Comparing docosahexaenoic acid (DHA) concomitant with neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in the treatment of breast cancer (DHA WIN): protocol of a double-blind, phase II, randomised controlled trial

Marnie Newell, John R Mackey, Gilbert Bigras, Mirey Alvarez-Camacho, Susan Goruk, Sunita Ghosh, Alison Schmidt, Deborah Miede, Ann Chisotti, Lynne Postovit, Kristi Baker, Vera Mazurak, Kerry Courneya, Richard Berendt, Wei-Feng Dong, George Wood, Sanraj K Basi, Anil Abraham Joy, Karen King, Judith Meza-Junco, Xiaofu Zhu, Catherine Field, Marnie Newell, John R Mackey, Gilbert Bigras, Mirey Alvarez-Camacho, Susan Goruk, Sunita Ghosh, Alison Schmidt, Deborah Miede, Ann Chisotti, Lynne Postovit, Kristi Baker, Vera Mazurak, Kerry Courneya, Richard Berendt, Wei-Feng Dong, George Wood, Sanraj K Basi, Anil Abraham Joy, Karen King, Judith Meza-Junco, Xiaofu Zhu, Catherine Field

Abstract

Introduction: Neoadjuvant chemotherapy for breast cancer treatment is prescribed to facilitate surgery and provide confirmation of drug-sensitive disease, and the achievement of pathological complete response (pCR) predicts improved long-term outcomes. Docosahexaenoic acid (DHA) has been shown to reduce tumour growth in preclinical models when combined with chemotherapy and is known to beneficially modulate systemic immune function. The purpose of this trial is to investigate the benefit of DHA supplementation in combination with neoadjuvant chemotherapy in patients with breast cancer.

Methods and analysis: This is a double-blind, phase II, randomised controlled trial of 52 women prescribed neoadjuvant chemotherapy to test if DHA supplementation enhances chemotherapy efficacy. The DHA supplementation group will take 4.4 g/day DHA orally, and the placebo group will take an equal fat supplement of vegetable oil. The primary outcome will be change in Ki67 labelling index from prechemotherapy core needle biopsy to definitive surgical specimen. The secondary endpoints include assessment of (1) DHA plasma phospholipid content; (2) systemic immune cell types, plasma cytokines and inflammatory markers; (3) tumour markers for apoptosis and tumour infiltrating lymphocytes; (4) rate of pCR in breast and in axillary nodes; (5) frequency of grade 3 and 4 chemotherapy-associated toxicities; and (6) patient-perceived quality of life. The trial has 81% power to detect a significant between-group difference in Ki67 index with a two-sided t-test of less than 0.0497, and accounts for 10% dropout rate.

Ethics and dissemination: This study has full approval from the Health Research Ethics Board of Alberta - Cancer Committee (Protocol #: HREBA.CC-18-0381). We expect to present the findings of this study to the scientific community in peer-reviewed journals and at conferences. The results of this study will provide evidence for supplementing with DHA during neoadjuvant chemotherapy treatment for breast cancer.

Trial registration number: NCT03831178.

Keywords: Ki67; apoptosis; fatty acids; immune function; omega-3; phospholipids; proliferation.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart of trial design with endpoints and proposed experimental analyses. DHA, docosahexaenoic acid; IHC, immunohistochemistry.
Figure 2
Figure 2
SPIRIT patient flow diagram of the“Docosahexaenoic acid (DHA) for Women with Breast Cancer in the Neoadjuvant Setting” (DHA WIN) trial. DHA, docosahexaenoic acid; SPIRIT, Standard Protocol Items: Recommendations for Interventional Trials.

