Advertisement

Internal and Emergency Medicine

, Volume 11, Issue 1, pp 123–140 | Cite as

Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer

  • Stefania Mantarro
  • Marta Rossi
  • Martina Bonifazi
  • Roberto D’Amico
  • Corrado Blandizzi
  • Carlo La Vecchia
  • Eva Negri
  • Lorenzo Moja
HTA-ORIGINAL

Abstract

Trastuzumab prolongs survival in women with HER2-positive breast cancer, but may increase the risk of heart disease. The occurrence of severe cardiotoxicity, however, is not defined in real-life settings. We performed a meta-analysis of clinical trials and cohort studies to estimate the frequency of cardiotoxicities following trastuzumab treatment. We searched MEDLINE, EMBASE, and the Cochrane Library (1996–January 2014). The primary outcome was the frequency of severe cardiotoxicities up to 3-years after trastuzumab initiation. Among 58 studies (29,598 patients), severe cardiotoxicity occurred in 3.00 % (95 % CI 2.41–3.64), 2.62 % (95 % CI 1.97–3.35), and 3.14 % (95 % CI 2.12–4.37) of overall, early (EBC) and metastatic (MBC) breast cancer patients, respectively. In EBC, the proportion increased from 2.40 % at the first year to a plateau of approximately 3 % after the second year. In MBC, the proportion increased from 3.00 to 3.68 % when trastuzumab was used as first line or further lines of therapy, respectively. In EBC, cardiotoxicity occurred in 2.90 % of patients treated with taxanes and anthracyclines compared to 0.92 % in patients treated with taxanes without anthracyclines. The occurrence of cardiotoxicity varied according to age, increasing from 2.31 % in individuals <50 years, to 3.46 % in those 50–59 years, to 4.91 % in those >60 years of age. Cardiotoxicity was higher in smokers (5.3 %), dyslipidemic patients (3.9 %), BMI ≥25 (6.5 %), diabetes (6.2 %), hypertension (5.5 %), or positive history of cardiac disease (19.1 %). RCTs consistently report lower cardiac toxicity rates than observational studies (EBC: 1.7 versus 3.2; MBC: 2.8 versus 4.4). Following trastuzumab initiation, approximately three in 100 patients develop severe cardiotoxicity after 2 years. Patients enrolled in cohort studies, who more closely reflect women treated for breast cancer in real-life settings compared to RCTs, are at higher risk of developing cardiac events.

Keywords

Trastuzumab Cardiotoxicity Early breast cancer Metastatic breast cancer Heart failure Meta-analysis 

Notes

Acknowledgments

Dr. Bonifazi was supported by a fellowship from the Italian Foundation for Cancer and Research (FIRC).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

The authors hereby declare that this article does not contain any studies with animals performed by any of the authors.

Informed consent

None.

Supplementary material

11739_2015_1362_MOESM1_ESM.docx (944 kb)
Supplementary material 1 (DOCX 944 kb)

