Article

PDF
Access to the PDF text
Advertising


Free Article !

Archives of cardiovascular diseases
Volume 110, n° 2
pages 69-71 (février 2017)
Doi : 10.1016/j.acvd.2016.12.004
Received : 12 September 2016 ;  accepted : 14 December 2016
Implications of excess weight in the cardiotoxicity of anthracyclines and trastuzumab in breast cancer
Implications du surpoids et de l’obésité dans la cardiotoxicité des anthracyclines et du trastuzmab dans le cancer du sein
 

Charles Guenancia a, b, , Sylvain Ladoire c, d, François Ghiringelli c, d, Luc Rochette b, Catherine Vergely b, Yves Cottin a, b
a Department of Cardiology, University Hospital, Dijon, France 
b INSERM U866, LPPCM, Dijon, France 
c Department of Medical Oncology, Georges François Leclerc Cancer Centre, Dijon, France 
d Institut National de la Santé et de la Recherche Médicale, Avenir Team, INSERM CRI-866, University of Burgundy, Dijon, France 

Corresponding author at: Service de Cardiologie, CHU Dijon, 14 rue Paul Gaffarel, 21079 Dijon Cedex, France.Service de Cardiologie, CHU Dijon14 rue Paul GaffarelDijon Cedex21079France

Keywords : Cardiotoxicity, Anthracycline, Trastuzumab, Breast cancer, Obesity, Overweight

Mots clés : Cardiotoxicité, Anthracycline, Trastuzumab, Cancer du sein, Obésité, Surpoids

Abbreviations : ABCB, BMI, CI


Anthracyclines are anticancer agents with a broad spectrum of activity in oncological practice. However, the use of anthracyclines is limited by the cardiotoxicity they may induce [1]. Following the administration of anthracyclines in the setting of adjuvant therapy for breast cancer, trastuzumab (Herceptin®), a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER 2) protein, is effective in patients that overexpress this receptor [1]. The addition of trastuzumab therapy to sequential anthracycline and taxane adjuvant treatment reduced the risk of breast cancer recurrence by nearly one-half, and the risk of death by one-third [2]. However, while preclinical studies did not reveal cardiotoxicity, later clinical studies showed that treatment with trastuzumab led to an unexpected incidence of cardiac side-effects [3]. The most frequent effect was reduced systolic ventricular function, asymptomatic or associated with heart failure.

In patients treated with cardiotoxic chemotherapies, the presence of cardiovascular risk factors and previous cardiac disease has been strongly correlated to the onset of cardiotoxicity. Among these factors, age is one of the major predictors of cardiac events after anthracycline treatment, increasing the risk of cardiotoxicity 2.25-fold in patients aged >65 years [4]. Diabetes and dyslipidaemia have also been shown to be associated with a higher incidence of anthracycline cardiomyopathy [5].

Being overweight or obese is a complex health problem that affects a growing number of populations, and several factors increase the incidence of cancer in overweight and obese individuals [6]. Obesity has been associated with poor outcome in patients with breast cancer treated with anthracycline-based chemotherapy, affecting both overall survival and disease-free survival, and is an important prognostic factor, independent of treatment dose [7]. Conversely, other studies have indicated that body mass index (BMI) has no effect on disease-free survival, but only has a significant negative impact on overall survival [8], suggesting that obese women with breast cancer have poorer overall survival, possibly because of a higher risk of non-cancer-related causes of death. This may be explained, in part, by the potentially higher likelihood of cardiac adverse events in obese patients treated with anthracyclines or trastuzumab. Thus, obesity may increase cancer mortality indirectly, through the cardiovascular system [9].