References

    1. World Health Organization Cancer. Available:
    1. Mamounas EP, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol 2001;28:389–99. 10.1016/S0093-7754(01)90132-0
    1. Teshome M, Hunt KK. Neoadjuvant therapy in the treatment of breast cancer. Surg Oncol Clin N Am 2014;23:505–23. 10.1016/j.soc.2014.03.006
    1. Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to palmitic, palmitoleic, stearic and oleic acids in men and women. Prostaglandins Leukot Essent Fatty Acids 2003;69:283–90. 10.1016/S0952-3278(03)00111-X
    1. Calder PC. Docosahexaenoic acid. Ann Nutr Metab 2016;69:8–21. 10.1159/000448262
    1. Plourde M, Chouinard-Watkins R, Vandal M, et al. . Plasma incorporation, apparent retroconversion and β-oxidation of 13C-docosahexaenoic acid in the elderly. Nutr Metab 2011;8 10.1186/1743-7075-8-5
    1. Chapkin RS, McMurray DN, Davidson LA, et al. . Bioactive dietary long-chain fatty acids: emerging mechanisms of action. Br J Nutr 2008;100:1152–7. 10.1017/S0007114508992576
    1. Schley PD, Brindley DN, Field CJ. (n-3) PUFA alter raft lipid composition and decrease epidermal growth factor receptor levels in lipid rafts of human breast cancer cells. J Nutr 2007;137:548–53. 10.1093/jn/137.3.548
    1. Rogers KR, Kikawa KD, Mouradian M, et al. . Docosahexaenoic acid alters epidermal growth factor receptor-related signaling by disrupting its lipid raft association. Carcinogenesis 2010;31:1523–30. 10.1093/carcin/bgq111
    1. Lee EJ, Yun U-J, Koo KH, et al. . Down-Regulation of lipid raft-associated onco-proteins via cholesterol-dependent lipid raft internalization in docosahexaenoic acid-induced apoptosis. Biochim Biophys Acta 2014;1841:190–203. 10.1016/j.bbalip.2013.10.006
    1. Ewaschuk JB, Newell M, Field CJ. Docosahexanoic acid improves chemotherapy efficacy by inducing CD95 translocation to lipid rafts in ER(-) breast cancer cells. Lipids 2012;47:1019–30. 10.1007/s11745-012-3717-7
    1. Newell M, Brun M, Field CJ. Treatment with DHA modifies the response of MDA-MB-231 breast cancer cells and tumors from nu/nu mice to doxorubicin through apoptosis and cell cycle arrest. J Nutr 2019;149:46–56. 10.1093/jn/nxy224
    1. Kang KS, Wang P, Yamabe N, et al. . Docosahexaenoic acid induces apoptosis in MCF-7 cells in vitro and in vivo via reactive oxygen species formation and caspase 8 activation. PLoS One 2010;5:e10296 10.1371/journal.pone.0010296
    1. Schley PD, Jijon HB, Robinson LE, et al. . Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 2005;92:187–95. 10.1007/s10549-005-2415-z
    1. Ghosh-Choudhury T, Mandal CC, Woodruff K, et al. . Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res Treat 2009;118:213–28. 10.1007/s10549-008-0227-7
    1. Manni A, Richie JP, Xu H, et al. . Influence of omega-3 fatty acids on tamoxifen-induced suppression of rat mammary carcinogenesis. Int J Cancer 2014;134:1549–57. 10.1002/ijc.28490
    1. Mason JK, Klaire S, Kharotia S, et al. . α-linolenic acid and docosahexaenoic acid, alone and combined with trastuzumab, reduce HER2-overexpressing breast cancer cell growth but differentially regulate HER2 signaling pathways. Lipids Health Dis 2015;14:91 10.1186/s12944-015-0090-6
    1. Chauvin L, Goupille C, Blanc C, et al. . Long chain n-3 polyunsaturated fatty acids increase the efficacy of docetaxel in mammary cancer cells by downregulating Akt and PKCε/δ-induced ERK pathways. Biochim Biophys Acta 2016;1861:380–90. 10.1016/j.bbalip.2016.01.012
    1. Barascu A, Besson P, Le Floch O, et al. . Cdk1-Cyclin B1 mediates the inhibition of proliferation induced by omega-3 fatty acids in MDA-MB-231 breast cancer cells. Int J Biochem Cell Biol 2006;38:196–208. 10.1016/j.biocel.2005.08.015
    1. Yee LD, Lester JL, Cole RM, et al. . Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition. Am J Clin Nutr 2010;91:1185–94. 10.3945/ajcn.2009.29036
    1. Bougnoux P, Germain E, Chajès V, et al. . Cytotoxic drugs efficacy correlates with adipose tissue docosahexaenoic acid level in locally advanced breast carcinoma. Br J Cancer 1999;79:1765–9. 10.1038/sj.bjc.6690281
    1. Bougnoux P, Hajjaji N, Ferrasson MN, et al. . Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer 2009;101:1978–85. 10.1038/sj.bjc.6605441
    1. Morland SL, Martins KJB, Mazurak VC. N-3 polyunsaturated fatty acid supplementation during cancer chemotherapy. J Nutr Intermed Metab 2016;5:107–16. 10.1016/j.jnim.2016.05.001
    1. Dowsett M, Nielsen TO, A'Hern R, et al. . Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in breast cancer Working group. J Natl Cancer Inst 2011;103:1656–64. 10.1093/jnci/djr393
    1. Gerdes J, Lemke H, Baisch H, et al. . Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710–5.
    1. Scholzen T, Gerdes J, Thomas S. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000;182:311–22. 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>;2-9
    1. Jones RL, Salter J, A'Hern R, et al. . The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 2009;116:53–68. 10.1007/s10549-008-0081-7
    1. Matsubara N, Mukai H, Fujii S, et al. . Different prognostic significance of Ki-67 change between pre- and post-neoadjuvant chemotherapy in various subtypes of breast cancer. Breast Cancer Res Treat 2013;137:203–12. 10.1007/s10549-012-2344-6
