High intensity exercise during breast cancer chemotherapy - effects on long-term myocardial damage and physical capacity - data from the OptiTrain RCT

Josefin Ansund, Sara Mijwel, Kate A Bolam, Renske Altena, Yvonne Wengström, Eric Rullman, Helene Rundqvist, Josefin Ansund, Sara Mijwel, Kate A Bolam, Renske Altena, Yvonne Wengström, Eric Rullman, Helene Rundqvist

Abstract

Background: Adjuvant systemic breast cancer treatment improves disease specific outcomes, but also presents with cardiac toxicity. In this post-hoc exploratory analysis of the OptiTrain trial, the effects of exercise on cardiotoxicity were monitored by assessing fitness and biomarkers over the intervention and into survivorship. Methods; Women starting chemotherapy were randomized to 16-weeks of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). Outcome measures included plasma troponin-T (cTnT), Nt-pro-BNP and peak oxygen uptake (VO2peak), assessed at baseline, post-intervention, and at 1- and 2-years.

Results: For this per-protocol analysis, 88 women met criteria for inclusion. Plasma cTnT increased in all groups post-intervention. At the 1-year follow-up, Nt-pro-BNP was lower in the exercise groups compared to UC. At 2-years there was a drop in VO2peak for patients with high cTnT and Nt-pro-BNP. Fewer patients in the RT-HIIT group fulfilled biomarker risk criteria compared to UC (OR 0.200; 95% CI = 0.055-0.734).

Conclusions: In this cohort, high-intensity exercise was associated with lower levels of NT-proBNP 1-year post-baseline, but not with cTnT directly after treatment completion. This may, together with the preserved VO2peak in patients with low levels of biomarkers, indicate a long-term cardioprotective effect of exercise.

Trial registration: Clinicaltrials. govNCT02522260 , Registered 13th of august 2015 - Retrospectively Registered.

Keywords: Biomarkers; Cardiotoxicity; Exercise oncology.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
CONSORT diagram. RT–HIIT resistance and high-intensity interval training, AT–HIIT moderate-intensity aerobic and high-intensity interval training, UC usual care. *Eligibility for inclusion in cardiotoxicity analysis was determined by completion of at least 16 out of 26 supervised training sessions and blood samples from baseline, after chemotherapy, and at the 1-year follow up
Fig. 2
Fig. 2
Plasma biomarkers. Left panel, Plasma levels of cTnT post treatment (16-weeks) per training allocation. RT–HIIT resistance and high-intensity interval training, AT– HIIT moderate-intensity aerobic and high-intensity interval training, UC usual care. Right panel, Plasma Nt-pro-BNP levels between the groups at the 1-year follow up. ANCOVA. Data is presented as scatterplots and mean ± SD, * denotes p < 0.05
Fig. 3
Fig. 3
Levels of Nt-pro-BNP divided into groups of no TnT release, TnT  10. One-way ANOVA Data is presented as scatterplots and mean ± SD, * denotes p < 0.05
Fig. 4
Fig. 4
Number of patients with release of cTnT of > 10 (a) & Nt-pro-BNP > 100 (b) by training allocation. RT–HIIT resistance and high-intensity interval training, AT–HIIT moderate-intensity aerobic and high-intensity interval training, UC usual care. c Number of patients fulfilling biomarker criteria by training allocation. RT–HIIT resistance and high-intensity interval training, AT–HIIT moderate-intensity aerobic and high-intensity interval training, UC usual care. χ2 between group analysis. * denotes p < 0.05
Fig. 5
Fig. 5
Change in VO2peak (expressed as ratio of baseline) between baseline and 1-year (a) and 2-year (b) follow-up respectively, separated by patients fulfilling biomarker criteria and patients not fulfilling the biomarker criteria. Data is presented as scatterplots and mean ± SD, ANCOVA * denotes p < 0.05

