Targeting the PI3-kinase pathway in triple-negative breast cancer

Ann Oncol. 2019 Jul 1;30(7):1051-1060. doi: 10.1093/annonc/mdz133.

Abstract

Triple-negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the phosphoinositide 3 (PI3)-kinase and AKT signalling pathway is one of the most frequent oncogenic aberrations of TNBC. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in phosphatase and tensin homologue, occur in ∼25%‒30% of advanced TNBC. Recent randomised trials suggest improved progression-free survival (PFS) with AKT-inhibitors in combination with first-line chemotherapy for patients with TNBC and pathway genetic aberrations. We review the evidence for PI3K pathway activation in TNBC, and clinical trial data for PI3K, AKT and mammalian target of rapamycin inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.

Keywords: AKT; PI3K; PTEN; predictive biomarkers; targeted therapy; triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / chemistry
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Female
  • Humans
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Signal Transduction / drug effects
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / enzymology*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Protein Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human