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

Umberto Malapelle1, Simonetta Buglioni2, Isabella Castellano3

  • 1Department of Public Health, University Federico II of Naples, Naples, Italy.

Pathologica
|April 9, 2026
PubMed

Insights

Alterations in the PI3K/AKT/PTEN pathway drive resistance in metastatic breast cancer. Identifying these genetic changes offers new targeted therapy options for patients progressing on standard treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT/PTEN pathway is frequently altered in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), contributing to therapeutic resistance.
  • Somatic mutations in PIK3CA (40-45%) and AKT1 (5%), along with PTEN loss-of-function (5-10%), are the primary alterations observed in approximately half of these patients.

Purpose of the Study:

  • To review the clinical and biological significance of PI3K pathway alterations in HR+/HER2- mBC, particularly in tumors resistant to endocrine therapy and CDK4/6 inhibitors.
  • To emphasize the importance of determining the mutational status of PI3K pathway genes for guiding targeted therapy selection.

Main Methods:

  • This review synthesizes current literature on PI3K pathway alterations in HR+/HER2- mBC.
  • It discusses the clinical implications of these alterations and the role of targeted agents.
  • Diagnostic strategies for identifying eligible patients are also examined.

Main Results:

  • PI3K pathway alterations are a key mechanism of resistance in HR+/HER2- mBC, impacting treatment outcomes.
  • New targeted therapies are emerging for patients with specific PI3K pathway alterations.
  • Effective molecular diagnostics are crucial for patient stratification.

Conclusions:

  • Understanding PI3K pathway alterations is vital for managing HR+/HER2- mBC.
  • Accurate and timely molecular testing can identify patients who may benefit from targeted therapies.
  • Integrating molecular diagnostics into clinical care is essential for advancing treatment strategies.
Keywords:
Next-generation sequencingPI3K pathwaymetastatic breast cancersomatic mutation

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