References

    1. Bradshaw PT, et al. Cardiovascular disease mortality among breast cancer survivors. Epidemiology. 2016;27:6–13. doi: 10.1097/ede.0000000000000394.
    1. Henry ML, Niu J, Zhang N, Giordano SH, Chavez-MacGregor M. Cardiotoxicity and cardiac monitoring among chemotherapy-treated breast Cancer patients. J Am Coll Cardiol Img. 2018;11:1084–1093. doi: 10.1016/j.jcmg.2018.06.005.
    1. Upshaw, J. N. Cardio-oncology: protecting the heart from curative breast cancer treatment. Gland Surg 7, 350–365, doi:10.21037/gs.2017.11.09 (2018).
    1. Lee Chuy K, Yu AF. Cardiotoxicity of contemporary breast Cancer treatments. Curr Treat Options in Oncol. 2019;20:51. doi: 10.1007/s11864-019-0646-1.
    1. Levis BE, Binkley PF, Shapiro CL. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms? Lancet Oncol. 2017;18:e445–e456. doi: 10.1016/s1470-2045(17)30535-1.
    1. McGowan JV, et al. Anthracycline chemotherapy and Cardiotoxicity. Cardiovasc Drugs Ther. 2017;31:63–75. doi: 10.1007/s10557-016-6711-0.
    1. Volkova M, Russell R., 3rd Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7:214–220. doi: 10.2174/157340311799960645.
    1. Tian S, et al. Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol. 2014;4:277. doi: 10.3389/fonc.2014.00277.
    1. Felker GM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077–1084. doi: 10.1056/nejm200004133421502.
    1. Boekel NB, et al. Cardiovascular disease risk in a large, population-based cohort of breast Cancer survivors. Int J Radiat Oncol Biol Phys. 2016;94:1061–1072. doi: 10.1016/j.ijrobp.2015.11.040.
    1. Cavarretta E, Mastroiacovo G, Lupieri A, Frati G, Peruzzi M. The positive effects of exercise in chemotherapy-related cardiomyopathy. Adv Exp Med Biol. 2017;1000:103–129. doi: 10.1007/978-981-10-4304-8_8.
    1. Lipshultz SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96:2641–2648. doi: 10.1161/01.CIR.96.8.2641.
    1. Malik A, et al. Are biomarkers predictive of Anthracycline-induced cardiac dysfunction? Asian Pac J Cancer Prev. 2016;17:2301–2305. doi: 10.7314/APJCP.2016.17.4.2301.
    1. Cardinale D, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109:2749–2754. doi: 10.1161/.
    1. Kilickap S, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005;16:798–804. doi: 10.1093/annonc/mdi152.
    1. Romano S, et al. Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer. 2011;105:1663–1668. doi: 10.1038/bjc.2011.439.
    1. Payne DL, Nohria A. Prevention of chemotherapy induced cardiomyopathy. Curr Heart Fail Rep. 2017;14:398–403. doi: 10.1007/s11897-017-0353-9.
    1. Tajiri K, Aonuma K, Sekine I. Cardio-oncology: a multidisciplinary approach for detection, prevention and management of cardiac dysfunction in cancer patients. Jpn J Clin Oncol. 2017;47:678–682. doi: 10.1093/jjco/hyx068.
    1. Mijwel S, et al. Highly favorable physiological responses to concurrent resistance and high-intensity interval training during chemotherapy: the OptiTrain breast cancer trial. Breast Cancer Res Treat. 2018;169:93–103. doi: 10.1007/s10549-018-4663-8.
    1. Mijwel S, et al. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer. FASEB J. 2018;32:5495–5505. doi: 10.1096/fj.201700968R.
    1. Jacquinot Q, et al. A phase 2 randomized trial to evaluate the impact of a supervised exercise program on cardiotoxicity at 3 months in patients with HER2 overexpressing breast cancer undergoing adjuvant treatment by trastuzumab: design of the CARDAPAC study. BMC Cancer. 2017;17:425. doi: 10.1186/s12885-017-3420-4.
    1. Schneider CM, Hsieh CC, Sprod LK, Carter SD, Hayward R. Effects of supervised exercise training on cardiopulmonary function and fatigue in breast cancer survivors during and after treatment. Cancer. 2007;110:918–925. doi: 10.1002/cncr.22862.
    1. Sprod LK, Hsieh CC, Hayward R, Schneider CM. Three versus six months of exercise training in breast cancer survivors. Breast Cancer Res Treat. 2010;121:413–419. doi: 10.1007/s10549-010-0913-0.
    1. Furmaniak AC, Menig M, Markes MH. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev. 2016;9:CD005001. doi: 10.1002/14651858.CD005001.pub3.
    1. Christensen JF, Simonsen C, Hojman P. Exercise training in Cancer control and treatment. Compr Physiol. 2018;9:165–205. doi: 10.1002/cphy.c180016.
    1. Howden EJ, et al. Exercise as a diagnostic and therapeutic tool for the prevention of cardiovascular dysfunction in breast cancer patients. Eur J Prev Cardiol. 2018:2047487318811181. 10.1177/2047487318811181.
    1. Kirkham AA, et al. The effect of an aerobic exercise bout 24 h prior to each doxorubicin treatment for breast cancer on markers of cardiotoxicity and treatment symptoms: a RCT. Breast Cancer Res Treat. 2018;167:719–729. doi: 10.1007/s10549-017-4554-4.
    1. Zaphiriou A, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail. 2005;7:537–541. doi: 10.1016/j.ejheart.2005.01.022.
    1. Lee K, et al. Effect of aerobic and resistance exercise intervention on cardiovascular disease risk in women with early-stage breast cancer: a randomized clinical trial. JAMA Oncol. 2019. 10.1001/jamaoncol.2019.0038.
    1. Wengstrom Y, et al. Optitrain: a randomised controlled exercise trial for women with breast cancer undergoing chemotherapy. BMC Cancer. 2017;17:100. doi: 10.1186/s12885-017-3079-x.
    1. Bolam KA, Mijwel S, Rundqvist H, Wengstrom Y. Two-year follow-up of the OptiTrain randomised controlled exercise trial. Breast Cancer Res Treat. 2019. 10.1007/s10549-019-05204-0.
    1. Mijwel S, et al. High-intensity exercise during chemotherapy induces beneficial effects 12 months into breast cancer survivorship. J Cancer Surviv. 2019. 10.1007/s11764-019-00747-z.
    1. Mijwel S, et al. Adding high-intensity interval training to conventional training modalities: optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial. Breast Cancer Res Treat. 2018;168:79–93. doi: 10.1007/s10549-017-4571-3.
    1. Mijwel S, et al. Effects of exercise on chemotherapy completion and hospitalization rates: the optitrain breast cancer trial. Oncologist. 2019. 10.1634/theoncologist.2019-0262.
    1. Schmitz KH, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409–1426. doi: 10.1249/MSS.0b013e3181e0c112.
    1. Mijwel S, et al. Validation of 2 submaximal cardiorespiratory fitness tests in patients with breast cancer undergoing chemotherapy. Rehabil Oncol Am Phys Ther Assoc Oncol Sect. 2016;34:137–143. doi: 10.1097/01.reo.0000000000000030.
    1. Hall C. Essential biochemistry and physiology of (NT-pro)BNP. Eur J Heart Fail. 2004;6:257–260. doi: 10.1016/j.ejheart.2003.12.015.
    1. Leistner DM, et al. Prognostic value of NT-pro-BNP and hs-CRP for risk stratification in primary care: results from the population-based DETECT study. Clin Res Cardiol. 2013;102:259–268. doi: 10.1007/s00392-012-0530-5.
    1. Sturgeon KM, et al. Patient preference and timing for exercise in breast cancer care. Support Care Cancer. 2018;26:507–514. doi: 10.1007/s00520-017-3856-8.
    1. Cattadori G, Segurini C, Picozzi A, Padeletti L, Anza C. Exercise and heart failure: an update. ESC Heart Fail. 2018;5:222–232. doi: 10.1002/ehf2.12225.
    1. Beaudry RI, et al. Determinants of exercise intolerance in breast cancer patients prior to anthracycline chemotherapy. Physiol Rep. 2019;7:e13971. doi: 10.14814/phy2.13971.
    1. Scott JM, et al. Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer: current evidence and underlying mechanisms. Circulation. 2011;124:642–650. doi: 10.1161/circulationaha.111.021774.
    1. Park KC, Gaze DC, Collinson PO, Marber MS. Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc Res. 2017;113:1708–1718. doi: 10.1093/cvr/cvx183.
    1. Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 2011;13:R64. doi: 10.1186/bcr2901.

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