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Role of renal function on the development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer

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Abstract

Anthracyclines, taxanes and trastuzumab are used for therapy in early breast cancer (EBC) overexpressing Human Epidermal Growth Factor 2 (HER2+). These drugs, considered alone, do not present potential nephrotoxicity. However, renal dysfunction (RD) may increase the myocardial sensibility to the insult of these chemotherapies used in combination. The aim of the study is to assess the role of RD on the development of cardiotoxicity associated with trastuzumab-based adjuvant therapy (aTrastC) for EBC. Clinical and echocardiographic data of 499 women with ERB2+ EBC were analyzed. At 12-month evaluation, any symptoms of heart failure or decrease in left ventricular ejection fraction (LVEF) were recorded. Patients who had cardiotoxicity (n = 130, 26 %) were older (57 ± 11 vs. 55 ± 11 years; p = 0.03), had lower glomerular filtration rate (GFR) (76 ± 15 vs. 83 ± 19 ml/min/1.73 m2; p = 0.003), higher LVEF (69 ± 6 vs. 63 ± 5 %; p < 0.001) and received more frequent doses of doxorubicin (18 vs. 9 %; p = 0.01) than those who did not. In patients with GFR 60–90 and <60 ml/min/1.73 m2, the 1-year event rate of cardiotoxicity was 25 and 38 %, respectively. ROC analysis showed that the best cut-off point of GFR for predicting cardiotoxicity was 78 ml/min/1.73 m2 (AUC = 0.66, [95 % CI 0.57–0.74]). Multiple logistic regression revealed that GRF <78 ml/min/1.73 m2 was the strongest predictor of cardiotoxicity (OR 3.32 [CI = 1.30–8.65]), independent of doxorubicin treatment and left ventricular ejection fraction. A reduced renal function represents a condition of higher risk of developing cardiotoxicity at 12-month follow-up in patients with HER2 + EBC treated with aTrastC.

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References

  1. Ewer SM, Ewer MS (2008) Cardiotoxicity profile of trastuzumab. Drug Saf 31:459–467

    Article  CAS  PubMed  Google Scholar 

  2. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465

    Article  CAS  PubMed  Google Scholar 

  3. Pugatsch T, Abedat S, Lotan C, Beeri R (2006) Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res 8:R35

    Article  PubMed  Google Scholar 

  4. Kintzel PE, Dorr RT (1995) Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 21:33–64

    Article  CAS  PubMed  Google Scholar 

  5. Launay-Vacher V, Gligorov J, Le Tourneau C, Janus N, Spano JP, Ray-Coquard I, Oudard S, Pourrat X, Morere JF, Deray G,Beuzeboc P, Renal Insufficiency and Anticancer Medications (IRMA) Study Group (2010) Prevalence of renal insufficiency in breast cancer patients and related pharmacological issues. Breast Cancer Res Treat 124:745–753

    Google Scholar 

  6. Lam CS, Lyass A, Kraigher-Krainer E, Massaro JM, Lee DS, Ho JE, Levy D, Redfield MM, Pieske BM, Benjamin EJ, Vasan RS (2011) Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community. Circulation 124:24–30

    Article  CAS  PubMed  Google Scholar 

  7. Kottgen A, Russell SD, Loehr LR, Crainiceanu CM, Rosamond WD, Chang PP, Chambless LE, Coresh J (2007) Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol 18:1307–1315

    Article  CAS  PubMed  Google Scholar 

  8. Launay-Vacher V, Oudart S, Janus N, Gligorov J, Pourrat X, Rixe O, Morere JF, Beuzeboc P, Deray G, On behalf of the Renal Insufficiency and Cancer Medications (IRMA) Study Group (2007) Prevalence of renal insufficiency in cancer patients and implication for anticarcer drug management Cancer 110:1376–1384

  9. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Scholte op Reimer W, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A (2007) European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG). European guidelines on cardiovascular disease prevention in clinical practice: executive summary: fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). Eur Heart J 28:2375–2414

    Article  PubMed  Google Scholar 

  10. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  CAS  PubMed  Google Scholar 

  11. 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, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Herceptin Adjuvant (HERA) Trial Study Team Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672

    Article  CAS  PubMed  Google Scholar 

  12. Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, Redfield MM (1998) Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 98:2282–2289

    Article  CAS  PubMed  Google Scholar 

  13. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al (2003) Nationl Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 139:137–147

    PubMed  Google Scholar 

  14. Lichtman SM, Wildiers H, Launay-Vacher V, Steer C, Chatelut E, Aapro M (2007) International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 43:14–34

    Article  PubMed  Google Scholar 

  15. Launay-Vacher V, Spano JP, Janus N, Gligorov J, Ray-Coquard I, Oudard S, Pourrat X, Morere JF, Beuzeboc P, Deray G (2009) Renal insufficiency and anticancer drugs in elderly cancer patients: a subgroup analysis of the IRMA study. Crit Rev Oncol Hematol 70:124–133

    Article  PubMed  Google Scholar 

  16. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375:2073–2081

  17. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House AA, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P, Acute Dialysis Quality Initiative (ADQI) consensus group (2010) Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 31:703–711

    Google Scholar 

  18. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA (2008) Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol 51:1268–1274

    Article  PubMed  Google Scholar 

  19. Iwanaga Y, Miyazaki S (2010) Heart failure, chronic kidney disease, and biomarkers—an integrated viewpoint. S Circ J 74:1274–1282

    Article  CAS  Google Scholar 

  20. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B (2005) The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 26:11–17

    Article  PubMed  Google Scholar 

  21. Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, Esler MD, Lambert GW (2009) Sympathetic activation in chronic renal failure. J Am Soc Nephrol 20:933–939

    Article  PubMed  Google Scholar 

  22. Gille L, Nohl H (2007) Analyses of molecular mechanism of adriamicin-induced cardiotoxicity. Free Radical Biol Med 23:775–782

    Article  Google Scholar 

  23. Liu FF, Stone JR, Schuldt AJ, Okoshi K, Okoshi MP, Nakayama M, Ho KK, Manning WJ, Marchionni MA, Lorell BH, Morgan JP, Yan X et al (2005) Heterozygous knock-out of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol 289:660–666

    Article  Google Scholar 

  24. Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398

    Article  CAS  PubMed  Google Scholar 

  25. Lemmens K, Doggen K, De Keulenaer GW (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960

    Article  CAS  PubMed  Google Scholar 

  26. De Keulenaer GW, Doggen K, Lemmens K (2010) The vulnerability of the heart as a pluricellular paracrine organ. Circ Res 106:35–46

    Article  PubMed  Google Scholar 

  27. Wen XF, Yang G, Mao W, Thornton A, Liu J, Bast RC Jr, Le XF (2006) HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25:6986–6996

    Article  CAS  PubMed  Google Scholar 

  28. Friehs I, Barillas R, Vasilyev NV, Roy N, McGowan FX, del Nido PJ (2009) Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heart. Circulation 114:290–295

    Google Scholar 

  29. Martin FL, McKie PM, Cataliotti A, Sangaralingham J, Korinek J, Huntley BK, Oehler EA, Handers GE, Ichiki T, Mangiafico S, Nath KA, Redfield MM, Chen HH, Burnett JC (2011) Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis and diastolic dysfunction: a kidney—Cardiac connection. Am J Physiol Regul Integr Comp Physiol. doi:10.1152/ajpregu.00194.2011

    Google Scholar 

  30. Albini A, Cesana E, Donatelli F, Cammarota R, Bucci EO, Baravelli M, Anzà C, Noonan DM (2011) Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors. Future Cardiol 7:693–704

    Article  CAS  PubMed  Google Scholar 

  31. Raschi E, De Ponti F (2012) Cardiovascular toxicity of anticancer-targeted therapy: emerging issues in the era of cardio-oncology. Intern Emerg Med 7:113–131

    Google Scholar 

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Authors and Affiliations

  1. Centro Cardiovascolare ASS1 Triestina, Via Slataper, 9 34125, Trieste, Italy

    Giulia Russo & Andrea Di Lenarda

  2. Department of Cardiology, Villa Bianca Hospital, Trento, Italy

    Giovanni Cioffi

  3. Department of Cardiology, “S. Martino” Hospital of Belluno, Belluno, Italy

    Luigi Tarantini

  4. Department of Cardiology, Santa Maria Hospital, Terni, Italy

    Daniella Bovelli

  5. Department of Cardiology, Ospedale Civile, Cremona, Italy

    Giuseppe Di Tano

  6. Department of Cardiology, Ospedale S.M. della Misericordia, Perugia, Italy

    Gianfranco Alunni & Stefania Gori

  7. Department of Cardiology, Spedali Civili, Brescia, Italy

    Pompilio Faggiano

  8. Department of Oncology, “S. Martino” Hospital of Belluno, Belluno, Italy

    Fausto Tuccia

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  1. Giulia Russo
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  2. Giovanni Cioffi
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Correspondence to Giulia Russo.

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On behalf of ICARO (Italian CARdio-Oncologic) network.

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Russo, G., Cioffi, G., Di Lenarda, A. et al. Role of renal function on the development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer. Intern Emerg Med 7, 439–446 (2012). https://doi.org/10.1007/s11739-012-0794-9

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  • DOI: https://doi.org/10.1007/s11739-012-0794-9

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