Both total obesity, measured by BMI, and central obesity, measured as waist circumference or waist-to-hip ratio, are associated with an increased risk of cardiovascular death [9]. Although it has been reported for many years that patients with metabolic syndrome have a higher risk of cardiovascular pathologies, their susceptibility to developing chemotherapy-induced cardiac disease was not well documented until recently. In fact, a study has shown that rats fed a high-lipid diet [10] are more sensitive to the cardiotoxic effects of anthracyclines. We recently demonstrated in an “overweight” rodent model (induced by post-natal overfeeding) that these mice are prone to develop cardiac alterations following the administration of anthracyclines and trastuzumab [11]. Consequently, we aimed to transpose our results to humans. We performed a random-effects and a network meta-analysis that included 15 studies and 8745 patients with localized and metastatic breast cancer, treated with adjuvant or neoadjuvant anthracyclines and/or trastuzumab [12]. Being overweight or obese was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and sequential anthracyclines plus a trastuzumab regimen in patients with breast cancer. The pooled odds ratio for cardiotoxicity was 1.38 (95% confidence interval [CI] 1.06–1.80; I 2=43%; n =8745) for being overweight or obese (BMI>25kg/m2), 1.47 (95% CI 0.95–2.28; I 2=47%; n =2615) for being obese, and 1.15 (95% CI 0.83–1.58; I 2=27%; n =2708) for being overweight. Associations were independent of the study design, year of publication, drug regimen (anthracyclines alone versus sequential anthracyclines plus trastuzumab) and definitions of cardiotoxicity and overweight/obese. However, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.

Potential mechanisms involved in the relationship between obesity and cardiotoxicity

One of the first hypotheses raised to explain the higher rates of adverse events in obese patients was that adjustment of the chemotherapy dose to the real weight (instead of the theoretical weight) would lead to higher doses than recommended, and then to higher rates of toxicities [5].

The molecular mechanisms by which obesity can promote anthracycline-induced cardiotoxicity may also involve adiponectin down-regulation [13]. Adiponectin confers resistance to anthracycline-induced myocardial damage through activation of Akt signalling within cardiomyocytes. Adiponectin knockout mice showed exacerbated left ventricle contractile dysfunction following doxorubicin injection, whereas exogenous adiponectin improved doxorubicin-induced left ventricular dysfunction in wild-type and adiponectin knockout mice [13]. However, no study has been performed to elucidate the role of adiponectin in trastuzumab-induced cardiac dysfunction.

Another explanation for the excess risk of cardiotoxicity carried by obese patients may be related to genetic background. Gene expression profiles have revealed perturbed pathways involved in crosstalk between tumours and cardiac function [14]. In fact, the adenosine triphosphate binding cassette, subfamily B, member 1 gene (ABCB-1 ) genotype has been associated with a genetic risk of obesity, but also with varying responses to chemotherapy in patients with cancer. Moreover, another ABC family member, ABCB-8 , which regulates iron export inside mitochondria, has recently been described as a target of anthracyclines, leading to iron accumulation within these organelles, and thus to oxidative damage [15]. Mitochondria appear to be at the crossroads of all the modifications in the cell redox potential induced by ErbB2 overexpression and anthracycline administration [16]; a recently identified adipocytokine, omentin, has been demonstrated to prevent anthracycline-induced cardiomyocyte damage in vitro by inhibiting the production of mitochondrial reactive oxygen species [17]. Interestingly, blood concentrations of omentin, which is mainly expressed in visceral adipose tissues of healthy individuals, are markedly decreased in obese patients.

Perspectives

The first step after this study would be to confirm using prospective data that being overweight and being obese are independent risk factors for cardiotoxicity, i.e. the higher risk is not the result of a higher prevalence of other risk factors in obese patients than in lean patients. As discussed in our paper, because of the specific design of the meta-analysis, and because most of the studies did not include obesity or BMI in the multivariable analysis of the risk factors for cardiotoxicity, it was not possible to adjust the obesity odds ratio for potential confounding factors such as hypertension, previous cardiovascular disease or diabetes. However, in unpublished data that combined the breast cancer populations from two studies by Dr. D. Cardinale, we found that among patients with breast cancer experiencing cardiotoxicity from anthracycline and sequential anthracyclines plus trastuzumab, obese patients were not statistically different from normal-weight patients in terms of rates of hypertension, dyslipidaemia, family history of coronary artery disease and smoking, suggesting that the cardiovascular risk profile of obese women with breast cancer was not significantly (or markedly) different from that of normal-weight patients. If our results are confirmed, overweight and obese patients should certainly benefit from careful cardiac screening and follow-up during and after chemotherapy.

