Changes in Cardiovascular Biomarkers With Breast Cancer Therapy and Associations With Cardiac Dysfunction

Biniyam G Demissei, Rebecca A Hubbard, Liyong Zhang, Amanda M Smith, Karyn Sheline, Caitlin McDonald, Vivek Narayan, Susan M Domchek, Angela DeMichele, Payal Shah, Amy S Clark, Kevin Fox, Jennifer Matro, Angela R Bradbury, Hayley Knollman, Kelly D Getz, Saro H Armenian, James L Januzzi, W H Wilson Tang, Peter Liu, Bonnie Ky, Biniyam G Demissei, Rebecca A Hubbard, Liyong Zhang, Amanda M Smith, Karyn Sheline, Caitlin McDonald, Vivek Narayan, Susan M Domchek, Angela DeMichele, Payal Shah, Amy S Clark, Kevin Fox, Jennifer Matro, Angela R Bradbury, Hayley Knollman, Kelly D Getz, Saro H Armenian, James L Januzzi, W H Wilson Tang, Peter Liu, Bonnie Ky

Abstract

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.

Keywords: biomarker; cardiomyopathy; cardiotoxicity; cardio‐oncology.

Figures

Figure 1
Figure 1
Study protocol. Timeline of blood draws and echocardiography assessment according to cancer therapy regimen.
Figure 2
Figure 2
Mean estimated changes in biomarkers over time according to cancer therapy regimen. The solid line represents mean estimated changes over time and the width of the surrounding band represents the corresponding 95% CI. Biomarker levels were log2 transformed (a unit increment from baseline should be interpreted as doubling); (A) high‐sensitivity cardiac troponin T (hs‐cTnT), (B) NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), (C) placental growth factor (PIGF), (D) growth differentiation factor 15 (GDF‐15), and (E) myeloperoxidase.
Figure 3
Figure 3
Associations between changes in biomarkers and changes in left ventricular ejection fraction (LVEF) according to cancer therapy regimen. Each point corresponds to mean absolute change in LVEF from baseline for each doubling of a biomarker from baseline to the same visit. The last column on the right side presents P values for interaction. GDF‐15 indicates growth differentiation factor 15; hs‐cTnT, high‐sensitivity cardiac troponin T; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PIGF, placental growth factor.

References

    1. Abdel‐Qadir H, Austin PC, Lee DS, Amir E, Tu JV, Thavendiranathan P, Fung K, Anderson GM. A population‐based study of cardiovascular mortality following early‐stage breast cancer. JAMA Cardiol. 2017;2:88–93.
    1. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high‐dose chemotherapy‐induced cardiotoxicity in high‐risk patients by angiotensin‐converting enzyme inhibition. Circulation. 2006;114:2474–2481.
    1. Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz‐Menger J, Fagerland MW, Gravdehaug B, von Knobelsdorff‐Brenkenhoff F, Bratland A, Storas TH, Hagve TA, Rosjo H, Steine K, Geisler J, Omland T. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo‐controlled, double‐blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37:1671–1680.
    1. Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, Dent S, Douglas PS, Durand JB, Ewer M, Fabian C, Hudson M, Jessup M, Jones LW, Ky B, Mayer EL, Moslehi J, Oeffinger K, Ray K, Ruddy K, Lenihan D. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2017;35:893–911.
    1. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, Habib G, Lenihan DJ, Lip GY, Lyon AR, Lopez Fernandez T, Mohty D, Piepoli MF, Tamargo J, Torbicki A, Suter TM; ESC Scientific Document Group . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768–2801.
    1. Hamo CE, Bloom MW, Cardinale D, Ky B, Nohria A, Baer L, Skopicki H, Lenihan DJ, Gheorghiade M, Lyon AR, Butler J. Cancer therapy‐related cardiac dysfunction and heart failure: part 2: prevention, treatment, guidelines, and future directions. Circ Heart Fail. 2016;9:e002843.
    1. Yu AF, Ky B. Roadmap for biomarkers of cancer therapy cardiotoxicity. Heart. 2016;102:425–430.
    1. Ky B, Carver JR. Biomarker approach to the detection and cardioprotective strategies during anthracycline chemotherapy. Heart Fail Clin. 2011;7:323–331.
    1. Shah KS, Yang EH, Maisel AS, Fonarow GC. The role of biomarkers in detection of cardio‐toxicity. Curr Oncol Rep. 2017;19:42.
    1. Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. Left ventricular dysfunction predicted by early troponin I release after high‐dose chemotherapy. J Am Coll Cardiol. 2000;36:517–522.
    1. Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high‐dose chemotherapy. Circulation. 2004;109:2749–2754.
    1. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, Lamantia G, Colombo N, Cortinovis S, Dessanai MA, Nole F, Veglia F, Cipolla CM. Trastuzumab‐induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–3916.
    1. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Early detection and prediction of cardiotoxicity in chemotherapy‐treated patients. Am J Cardiol. 2011;107:1375–1380.
    1. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5:596–603.
    1. Morris PG, Chen C, Steingart R, Fleisher M, Lin N, Moy B, Come S, Sugarman S, Abbruzzi A, Lehman R, Patil S, Dickler M, McArthur HL, Winer E, Norton L, Hudis CA, Dang CT. Troponin I and C‐reactive protein are commonly detected in patients with breast cancer treated with dose‐dense chemotherapy incorporating trastuzumab and lapatinib. Clin Cancer Res. 2011;17:3490–3499.
    1. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, Plana JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63:809–816.
    1. Putt M, Hahn VS, Januzzi JL, Sawaya H, Sebag IA, Plana JC, Picard MH, Carver JR, Halpern EF, Kuter I, Passeri J, Cohen V, Banchs J, Martin RP, Gerszten RE, Scherrer‐Crosbie M, Ky B. Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem. 2015;61:1164–1172.
    1. Zardavas D, Suter TM, Van Veldhuisen DJ, Steinseifer J, Noe J, Lauer S, Al‐Sakaff N, Piccart‐Gebhart MJ, de Azambuja E. Role of troponins I and T and N‐terminal prohormone of brain natriuretic peptide in monitoring cardiac safety of patients with early‐stage human epidermal growth factor receptor 2‐positive breast cancer receiving trastuzumab: a herceptin adjuvant study cardiac marker substudy. J Clin Oncol. 2017;35:878–884.
    1. de Vries Schultink AH, Boekhout AH, Gietema JA, Burylo AM, Dorlo TPC, van Hasselt JG, Schellens JH, Huitema AD. Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens. J Pharmacokinet Pharmacodyn. 2018;45:431–442.
    1. Romano S, Fratini S, Ricevuto E, Procaccini V, Stifano G, Mancini M, Di Mauro M, Ficorella C, Penco M. Serial measurements of NT‐proBNP are predictive of not‐high‐dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer. 2011;105:1663–1668.
    1. Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy‐related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One. 2014;9:e96736.
    1. Finkelman BS, Putt M, Wang T, Wang L, Narayan H, Domchek S, DeMichele A, Fox K, Matro J, Shah P, Clark A, Bradbury A, Narayan V, Carver JR, Tang WHW, Ky B. Arginine‐nitric oxide metabolites and cardiac dysfunction in patients with breast cancer. J Am Coll Cardiol. 2017;70:152–162.
    1. Narayan HK, French B, Khan AM, Plappert T, Hyman D, Bajulaiye A, Domchek S, DeMichele A, Clark A, Matro J, Bradbury A, Fox K, Carver JR, Ky B. Noninvasive measures of ventricular‐arterial coupling and circumferential strain predict cancer therapeutics‐related cardiac dysfunction. JACC Cardiovasc Imaging. 2016;9:1131–1141.
    1. Piccart‐Gebhart MJ, Procter M, Leyland‐Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin adjuvant (HERA) Trial Study Team . Trastuzumab after adjuvant chemotherapy in HER2‐positive breast cancer. N Engl J Med. 2005;353:1659–1672.
