16IN - New targeted agents in luminal BC

Date 30 September 2012
Event ESMO Congress 2012
Session Optimizing treatment in luminal breast cancer
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer, Early Stage
Presenter José Baselga
Authors J. Baselga
  • Massachusetts General Hospital Cancer Center And Harvard Medical School, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston/US

Abstract

In recent years the description of well-defined molecular subtypes of breast cancer, together with the identification of driving genetic alterations and signaling pathways, has led to the clinical development of a number of successful molecular targeted agents. Among them, luminal B breast cancer is emerging as an important subset of ER+ tumors that are less responsive to hormonal therapy. Novel targets under exploration in this group of patients include inhibitors of the PI3K-AKT-mTOR. In this regard, a recently reported phase III study the mTOR inhibitor everolimus and exemestane to exemestane and placebo in 724 patients with HR+ breast cancer refractory to nonsteroidal aromatase inhibitors showed that the combination of everolimus and exemestane resulted in marked improvement in progression-free survival as determined by local investigator assessment (6.9 vs. 2.8 months; hazard ratio [HR], 0.43; P = 1.4 × 10−15) 1.The clinical benefit observed in the combination arm also far exceeds the clinical benefit of single-agent everolimus in a similar population of patients. In addition novel PI3K inhibitors are being tested in patients with breast cancer including PI3K alpha specific agents that have shown activity in patients with breast cancer harboring PI3K mutations. Other approaches include inhibitors against the MEK pathways, as well as receptor tyrosine kinase inhibitors such as the Insulin-like growth factor receptor (IGF-1R) and the fibroblast growth factor receptor (FGFR). The clinical development of these agents will require a change from the current large randomized trials in unselected patient populations to smaller trials in molecular defined tumor types that incorporate tumor biomarker endpoints as well as functional imaging. New challenges include the appearance of resistance either by acquired secondary mutations, or via induction of adaptive activation of compensatory pathways that prevent cell death. It is anticipated that combinatorial approaches, acting on the secondary mutations and/or compensatory pathways, may markedly improve on the effects of targeted agents used alone. 1. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9.

Disclosure

J. Baselga: Consulting activity with Novartis and Genentech