Everolimus may be the new hope for resistant breast cancer
A new study led by researchers from France and presented at the 5th IMPAKT Breast Cancer Conference in Brussels, Belgium, shows that everolimus can overcome transtuzumab resistant breast cancer. The study however showed no statistically significant difference in clinical response rates in some patients with breast cancer when everolimus was added to trastuzumab. This means that the benefit of the everolimus is due to independent molecular mechanisms other than the researchers thought.
Prof Mario Campona, Principal Investigator at the Institute Cancerologie de l’Ouest in Nantes, France, said that as new targeted drugs are discovered, the challenge is to identify patients who will benefit from these individual agents. Prof Campona added that one of the aims of the study was to discover molecular biomarkers that predict whether a cancer patient will respond to combination treatment everolimus-transtuzumab compared to transtuzumab alone.
Transtuzumab, a monoclonal antibody directed against HER2/ neu receptor, is used to treat primary breast cancer, but there are ongoing studies to verify the effectiveness of this drug in the treatment of other cancers. Clinical trials conducted so far have shown that transtuzumab prolongs survival of patients with advanced breast cancer; in early stages it appears to decrease the risk of tumor recurrence after surgery. Although treatment response is good at first, many patients go on to develop resistance.
However, preclinical studies have shown that everolimus can overcome resistance to trastuzumab, which is a major benefit. Everolimus is an oral inhibitor of mTOR, that is mammalian target of rapamycin. The way everolimus overcomes resistance to transtuzumab is not yet fully understood. Prof Campona explained that resistance can occur due to molecular alterations that appear at different levels in the PI3K/Akt pathway. mTOR inhibits a major effector in this pathway, therefore it can restore sensitivity to transtuzumab. In preclinical trials it was demonstrated that everolimus can overcome resistance to transtuzumab caused by upregulation of IGF-1R expression, an alternative pathway that leads to tumor growth and proliferation. The clinical response rate was 35% in patients who received only transtuzumab and 45% in patients who received transtuzumab and everolimus.
Researchers also wanted to find biomarkers that predict which patients respond to combined treatment transtuzumab-everolimus. But of the 7 biomarkers identified, none was able to predict which patients will benefit from the combination of the two drugs. “It appears the combination of everolimus and trastuzumab is effective independently of the activation of the PI3K/AKT/mTOR pathway and without any anti-proliferative and pro-apoptotic effect”, Porf Campona explained.