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

Triple negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the PI3 kinase and AKT signalling pathway is one of the most frequent oncogenic aberrations of triple negative breast cancer. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in PTEN, occur in approximately 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 PI3 kinase pathway activation in TNBC, and clinical trial data for PI3 kinase, AKT and mTOR inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.

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