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . Spirit 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7. 10.7326/0003-4819-158-3-201302050-00583
    1. Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. . Spirit 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586 10.1136/bmj.e7586
    1. Arnaout A, Lee J, Gelmon K, et al. . Neoadjuvant therapy for breast cancer: updates and proceedings from the seventh annual meeting of the Canadian Consortium for locally advanced breast cancer. Curr Oncol 2018;25:e490–8. 10.3747/co.25.4153
    1. Roché H, Fumoleau P, Spielmann M, et al. . Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 trial. J Clin Oncol 2006;24:5664–71. 10.1200/JCO.2006.07.3916
    1. Slamon D, Eiermann W, Robert N, et al. . Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273–83. 10.1056/NEJMoa0910383
    1. Johnson GH, Fritsche K. Effect of dietary linoleic acid on markers of inflammation in healthy persons: a systematic review of randomized controlled trials. J Acad Nutr Diet 2012;112:1029–41. 10.1016/j.jand.2012.03.029
    1. Yu Howe-Ming NM, Kalpana S, Weselake Randall J. Bypassing the Δ6‐desaturase enzyme and directly providing n‐3 and n‐6 PUFA pathway intermediates reduces the survival of two human breast cancer cell lines. Eur J Lipid Sci Technol 2015;117:1378–90.
    1. Acs B, Pelekanou V, Bai Y, et al. . Ki67 reproducibility using digital image analysis: an inter-platform and inter-operator study. Lab Invest 2019;99:107–17. 10.1038/s41374-018-0123-7
    1. Bankhead P, Loughrey MB, Fernández JA, et al. . QuPath: open source software for digital pathology image analysis. Sci Rep 2017;7:16878 10.1038/s41598-017-17204-5
    1. Brenna JT, Plourde M, Stark KD, et al. . Best practices for the design, laboratory analysis, and reporting of trials involving fatty acids. Am J Clin Nutr 2018;108:211–27. 10.1093/ajcn/nqy089
    1. Watson PD, Joy PS, Nkonde C, et al. . Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel--versus--aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol 2009;104:1052–4. 10.1016/j.amjcard.2009.05.055
    1. Eritsland J, Arnesen H, Seljeflot I, et al. . Long-Term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul Fibrinolysis 1995;6:17–22. 10.1097/00001721-199502000-00003
    1. Knapp HR, Reilly IA, Alessandrini P, et al. . In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis. N Engl J Med 1986;314:937–42. 10.1056/NEJM198604103141501
    1. Ishibashi H, Suzuki T, Suzuki S, et al. . Sex steroid hormone receptors in human thymoma. J Clin Endocrinol Metab 2003;88:2309–17. 10.1210/jc.2002-021353
    1. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957;226:497–509.
    1. Field CJ, Ryan EA, Thomson AB, et al. . Dietary fat and the diabetic state alter insulin binding and the fatty acyl composition of the adipocyte plasma membrane. Biochem J 1988;253:417–24. 10.1042/bj2530417
    1. Schønberg S, Krokan HE. The inhibitory effect of conjugated dienoic derivatives (CLA) of linoleic acid on the growth of human tumor cell lines is in part due to increased lipid peroxidation. Anticancer Res 1995;15:1241–6.
    1. Field CJ, Van Aerde JE, Robinson LE, et al. . Effect of providing a formula supplemented with long-chain polyunsaturated fatty acids on immunity in full-term neonates. Br J Nutr 2008;99:91–9. 10.1017/S0007114507791845
    1. Field CJ, Thomson CA, Van Aerde JE, et al. . Lower proportion of CD45R0+ cells and deficient interleukin-10 production by formula-fed infants, compared with human-fed, is corrected with supplementation of long-chain polyunsaturated fatty acids. J Pediatr Gastroenterol Nutr 2000;31:291–9. 10.1097/00005176-200009000-00017
    1. Richard C, Wadowski M, Goruk S, et al. . Individuals with obesity and type 2 diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy. BMJ Open Diabetes Res Care 2017;5:e000379 10.1136/bmjdrc-2016-000379
    1. Lewis ED, Goruk S, Richard C, et al. . Feeding a diet devoid of choline to lactating rodents restricts growth and lymphocyte development in offspring. Br J Nutr 2016;116:1001–12. 10.1017/S0007114516002919
    1. Thompson FE, Subar AF, Brown CC, et al. . Cognitive research enhances accuracy of food frequency questionnaire reports: results of an experimental validation study. J Am Diet Assoc 2002;102:212–25. 10.1016/S0002-8223(02)90050-7
    1. Subar AF, Thompson FE, Kipnis V, et al. . Comparative validation of the Block, Willett, and National Cancer Institute food frequency questionnaires : the Eating at America's Table Study. Am J Epidemiol 2001;154:1089–99. 10.1093/aje/154.12.1089
    1. Kipnis V, Subar AF, Midthune D, et al. . Structure of dietary measurement error: results of the open biomarker study. Am J Epidemiol 2003;158:14–21. 10.1093/aje/kwg091
    1. Aaronson NK, Ahmedzai S, Bergman B, et al. . The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76. 10.1093/jnci/85.5.365
    1. Godin G, Shephard RJ. Godin leisure-time exercise questionnaire. Medicine & Science in Sports & Exercise 1997;26:S36–8.
    1. Courneya KS, Friedenreich CM. Utility of the theory of planned behavior for understanding exercise during breast cancer treatment. Psychooncology 1999;8:112–22. 10.1002/(SICI)1099-1611(199903/04)8:2<112::AID-PON341>;2-L

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel