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Metabolite and lipoprotein responses and prediction of weight gain during breast cancer treatment

British Journal of Cancervolume 119pages11441154 (2018) | Download Citation



Breast cancer treatment has metabolic side effects, potentially affecting risk of cardiovascular disease (CVD) and recurrence. We aimed to compare alterations in serum metabolites and lipoproteins during treatment between recipients and non-recipients of chemotherapy, and describe metabolite profiles associated with treatment-related weight gain.


This pilot study includes 60 stage I/II breast cancer patients who underwent surgery and were treated according to national guidelines. Serum sampled pre-surgery and after 6 and 12 months was analysed by MR spectroscopy and mass spectrometry. In all, 170 metabolites and 105 lipoprotein subfractions were quantified.


The metabolite and lipoprotein profiles of chemotherapy recipients and non-recipients changed significantly 6 months after surgery (p < 0.001). Kynurenine, the lipid signal at 1.55–1.60 ppm, ADMA, 2 phosphatidylcholines (PC aa C38:3, PC ae C42:1), alpha-aminoadipic acid, hexoses and sphingolipids were increased in chemotherapy recipients after 6 months. VLDL and small dense LDL increased after 6 months, while HDL decreased, with triglyceride enrichment in HDL and LDL. At baseline, weight gainers had less acylcarnitines, phosphatidylcholines, lyso-phosphatidylcholines and sphingolipids, and showed an inflammatory lipid profile.


Chemotherapy recipients exhibit metabolic changes associated with inflammation, altered immune response and increased risk of CVD. Altered lipid metabolism may predispose for treatment-related weight gain.

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  1. 1.

    Shapiro, C. L. & Recht, A. Side effects of adjuvant treatment of breast cancer. New Engl. J. Med. 344, 1997–2008 (2001).

  2. 2.

    Velasco, R. & Bruna, J. Taxane-induced peripheral neurotoxicity. Toxics 3, 152–169 (2015).

  3. 3.

    Mehta, L. S. et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation 137, e30–e66 (2018).

  4. 4.

    Dieli-Conwright, C. M. et al. An observational study to examine changes in metabolic syndrome components in patients with breast cancer receiving neoadjuvant or adjuvant chemotherapy. Cancer 122, 2646–2653 (2016).

  5. 5.

    Sharma, M. et al. Chemotherapy agents alter plasma lipids in breast cancer patients and show differential effects on lipid metabolism genes in liver cells. PLoS ONE 11, e0148049 (2016).

  6. 6.

    van den Berg, M. M. et al. Weight change during chemotherapy in breast cancer patients: a meta-analysis. BMC Cancer 17, 259 (2017).

  7. 7.

    Bradshaw, P. T. Cardiovascular disease mortality among breast cancer survivors. Epidemiology 27, 6–13 (2016).

  8. 8.

    Cheng, Y. J. et al. Long‐term cardiovascular risk after radiotherapy in women with breast cancer. J. Am. Heart Assoc. 6, pii: e005633 (2017).

  9. 9.

    Schvartsman, G. et al. Association between weight gain during adjuvant chemotherapy for early-stage breast cancer and survival outcomes. Cancer Med. 6, 2515–2522 (2017).

  10. 10.

    Liu, L. N., Lin, Y. C., Miaskowski, C., Chen, S. C. & Chen, M. L. Association between changes in body fat and disease progression after breast cancer surgery is moderated by menopausal status. BMC Cancer 17, 863 (2017).

  11. 11.

    Emaus, A. et al. Metabolic profile, physical activity, and mortality in breast cancer patients. Breast Cancer Res. Treat. 121, 651–660 (2010).

  12. 12.

    Ferroni, P. et al. Pretreatment insulin levels as a prognostic factor for breast cancer progression. Oncologist 21, 1041–1049 (2016).

  13. 13.

    Gadéa, E., Thivat, E., Planchat, E., Morio, B. & Durando, X. Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms. Obes. Rev. 13, 368–380 (2012).

  14. 14.

    Picon-Ruiz, M., Morata-Tarifa, C., Valle-Goffin, J. J., Friedman, E. R. & Slingerland, J. M. Obesity and adverse breast cancer risk and outcome: mechanistic insights and strategies for intervention. CA Cancer J. Clin. 67, 378–397 (2017).

  15. 15.

    Richard, V., Conotte, R., Mayne, D. & Colet, J. M. Does the 1H-NMR plasma metabolome reflect the host-tumor interactions in human breast cancer? Oncotarget 8, 49915–49930 (2017).

  16. 16.

    Jove, M. et al. A plasma metabolomic signature discloses human breast cancer. Oncotarget 8, 19522–19533 (2017).

  17. 17.

    Giskeodegard G. F., et al. NMR-based metabolomics of biofluids in cancer. NMR Biomed. 2018:e3927.

  18. 18.

    Norsk Bryst Cancer Gruppe (NBCG). Nasjonalt handlingsprogram med retningslinjer for diagnostikk, behandling og oppfølging av pasienter med brystkreft (Helsedirektoratet, Oslo, 2016).

  19. 19.

    Keun, H. C. et al. Serum molecular signatures of weight change during early breast cancer chemotherapy. Clin. Cancer Res. 15, 6716–6723 (2009).

  20. 20.

    Bruker. Lipoprotein subclass analysis. Available from:

  21. 21.

    Flote, V. G. et al. Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer. Lipids Health Dis. 15, 56 (2016).

  22. 22.

    Bruker. Study on NMR based lipoprotein subclass analysis. Available from:

  23. 23.

    van Velzen, E. J. J. et al. Multilevel data analysis of a crossover designed Human Nutritional Intervention Study. J. Proteome Res. 7, 4483–4491 (2008).

  24. 24.

    Westerhuis, J. A., van Velzen, E. J., Hoefsloot, H. C. & Smilde, A. K. Multivariate paired data analysis: multilevel PLSDA versus OPLSDA. Metabolomics 6, 119–128 (2010).

  25. 25.

    Chong, I.-G. & Jun, C.-H. Performance of some variable selection methods when multicollinearity is present. Chemom. Intell. Lab Syst. 78, 103–112 (2005).

  26. 26.

    Heng, B. et al. Understanding the role of the kynurenine pathway in human breast cancer immunobiology. Oncotarget 7, 6506–6520 (2016).

  27. 27.

    Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357, pii: eaaf9794 (2017).

  28. 28.

    Yamashita, M. & Yamamoto, T. Tryptophan circuit in fatigue: From blood to brain and cognition. Brain Res. 1675, 116–126 (2017).

  29. 29.

    Vyas, D., Laput, G. & Vyas, A. K. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco. Targets Ther. 7, 1015–1023 (2014).

  30. 30.

    Xia, W., Shao, Y., Wang, Y., Wang, X. & Chi, Y. Asymmetric dimethylarginine and carotid atherosclerosis in type 2 diabetes mellitus. J. Endocrinol. Invest. 35, 824–827 (2012).

  31. 31.

    Hsu, C. P., Lin, S. J., Chung, M. Y. & Lu, T. M. Asymmetric dimethylarginine predicts clinical outcomes in ischemic chronic heart failure. Atherosclerosis 225, 504–510 (2012).

  32. 32.

    Savvidou, M. D. et al. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361, 1511–1517 (2003).

  33. 33.

    van der Zwan, L. P. et al. Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study. Clin. Sci. (Lond). 121, 71–78 (2011).

  34. 34.

    Sibal, L., Agarwal, S. C., Home, P. D. & Boger, R. H. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr. Cardiol. Rev. 6, 82–90 (2010).

  35. 35.

    Li, H. et al. Asymmetric dimethylarginine attenuates serum starvation-induced apoptosis via suppression of the Fas (APO-1/CD95)/JNK (SAPK) pathway. Cell Death Dis. 4, e830 (2013).

  36. 36.

    Alacacioglu, A. et al. Taxane-based adjuvant chemotherapy reduces endothelin-1 and symmetric dimethylarginine levels in patients with breast cancer. J. Buon. 15, 572–576 (2010).

  37. 37.

    Sulicka, J. et al. Elevated asymmetric dimethylarginine in young adult survivors of childhood acute lymphoblastic leukemia: a preliminary report. Dis. Markers 33, 69–76 (2012).

  38. 38.

    Wang, T. J. et al. 2-Aminoadipic acid is a biomarker for diabetes risk. J. Clin. Invest. 123, 4309–4317 (2013).

  39. 39.

    Ozben, T. Oxidative stress and apoptosis: Impact on cancer therapy. J. Pharm. Sci. 96, 2181–2196 (2007).

  40. 40.

    Reaven, P. et al. Feasibility of using an oleate-rich diet to reduce the susceptibility of low-density lipoprotein to oxidative modification in humans. Am. J. Clin. Nutr. 54, 701–706 (1991).

  41. 41.

    Giron-Calle, J., Schmid, P. C. & Schmid, H. H. Effects of oxidative stress on glycerolipid acyl turnover in rat hepatocytes. Lipids 32, 917–923 (1997).

  42. 42.

    Khovidhunkit, W. et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J. Lipid Res. 45, 1169–1196 (2004).

  43. 43.

    Brice, S. E.& Cowart, L. A. in Sphingolipids and Metabolic Disease (ed. Cowart, L.A.) 1–17 (Springer, New York, 2011).

  44. 44.

    Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405–414 (1995).

  45. 45.

    Kitatani, K., Nemoto, M., Akiba, S. & Sato, T. Stimulation by de novo-synthesized ceramide of phospholipase A(2)-dependent cholesterol esterification promoted by the uptake of oxidized low-density lipoprotein in macrophages. Cell. Signal. 14, 695–701 (2002).

  46. 46.

    Coen, P. M. et al. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 59, 80–88 (2010).

  47. 47.

    Morad, S. A. & Cabot, M. C. Ceramide-orchestrated signalling in cancer cells. Nat. Rev. Cancer 13, 51–65 (2013).

  48. 48.

    Chavez, J. A. & Summers, S. A. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 419, 101–109 (2003).

  49. 49.

    Alexopoulos, C. G., Pournaras, S., Vaslamatzis, M., Avgerinos, A. & Raptis, S. Changes in serum lipids and lipoproteins in cancer patients during chemotherapy. Cancer Chemother. Pharmacol. 30, 412–416 (1992).

  50. 50.

    Yeo, W. et al. Dyslipidaemias after adjuvant chemotherapy in young Chinese breast cancer patients. Ann. Oncol. 27(Suppl. 6), 201P (2016).

  51. 51.

    Hoogeveen, R. C. et al. Small dense LDL cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler. Thromb. Vasc. Biol. 34, 1069–1077 (2014).

  52. 52.

    Merz, B. et al. Specific metabolic markers are associated with future waist-gaining phenotype in women. PLoS ONE 11, e0157733 (2016).

  53. 53.

    Meikle, P. J. et al. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS ONE 8, e74341 (2013).

  54. 54.

    Lee, H. S. et al. Beneficial effects of phosphatidylcholine on high-fat diet-induced obesity, hyperlipidemia and fatty liver in mice. Life. Sci. 118, 7–14 (2014).

  55. 55.

    Barber, M. N. et al. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS ONE 7, e41456 (2012).

  56. 56.

    Pickens, C. A., Vazquez, A. I., Jones, A. D. & Fenton, J. I. Obesity, adipokines, and C-peptide are associated with distinct plasma phospholipid profiles in adult males, an untargeted lipidomic approach. Sci. Rep. 7, 6335 (2017).

  57. 57.

    Pietilainen, K. H. et al. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects--a monozygotic twin study. PLoS ONE 2, e218 (2007).

  58. 58.

    Ramsay, R. R., Gandour, R. D. & van der Leij, F. R. Molecular enzymology of carnitine transfer and transport. Biochim. Biophys. Acta 1546, 21–43 (2001).

  59. 59.

    Mihalik, S. J. et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring) 18, 1695–1700 (2010).

  60. 60.

    Sampey, B. P. et al. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS ONE 7, e38812 (2012).

  61. 61.

    Heckmann, B. L. et al. Defective adipose lipolysis and altered global energy metabolism in mice with adipose overexpression of the lipolytic inhibitor G0/G1 switch gene 2 (G0S2). J. Biol. Chem. 289, 1905–1916 (2014).

