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Evaluation of metabolomic changes during neoadjuvant chemotherapy combined with bevacizumab in breast cancer using MR spectroscopy

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Abstract

Introduction

Metabolomics investigates biochemical processes directly, potentially complementing transcriptomics and proteomics in providing insight into treatment outcome.

Objectives

This study aimed to use magnetic resonance (MR) spectroscopy on breast tumor tissue to explore the effect of neoadjuvant therapy on metabolic profiles, determine metabolic effects of the antiangiogenic drug bevacizumab, and investigate metabolic differences between responders and non-responders.

Methods

Breast tumors from 122 patients were profiled using high resolution magic angle spinning MR spectroscopy. All patients received neoadjuvant chemotherapy, and were randomized to receive bevacizumab or not. Tumors were biopsied prior, during, and after treatment.

Results

Principal component analysis showed clear metabolic changes indicating a decline in glucose consumption and a transition to normal breast adipose tissue as an effect of chemotherapy. Partial least squares-discriminant analysis revealed metabolic differences between pathological minimal residual disease patients and pathological non-responders after treatment (accuracy of 77%, p < 0.001), but not before or during treatment. Lower glucose and higher lactate was observed in patients exhibiting a good response (≥90% tumor reduction) compared to those with no response (≤10% tumor reduction) before treatment, while the opposite was observed after treatment. Bevacizumab-receiving and chemotherapy-only patients could not be discriminated at any time point. Linear mixed-effects models revealed a significant interaction between time and bevacizumab for glutathione, indicating higher levels of this antioxidant in chemotherapy-only patients than in bevacizumab receivers after treatment.

Conclusion

MR spectroscopy showed potential in detecting metabolic response to treatment and complementing other molecular assays for the elucidation of underlying mechanisms affecting pathological response.

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Abbreviations

Ala:

Alanine

Asc:

Ascorbate

ATP:

Adenosine triphosphate

Cho:

Choline

Cr:

Creatine

CV:

Cross validation

ER:

Estrogen receptor

FDR:

False discovery rate

FEC:

5-Fluorouracil-epirubicin-cyclophosphamide

Glc:

Glucose

Glu:

Glutamate

Gly:

Glycine

GPC:

Glycerophosphocholine

GR:

Good response

GSH:

Glutathione

HER2:

Human epidermal growth factor receptor 2

HIF:

Hypoxia-inducible factor

HR MAS MRS:

High resolution magic angle spinning magnetic resonance spectroscopy

IL-8:

Interleukin 8

IR:

Intermediate response

Lac:

Lactate

LMM:

Linear mixed-effects model

LV:

Latent variable

MICE:

Multiple imputation by chained equations

MR:

Magnetic resonance

MRI:

Magnetic resonance imaging

NR:

No response

OPLS:

Orthogonal partial least squares

OS:

Overall survival

PAM50:

Prediction analysis of microarrays 50

PC:

Principal component

PCA:

Principal component analysis

PCh:

Phosphocholine

pCR:

Pathological complete response

PFS:

Progression-free survival

PLS-DA:

Partial least squares-discriminant analysis

pMRD:

Pathological minimal residual disease

pNR:

Pathological non-responder

PQN:

Probabilistic quotient normalization

q–q:

Quantile–quantile

RMSE:

Root mean square error

ROS:

Reactive oxygen species

R2 :

Coefficient of determination

SDH:

Succinate dehydrogenase

Succ:

Succinate

Tau:

Taurine

TCA:

Tricarboxylic acid

TP:

Time point

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors would like to thank Øyvind Salvesen for useful discussions regarding linear mixed-effects models and Santosh Lamichhane for technical support during HR MAS MRS acquisition. The HR MAS MRS analysis was performed at the MR Core Facility, Norwegian University of Science and Technology (NTNU), which is funded by the Faculty of Medicine and Health Sciences at NTNU and the Central Norway Regional Health Authority. The study was funded in part by generous grants from: (1) The Research Council of Norway, Imaging the breast cancer metabolome, Project no 221879, (2) The Pink Ribbon Movement and Norwegian Breast Cancer Society, (3) K. G. Jebsen Center for Breast Cancer Research, (4) Roche Norway, (5) Sanofi-Aventis Norway. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests

The NeoAva study was co-sponsored by Roche Norway and Sanofi-Aventis Norway. Oslo University Hospital is the main sponsor for the NeoAva study.

Authors' contributions

LRE, THH, GFG, RV, JE, LSP, GP, LMCB, ALBD, OE, and TFB participated in the design of the study. ALBD, OE, and TFB conceived the study. LRE, THH, GFG, RV, JE, GP, LMCB, ALBD, OE, and TFB interpreted the data. LRE performed the HR MAS MRS acquisition, statistical analysis, and drafted the manuscript. LSP, SL, EB, OG, ALBD, OE, and TFB participated in acquisition of the data. All authors have read and helped to revise the manuscript. The final manuscript is approved by all the authors.

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Authors and Affiliations

  1. Department of Circulation and Medical Imaging - MR Center, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Postboks 8905, Medisinsk Teknisk Forskningssenter, 7491, Trondheim, Norway

    Leslie R. Euceda, Tonje H. Haukaas, Guro F. Giskeødegård, Riyas Vettukattil & Tone F. Bathen

  2. K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Tonje H. Haukaas, Laxmi Silwal-Pandit, Elin Borgen, Øystein Garred, Anne-Lise Børresen-Dale, Olav Engebraaten & Tone F. Bathen

  3. St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    Guro F. Giskeødegård

  4. NERC Biomolecular Analysis Facility Metabolomics Node (NBAF-B), School of Biosciences, University of Birmingham, Birmingham, UK

    Jasper Engel

  5. Department of Cancer Genetics, Oslo University Hospital, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

    Laxmi Silwal-Pandit & Anne-Lise Børresen-Dale

  6. Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway

    Steinar Lundgren

  7. Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    Steinar Lundgren

  8. Department of Pathology, Division of Diagnostics and Intervention, Oslo University Hospital, Oslo, Norway

    Elin Borgen & Øystein Garred

  9. Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands

    Geert Postma & Lutgarde M. C. Buydens

  10. Departments of Oncology and Tumor Biology, Oslo University Hospital, Oslo, Norway

    Olav Engebraaten

  11. Department of Clinical Medicine, University of Oslo, Oslo, Norway

    Olav Engebraaten

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  1. Leslie R. Euceda
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Correspondence to Leslie R. Euceda.

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The study was approved for all centers involved by the Regional Ethics Committee (Approval number S-08354a) and the Norwegian Medical Agency.

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All procedures performed in studies involving human participants were in accordance with the Declaration of Helsinki, International Conference on Harmony/Good Clinical practice.

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Euceda, L.R., Haukaas, T.H., Giskeødegård, G.F. et al. Evaluation of metabolomic changes during neoadjuvant chemotherapy combined with bevacizumab in breast cancer using MR spectroscopy. Metabolomics 13, 37 (2017). https://doi.org/10.1007/s11306-017-1168-0

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