    1. Zheng Y, Heagerty PJ. Partly conditional survival models for longitudinal data. Biometrics. 2005;61:379–391.
    1. Maziarz M, Heagerty P, Cai T, Zheng Y. On longitudinal prediction with time‐to‐event outcome: comparison of modeling options. Biometrics. 2017;73:83–93.
    1. Gustafsson F, Steensgaard‐Hansen F, Badskjaer J, Poulsen AH, Corell P, Hildebrandt P. Diagnostic and prognostic performance of N‐terminal ProBNP in primary care patients with suspected heart failure. J Card Fail. 2005;11:S15–S20.
    1. Januzzi JL Jr, Chen‐Tournoux AA, Christenson RH, Doros G, Hollander JE, Levy PD, Nagurney JT, Nowak RM, Pang PS, Patel D, Peacock WF, Rivers EJ, Walters EL, Gaggin HK; ICON‐RELOADED Investigators . N‐terminal pro‐B‐type natriuretic peptide in the emergency department: the ICON‐RELOADED study. J Am Coll Cardiol. 2018;71:1191–1200.
    1. Taylor CJ, Roalfe AK, Iles R, Hobbs FD. The potential role of NT‐proBNP in screening for and predicting prognosis in heart failure: a survival analysis. BMJ Open. 2014;4:e004675.
    1. Jordan JH, D'Agostino RB Jr, Hamilton CA, Vasu S, Hall ME, Kitzman DW, Thohan V, Lawrence JA, Ellis LR, Lash TL, Hundley WG. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1‐weighted and T2‐weighted cardiovascular magnetic resonance. Circ Cardiovasc Imaging. 2014;7:872–879.
    1. Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, Pagano JJ, Chow K, Thompson RB, Vos LJ, Ghosh S, Oudit GY, Ezekowitz JA, Paterson DI. Multidisciplinary approach to novel therapies in cardio‐oncology research (MANTICORE 101‐Breast): a randomized trial for the prevention of trastuzumab‐associated cardiotoxicity. J Clin Oncol. 2017;35:870–877.
    1. Gulati G, Heck SL, Rosjo H, Ree AH, Hoffmann P, Hagve TA, Norseth J, Gravdehaug B, Steine K, Geisler J, Omland T. Neurohormonal blockade and circulating cardiovascular biomarkers during anthracycline therapy in breast cancer patients: results from the PRADA (prevention of cardiac dysfunction during adjuvant breast cancer therapy) study. J Am Heart Assoc. 2017;6:s006513 DOI: 10.1161/JAHA.117.006513.
    1. Cardinale D, Ciceri F, Latini R, Franzosi MG, Sandri MT, Civelli M, Cucchi G, Menatti E, Mangiavacchi M, Cavina R, Barbieri E, Gori S, Colombo A, Curigliano G, Salvatici M, Rizzo A, Ghisoni F, Bianchi A, Falci C, Aquilina M, Rocca A, Monopoli A, Milandri C, Rossetti G, Bregni M, Sicuro M, Malossi A, Nassiacos D, Verusio C, Giordano M, Staszewsky L, Barlera S, Nicolis EB, Magnoli M, Masson S, Cipolla CM; ICOS‐ONE Study Investigators . Anthracycline‐induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: the International CardioOncology Society‐one trial. Eur J Cancer. 2018;94:126–137.
    1. Avila MS, Ayub‐Ferreira SM, de Barros Wanderley MR Jr, das Dores Cruz F, Goncalves Brandao SM, Rigaud VO, Higuchi‐Dos‐Santos MH, Hajjar LA, Kalil Filho R, Hoff PM, Sahade M, Ferrari MSM, de Paula Costa RL, Mano MS, Bittencourt Viana Cruz CB, Abduch MC, Lofrano Alves MS, Guimaraes GV, Issa VS, Bittencourt MS, Bocchi EA. Carvedilol for prevention of chemotherapy‐related cardiotoxicity: the CECCY trial. J Am Coll Cardiol. 2018;71:2281–2290.
    1. Ford I, Shah AS, Zhang R, McAllister DA, Strachan FE, Caslake M, Newby DE, Packard CJ, Mills NL. High‐sensitivity cardiac troponin, statin therapy, and risk of coronary heart disease. J Am Coll Cardiol. 2016;68:2719–2728.
    1. Jhund PS, Claggett BL, Voors AA, Zile MR, Packer M, Pieske BM, Kraigher‐Krainer E, Shah AM, Prescott MF, Shi V, Lefkowitz M, McMurray JJ, Solomon SD; PARAMOUNT Investigators . Elevation in high‐sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696. Circ Heart Fail. 2014;7:953–959.
    1. Metra M, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld L, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Prescott MF, Edwards C, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin T, Teerlink JR; RELAX‐AHF Investigators . Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX‐AHF) development program: correlation with outcomes. J Am Coll Cardiol. 2013;61:196–206.
    1. Ponde N, Bradbury I, Lambertini M, Ewer M, Campbell C, Ameels H, Zardavas D, Di Cosimo S, Baselga J, Huober J, Izquierdo M, Fumagalli D, Bozovic‐Spasojevic I, Maetens M, Harbeck N, Pusztai L, Berghorn M, Im YH, Borrego MR, Chen DR, Rodeheffer R, Piccart M, Suter T, de Azambuja E. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib‐induced cardiotoxicity in patients with HER2‐positive early‐stage breast cancer: a NeoALTTO sub‐study (BIG 1‐06). Breast Cancer Res Treat. 2018;168:631–638.
    1. Ledwidge M, Gallagher J, Conlon C, Tallon E, O'Connell E, Dawkins I, Watson C, O'Hanlon R, Bermingham M, Patle A, Badabhagni MR, Murtagh G, Voon V, Tilson L, Barry M, McDonald L, Maurer B, McDonald K. Natriuretic peptide‐based screening and collaborative care for heart failure: the STOP‐HF randomized trial. JAMA. 2013;310:66–74.
    1. Brennan ML, Hazen SL. Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr Opin Lipidol. 2003;14:353–359.
    1. Schindhelm RK, van der Zwan LP, Teerlink T, Scheffer PG. Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification? Clin Chem. 2009;55:1462–1470.
    1. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215–21.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera