Review

Vol. 117: Issue 6 - December 2025

Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2− metastatic breast cancer

Authors

Umberto Malapelle , Simonetta Buglioni , Isabella Castellano , Carmen Criscitiello , Giuseppe Curigliano , Giulia d’Amati , Carmine De Angelis , Dario de Biase , Francesco Pepe , Giuseppe Perrone , Cristian Scatena , Maria Scatolini , Dario Trapani , Konstantinos Venetis , Nicola Fusco

Key words: next-generation sequencing, PI3K pathway, metastatic breast cancer, somatic mutation
DOI: 10.32074/1591-951X-1531
Publication Date: 2026-02-06

Abstract

Alterations in the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway are a well-recognized mechanism of resistance in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC). These alterations are present in approximately half of patients with HR+/HER2- mBC. The major alterations in the pathway are somatic mutations in the PIK3CA (40–45%) and AKT1 (5%) genes, and loss-of-function alterations in PTEN (5–10%). New targeted agents that act against these alterations have been developed. Therefore, it is important to determine the mutational status of genes in this pathway to potentially offer a therapeutic alternative for these patients. In this review, we discuss the clinical and biological significance of PI3K pathway alterations in HR+/HER2− mBC, focusing on tumors that progress following endocrine therapy and CDK4/6 inhibitor treatment. We then highlight how different diagnostic strategies, including sample type, testing methodology, and timing, can improve the identification of patients who are eligible for targeted therapies and promote the effective integration of molecular diagnostics into routine clinical care.

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Authors

Umberto Malapelle - Department of Public Health, University Federico II of Naples, Naples, Italy

Simonetta Buglioni - Department of Pathology, IRCCS National Cancer Institute Regina Elena, Rome, Italy

Isabella Castellano - Department of Medical Sciences, University of Turin, Turin, Italy

Carmen Criscitiello - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy

Giuseppe Curigliano - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy

Giulia d’Amati - Department of Radiological, Oncological and Pathological Sciences, Sapienza-University of Rome, Rome, Italy

Carmine De Angelis - Clinical and Translational Oncology, Scuola Superiore Meridionale, Naples, Italy

Dario de Biase - Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy; Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

Francesco Pepe - Department of Public Health, University Federico II of Naples, Naples, Italy

Giuseppe Perrone - Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Department of Medicine, Research Unit of Anatomical Pathology, Università Campus Bio-Medico di Roma, Rome, Italy

Cristian Scatena - Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Department of Oncology, Pisa University Hospital, Pisa, Italy

Maria Scatolini - Molecular Oncology Laboratory, Fondazione Edo ed Elvo Tempia, Ponderano, Biella, Italy

Dario Trapani - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy

Konstantinos Venetis - Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy

Nicola Fusco - Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy

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Copyright

Copyright (c) 2026 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology

How to Cite
Malapelle, U., Buglioni, S., Castellano, I., Criscitiello, C., Curigliano, G., d’Amati, G., De Angelis, C., de Biase, D., Pepe, F., Perrone, G., Scatena, C., Scatolini, M., Trapani, D., Venetis, K., & Fusco, N. (2026). Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2− metastatic breast cancer. Pathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, 117(6). https://doi.org/10.32074/1591-951X-1531
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