Cardiotoxicity as undesired side effect in the treatment of breast cancer
Michalina Gramatyka 1Abstract
Improvement of methods used in breast cancer therapy resulted in increased treatment effectiveness and prolonged survival of patients. However, this is accompanied by increased frequency of adverse side effects, including cardiac toxicity, which is becoming a serious problem affecting the quality of life and overall survival of cancer patients. The risk of developing cardiovascular complications depends on the type and dose of therapeutic agent used. The highest risk of cardiotoxicity is associated with anthracyclines. They are used frequently in cancer therapy due to their high efficiency but show a dose-dependent toxicity to the cardiovascular system. Cardiotoxicity can also occur with other substances used in breast cancer chemotherapy, as well as with radiotherapy. Combining potentially cardiotoxic therapeutic agents, commonly used in combination therapy, may result in escalation of toxic side effects. Mechanisms of heart damage are different for various cardiotoxic agents, but symptoms usually involve heart failure, ischemic heart disease, arrhythmias, hypertension, valvular diseases or pericarditis and myocarditis. The practices used to reduce the risk of cardiotoxic effects of cancer therapy include evaluation of cardiac functions before treatment and constant monitoring during and after treatment. Furthermore, limited doses and modifications of anticancer agent administration patterns are employed, as well as simultaneous application of cardioprotective agents. Understanding of cardiotoxic mechanisms of agents used in breast cancer treatment can help to develop efficient cardioprotective substances. Because oxidative stress plays an important role in the toxicity of cancer therapy, compounds with antioxidant properties are a very promising target of research.
References
- 1. Acar Z., Kale A., Turgut M., Demircan S., Durna K., Demir S., MericM., Agac M.T.: Efficiency of atorvastatin in the protection of anthracycline-inducedcardiomyopathy. J. Am. Coll. Cardiol., 2011;58: 988-989 2 Adamowicz K., Jassem J.: Kojarzenie radioterapii z hormonoterapiąi leczeniem celowanym u chorych na raka piersi. Onkol. Prak.Klin., 2010; 6: 1-6
Google Scholar - 2. – positive metastatic breast cancer: cardiac safety and efficacy datafrom the herceptin, cyclophosphamide, and epirubicin (HERCULES)Trial. J. Clin. Oncol., 2010; 28: 1473-1480
Google Scholar - 3. Adamowicz K., Marczewska M., Jassem J.: Kojarzenie radioterapiii chemioterapii u chorych na raka piersi. Onkol. Prak. Klin.,2008; 4: 127-134
Google Scholar - 4. Adams M.J., Hardenbergh P.H., Constine L.S., Lipshultz S.E.: Radiation-associatedcardiovascular disease. Crit. Rev. Oncol. Hematol.,2003; 45: 55-75
Google Scholar - 5. Arriola E., Rodriguez-Pinilla S.M., Lambros M.B., Jones R.L., James M.,Savage K., Smith I.E., Dowsett M., Reis-Filho J.S.: Topoisomerase II alphaamplification may predict benefit from adjuvant anthracyclines in HER2positive early breast cancer. Breast Cancer Res. Treat., 2007; 106: 181-189
Google Scholar - 6. Asensio-Lopez M.C., Lax A., Pascual-Figal D.A., Valdes M., Sanchez-MasJ.: Metformin protects against doxorubicin-induced cardiotoxicity:involvement of the adiponectin cardiac system. FreeRadic. Biol. Med., 2011; 51: 1861-1871
Google Scholar - 7. Ashour A.E., Sayed-Ahmed M.M., Abd-Allah A.R., Korashy H.M.,Maayah Z.H., Alkhalidi H., Mubarak M., Alhaider A.: Metformin rescuesthe myocardium from doxorubicin-induced energy starvationand mitochondrial damage in rats. Oxid. Med. Cell. Longev., 2012;2012: 434195
