Clinical and Translational Oncology

, Volume 21, Issue 4, pp 489–498 | Cite as

A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: results of a pilot study

  • N. Martínez
  • M. Herrera
  • L. Frías
  • M. Provencio
  • R. Pérez-Carrión
  • V. Díaz
  • Michael MorseEmail author
  • M. C. Crespo
Research Article



Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies.

Experimental design

This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy.


CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events.


The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.


CRP AI-musculoskeletal syndrome Brief pain index 



The authors thank Francesco Visioli, PhD for his advice during study design and management and for his helpful review of the manuscript, and APICES for data collection and statistical analysis.


PhytoMed Medical Foods, S.L. has privately funded this research.

Compliance with ethical standards

Conflict of interest

Martinez N declares that she has no conflict of interest. Herrera M declares that she has no conflict of interest. Frías L declares that she has no conflict of interest. Provencio M declares that he has no conflict of interest. Pérez Carrión R declares that he has no conflict of interest. Díaz V declares that she has no conflict of interest. Morse M owns stock options in Oliventures. Crespo MC declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12094_2018_1950_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 kb)


  1. 1.
    Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738–46.Google Scholar
  2. 2.
    Esserman LJ, Moore DH, Tsing PJ, Chu PW, Yau C, Ozanne E, Chung RE, Tandon VJ, Park JW, Baehner FL, Kreps S, Tutt AN, Gillett CE, Benz CC. Biologic markers determine both the risk and the timing of recurrence in breast cancer. Breast Cancer Res Treat. 2011;129(2):607–16.Google Scholar
  3. 3.
    Gernaat SAM, Ho PJ, Rijnberg N, Emaus MJ, Baak LM, Hartman M, Grobbee DE, Verkooijen HM. Risk of death from cardiovascular disease following breast cancer: a systematic review. Breast Cancer Res Treat. 2017;164(3):537–55.Google Scholar
  4. 4.
    Murphy CC, Bartholomew LK, Carpentier MY, et al. Adherence to adjuvant hormonal therapy among breast cancer patients in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134:459–78.Google Scholar
  5. 5.
    Sestak I, Cuzick J, Sapunar F, et al. Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol. 2008;9:866–72.Google Scholar
  6. 6.
    Crew KD, Greenlee H, Capodice J, et al. Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol. 2007;25:3877–83.Google Scholar
  7. 7.
    Henry NL, Giles JT, Ang D, et al. Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Res Treat. 2008;111:365–72.Google Scholar
  8. 8.
    Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120–8.Google Scholar
  9. 9.
    Chim K, Xie SX, Stricker CT, et al. Joint pain severity predicts premature discontinuation of aromatase inhibitors in breast cancer patients. BMC Cancer. 2013;13:401.Google Scholar
  10. 10.
    Kadakia K, Snyder C, Kidwell K. Patient-reported outcomes and early discontinuation in aromatase inhibitor-treated postmenopausal women with early stage breast cancer. Oncologist. 2016;21(5):539–46.Google Scholar
  11. 11.
    Hershman DL, Shao T, Kushi LH. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126:529–37.Google Scholar
  12. 12.
    Adraskela K, Veisaki E, Koutsilieris M, Philippou A. Physical exercise positively influences breast cancer evolution. Clin Breast Cancer. 2017;17:408–17.Google Scholar
  13. 13.
    Kraschnewski JL, Schmitz KH. Exercise in the prevention and treatment of breast cancer: What clinicians need to tell their patients. Curr Sports Med Rep. 2017;16(4):263–7.Google Scholar
  14. 14.
    Nyrop KA, Callahan LF, Cleveland RJ, Arbeeva LL, Hackney BS, Muss HB. Randomized Controlled Trial of a Home-Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor-Associated Arthralgia in Breast Cancer Patients. Oncologist. 2017;22:1238–49.Google Scholar
  15. 15.
    Pierce JP, Stefanick ML, Flatt SW, Natarajan L, Sternfeld B, Madlensky L, Al-Delaimy WK, Thomson CA, Kealey S, Hajek R, Parker BA, Newman VA, Caan B, Rock CL. Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol. 2007;25(17):2345–51.Google Scholar
