20IN - Development of new targeted agents for TNBC

Date 30 September 2012
Event ESMO Congress 2012
Session How to integrate new drugs in the current therapeutic landscape of metastatic triple negative breast cancer
Topics Drug Development
Breast Cancer, Metastatic
Presenter Nicholas Turner
Authors N. Turner
  • Breast Unit, Institute of Cancer Research, London/UK

Abstract

Triple negative breast cancers are a highly diverse and heterogenous group of tumours. A number of different approaches to tackling this heterogeneity are emerging for the targeted treatment of TNBC. Targeting common genetic events of TNBCs. TNBCs have a high frequency of TP53 mutations in ∼60% of TNBC, a rate substantially higher than other breast cancer subtypes. Targeting TP53 inactivation has historically been challenging, although preclinical data suggests that combinations of DNA damaging chemotherapy with CHK1 or WEE1 inhibitors has the potential to target TP53 deficiency. Other common targetable events include genetic activation of the PI3 kinase pathway in ∼15-20% cancers, through PTEN deletions/ inactivating mutations and PIK3CA activating mutations, and loss of HR based DNA repair, though mutation of BRCA1/2 and BRCA1 promoter methylation, that could be targeted with PARP inhibitors. A further potentially targetable common event includes loss of the phosphatase PTPN12 and upregulation of specific receptor tyrosine kinases. Targeting TNBC subtype specific features. Gene expression studies have revealed multiple different gene expression subtypes in TNBC. The luminal AR subtype expresses the androgen receptor (AR) and now both preclinical and tentative clinical data to support AR as a therapeutic target. Mesenchymal-like basal TNBC express autocrine FGF2 ligand that is important for their biology.

Targeting individual rare events. A diverse set of potentially targetable oncogenic mutations and amplifications occur in TNBC that are likely important therapeutic targets for individual cancers, but these present a substantial challenge to drug development due to their individual rarity. Through such strategies to sub-segment TNBC progress will be made in delivering targeted therapies for TNBC.

Disclosure

N. Turner: Dr Nicholas Turner has received honoraria from Novartis, Astra Zeneca, Roche, Clovis, EOS