Google Scholar - 8. Balsam P., Szmit S.: Diagnostyka i monitorowanie sercowo-naczyniowychpowikłań chemioterapii. Pol. Przegl. Kardiol., 2010; 12: 219-224
Google Scholar - 9. Bednar F., Simeone D.M.: Metformin and cancer stem cells: olddrug, new targets. Cancer Prev. Res., 2012; 5: 351-354
Google Scholar - 10. Błażejewski J., Sinkiewicz W., Karasek D.: Sercowo-naczyniowepowikłania chemioterapii. Pol. Przegl. Kardiol., 2010; 12: 301-305
Google Scholar - 11. Cardinale D., Colombo A., Torrisi R., Sandri M.T., Civelli M.,Salvatici M., Lamantia G., Colombo N., Cortinovis S., Dessanai M.A.,Nole F., Veglia F., Cipolla C.M.: Trastuzumab-induced cardiotoxicity:clinical and prognostic implications of troponin I evaluation. J. Clin.Oncol., 2010; 28: 3910-3916
Google Scholar - 12. Choueiri T.K., Mayer E.L., Je Y., Rosenberg J.E., Nguyen P.L., AzziG.R., Bellmunt J., Burstein H.J., Schutz F.A.: Congestive heart failurerisk in patients with breast cancer treated with bevacizumab. J. Clin.Oncol., 2011; 29: 632-638
Google Scholar - 13. Cottin Y., Touzery C., Dalloz F., Coudert B., Toubeau M., RiedingerA., Louis P., Wolf J.E., Brunotte F.: Comparison of epirubicin anddoxorubicin cardiotoxicity induced by low doses: evolution of thediastolic and systolic parameters studied by radionucide angiography.Clin. Cardiol., 1998; 21: 665-670
Google Scholar - 14. Czerepińska A.: Wpływ terapii celowanej opartej na lapatynibiena czynność serca. Implikacje kliniczne. Onkol. Prak. Klin.,2011; 7: E6-E10
Google Scholar - 15. De Angelis A., Piegari E., Cappetta D., Marino L., Filippelli A.,Berrino L., Fereira-Martins J., Zheng H., Hosoda T., Rota M., UrbanekK., Kajstura J., Leri A., Rossi F., Anversa P.: Anthracycline cardiomyopathyis mediated by depletion of the cardiac stem cell pool andis rescued by restoration of progenitor cell function. Circulation,2010; 121: 276-292
Google Scholar - 16. Deboever G., Hiltrop N., Cool M., Lambrecht G.: Alternativetreatment options in colorectal cancer patients with 5-fluorouracilor capecitabine-induced cardiotoxicity. Clin. Colorectal Cancer,2013; 12: 8-14
Google Scholar - 17. Dessi M., Madeddu C., Cadeddu C., Piras A., Mercuro G., MantovaniG.: Cardioprotective effect of telmisartan in cancer patientstreated with epirubicin. J. Clin. Oncol. (Meeting Abstracts), 2010;27: e20671
Google Scholar - 18. Dhesi S., Chu M., Blevins G., Paterson I., Larratt L., Oudit G., KimD.: Cyclophosphamide-induced cardiomyopathy: a case report, review,and recommendations for management. J. Investig. Med. HighImpact Case Reports, 2013; 1: 1-7
Google Scholar - 19. Dowling R.J., Zakikhani M., Fantus I.G., Pollak M., SonenbergN.: Metformin inhibits mammalian target of rapamycin–dependenttranslation initiation in breast cancer cells. Cancer Res., 2007;67: 10804-10812
Google Scholar - 20. Ejlertsen B., Jensen M.B., Nielsen K.V., Balslev E., RasmussenB.B., Willemoe G.L., Hertel P.B., Knoop A.S., Mouridsen H.T., BrunnerN.: HER2, TOP2A, and TIMP-1 and responsiveness to adjuvantanthracycline-containing chemotherapy in high-risk breast cancerpatients. J. Clin. Oncol., 2010; 28: 984-990
Google Scholar - 21. El-Awady el-S.E., Moustafa Y.M., Abo-Elmatty D.M., Radwan A.:Cisplatin-induced cardiotoxicity: mechanisms and cardioprotectivestrategies. Eur. J. Pharmacol., 2011; 650: 335-341
Google Scholar - 22. Ewer M.S., Ewer S.M.: Cardiotoxicity of anticancer treatments:what the cardiologist needs to know. Nat. Rev. Cardiol., 2010; 7: 564-575
Google Scholar - 23. Ferreira A.L., Matsubara L.S., Matsubara B.B.: Anthracyclineinducedcardiotoxicity. Cardiovasc. Hematol. Agents. Med. Chem.,2008; 6: 278-281
Google Scholar - 24. Fiuza M., Magalhaes A.: Trastuzumab and cardiotoxicity. W:Cardiotoxicity of Oncologic Treatments, red.: M. Fiuza. InTech, 2012,131-152
Google Scholar - 25. Gaya A.M., Ashford R.F.: Cardiac complications of radiation therapy.Clin. Oncol., 2005; 17: 153-159
Google Scholar - 26. Gennari A., De Tursi M., Carella C., Ricevuto E., Orlandini C.,Frassoldati A., Conte P., Bruzzi P., Iacobelli S.: Epirubicin plus lowdosetrastuzumab in HER2 positive metastatic breast cancer. BreastCancer Res. Treat., 2009; 115: 131-136
Google Scholar - 27. Gewirtz D.A.: A critical evaluation of the mechanisms of actionproposed for the antitumor effects of the anthracycline antibioticsadriamycin and daunorubicin. Biochem. Pharmacol., 1999; 57: 727-741
Google Scholar - 28. Gianni L., Salvatorelli E., Minotti G.: Anthracycline cardiotoxicityin breast cancer patients: synergism with trastuzumab and taxanes.Cardiovasc. Toxicol., 2007; 7: 67-71
Google Scholar - 29. Giordano S.H., Kuo Y.F., Freeman J.L., Buchholz T.A., HortobagyiG.N., Goodwin J.S.: Risk of cardiac death after adjuvant radiotherapyfor breast cancer. J. Natl. Cancer Inst., 2005; 97: 419-424
Google Scholar - 30. Gligorov J., Lotz J.P.: Preclinical pharmacology of the taxanes:implications of the differences. Oncologist, 2004; 9: 3-8
Google Scholar - 31. Goldberg M.A., Antin J.H., Guinan E.C., Rappeport J.M.: Cyclophosphamidecardiotoxicity: an analysis of dosing as a risk factor.Blood, 1986; 68: 1114-1118
Google Scholar - 32. Harris E.E., Correa C., Hwang W.T., Liao J., Litt H.I., Ferrari V.A.,Solin L.J.: Late cardiac mortality and morbidity in early-stage breastcancer patients after breast-conservation treatment. J. Clin. Oncol.,2006; 24: 4100-4106
Google Scholar - 33. Hawkes E.A., Okines A.F., Plummer C., Cunningham D.: Cardiotoxicityin patients treated with bevacizumab is potentially reversible.J. Clin. Oncol., 2011; 29: e560-e562
Google Scholar - 34. Healey Bird B.R., Swain S.M.: Cardiac toxicity in breast cancersurvivors: review of potential cardiac problems. Clin. Cancer Res.,2008; 14: 14-24
Google Scholar - 35. Jensen S.A., Sorensen J.B.: 5-Fluorouracil-based therapy inducesendovascular injury having potential significance to developmentof clinically overt cardiotoxicity. Cancer Chemother. Pharmacol.,2012; 69: 57-64
Google Scholar - 36. Katayama M., Imai Y., Hashimoto H., Kurata M., Nagai K., TamitaK., Morioka S., Frukawa Y.: Fulminant fatal cardiotoxicity followingcyclophosphamide therapy. J. Cardiol., 2009; 54: 330-334
Google Scholar - 37. Khasraw M., Bell R., Dang C.: Epirubicin: is it like doxorubicin inbreast cancer? A clinical review. Breast, 2012; 21: 142-149
Google Scholar - 38. Kik K., Szmigiero L.: Deksrazoksan (ICRF-187) – czynnik kardioochronnyi modulator działania niektórych leków przeciwnowotworowych.Postępy Hig. Med. Dośw., 2006; 60: 584-590
Google Scholar - 39. Kopeć A., Piątkowska E., Leszczyńska T., Bieżanowska-Kopeć R.:Prozdrowotne właściwości resweratrolu. Żywność Nauka TechnologiaJakość, 2011; 5: 5-15
Google Scholar - 40. Kourelis T.V., Siegel R.D.: Metformin and cancer: new applicationsfor an old drug. Med. Oncol., 2011; 29: 1314-1327
Google Scholar - 41. Krzakowski M., Jassem J., Olszewski W., Pieńkowski T., Steffen J.,Tchórzewska H., Towpik E., Wesołowska E.: Rak piersi. W: Zaleceniapostępowania diagnostyczno-terapeutycznego w nowotworach zło-śliwych u dorosłych, red. Krzakowski M. PUO, Warszawa 2003, 107-140
Google Scholar - 42. Kucharska W., Negrusz-Kawecka M., Gromkowska M.: Cardiotoxicityof oncological treatment in children. Adv. Clin. Exp. Med.,2012; 21: 281-288
Google Scholar - 43. Liu B., Fan Z., Edgerton S.M., Yang X., Lind S.E., Thor A.D.: Potentanti-proliferative effects of metformin on trastuzumab-resistantbreast cancer cells via inhibition of erbB2/IGF-1 receptor interactions.Cell Cycle, 2011; 10: 2959-2966
Google Scholar - 44. Martin M., Esteva F.J., Alba E., Khandheria B., Perez-Isla L., Garcia-SaenzJ.A., Marquez A., Sengupta P., Zamorano J.: Minimizingcardiotoxicity while optimizing treatment efficacy with trastuzumab:review and expert recommendations. Oncologist, 2009; 14: 1-11
Google Scholar - 45. Mokni M., Hamlaoui-Guesmi S., Amri M., Marzouki L., Limam F.,Aouani E.: Grape seed and skin extract protects against acute chemotherapytoxicity induced by doxorubicin in rat heart. Cardiovasc.Toxicol., 2012; 12: 158-165
Google Scholar - 46. Monsuez J.J., Charniot J.C., Vignat N., Artigou J.Y.: Cardiac sideeffectsof cancer chemotherapy. Int. J. Cardiol., 2010; 144: 3-15
Google Scholar - 47. Morabito A., Piccirillo M.C., De Maio E., Di Maio M., Perrone F.:Trastuzumab beyond progression: is the risk of cardiac toxicity reallynot increased? J. Clin. Oncol., 2009; 27: e123
Google Scholar - 48. Morris P.G., Hudis C.A.: Trastuzumab-related cardiotoxicity followinganthracycline-based adjuvant chemotherapy: how worriedshould we be? J. Clin. Oncol., 2010; 28: 3407-3410
Google Scholar - 49. Nitiss J.L.: Targeting DNA topoisomerase II in cancer chemotherapy.Nat. Rev. Cancer, 2009; 9: 338-350
Google Scholar - 50. Okura Y., Kawasaki T., Kanbayashi C., Sato N.: A case of epirubicinassociatedcardiotoxicity progressing to life-threatening heart failureand splenic thromboembolism. Intern. Med., 2012; 51: 1355-1360
Google Scholar - 51. O’Malley F.P., Chia S., Tu D., Shepherd L.E., Levine M.N., BramwellV.H., Andrulis I.L., Pritchard K.I.: Topoisomerase II alpha andresponsiveness of breast cancer to adjuvant chemotherapy. J. Natl.Cancer Inst., 2009; 101: 644-650
Google Scholar - 52. Partridge A.H., Burstein H.J., Winer E.P.: Side effects of chemotherapyand combined chemohormonal therapy in women with early-stagebreast cancer. J. Natl. Cancer Inst. Monogr., 2001; 30: 135-142
Google Scholar - 53. Piasek A., Bartoszek A., Namieśnik J.: Substancje pochodzeniaroślinnego przeciwdziałające kardiotoksyczności towarzyszącej chemioterapiinowotworów. Postępy Hig. Med. Dośw., 2009; 63: 142-158
Google Scholar - 54. Pritchard K.I., Messersmith H., Elavathil L., Trudeau M., O’MalleyF., Dhesy-Thind B.: HER-2 and topoisomerase II as predictors of responseto chemotherapy. J. Clin. Oncol., 2008; 26: 736-744
Google Scholar - 55. Prosnitz R.G., Hubbs J.L., Evans E.S., Zhou S.M., Yu X., BlazingM.A., Hollis D.R., Tisch A., Wong T.Z., Borges-Neto S., HardenberghP.H., Marks L.B.: Prospective assessment of radiotherapy-associatedcardiac toxicity in breast cancer patients: analysis of data 3 to 6 yearsafter treatment. Cancer, 2007; 110: 1840-1850
Google Scholar - 56. Przybyszewski W., Wideł M., Rzeszowska-Wolny J.: Kardiotoksycznenastępstwa promieniowania jonizującego i antracyklin.Postępy Hig. Med. Dośw., 2006; 60: 397-405
Google Scholar - 57. Rahman A.M., Yusuf S.W., Ewer M.S.: Anthracycline-inducedcardiotoxicity and the cardiac-sparing effect of liposomal formulation.Int. J. Nanomedicine, 2007; 2: 567-583
Google Scholar - 58. Rezk Y.A., Balulad S.S., Keller R.S., Bennett J.A.: Use of resveratrolto improve the effectiveness of cisplatin and doxorubicin: studyin human gynecologic cancer cell lines and in rodent heart. Am. J.Obstet. Gynecol., 2006; 194: e23-e26
Google Scholar - 59. Ryberg M., Nielsen D., Cortese G., Nielsen G., Skovsgaard T., AndersenP.K.: New insight into epirubicin cardiac toxicity: competingrisks analysis of 1097 breast cancer patients. J. Natl. Cancer Inst.,2008; 100: 1058-1067
