Abstract
Purpose
Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults.
Methods
We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated.
Results
We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556).
Conclusions
This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.
Similar content being viewed by others
References
Buzdar AU, Marcus C, Smith TL, Blumenschein GR (1985) Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 55(12):2761–2765
Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869–2879. doi:10.1002/cncr.11407
Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339(13):900–905. doi:10.1056/NEJM199809243391307
Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA (2001) Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol: Off J Am Soc Clin Oncol 19(1):191–196
Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717
Perez EA, Suman VJ, Davidson NE, Kaufman PA, Martino S, Dakhil SR, Ingle JN, Rodeheffer RJ, Gersh BJ, Jaffe AS (2004) Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the north central cancer treatment group N9831 intergroup adjuvant trial. J Clin Oncol: Off J Am Soc Clin Oncol 22(18):3700–3704. doi:10.1200/JCO.2004.03.516
Rahman AM, Yusuf SW, Ewer MS (2007) Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomed 2(4):567–583
Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL (2005) Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. J Clin Oncol: Off J Am Soc Clin Oncol 23(34):8597–8605. doi:10.1200/JCO.2005.02.5841
Yoon GJ, Telli ML, Kao DP, Matsuda KY, Carlson RW, Witteles RM (2010) Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies are clinicians responding optimally? J Am Coll Cardiol 56(20):1644–1650. doi:10.1016/j.jacc.2010.07.023
Gajria D, Chandarlapaty S (2011) HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Exp Rev Anticancer Ther 11(2):263–275. doi:10.1586/era.10.226
Ewer MS, Ewer SM (2010) Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol 7(10):564–575. doi:10.1038/nrcardio.2010.121
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 Treatment 117(2):357–364. doi:10.1007/s10549-008-0260-6
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
Volkova M, Russell R 3rd (2011) Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev 7(4):214–220
Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD, Plummer CJ, Wardley AM, Verrill MW (2009) Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer 100(5):684–692. doi:10.1038/sj.bjc.6604909
Heibein AD, Guo B, Sprowl JA, Maclean DA, Parissenti AM (2012) Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization. BMC Cancer 12:381. doi:10.1186/1471-2407-12-381
Mushlin PS, Cusack BJ, Boucek RJ Jr, Andrejuk T, Li X, Olson RD (1993) Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol 110(3):975–982
Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, Mays A, Friedman DL, Ginsberg JP, Hudson MM, Neglia JP, Oeffinger KC, Ritchey AK, Villaluna D, Relling MV, Bhatia S (2012) Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes—a report from the Children's Oncology Group. J Clin Oncol: Off J Am Soc Clin Oncol 30(13):1415–1421. doi:10.1200/JCO.2011.34.8987
Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, Chowbay B (2008) CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Sci 99(10):2045–2054. doi:10.1111/j.1349-7006.2008.00903.x
Bonadonna G, Monfardini S (1969) Cardiac toxicity of daunorubicin. Lancet 1(7599):837
Beauclair S, Formento P, Fischel JL, Lescaut W, Largillier R, Chamorey E, Hofman P, Ferrero JM, Pages G, Milano G (2007) Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity. Ann Oncol: Off J Eur Soc Med Oncol / ESMO 18(8):1335–1341. doi:10.1093/annonc/mdm181
Lemieux J, Diorio C, Cote MA, Provencher L, Barabe F, Jacob S, St-Pierre C, Demers E, Tremblay-Lemay R, Nadeau-Larochelle C, Michaud A, Laflamme C (2013) Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab. Anticancer Res 33(6):2569–2576
Rossi D, Rasi S, Franceschetti S, Capello D, Castelli A, De Paoli L, Ramponi A, Chiappella A, Pogliani EM, Vitolo U, Kwee I, Bertoni F, Conconi A, Gaidano G (2009) Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21. Leukemia 23(6):1118–1126. doi:10.1038/leu.2008.398
Semsei AF, Erdelyi DJ, Ungvari I, Csagoly E, Hegyi MZ, Kiszel PS, Lautner-Csorba O, Szabolcs J, Masat P, Fekete G, Falus A, Szalai C, Kovacs GT (2012) ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol Int 36(1):79–86. doi:10.1042/CBI20110264
Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A, Vonhof S, Bickeboller H, Toliat MR, Suk EK, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nurnberg P, Pfreundschuh M, Trumper L, Brockmoller J, Hasenfuss G (2005) NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112(24):3754–3762. doi:10.1161/CIRCULATIONAHA.105.576850
Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dube MP, Al-Saloos H, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Brown AM, Rogers PC, Phillips MS, Rieder MJ, Carleton BC, Hayden MR, Canadian Pharmacogenomics Network for Drug Safety C, (2012) Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol: Off J Am Soc Clin Oncol 30(13):1422–1428. doi:10.1200/JCO.2010.34.3467
Forrest GL, Gonzalez B, Tseng W, Li X, Mann J (2000) Human carbonyl reductase overexpression in the heart advances the development of doxorubicin-induced cardiotoxicity in transgenic mice. Cancer Res 60(18):5158–5164
Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D'Ascenzo F, Malavasi V, Peruzzi M, Frati G, Palazzoni G (2013) Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol 112(12):1980–1984. doi:10.1016/j.amjcard.2013.08.026
Russell SD, Blackwell KL, Lawrence J, Pippen JE Jr, Roe MT, Wood F, Paton V, Holmgren E, Mahaffey KW (2010) Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol: Off J Am Soc Clin Oncol 28(21):3416–3421. doi:10.1200/JCO.2009.23.6950
Piano MR (2002) Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest 121(5):1638–1650
Obi N, Gornyk D, Heinz J, Vrieling A, Seibold P, Chang-Claude J, Flesch-Janys D (2014) Determinants of newly diagnosed comorbidities among breast cancer survivors. J Cancer Survivorship: Res Pract 8(3):384–393. doi:10.1007/s11764-013-0338-y
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: Off J Soc Cardiovasc Magn Res 10:5. doi:10.1186/1532-429X-10-5
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
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
Walker JR, Singal PK, Jassal DS (2009) The art of healing broken hearts in breast cancer patients: trastuzumab and heart failure. Exp Clin Cardiol 14(3):e62–e67
Zeglinski M, Ludke A, Jassal DS, Singal PK (2011) Trastuzumab-induced cardiac dysfunction: a 'dual-hit'. Exp Clin Cardiol 16(3):70–74
Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM (2002) Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105(13):1551–1554
Acknowledgments
None.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Raquel E. Reinbolt and Roshan Patel contributed equally to first authorship.
Rights and permissions
About this article
Cite this article
Reinbolt, R.E., Patel, R., Pan, X. et al. Risk factors for anthracycline-associated cardiotoxicity. Support Care Cancer 24, 2173–2180 (2016). https://doi.org/10.1007/s00520-015-3008-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00520-015-3008-y