Skip to main content

Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927)

Abstract

Purpose

Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results.

Methods

We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I–III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0–10).

Results

Among the 249 participants, 139 had BMI < 30 kg/m2 (56%) and 110 had BMI ≥ 30 kg/m2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively).

Conclusions

In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H et al (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366(9484):455–462

    CAS  Article  Google Scholar 

  2. 2.

    Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M et al (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25(5):486–492

    CAS  Article  Google Scholar 

  3. 3.

    Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369(9561):559–570

    CAS  Article  Google Scholar 

  4. 4.

    Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS et al (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365(9453):60–62

    CAS  Article  Google Scholar 

  5. 5.

    Mouridsen HT (2006) Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women. Curr Med Res Opin 22(8):1609–1621

    CAS  Article  Google Scholar 

  6. 6.

    Mao JJ, Stricker C, Bruner D, Xie S, Bowman MA, Farrar JT, Greene BT, DeMichele A (2009) Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors. Cancer 115(16):3631–3639

    CAS  Article  Google Scholar 

  7. 7.

    Presant CA, Bosserman L, Young T, Vakil M, Horns R, Upadhyaya G, Ebrahimi B, Yeon C, Howard F (2007) Aromatase inhibitor-associated arthralgia and/ or bone pain: frequency and characterization in non-clinical trial patients. Clin Breast Cancer 7(10):775–778

    CAS  Article  Google Scholar 

  8. 8.

    Henry NL, Azzouz F, Desta Z, Li L, Nguyen AT, Lemler S, Hayden J, Tarpinian K, Yakim E, Flockhart DA et al (2012) Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol 30(9):936–942

    CAS  Article  Google Scholar 

  9. 9.

    Chim K, Xie SX, Stricker CT, Li QS, Gross R, Farrar JT, DeMichele A, Mao JJ (2013) Joint pain severity predicts premature discontinuation of aromatase inhibitors in breast cancer survivors. BMC Cancer 13:401

    Article  Google Scholar 

  10. 10.

    Crew KD, Greenlee H, Capodice J, Raptis G, Brafman L, Fuentes D, Sierra A, Hershman DL (2007) Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol 25(25):3877–3883

    Article  Google Scholar 

  11. 11.

    Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, Buzdar AU, Group AT (2008) Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 9(9):866–872

    Article  Google Scholar 

  12. 12.

    Mieog JS, Morden JP, Bliss JM, Coombes RC, van de Velde CJ, Committee IESS (2012) Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study. Lancet Oncol 13(4):420–432

    Article  Google Scholar 

  13. 13.

    Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC, Sperling RI (1995) Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 48(11):1379–1390

    CAS  Article  Google Scholar 

  14. 14.

    Goldberg RJ, Katz J (2007) A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129(1–2):210–223

    CAS  Article  Google Scholar 

  15. 15.

    Lustberg MB, Orchard TS, Reinbolt R, Andridge R, Pan X, Belury M, Cole R, Logan A, Layman R, Ramaswamy B et al (2018) Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain. Breast Cancer Res Treat 167(3):709–718

    CAS  Article  Google Scholar 

  16. 16.

    Hershman DL, Unger JM, Crew KD, Awad D, Dakhil SR, Gralow J, Greenlee H, Lew DL, Minasian LM, Till C et al (2015) Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor-induced musculoskeletal pain: SWOG S0927. J Clin Oncol 33(17):1910–1917

    CAS  Article  Google Scholar 

  17. 17.

    Du Bois D, Du Bois EF (1916) A formula to estimate the approximate surface area if height and weight be known. Nutrition 1989 5(5):303–311; discussion 312–303

    Google Scholar 

  18. 18.

    Griffin MR, Yared A, Ray WA (2000) Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 151(5):488–496

    CAS  Article  Google Scholar 

  19. 19.

    Walt R, Katschinski B, Logan R, Ashley J, Langman M (1986) Rising frequency of ulcer perforation in elderly people in the United Kingdom. Lancet 1(8479):489–492

    CAS  Article  Google Scholar 

  20. 20.