  16. 16.
    Hamer J, Warner E. Lifestyle modifications for patients with breast cancer to improve prognosis and optimize overall health. CMAJ. 2017;189(7):E268–74.Google Scholar
  17. 17.
    Irwin ML, McTiernan A, Bernstein L, Gilliland FD, Baumgartner R, Baumgartner K, Ballard-Barbash R. Physical activity levels among breast cancer patients. Med Sci Sports Exerc. 2004;36:1484–91.Google Scholar
  18. 18.
    Chan DS, Bandera EV, Greenwood DC, Norat T. Circulating C-Reactive Protein and Breast Cancer Risk-Systematic Literature Review and Meta-analysis of Prospective Cohort Studies. Cancer Epidemiol Biomarkers Prev. 2015;24(10):1439–49.Google Scholar
  19. 19.
    Suman S, Sharma PK, Rai G, Mishra S, Arora D, Gupta P, Shukla Y. Current perspectives of molecular pathways involved in chronic inflammation-mediated breast cancer. Biochem Biophys Res Commun. 2016;472(3):401–9.Google Scholar
  20. 20.
    Allen MD, Jones LJ. The role of inflammation in progression of breast cancer: Friend or foe? (Review). Int J Oncol. 2015;47(3):797–805.Google Scholar
  21. 21.
    Pecoraro M, Del Pizzo M, Marzocco S, Sorrentino R, Ciccarelli M, Iaccarino G, Pinto A, Popolo A. Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol. 2016;293:44–52.Google Scholar
  22. 22.
    Borrie AE, Kim RB. Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers. Expert Opin Drug Metab Toxicol. 2017;13(2):149–56.Google Scholar
  23. 23.
    Wright F, Hammer M, Paul SM, Aouizerat BE, Kober KM, Conley YP, Cooper BA, Dunn LB, Levine JD. DEramo Melkus G, Miaskowski C. Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy. Cytokine. 2017;91:187–210.Google Scholar
  24. 24.
    DeNardo DG, Coussens LM. Inflammation and breast cancer: Balancing immune response—crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res. 2007;9:212.Google Scholar
  25. 25.
    Asegaonkar SB, Asegaonkar BN, Takalkar UV, Advani S, Thorat AP. C-reactive protein and breast cancer: new insights from old molecule. Int J Breast Cancer. 2015;2015:145647.Google Scholar
  26. 26.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.Google Scholar
  27. 27.
    Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185.Google Scholar
  28. 28.
    Baum J, Chen L, Chen J, et al. Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia? Breast Cancer Res. 2015;17:89.Google Scholar
  29. 29.
    Morales L, Pans S, Paridaens R, et al. Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat. 2007;104:87–91.Google Scholar
  30. 30.
    Dizdar O, Ozcakar L, Malas FU, et al. Sonographic and electrodiagnostic evaluations in patients with aromatase inhibitor-related arthralgia. J Clin Oncol. 2009;27:4955–60.Google Scholar
  31. 31.
    Morales L, Pans S, Verschueren K, Van Calster B, Paridaens R, Westhovens R, Timmerman D, De Smet L, Vergote I, Christiaens MR, Neven P. Prospective Study to Assess Short-Term Intra-Articular and Tenosynovial Changes in the Aromatase Inhibitor-Associated Arthralgia Syndrome. J Clin Oncol. 2008;26:3147–52.Google Scholar
  32. 32.
    Karki R, Man SM, Kanneganti TD. Inflammasomes and Cancer. Cancer Immunol Res. 2017;5(2):94–9.Google Scholar
  33. 33.
    Ridker PM. From C-Reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145–56.Google Scholar
  34. 34.
    Singh TP, Morris DR, Smith S, Moxon JV, Golledge J. Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease. Eur J Vasc Endovasc Surg. 2017;54(2):220–33.Google Scholar
  35. 35.
    Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65(12 Pt 2):S253–9.Google Scholar
  36. 36.
    Mahmoud FA, Rivera NI. The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep. 2002;4:250–5.Google Scholar
  37. 37.
    Pierce BL, Ballard-Barbash R, Bernstein L, et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol. 2009;27(21):3437–44.Google Scholar
  38. 38.
    Allin KH, Nordestgaard BG, Flyger H, et al. Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study. Breast Cancer Res. 2011;13(3):R55.Google Scholar
  39. 39.
    Han Y, Mao F, Wu Y, Fu X, Zhu X, Zhou S, Zhang W, Sun Q, Zhao Y. Prognostic role of C-reactive protein in breast cancer: a systematic review and meta-analysis. Int J Biol Markers. 2011;26(4):209–15.Google Scholar