The second step would be to identify the molecular pathways and mechanisms involved in the interaction between obesity and the heart, which lead to a higher likelihood of heart failure after treatment with anthracyclines and trastuzumab. The adipocytokines appear to play a key role in these pathophysiological processes, and elucidation of the paths involved could potentially lead to the development of new therapeutic strategies or targeted drugs.

Sources of funding

None.

Disclosure of interest

The authors declare that they have no competing interest.

References

Rochette L., Guenancia C., Gudjoncik A., and al. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms Trends Pharmacol Sci 2015 ;  36 : 326-348 [cross-ref]
Yu A.F., Yadav N.U., Lung B.Y., and al. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer Breast Cancer Res Treat 2015 ;  149 : 489-495 [cross-ref]
Perez E.A., Rodeheffer R. Clinical cardiac tolerability of trastuzumab J Clin Oncol 2004 ;  22 : 322-329 [cross-ref]
Swain S.M., Whaley F.S., Ewer M.S. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials Cancer 2003 ;  97 : 2869-2879 [cross-ref]
Barrett-Lee P.J., Dixon J.M., Farrell C., and al. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk Ann Oncol 2009 ;  20 : 816-827 [cross-ref]
De Pergola G., Silvestris F. Obesity as a major risk factor for cancer J Obes 2013 ;  2013 : 291546
Renehan A.G., Tyson M., Egger M., Heller R.F., Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies Lancet 2008 ;  371 : 569-578 [cross-ref]
Ladoire S., Dalban C., Roche H., and al. Effect of obesity on disease-free and overall survival in node-positive breast cancer patients in a large French population: a pooled analysis of two randomised trials Eur J Cancer 2014 ;  50 : 506-516 [cross-ref]
Johnson C.B., Davis M.K., Law A., Sulpher J. Shared risk factors for cardiovascular disease and cancer: implications for preventive health and clinical care in oncology patients Can J Cardiol 2016 ;  32 : 900-907 [cross-ref]
Mitra M.S., Donthamsetty S., White B., Mehendale H.M. High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity Toxicol Appl Pharmacol 2008 ;  231 : 413-422 [cross-ref]
Guenancia C., Hachet O., Aboutabl M., and al. Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity Cancer Chemother Pharmacol 2016 ;  77 : 777-785 [cross-ref]
Guenancia C., Lefebvre A., Cardinale D., and al. Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis J Clin Oncol 2016 ;
Maruyama S., Shibata R., Ohashi K., and al. Adiponectin ameliorates doxorubicin-induced cardiotoxicity through akt protein-dependent mechanism J Biol Chem 2011 ;  286 : 32790-32800 [cross-ref]
Brown S.A., Sandhu N., Herrmann J. Systems biology approaches to adverse drug effects: the example of cardio-oncology Nat Rev Clin Oncol 2015 ;  12 : 718-731 [cross-ref]
Ichikawa Y., Ghanefar M., Bayeva M., and al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation J Clin Invest 2014 ;  124 : 617-630 [cross-ref]
Guenancia C., Li N., Rochette L., Vergely C. Letter to the editor: “Doxorubicin and ErbB2 overexpression: another piece in the mitochondrial jigsaw” Am J Physiol Heart Circ Physiol 2016 ;  310 : H1275-H1276
Kazama K., Okada M., Yamawaki H. Adipocytokine, omentin inhibits doxorubicin-induced H9c2 cardiomyoblasts apoptosis through the inhibition of mitochondrial reactive oxygen species Biochem Biophys Res Commun 2015 ;  457 : 602-607 [cross-ref]



© 2017  Elsevier Masson SAS. All Rights Reserved.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline