Navigating the complexity of PI3K/AKT pathway in HER-2 negative breast cancer: biomarkers and beyond

Crit Rev Oncol Hematol. 2024 Aug:200:104404. doi: 10.1016/j.critrevonc.2024.104404. Epub 2024 May 28.

Abstract

The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, 18 F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.

Keywords: Breast cancer; Companion diagnostic; Genomic assays; Predictive biomarker; Targeted therapies.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor* / genetics
  • Biomarkers, Tumor* / metabolism
  • Breast Neoplasms* / diagnosis
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Female
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors / therapeutic use
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Receptor, ErbB-2* / genetics
  • Receptor, ErbB-2* / metabolism
  • Signal Transduction / drug effects

Substances

  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Biomarkers, Tumor
  • ERBB2 protein, human
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • Antineoplastic Agents