Google Scholar - 60. Salvatorelli E., Menna P., Cascegna S., Liberi G., Calafiore A.M.,Gianni L., Minotti G.: Paclitaxel and docetaxel stimulation of doxorubicinolformation in the human heart: implications for cardiotoxicityof doxorubicin-taxane chemotherapies. J. Pharmacol. Exp.Ther., 2006; 318: 424-433
Google Scholar - 61. Senkus-Konefka E., Jassem J.: Cardiovascular effects of breastcancer radiotherapy. Cancer Treat. Rev., 2007; 33: 578-593
Google Scholar - 62. Shaffer R., Tyldesley S., Rolles M., Chia S., Mohamed I.: Acute cardiotoxicitywith concurrent trastuzumab and radiotherapy includinginternal mammary chain nodes: a retrospective single-institutionstudy. Radiother. Oncol., 2008; 90: 122-126
Google Scholar - 63. Shaikh A.Y., Shih J.A.: Chemotherapy-induced cardiotoxicity.Curr. Heart Fail. Rep., 2012; 9: 117-127
Google Scholar - 64. Simunek T., Sterba M., Popelova O., Adamcova M., Hrdina R.,Gersl V.: Anthracycline-induced cardiotoxicity: overview of studiesexamining the roles of oxidative stress and free cellular iron. Pharmacol.Rep., 2009; 61: 154-171
Google Scholar - 65. Sinkiewicz W., Banach J.: Powikłania sercowo-naczyniowe u chorychna raka piersi – aspekty diagnostyczne. Onkol. Prak. Klin., 2010;6: 171-180
Google Scholar - 66. Szuławska A., Czyż M.: Molekularne mechanizmy działania antracyklin.Postępy Hig. Med. Dośw., 2006; 60: 78-100
Google Scholar - 67. Tabaczar S., Koceva-Chyła A., Matczak K., Gwoździński K.: Molekularnemechanizmy aktywności przeciwnowotworowej taksanów.I. Oddziaływanie docetakselu na microtubule. Postępy Hig. Med.Dośw., 2010; 64: 568-581
Google Scholar - 68. Todorova V., Vanderpool D., Blossom S., Nwokedi E., HenningsL., Mrak R., Klimberg V.S.: Oral glutamine protects against cyclophosphamide-inducedcardiotoxicity in experimental rats throughincrease of cardiac glutathione. Nutrition, 2009; 25: 812-817
Google Scholar - 69. Trudeau M., Pagani O.: Epirubicin in combination with the taxanes.Semin. Oncol., 2001; 28 (4 Suppl. 12): 41-50
Google Scholar - 70. Untch M., Muscholl M., Tjulandin S., Jonat W., Meerpohl H.G.,Lichinitser M., Manikhas A.G., Coumbos A., Kreinberg R., du BoisA., Harbeck N., Jackisch C., Muller V., Pauschinger M., ThomssenC.: First-line trastuzumab plus epirubicin and cyclophosphamidetherapy in patients with human epidermal growth factor receptor
Google Scholar - 71. Wadhwa D., Fallah-Rad N., Grenier D., Krahn M., Fang T., AhmadieR., Walker J.R., Lister D., Arora R.C., Barac I., Morris A., JassalD.S.: Trastuzumab mediated cardiotoxicity in the setting of adjuvantchemotherapy for breast cancer: a retrospective study. Breast CancerRes. Treat., 2009; 117: 357-364
Google Scholar - 72. Willmore E., Frank A., Padget K., Tilby M.J., Austin C.A.: Etoposidetargets topoisomerase IIα and IIβ in leukemic cells: isoform-specificcleavable complexes visualized and quantified in situ by a novelimmunofluorescence technique. Mol. Pharmacol., 1998; 53: 78-85
Google Scholar - 73. Wysocki P., Hutka M.: Cardiotoxicity of 5-fluorouracil in a youngcolorectal cancer patient – case report and review of literature. Arch.Med. Sci., 2009; 5: 277-280
Google Scholar - 74. Zakikhani M., Dowling R., Fantus I.G., Sonenberg N., Pollak M.:Metformin is an AMP kinase-dependent growth inhibitor for breastcancer cells. Cancer Res., 2006; 66: 10269-10273
Google Scholar - 75. Zeglinski M., Ludke A., Jassal D.S., Singal P.K.: Trastuzumabinducedcardiac dysfunction: a ‘dual-hit’. Exp. Clin. Cardiol., 2011;16: 70-74
Google Scholar - 76. Ziółkowska E., Woźniak-Wiśniewska A., Wiśniewski T., MakarewiczR., Sinkiewicz W.: Wpływ radioterapii na zaburzenia pracyserca. Współczesna Onkologia, 2009; 13: 16-21
Google Scholar