK3CA Mutations in Advanced or Recurrent Endometrial Cancer: An Exploratory Molecular Profiling From the Phase II MITO END-3 Study.}},
author = {Anna Passarelli and Giovanni Luca Scaglione and Daniela Califano and Michele Bartoletti and Domenica Lorusso and Sabrina Chiara Cecere and Anna Fagotti and Alberto Farolfi and Claudia Andreetta and Jole Ventriglia and Laura Arenare and Carmela Pisano and Daniela Russo and Maria Teresa Perri and Saverio Cinieri and Simona Scalone and Ugo De Giorgi and Valentina Arcangeli and Elena Zafarana and Maria Chiara Cannizzaro and Serafina Mammoliti and Tommaso Ambrosio and Rossella De Cecio and Clorinda Schettino and Francesco Perrone and Sandro Pignata},
journal = {JCO precision oncology},
year = {2026},
month = oct,
doi = {10.1200/po-26-00484},
url = {https://europepmc.org/article/MED/42886889},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - PIK3CA Mutations in Advanced or Recurrent Endometrial Cancer: An Exploratory Molecular Profiling From the Phase II MITO END-3 Study.
AU - Anna Passarelli
AU - Giovanni Luca Scaglione
AU - Daniela Califano
AU - Michele Bartoletti
AU - Domenica Lorusso
AU - Sabrina Chiara Cecere
AU - Anna Fagotti
AU - Alberto Farolfi
AU - Claudia Andreetta
AU - Jole Ventriglia
AU - Laura Arenare
AU - Carmela Pisano
AU - Daniela Russo
AU - Maria Teresa Perri
AU - Saverio Cinieri
AU - Simona Scalone
AU - Ugo De Giorgi
AU - Valentina Arcangeli
AU - Elena Zafarana
AU - Maria Chiara Cannizzaro
AU - Serafina Mammoliti
AU - Tommaso Ambrosio
AU - Rossella De Cecio
AU - Clorinda Schettino
AU - Francesco Perrone
AU - Sandro Pignata
PY - 2026
DA - 2026/10/16
JO - JCO precision oncology
DO - 10.1200/po-26-00484
UR - https://europepmc.org/article/MED/42886889
AB - Purpose 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 postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target.Patients and methods In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on PIK3CA mutational status.Results In our analysis, the four most frequently mutated genes were TP53, PIK3CA, ARID1A, and PTEN. PIK3CA mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different PIK3CA mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent PIK3CA mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all The Cancer Genome Atlas 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.
SN - 2473-4284
ER -