NMR investigation of targeted therapy effects on the host metabolism for HER-2 positive breast cancer

Elodie Jobard (1, 2) , Thomas Bachelot (3, 4) , Mario Campone (5) , Olivier Trédan (4) , Bénédicte Elena-Herrmann (1)

1 ISA NMR Methods for Metabolism - Methodes RMN en métabolomique (2014-2018)
2 Dept Rech Translat & Innovat
3 Oncogénèse et progression tumorale
4 Département de Médecine Nucléaire
5 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers

Many advances in recent years, such as the use of targeted therapies, have enabled to improve the management of cancer patients. Understanding the effect of targeted therapies on the human metabolism is essential to predict the response to treatments and adjust personalized therapy. mTOR is an attractive target for cancer’s therapeutic intervention because of its key role in the regulation of protein translation, 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. We detail the metabolic signatures associated with the response to an HER-2 inhibitor standard treatment (trastuzumab), or a combined HER-2 and mTOR (everolimus) inhibitors therapy. Pre-treatment, on-treatment and post-treatment serum samples were available for 79 patients with HER-2 positive breast cancer from the French multicentre, randomized phase II trial RADHER. Fasting patients were randomized between two treatments: trastuzumab (group A) and a trastuzumab and everolimus combination (experimental group B). For each patient, clinicopathological data were recorded. 340 serum metabolic profiles were obtained using 1H NMR spectroscopy (800MHz). Statistical multivariate methods were exploited to build models for sample classification and extract group-specific metabolic signatures. ANOVA analysis and multiple testing corrections of the p-values were used to derive statistically significant associations of individual metabolites. The longitudinal series of serum samples available for each patient was exploited to investigate the effect of the combination B on the patient’s metabolism over time and to compare it with the standard reference treatment A. For each arm, serum metabolic profiles are compared before, over and after treatment. Similarly, the fingerprints are compared between treatments. Clear and significant O-PLS discrimination is observed only for the arm B between metabolic profiles at baseline and after one week of treatment (N: 57, R2Y = 0.404, Q2 = 0.199), after four weeks of treatment (N: 54, R2Y = 0.603, Q2 = 0.301), one week after the end of treatment (N: 53, R2Y = 0.734, Q2 = 0.569), three weeks after the end of treatment (N =51, R2Y = 0.767, Q2 = 0.493). The trastuzumab and everolimus combination causes faster changes in patient metabolism than standard treatment and a residual effect is also observed several weeks after ending of the treatment (up to 3 weeks). Analysis of metabolic fingerprints highlights the involvement of several metabolic pathways reflecting a systemic effect, particularly on the liver and visceral fat. Furthermore, comparison of the metabolic profiles between the two arms (either four or seven weeks after the beginning of the treatment) shows that everolimus, an mTOR inhibitor, is responsible for the host metabolism modification observed in the experimental arm

Mots clés: serum; breast cancer; RMN; targeted therapies; mTOR inhibitor

Domaines: Chimie analytique

Elodie Jobard, Thomas Bachelot, Mario Campone, Olivier Trédan, Bénédicte Elena-Herrmann. NMR investigation of targeted therapy effects on the host metabolism for HER-2 positive breast cancer. 10èmes Journées Scientifiques du Réseau Francophone de Métabolomique et Fluxomique , RFMF - Réseau Francophone de Métabolomique et Fluxomique May 2016, Montpellier, France. ⟨hal-01575749⟩