Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is an attractive target for HER-2 positive breast cancer therapy because of its key role in protein translation regulation, cell growth and metabolism. We present here a metabolomic investigation exploring the impact of mTOR inhibition on serum metabolic profiles from patients with non-metastatic breast cancer overexpressing HER-2.Baseline, treatment-related and post-treatment serum samples were analyzed for 79 patients participating in the French clinical trial RADHER, in which randomized patients with HER-2 positive breast cancer received either trastuzumab alone (arm T) or a trastuzumab and everolimus combination (arm T+E). Longitudinal series of NMR serum metabolic profiles were exploited to investigate treatment effects on the patients metabolism over time, in both group.Trastuzumab and everolimus combination induces faster changes in patients metabolism than trastuzumab alone, visible after only one week of treatment as well as a residual effect detectable up to three weeks after ending the treatment. These metabolic fingerprints highlight the involvement of several metabolic pathways reflecting a systemic effect, particularly on the liver and visceral fat. Comparison of serum metabolic profiles between the two arms shows that everolimus, an mTORC1 inhibitor, is responsible for host metabolism modifications observed in arm T+E.In HER-2 positive breast cancer, our metabolomic approach confirms a fast and persistent host metabolism modification caused by mTOR inhibition.
Highlights
For about 20-30% of patients with breast cancer, cancer cells overexpress a growth-promoting HER/neu protein on their surface
We present here a metabolomic investigation exploring the impact of mammalian target of rapamycin (mTOR) inhibition on serum metabolic profiles from patients with non-metastatic breast cancer overexpressing HER-2
We present a metabolomic investigation exploring the impact of mTOR inhibition on the serum metabolic profiles of patients with early breast cancer (EBC) overexpressing HER-2
Summary
For about 20-30% of patients with breast cancer, cancer cells overexpress a growth-promoting HER/neu protein on their surface. This cancer, known as HER2 positive breast cancer (HER-2+) is characterized by an aggressive disease progression and poor prognosis [1]. Many advances in recent years, such as the use of targeted therapies, have enabled improvement in the management of HER-2+ breast cancer patients. Administration of trastuzumab, a recombinant monoclonal antibody against HER-2, proved as a truly appropriate treatment for patients with HER-2+ breast cancer and has improved their prognosis. In recent years, several targeted therapies for HER-2+ tumors including pertuzumab, lapatinib and trastuzumab emtansine have been approved for treatment of metastatic HER-2+ breast cancer. Others agents targeting several molecular pathways implicated in trastuzumab resistance have shown encouraging results in advanced HER-2+ disease [1], notably the mammalian target of rapamycin (mTOR) inhibitor everolimus [4,5,6]
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