    Johnsen SP, Larsson H, Tarone RE, McLaughlin JK, Norgard B, Friis S, Sorensen HT (2005) Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case–control study. Arch Intern Med 165(9):978–984

    CAS  Article  Google Scholar 

  21. 21.

    Irwin ML, Cartmel B, Gross CP, Ercolano E, Li F, Yao X, Fiellin M, Capozza S, Rothbard M, Zhou Y et al (2015) Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol 33(10):1104–1111

    Article  Google Scholar 

  22. 22.

    Crew KD, Capodice JL, Greenlee H, Brafman L, Fuentes D, Awad D, Yann Tsai W, Hershman DL (2010) 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 28(7):1154–1160

    CAS  Article  Google Scholar 

  23. 23.

    Henry NL, Unger JM, Schott AF, Fehrenbacher L, Flynn PJ, Prow DM, Sharer CW, Burton GV, Kuzma CS, Moseley A et al (2018) Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202. J Clin Oncol 36(4):326–332

    Article  Google Scholar 

  24. 24.

    Rastelli AL, Taylor ME, Gao F, Armamento-Villareal R, Jamalabadi-Majidi S, Napoli N, Ellis MJ (2011) Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 129(1):107–116

    CAS  Article  Google Scholar 

  25. 25.

    Wright NC, Riggs GK, Lisse JR, Chen Z, Women’s Health I (2008) Self-reported osteoarthritis, ethnicity, body mass index, and other associated risk factors in postmenopausal women-results from the Women’s Health Initiative. J Am Geriatr Soc 56(9):1736–1743

    Article  Google Scholar 

  26. 26.

    Cimmino MA, Parodi M (2004) Risk factors for osteoarthritis. Semin Arthritis Rheum 34(6):29–34

    Article  Google Scholar 

  27. 27.

    Sowers MR, Karvonen-Gutierrez CA (2010) The evolving role of obesity in knee osteoarthritis. Curr Opin Rheumatol 22(5):533–537

    Article  Google Scholar 

  28. 28.

    Hoegh-Andersen P, Tanko LB, Andersen TL, Lundberg CV, Mo JA, Heegaard AM, Delaisse JM, Christgau S (2004) Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther 6(2):R169–R180

    CAS  Article  Google Scholar 

  29. 29.

    Bauml J, Chen L, Chen J, Boyer J, Kalos M, Li SQ, DeMichele A, Mao JJ (2015) Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia? Breast Cancer Res (BCR) 17:89

    Article  Google Scholar 

  30. 30.

    Hubalek M, Oberguggenberger A, Beer B, Meraner V, Sztankay M, Oberacher H, Schubert B, Wildt L, Seeber B, Giesinger J et al (2014) Does obesity interfere with anastrozole treatment? Positive association between body mass index and anastrozole plasma levels. Clin Breast Cancer 14(4):291–296

    CAS  Article  Google Scholar 

  31. 31.

    Calder PC (2008) Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases. Mol Nutr Food Res 52(8):885–897

    CAS  Article  Google Scholar 

  32. 32.

    Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83(6 Suppl):1505S–1519S

    CAS  Article  Google Scholar 

  33. 33.

    Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J (2006) Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis 189(1):19–30

    CAS  Article  Google Scholar 

  34. 34.

    Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, Geleijnse JM, Rauch B, Ness A, Galan P et al (2018) Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 3(3):225–234

    Article  Google Scholar 

  35. 35.

    Hokanson JE, Austin MA (1996) Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 3(2):213–219

    CAS  Article  Google Scholar 

  36. 36.

    Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM et al (2011) Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123(20):2292–2333

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by BCRF, NCI, and SWOG.

Funding

This study was funded by the Breast Cancer Research Foundation; National Cancer Institute, Division of Cancer Prevention, NCORP Research Base grant 1UG1CA189974-01.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Dawn L. Hershman.

Ethics declarations

Conflict of interest

The authors declare that they have 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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 33 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shen, S., Unger, J.M., Crew, K.D. et al. Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927). Breast Cancer Res Treat 172, 603–610 (2018). https://doi.org/10.1007/s10549-018-4946-0

Download citation

Keywords

  • Breast cancer
  • Omega-3 fatty acids
  • Aromatase inhibitor
  • Obesity
  • Arthralgia