  62. 62.

    Frankl, J., Piaggi, P., Foley, J. E., Krakoff, J., & Votruba, S. B. In vitro lipolysis is associated with whole-body lipid oxidation and weight gain in humans. Obesity (Silver Spring) 25, 207–214 (2017).

  63. 63.

    Engström, G. et al. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 52, 2097–2101 (2003).

  64. 64.

    Winters-Stone, K. M., Wood, L. J., Stoyles, S. & Dieckmann, N. F. The effects of resistance exercise on biomarkers of breast cancer prognosis: a pooled analysis of three randomized trials. Cancer Epidemiol. Biomarkers Prev. 27, 146–153 (2018).

  65. 65.

    Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

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We acknowledge each woman who participated in this clinical study, and our nurses Ragnhild Tveit, Alexandra Ødegaard and Harriet Børset.

Author information


  1. Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU–Norwegian University of Science and Technology, P.O. Box 8905 MTFS, Trondheim, 7491, Norway

    • Torfinn S. Madssen
    • , Tone F. Bathen
    •  & Guro F. Giskeødegård
  2. Department of Oncology, Oslo University Hospital, Oslo, 0424, Norway

    • Inger Thune
    • , Vidar G. Flote
    • , Hanne Frydenberg
    •  & Erik Wist
  3. Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, 9037, Norway

    • Inger Thune
  4. Department of Oncology, St. Olavs University Hospital, P.O. Box 3250 Sluppen, Trondheim, 7006, Norway

    • Steinar Lundgren
  5. Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU–Norwegian University of Science and Technology, P.O. Box 8905 MTFS, Trondheim, 7491, Norway

    • Steinar Lundgren
    •  & Hans E. Fjøsne
  6. Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU–Norwegian University of Science and Technology, Trondheim, 7491, Norway

    • Gro F. Bertheussen
  7. Department of Physical Medicine and Rehabilitation, St. Olav University Hospital of Trondheim, P.O. Box 3250 Sluppen, Trondheim, 7006, Norway

    • Gro F. Bertheussen
  8. Department of Breast and Endocrine Surgery, Oslo University Hospital, P.O. Box 4953 Nydalen, Oslo, 0424, Norway

    • Ellen Schlichting
  9. Bruker BioSpin GmbH, Application Method Development Group, Silberstreifen, 76287, Rheinstetten, Germany

    • Hartmut Schäfer
  10. Department of Surgery, St. Olavs University Hospital, P.O. Box 3250 Sluppen, Trondheim, 7006, Norway

    • Hans E. Fjøsne
  11. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O Box 1171 Blindern, Oslo, 0318, Norway

    • Riyas Vettukattil
  12. Division of Paediatric and Adolescent Medicine, Oslo University Hospital, P.O. Box 4956 Nydalen, 0424, Oslo, Norway

    • Riyas Vettukattil
  13. Department of Pathology, Oslo University Hospital, P.O. Box 4953 Nydalen, Oslo, 0424, Norway

    • Jon Lømo


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Study concept and design: T.S.M., I.T., V.G.F., S.L., G.F.B., H.F., E.W., E.S., H.E.F., J.L., T.F.B. and G.F.G. Data collection and acquisition: I.T., V.G.F., S.L., G.F.B., H.F., H.S., H.E.F., R.V., T.F.B. and G.F.G. Data analysis and interpretation: T.S.M., I.T., T.F.B. and G.F.G. Manuscript writing: T.S.M., T.F.B. and G.F.G. Manuscript editing: all authors. All authors read and approved the final version of the paper.

Ethics approval and consent to participate:

The study was approved by The Regional Committee for Medical and Health Research Ethics South East (REK 2011/500), and all patients gave informed written consent to participate. The study was performed in accordance with the Declaration of Helsinki.


This work was supported by grants from the South–East Norwegian Health Authority (Grant 2012064), Norwegian Research Council (Grant 213997), Active Against Cancer-Gjensidige Siftelsen (Grant 2012) and the Norwegian Cancer Society (Grant 163243).

Data availability:

The metabolomics data can be made available from the authors upon request.

Competing interests

The authors declare no competing interests.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Guro F. Giskeødegård.

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