  40. 40.
    Guo L, Liu S, Zhang S, Chen Q, Zhang M, Quan P, Lu J, Sun X. C-reactive protein and risk of breast cancer: a systematic review and meta-analysis. Sci Rep. 2015;5:10508.Google Scholar
  41. 41.
    Kapoor D, Trikha D, Vijayvergiya R, Kaul D, Dhawan V. Conventional therapies fail to target inflammation and immune imbalance in subjects with stable coronary artery disease: a system-based approach. Atherosclerosis. 2014;237(2):623–31.Google Scholar
  42. 42.
    van den Brandt PA, Schulpen M. Mediterranean diet adherence and risk of postmenopausal breast cancer: results of a cohort study and meta-analysis. Int J Cancer. 2017;140(10):2220–31.Google Scholar
  43. 43.
    Psaltopoulou T, Kosti RI, Haidopoulos D, Dimopoulos M, Panagiotakos DB. Olive oil intake is inversely related to cancer prevalence: a systematic review and a meta-analysis of 13,800 patients and 23,340 controls in 19 observational studies. Lipids Health Dis. 2011;10:127.Google Scholar
  44. 44.
    Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA. Martínez-González MA; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279–90.Google Scholar
  45. 45.
    Casas R, Sacanella E, Urpí-Sardà M, Corella D, Castañer O, Lamuela-Raventos RM, Salas-Salvadó J, Martínez-González MA, Ros E, Estruch R. Long-Term Immunomodulatory Effects of a Mediterranean Diet in Adults at High Risk of Cardiovascular Disease in the PREvención con DIeta MEDiterránea (PREDIMED)Randomized Controlled Trial. J Nutr. 2016;146(9):1684–93.Google Scholar
  46. 46.
    Braakhuis AJ, Campion P, Bishop KS. Reducing breast cancer recurrence: the role of dietary polyphenolics. Nutrients. 2016;8:547. Scholar
  47. 47.
    Rigacci S, Stefani M. Nutraceutical properties of olive oil polyphenols. an itinerary from cultured cells through animal models to humans. Int J Mol Sci. 2016;17:843. Scholar
  48. 48.
    Rafehi H, Ververis K, Karagiannis TC. Mechanisms of action of phenolic compounds in olive. J Diet Suppl. 2012;9(2):96–109.Google Scholar
  49. 49.
    Liu YN, Jung JH, Park H, Kim H. Olive leaf extract suppresses messenger RNA expression of proinflammatory cytokines and enhances insulin receptor substrate 1 expression in the rats with streptozotocin and high-fat diet-induced diabetes. Nutr Res. 2014;34(5):450–7.Google Scholar
  50. 50.
    Boss A, Kao CH, Murray PM, Marlow G, Barnett MP, Ferguson LR. Human intervention study to assess the effects of supplementation with olive leaf extract on peripheral blood mononuclear cell gene expression. Int J Mol Sci. 2016;17(12):E2019.Google Scholar
  51. 51.
    Facchini A, Cetrullo S, D’Adamo S, Guidotti S, Minguzzi M, Facchini A, Borzì RM, Flamigni F. Hydroxytyrosol prevents increase of osteoarthritis markers in human chondrocytes treated with hydrogen peroxide or growth-related oncogene α. PLoS One. 2014;9(10):e109724.Google Scholar
  52. 52.
    Fabian CJ, Kimler BF, Hursting SD. Omega-3 fatty acids for breast cancer prevention and patientship. Breast Cancer Res. 2015;4(17):62.Google Scholar
  53. 53.
    Fadus MC, Lau C, Bikhchandani J, Lynch HT. Curcumin: an age-old anti-inflammatory and anti-neoplastic agent. J Tradit Complement Med. 2016;7(3):339–46.Google Scholar
  54. 54.
    Molfino A, Amabile MI, Monti M, Arcieri S, Rossi Fanelli F, Muscaritoli M. The role of docosahexaenoic acid (DHA) in the control of obesity and metabolic derangements in breast cancer. Int J Mol Sci. 2016;17(4):505.Google Scholar
  55. 55.
    de Andrés Ares J, Cruces Prado LM, Canos Verdecho MA, Penide Villanueva L, Del Valle Hoyos M, Herdman M, Traseira Lugilde S, Velázquez Rivera I. Validation of the short form of the brief pain inventory (BPI-SF) in Spanish patients with non-cancer-related pain. Pain Pract. 2015;15(7):643–53.Google Scholar
  56. 56.
    Chang Q, Bournazou E, Sansone P, Berishaj M, Gao SP, Daly L, Wels J, Theilen T, Granitto S, Zhang X, Cotari J, Alpaugh ML, de Stanchina E, Manova K, Li M, Bonafe M, Ceccarelli C, Taffurelli M, Santini D, Altan-Bonnet G, Kaplan R, Norton L, Nishimoto N, Huszar D, Lyden D, Bromberg J. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013;15(7):848–62.Google Scholar
  57. 57.
    Jiang J, Li K, Wang F, Yang B, Fu Y, Zheng J, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on major eicosanoids: a systematic review and meta-analysis from 18 randomized controlled trials. PLoS One. 2016;11(1):e0147351.Google Scholar
  58. 58.
    Calder PC. Mechanisms of action of (n-3) fatty acids. J Nutr. 2012;142(3):592S–9S.Google Scholar
  59. 59.
    Li K, Huang T, Zheng J, Wu K, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: a meta-analysis. PLoS One. 2014;9(2):e88103.Google Scholar
  60. 60.
    Rangel-Huerta OD, Aguilera CM, Mesa MD, Gil A. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br J Nutr. 2012;107(Suppl 2):S159–70.Google Scholar
  61. 61.
    Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26:1719–25.Google Scholar
  62. 62.
    Visioli F, Bernardini E. Extra virgin olive oil’s polyphenols…) with: “Bernardini E and Visioli F. High quality, good health: the case for olive oil. Eur J Lipid Sci Technol. 2017;119:1500505.Google Scholar
  63. 63.
    Bernini R, Gilardini Montani MS, Merendino N, Romani A, Velotti F. Hydroxytyrosol-derived compounds: a basis for the creation of new pharmacological agents for cancer prevention and therapy. J Med Chem. 2015;58(23):9089–107.Google Scholar
  64. 64.
    Bitler CM, et al. Olive extract supplement decreases pain and improves daily activities in adults with osteoarthritis and decreases plasma homocysteine in those with rheumatoid arthritis. Nutr Res. 2007;27:470–7.Google Scholar
  65. 65.
    Crespo MC, Tomé-Carneiro J, Burgos-Ramos E, Loria Kohen V, Espinosa MI, Herranz J, Visioli F. One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes. Pharmacol Res. 2015;95–96:132–7.Google Scholar
  66. 66.
    Lopez-Huertas E, Fonolla J. Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial. Redox Biol. 2017;11:384–9.Google Scholar
  67. 67.
    Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131–9.Google Scholar
  68. 68.
    Greenlee H, Crew KD. Shao T Phase II study of glucosamine with chondroitin on aromatase inhibitor-associated joint symptoms in women with breast cancer. Support Care Cancer. 2013;21(4):1077–87.Google Scholar
  69. 69.
    Shapiro AC, Adlis SA. Robien K Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). Breast Cancer Res Treat. 2016;155(3):501–12.Google Scholar
  70. 70.
    Hershman DL, Unger JM, Crew KD, et al. Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor-induced musculoskeletal pain: SWOG S0927. J Clin Oncol. 2015;33:1910–7.Google Scholar
  71. 71.
    Kidwell KM, Seewald NJ, Snyder CF. Crossover from one aromatase inhibitor (AI) to another in the exemestane and letrozole pharmacogenetics (ELPh) trial. J Clin Oncol. 2016;34(3_suppl):158.Google Scholar
  72. 72.
    Arem H, Sorkin M, Cartmel B. Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer patients: the hormones and physical exercise (HOPE) study. J Cancer Surviv. 2016;10(4):654–62.Google Scholar
  73. 73.
    Crew KD, Capodice J, Greenlee H, et al. Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early stage breast cancer. J Clin Oncol. 2010;28:1154–60.Google Scholar
  74. 74.
    Henry NL, Unger JM, Schott A. A randomized placebo-controlled phase III study of duloxetine for treatment of aromatase inhibitor (AI)-associated musculoskeletal symptoms in women with early-stage breast cancer: SWOG S1202. In: 39th Breast Cancer Symposium. 2016.Google Scholar
  75. 75.
    Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105–21.Google Scholar
  76. 76.
    Henry NL, Speth K, Lintermans A, Kidwell KM, Carlson R, Hayes DF, Neven P. Associations between patient and anthropometric characteristics and aromatase inhibitor discontinuation. Clin Breast Cancer. 2017;17(5):350–355.e4.Google Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Hospital Universitario Ramón y CajalMadridSpain
  2. 2.Hospital Clínico San CarlosMadridSpain
  3. 3.Hospital Universitario La PazMadridSpain
  4. 4.Hospital Universitario Puerta de HierroMadridSpain
  5. 5.Hospital Universitario QuirónMadridSpain
  6. 6.Hospital Universitario Puerta del MarCádizSpain
  7. 7.IMDEA-Food, CEI UAM + CSICMadridSpain
  8. 8.OliventuresRaleighUSA

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