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917. doi: 10.1002/ijc.25516 CrossRefPubMedGoogle Scholar
  2. 2.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712CrossRefPubMedGoogle Scholar
  3. 3.
    Chia S, Norris B, Speers C, Cheang M, Gilks B, Gown AM, Huntsman D, Olivotto IA, Nielsen TO, Gelmon K (2008) Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 26(35):5697–5704. doi: 10.1200/JCO.2007.15.8659 CrossRefPubMedGoogle Scholar
  4. 4.
    Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D’Amico R (2012) Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 4:CD006243. doi: 10.1002/14651858.CD006243.pub2 PubMedGoogle Scholar
  5. 5.
    Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, D’Amico R (2014) Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 6:CD006242. doi: 10.1002/14651858.CD006242.pub2 PubMedGoogle Scholar
  6. 6.
    Perez EA, Rodeheffer R (2004) Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22(2):322–329. doi: 10.1200/JCO.2004.01.120 CrossRefPubMedGoogle Scholar
  7. 7.
    Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporte I, Kramar A (2013) 6 versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14(8):741–748. doi: 10.1016/s1470-2045(13)70225-0 CrossRefPubMedGoogle Scholar
  8. 8.
    Rugo HS, Brufsky AM, Ulcickas Yood M, Tripathy D, Kaufman PA, Mayer M, Yoo B, Abidoye OO, Yardley DA (2013) Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 141(3):461–470. doi: 10.1007/s10549-013-2697-5 PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Bonifazi M, Franchi M, Rossi M, Moja L, Zambelli A, Zambon A, Corrao G, La Vecchia C, Zocchetti C, Negri E (2013) Trastuzumab-related cardiotoxicity in early breast cancer: a cohort study. Oncologist 18(7):795–801. doi: 10.1634/theoncologist.2013-0065 PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Guarneri V, Lenihan DJ, Valero V, Durand JB, Broglio K, Hess KR, Michaud LB, Gonzalez-Angulo AM, Hortobagyi GN, Esteva FJ (2006) Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M. D. Anderson Cancer Center experience. J Clin Oncol 24(25):4107–4115. doi: 10.1200/jco.2005.04.9551 CrossRefPubMedGoogle Scholar
  11. 11.
    Gianni L, Salvatorelli E, Minotti G (2007) Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. Cardiovasc Toxicol 7(2):67–71. doi: 10.1007/s12012-007-0013-5 CrossRefPubMedGoogle Scholar
  12. 12.
    Administration FaD (1998) HERCEPTIN (trastuzumab) Label—FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf. Accessed 31 Jan 2014
  13. 13.
    Agency EM (2010) Herceptin: EPAR—product information. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000278/WC500074922.pdf. Accessed 31 Jan 2014
  14. 14.
    Cancer Therapy Evaluation Program. Common terminology criteria for adverse events (CTCAE) and common toxicity criteria (CTC) v (June 14, 2010) National Cancer Institute. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf Accessed 31 Jan 2014
  15. 15.
    New York Heart Association (NYHA) classification: classes of heart failure. http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp. Accessed 31 Jan 2014
  16. 16.
    Anand IS, Florea VG, Fisher L (2002) Surrogate end points in heart failure. J Am Coll Cardiol 39(9):1414–1421CrossRefPubMedGoogle Scholar
  17. 17.
    Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA, Gersh BJ, Jaffe AS, Rodeheffer RJ (2008) Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26(8):1231–1238. doi: 10.1200/jco.2007.13.5467 PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23(31):7811–7819. doi: 10.1200/jco.2005.02.4091 CrossRefPubMedGoogle Scholar
  19. 19.
    Simes RJ, Coates AS (2001) Patient preferences for adjuvant chemotherapy of early breast cancer: how much benefit is needed? J Natl Cancer Inst Monogr 30:146–152CrossRefPubMedGoogle Scholar
  20. 20.
    Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26(4):404–413. doi: 10.1093/biomet/26.4.404 CrossRefGoogle Scholar
  21. 21.
    Freeman MF, Tukey JW (1950) Transformations related to the angular and the square root. Ann Math Stat 21(4):607–611. doi: 10.1214/aoms/1177729756 CrossRefGoogle Scholar
  22. 22.
    Trikalinos TA, Trow P, Schmid CH (2013) Simulation-based comparison of methods for meta-analysis of proportions and rates. Agency for Healthcare Research and Quality (US), Rockville, MD 13(14):EHC084-EFGoogle Scholar
  23. 23.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefPubMedGoogle Scholar
  24. 24.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. doi: 10.1002/sim.1186 CrossRefPubMedGoogle Scholar
  25. 25.
    Aitelhaj M, Lkhouyaali S, Rais G, Mohtaram A, Raissouni S, Ghissassi B, Boutayeb S, Mrabti H, Bensouda Y, Errihani H (2013) Cardiac safety of the adjuvant Trastuzumab in a Moroccan population: observational monocentric study of about 100 patients. BMC Res Notes 6:339. doi: 10.1186/1756-0500-6-339 PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Bayraktar S, Gonzalez-Angulo AM, Lei X, Buzdar AU, Valero V, Melhem-Bertrandt A, Kuerer HM, Hortobagyi GN, Sahin AA, Meric-Bernstam F (2012) Efficacy of neoadjuvant therapy with trastuzumab concurrent with anthracycline- and nonanthracycline-based regimens for HER2-positive breast cancer. Cancer 118(9):2385–2393. doi: 10.1002/cncr.26555 PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, Allen LA, Nekhlyudov L, Goddard KA, Davis RL, Habel LA, Yood MU, McCarty C, Magid DJ, Wagner EH (2012) Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 104(17):1293–1305. doi: 10.1093/jnci/djs317 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Campiglio M, Bufalino R, Sasso M, Ferri E, Casalini P, Adamo V, Fabi A, Aiello R, Riccardi F, Valle E, Scotti V, Tabaro G, Giuffrida D, Tarenzi E, Bologna A, Mustacchi G, Bianchi F, Balsari A, Menard S, Tagliabue E (2013) Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study. Breast Cancer Res Treat 141(1):101–110. doi: 10.1007/s10549-013-2658-z PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Caussa L, Kirova YM, Gault N, Pierga JY, Savignoni A, Campana F, Dendale R, Fourquet A, Bollet MA (2011) The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study. Eur J Cancer 47(1):65–73. doi: 10.1016/j.ejca.2010.08.013 CrossRefPubMedGoogle Scholar
  30. 30.
    Cha C, Ahn SG, Lee HM, Lee HW, Lee SA, Jeong J (2013) Assessment of adjuvant trastuzumab-associated cardiac toxicity in korean patients with breast cancer: a single-center analysis. Oncology 85(4):228–234. doi: 10.1159/000354836 CrossRefPubMedGoogle Scholar
  31. 31.
    Chan A, McGregor SR (2012) Prevalence and management of HER2/neu-positive early breast cancer in a single institution following availability of adjuvant trastuzumab. Intern Med J 42(3):267–274. doi: 10.1111/j.1445-5994.2011.02432.x CrossRefPubMedGoogle Scholar
  32. 32.
    Cochet A, Quilichini G, Dygai-Cochet I, Touzery C, Toubeau M, Berriolo-Riedinger A, Coudert B, Cottin Y, Fumoleau P, Brunotte F (2011) Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat 130(3):845–854. doi: 10.1007/s10549-011-1714-9 CrossRefPubMedGoogle Scholar
  33. 33.
    Cook TS, S, Plana JC, Oliveira G, Budd GT, Marwick T (2011) Cardioprotective effect of beta-blockers and ACE-inhibitors in breast cancer patients treated with trastuzumab: a follow-up study of heart failure and cardiac function over 12 months. Circulation 124 (21 Suppl):A13988Google Scholar
  34. 34.
    Dall PL, G, Göhler T, Feisel-Schwickeradi G, Koch T, Heilmann V, Schindler C, Wilke J, Tesch H, Selbach J, Eggert J, Hinke A (2013) Trastuzumab treatment of early breast cancer: long-term results from a prospective observation study, including a large cohort of elderly patients. Abstracts from the 36th Annual SABCSGoogle Scholar
  35. 35.
    Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal DS (2008) Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson 10:5. doi: 10.1186/1532-429x-10-5 PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Farolfi A, Melegari E, Aquilina M, Scarpi E, Ibrahim T, Maltoni R, Sarti S, Cecconetto L, Pietri E, Ferrario C, Fedeli A, Faedi M, Nanni O, Frassineti GL, Amadori D, Rocca A (2013) Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart 99(9):634–639. doi: 10.1136/heartjnl-2012-303151 CrossRefPubMedGoogle Scholar
  37. 37.
    Freedman RVDL, IM, Lin N, Lii J, Winer EP, Keating Lynn N (2013) Completion of adjuvant trastuzumab for older patients with early-stage breast cancer (BC). J Clin Oncol 31(15 Suppl), abstract 616Google Scholar
  38. 38.
    Fried G, Regev T, Moskovitz M (2013) Trastuzumab-related cardiac events in the treatment of early breast cancer. Breast Cancer Res Treat 142(1):1–7. doi: 10.1007/s10549-013-2732-6 CrossRefPubMedGoogle Scholar
  39. 39.
    Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375(9712):377–384. doi: 10.1016/s0140-6736(09)61964-4 CrossRefPubMedGoogle Scholar
  40. 40.
    Guglin M, Hartlage G, Reynolds C, Chen R, Patel V (2009) Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study. J Card Fail 15(8):651–657. doi: 10.1016/j.cardfail.2009.04.011 CrossRefPubMedGoogle Scholar
  41. 41.
    Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O’Shaughnessy J (2013) Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 14(11):1121–1128. doi: 10.1016/s1470-2045(13)70384-x CrossRefPubMedGoogle Scholar
  42. 42.
    Nag D, Ferrusi I, Khong H, Earle C, Trudeau M, Marshall D, Leighl N (2012) Cardiac monitoring during adjuvant trastuzumab therapy for breast cancer. Cancer Res 72(24 Supplement):471s. doi: 10.1158/0008-5472.SABCS12-P5-18-14 Google Scholar
  43. 43.
    Palmieri C, Shah D, Krell J, Gojis O, Hogben K, Riddle P, Ahmad R, Tat T, Fox K, Porter A, Mahmoud S, Kirschke S, Shousha S, Gudi M, Coombes RC, Leonard R, Cleator S (2011) Management and outcome of HER2-positive early breast cancer treated with or without trastuzumab in the adjuvant trastuzumab era. Clin Breast Cancer 11(2):93–102. doi: 10.1016/j.clbc.2011.03.001 CrossRefPubMedGoogle Scholar
  44. 44.
    Piotrowski G, Gawor R, Stasiak A, Gawor Z, Potemski P, Banach M (2012) Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2—a prospective study. Arch Med Sci 8(2):227–235. doi: 10.5114/aoms.2012.28549 PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Rayson D, Suter TM, Jackisch C, van der Vegt S, Bermejo B, van den Bosch J, Vivanco GL, van Gent AM, Wildiers H, Torres A, Provencher L, Temizkan M, Chirgwin J, Canon JL, Ferrandina G, Srinivasan S, Zhang L, Richel DJ (2012) Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial. Ann Oncol 23(7):1780–1788. doi: 10.1093/annonc/mdr519 CrossRefPubMedGoogle Scholar
  46. 46.
    Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N (2013) Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 14(12):1183–1192. doi: 10.1016/s1470-2045(13)70411-x CrossRefPubMedGoogle Scholar
  47. 47.
    Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M, Falkson C, Pinter T, Fornander T, Shiftan T, Valero V, Von Minckwitz G, Mackey J, Tabah-Fisch I, Buyse M, Lindsay MA, Riva A, Bee V, Pegram M, Press M, Crown J, BCIRG 006 Investigators (2005) Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94(1 Supplement):s5Google Scholar
  48. 48.
    Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F (2009) Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol 27(36):6129–6134. doi: 10.1200/jco.2009.23.0946 CrossRefPubMedGoogle Scholar
  49. 49.
    Subar M, Lin W, Chen W, Pittman DG (2011) Lack of uniformity in cardiac assessment during trastuzumab therapy. Breast J 17(4):383–390. doi: 10.1111/j.1524-4741.2011.01101.x CrossRefPubMedGoogle Scholar
  50. 50.
    Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, Ageev FT, Hitre E, Groetz J, Iwata H, Knap M, Gnant M, Muehlbauer S, Spence A, Gelber RD, Piccart-Gebhart MJ (2007) Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25(25):3859–3865. doi: 10.1200/jco.2006.09.1611 CrossRefPubMedGoogle Scholar
  51. 51.
    Tarantini L, Gori S, Faggiano P, Pulignano G, Simoncini E, Tuccia F, Ceccherini R, Bovelli D, Lestuzzi C, Cioffi G (2012) Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis. Ann Oncol 23(12):3058–3063. doi: 10.1093/annonc/mds127 CrossRefPubMedGoogle Scholar
  52. 52.
    Tolaney SB, WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP (2013) A phase II study of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). Cancer Res 73(24 Suppl), abstract S1-04. doi: 10.1158/0008-5472.SABCS13-S1-04
  53. 53.
    Tonyali O, Coskun U, Sener N, Inanc M, Akman T, Oksuzoglu B, Ozdemir NY, Yazilitas D, Benekli M, Uner A, Yamac D, Demirci U, Yildiz R, Karaca H, Unal OU, Bal O, Gumus M, Buyukberber S (2012) Nine-week trastuzumab treatment versus 52-week trastuzumab treatment for HER2-positive early-stage breast cancer. J Cancer Res Clin Oncol 138(12):2145–2151. doi: 10.1007/s00432-012-1296-x CrossRefPubMedGoogle Scholar
  54. 54.
    Untch M, Fasching PA, Konecny GE, Hasmuller S, Lebeau A, Kreienberg R, Camara O, Muller V, du Bois A, Kuhn T, Stickeler E, Harbeck N, Hoss C, Kahlert S, Beck T, Fett W, Mehta KM, von Minckwitz G, Loibl S (2011) Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 29(25):3351–3357. doi: 10.1200/jco.2010.31.4930 CrossRefPubMedGoogle Scholar
  55. 55.
    Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R, Walker JR, Lister D, Arora RC, Barac I, Morris A, Jassal DS (2009) Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 117(2):357–364. doi: 10.1007/s10549-008-0260-6 CrossRefPubMedGoogle Scholar
  56. 56.
    Yamamoto NY, H, Iwata H, Masuda N, Ohtani S, Takahashi M, Yamazaki K, Kato M, Ohno S, Kuroi K, Yamagami K, Morimoto,T, Hasegawa Y, Takano T, Kadoya T, Hosoda M, Abe H, Morita S, Yasuno S, Toi M (2013) Safety of trastuzumab in HER2-positive primary breast cancer in Japan: INITIAL safety report for the large-scale cohort study (JBCRG C-01). J Clin Oncol 31 (15 (suppl; abstr 613))Google Scholar
  57. 57.
    Andersson M, Lidbrink E, Bjerre K, Wist E, Enevoldsen K, Jensen AB, Karlsson P, Tange UB, Sorensen PG, Moller S, Bergh J, Langkjer ST (2011) Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 29(3):264–271. doi: 10.1200/jco.2010.30.8213 CrossRefPubMedGoogle Scholar
  58. 58.
    Baselga J, Carbonell X, Castaneda-Soto NJ, Clemens M, Green M, Harvey V, Morales S, Barton C, Ghahramani P (2005) Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 23(10):2162–2171. doi: 10.1200/jco.2005.01.014 CrossRefPubMedGoogle Scholar
  59. 59.
    Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109–119. doi: 10.1056/NEJMoa1113216 CrossRefPubMedGoogle Scholar
  60. 60.
    De La Pena LC J, Manikhas A, Roman L, Semiglazov V, Biakhov MY, Dasappa L, Llombart A, Rozencweig M, Forenza S, Goldfarb RH, Matera J, Azarnia N, Hudis C, Baselga J (2013) Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2 + metastatic breast cancer (MBC). J Clin Oncol 31 (15 Suppl), abstract 517Google Scholar
  61. 61.
    Esposito A, Munzone E, Bagnardi V, Adamoli L, Sciandivasci A, Cullura D, Goldhirsch A, Nole F (2012) Are there benefits in routine clinical practice of continuing trastuzumab after progression for metastatic breast cancer patients? Anticancer Drugs 23(10):1089–1098. doi: 10.1097/CAD.0b013e32835679d3 CrossRefPubMedGoogle Scholar
  62. 62.
    Extra JM, Antoine EC, Vincent-Salomon A, Delozier T, Kerbrat P, Bethune-Volters A, Guastalla JP, Spielmann M, Mauriac L, Misset JL, Serin D, Campone M, Hebert C, Remblier C, Bergougnoux L, Campana F, Namer M (2010) Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study. Oncologist 15(8):799–809. doi: 10.1634/theoncologist.2009-0029 PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Gelmon KA, Mackey J, Verma S, Gertler SZ, Bangemann N, Klimo P, Schneeweiss A, Bremer K, Soulieres D, Tonkin K, Bell R, Heinrich B, Grenier D, Dias R (2004) Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer 5(1):52–58 (discussion 59–62) CrossRefPubMedGoogle Scholar
  64. 64.
    Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V (2013) AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31(14):1719–1725. doi: 10.1200/jco.2012.44.7912 CrossRefPubMedGoogle Scholar
  65. 65.
    John M, Hinke A, Stauch M, Wolf H, Mohr B, Hindenburg HJ, Papke J, Schlosser J (2012) Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines—a phase II multipractice study. BMC Cancer 12:165. doi: 10.1186/1471-2407-12-165 PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A (2009) Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 27(33):5529–5537. doi: 10.1200/jco.2008.20.6847 CrossRefPubMedGoogle Scholar
  67. 67.
    Kaufman PA, Brufsky AM, Mayer M, Rugo HS, Tripathy D, Yood MU, Feng S, Wang LI, Quah CS, Yardley DA (2012) Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study. Breast Cancer Res Treat 135(3):875–883. doi: 10.1007/s10549-012-2209-z PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D (2006) Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24(18):2786–2792. doi: 10.1200/jco.2005.04.1764 CrossRefPubMedGoogle Scholar
  69. 69.
    Shi YX, Tan YT, Yuan ZY, Wang SS, Peng RJ, An X, Cao Y, Jin Y, Cai XY, Sun YL, Teng XY, Liu DG (2012) Comparison of overall survival between the early use and delayed use of Trastuzumab therapy groups: a retrospective analysis of 128 patients with HER-2-positive advanced breast cancer. Med Oncol 29(1):39–47. doi: 10.1007/s12032-010-9798-3 CrossRefPubMedGoogle Scholar
  70. 70.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi: 10.1056/nejm200103153441101 CrossRefPubMedGoogle Scholar
  71. 71.
    Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, Murphy M, Stewart SJ (2004) Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22(6):1063–1070. doi: 10.1200/jco.2004.06.557 CrossRefPubMedGoogle Scholar
  72. 72.
    Untch M, Muscholl M, Tjulandin S, Jonat W, Meerpohl HG, Lichinitser M, Manikhas AG, Coumbos A, Kreienberg R, du Bois A, Harbeck N, Jackisch C, Muller V, Pauschinger M, Thomssen C, Lehle M, Catalani O, Luck HJ (2010) First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial. J Clin Oncol 28(9):1473–1480. doi: 10.1200/jco.2009.21.9709 CrossRefPubMedGoogle Scholar
  73. 73.
    Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ (2011) Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol 29(2):149–156. doi: 10.1200/jco.2010.28.6450 CrossRefPubMedGoogle Scholar
  74. 74.
    Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726CrossRefPubMedGoogle Scholar
  75. 75.
    Wardley AM, Pivot X, Morales-Vasquez F, Zetina LM, de Fatima Dias Gaui M, Reyes DO, Jassem J, Barton C, Button P, Hersberger V, Torres AA (2010) Randomized phase II trial of first-line trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J Clin Oncol 28(6):976–983. doi: 10.1200/jco.2008.21.6531 CrossRefPubMedGoogle Scholar
  76. 76.
    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 (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 28(25):3910–3916. doi: 10.1200/jco.2009.27.3615 CrossRefPubMedGoogle Scholar
  77. 77.
    Du XL, Xia R, Burau K, Liu CC (2011) Cardiac risk associated with the receipt of anthracycline and trastuzumab in a large nationwide cohort of older women with breast cancer, 1998–2005. Med Oncol 28(Suppl 1):S80–S90. doi: 10.1007/s12032-010-9717-7 CrossRefPubMedGoogle Scholar
  78. 78.
    Huszno J, Les D, Sarzyczny-Slota D, Nowara E (2013) Cardiac side effects of trastuzumab in breast cancer patients—single centere experiences. Contemp Oncol (Pozn) 17(2):190–195. doi: 10.5114/wo.2013.34624 Google Scholar
  79. 79.
    Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640. doi: 10.1016/s0140-6736(11)61847-3 CrossRefPubMedGoogle Scholar
  80. 80.
    Sun X, Briel M, Walter SD, Guyatt GH (2010) Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 340:c117. doi: 10.1136/bmj.c117 CrossRefPubMedGoogle Scholar
  81. 81.
    National Cancer Institute. Cancer of the breast. http://seer.cancer.gov/statfacts/html/breast.html. Accessed 27 Sept 2015
  82. 82.
    Golder S, Loke YK, Bland M (2011) Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview. PLoS Med 8(5):e1001026. doi: 10.1371/journal.pmed.1001026 PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Ezaz G, Long JB, Gross CP, Chen J (2014) Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 3(1):e000472. doi: 10.1161/JAHA.113.000472 PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.
    Chen T, Xu T, Li Y, Liang C, Chen J, Lu Y, Wu Z, Wu S (2011) Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis. Cancer Treat Rev 37(4):312–320. doi: 10.1016/j.ctrv.2010.09.001 CrossRefPubMedGoogle Scholar
  85. 85.
    Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP (2015) Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372(2):134–141. doi: 10.1056/NEJMoa1406281 PubMedCentralCrossRefPubMedGoogle Scholar
  86. 86.
    Albini A, Cesana E, Donatelli F, Cammarota R, Bucci EO, Baravelli M, Anza C, Noonan DM (2011) Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors. Future Cardiol 7(5):693–704. doi: 10.2217/fca.11.54 CrossRefPubMedGoogle Scholar
  87. 87.
    Hamza TH, van Houwelingen HC, Stijnen T (2008) The binomial distribution of meta-analysis was preferred to model within-study variability. J Clin Epidemiol 61(1):41–51. doi: 10.1016/j.jclinepi.2007.03.016 CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2015

Authors and Affiliations

  • Stefania Mantarro
    • 1
  • Marta Rossi
    • 2
    • 3
  • Martina Bonifazi
    • 2
  • Roberto D’Amico
    • 4
  • Corrado Blandizzi
    • 1
  • Carlo La Vecchia
    • 3
  • Eva Negri
    • 2
  • Lorenzo Moja
    • 5
    • 6
  1. 1.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Department of EpidemiologyIRCSS Institute for Pharmacological Research “Mario Negri”MilanItaly
  3. 3.Department of Clinical Medicine and Community HealthUniversity of MilanMilanItaly
  4. 4.Italian Cochrane CentreUniversity of Modena and Reggio EmiliaModenaItaly
  5. 5.Department of Biomedical Sciences for Public HealthUniversity of MilanMilanItaly
  6. 6.Clinical Epidemiology UnitIRCCS Orthopedic Institute GaleazziMilanItaly

Personalised recommendations