β-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced Cardiotoxicity
2013; Lippincott Williams & Wilkins; Volume: 6; Issue: 3 Linguagem: Inglês
10.1161/circheartfailure.113.000267
ISSN1941-3297
Autores Tópico(s)HER2/EGFR in Cancer Research
ResumoHomeCirculation: Heart FailureVol. 6, No. 3β-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced Cardiotoxicity Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBβ-Adrenergic Blockade for Anthracycline- and Trastuzumab-Induced CardiotoxicityIs Prevention Better Than Cure? Anju Nohria, MD Anju NohriaAnju Nohria From the Cardio-Oncology Program, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Originally published1 May 2013https://doi.org/10.1161/CIRCHEARTFAILURE.113.000267Circulation: Heart Failure. 2013;6:358–361IntroductionBreast cancer is the second leading cause of cancer-related death among women in the United States.1 Approximately 25% to 30% of breast cancers have overexpression of human epidermal growth factor receptor 2 (HER2), which is associated with an adverse prognosis.2 Adjuvant chemotherapy with trastuzumab, the humanized monoclonal antibody that directly targets HER2, significantly improves disease-free and overall survival in these patients.3 However, trastuzumab, especially when given in combination with anthracyclines, has been associated with asymptomatic and symptomatic left ventricular (LV) dysfunction3 that can lead to premature discontinuation of trastuzumab therapy and significant cardiac morbidity.Article see p 420In this issue of Circulation: Heart Failure, Seicean et al4 retrospectively evaluated the incidence of new symptomatic heart failure (HF) in patients with breast cancer treated with anthracyclines, trastuzumab, or both, at the Cleveland Clinic between 2005 and 2010. Using 1:2 propensity matching, they compared patients on continuous β-blockers during cancer treatment to those not on β-blockade, and assessed the effect of incidental β-blocker use on new symptomatic HF and noncardiac mortality during a median follow-up of ≈3 years. The results of this study show that trastuzumab, when given alone or in combination with anthracyclines, substantially increased the risk of symptomatic HF compared with anthracyclines alone (hazard ratio, 9.5; 95% confidence interval, 3.9–23.1). Furthermore, incidental β-blocker use significantly reduced the incidence of symptomatic HF (hazard ratio, 0.2; 95% confidence interval, 0.1–0.7) but did not affect noncardiac mortality in patients with breast cancer treated with trastuzumab, anthracyclines, or both.This article highlights 2 important issues: (1) it emphasizes the magnitude of trastuzumab cardiotoxicity in the real world, and (2) it provides support for the hypothesis that prophylactic β-blocker use may be cardioprotective in patients receiving trastuzumab, anthracyclines, or both.Mechanisms of Anthracycline and Trastuzumab CardiotoxicityAnthracyclines cause a dose-dependent toxicity that is felt to be irreversible.5 They induce myocardial injury by multiple mechanisms.6 A critical component seems to be the generation of oxygen free radicals that induce lipid peroxidation leading to membrane damage. Anthracyclines also directly and indirectly inhibit gene transcription, mitochondrial function, and energy production within the cell. In addition, they suppress the expression and activity of transcription factors that regulate sarcomere synthesis and survival and promote the degradation of sarcomeric proteins, such as titin.In contrast, trastuzumab-induced cardiomyopathy is dose-independent and largely reversible.7 Trastuzumab targets erbB2, a receptor tyrosine kinase, which is essential for cardiac development. In mice, deletion of erbB2 results in dilated cardiomyopathy.8 Under conditions of stress and anthracycline exposure, heterodimerization of erbB2 with other erbB receptors activates myocardial growth and survival pathways in response to the ligand, neuregulin-1.9,10 Thus, trastuzumab, when used in combination with anthracyclines, accentuates anthracycline-mediated myocardial damage by inhibiting the protective effects of neuregulin-1.Incidence of Trastuzumab-Induced Symptomatic LV DysfunctionPrevious studies suggest that trastuzumab use, especially in conjunction with anthracyclines, leads primarily to asymptomatic LV dysfunction.11,12 Early recognition, accompanied by withdrawal of trastuzumab and institution of standard HF therapies, leads to normalization of LV function in ≈60% of patients.13 Therefore, current guidelines recommend assessing LV function before anthracycline and trastuzumab therapy and then every 3 months during trastuzumab treatment.14 Seicean et al4 defined cases of cardiotoxicity by identifying the first hospitalization for new HF in patients receiving anthracyclines or trastuzumab. Their results show an alarmingly high rate of symptomatic HF in trastuzumab-treated patients (19.6%). In contrast, only 1% of those treated with anthracyclines alone developed new symptomatic HF. Previous studies have shown that older patients with pre-existing cardiac risk factors may be at an increased risk for developing cardiotoxicity.12 However, in this study, age was cardioprotective, and there was no association between hypertension and diabetes mellitus and the development of cardiotoxicity. Furthermore, at odds with other studies was the finding that the majority of the patients (78/98) with trastuzumab cardiotoxicity were not treated with anthracyclines.12 This makes one wonder whether the high rates of symptomatic HF observed in this study reflect less rigorous monitoring of LV function during trastuzumab therapy in a real-world setting as opposed to clinical trials. Despite its limitations, the results of this study and a recent analysis of the SEER (Surveillance Epidemiology and End Results) database12 make it clear that trastuzumab is associated with significant cardiotoxicity that poses a considerable clinical challenge for physicians attempting to balance the competing risks of cancer or cardiac mortality.β-Adrenergic Blockade to Prevent Anthracycline-Induced CardiomyopathyThe more intriguing finding of this article is the notion that concomitant β-blocker use may be cardioprotective in patients receiving trastuzumab, anthracyclines, or both.There are no published data assessing the effect of prophylactic β-antagonists on trastuzumab-induced cardiomyopathy. However, 3 studies have evaluated the use of β-blockers to prevent anthracycline-induced cardiotoxicity. Kalay et al15 examined early cardiotoxicity in 50 patients randomized to receive either carvedilol or placebo, while undergoing anthracycline chemotherapy. Although LV ejection fraction and dimensions did not change from baseline in the carvedilol group, LV ejection fraction decreased (P<0.001) and LV dimensions increased (P<0.01) significantly during a 6-month period in the control subjects. Georgakopoulos et al16 conducted an open label study, where they randomized 147 patients undergoing anthracycline chemotherapy to metoprolol, enalapril, or placebo for 1 year. They found that although the incidence of symptomatic HF was less in patients treated with either metoprolol or enalapril, the difference did not achieve clinical significance. Moreover, there was no difference in echocardiographic parameters of LV function among the 3 groups. A recent small study evaluated the effects of concomitant nebivolol in 45 patients with breast cancer and found that LV dimensions and ejection fraction did not change after 6 months in the nebivolol group but were worse in those treated with placebo (P=0.01).17 NT–pro-brain natriuretic peptide levels also remained unchanged at 6 months compared with baseline in the nebivolol group but were significantly increased with placebo (P=0.01).17 Although these results are encouraging, it remains unclear whether prophylactic β-blocker use reduces the incidence of symptomatic HF in patients undergoing anthracycline-based chemotherapy. Furthermore, the disparate effect of β-blockers on LV dimensions in the above mentioned studies15–17 raises the concern that all β-blockers may not be equally effective at reducing anthracycline-induced cardiotoxicity.Are all β-Blockers Equally Cardioprotective?Several preclinical studies provide a mechanistic basis by which β-blockers may confer protection against anthracycline-induced cardiotoxicity. However, these studies suggest that all β-blockers may not be equally effective in preventing chemotherapy-induced cardiotoxicity. In animal models of doxorubicin-induced cardiomyopathy, β2 receptor–deficient mice develop severe and lethal acute cardiotoxicity, and the additional deletion of the β1 receptor rescues this completely.18 Thus, in animals exposed to anthracyclines, β1 activation seems to be cardiotoxic, whereas β2 activation is cardioprotective. The cardioprotective effect of β2 receptor activation seems to be mediated, in part, via activation of prosurvival kinases and a decrease in the intracellular concentration of calcium, thus attenuating the mitochondrial dysfunction seen with anthracyclines.19 These data suggest that β1 selective antagonists, rather than nonselective β blockers, may offer greater protection against anthracycline-induced cardiomyopathy. However, an analysis of cancer registry data suggests that β2, but not β1 blockade, limits breast cancer–specific mortality.20 Therefore, the net effect of β1 versus β2 blockade in preventing cancer-related cardiotoxicity remains unclear.Carvedilol, a nonselective β and α1 adrenergic antagonist with antioxidant properties, has also been shown to reduce anthracycline-induced cardiotoxicity. Carvedilol protects cells against doxorubicin toxicity by reducing oxidative stress and apoptosis.21,22 Antioxidant activity of carvedilol, rather than its β-blocking action, seems to be responsible for its cardioprotective effects. A study comparing carvedilol to atenolol, a β1 selective antagonist without antioxidant properties, showed that carvedilol, but not atenolol, prevented mitochondrial damage and reduced the histopathologic changes associated with doxorubicin cardiotoxicity.23 Furthermore, in some tumor cells, carvedilol increases the cytotoxicity of doxorubicin by reversing tumor multidrug resistance via inhibition of the efflux protein, p-glycoprotein.24 Thus, carvedilol may be particularly attractive as a cardioprotective agent because it does not seem to impair the antineoplastic activity of anthracyclines.Nebivolol, a β1 selective antagonist with NO-dependent vasodilatory properties, has also been shown to reduce oxidative stress, decrease markers of myocardial injury, and improve LV function when coadministered with anthracyclines.25 The effect of nebivolol on the cytotoxic potential of chemotherapeutic agents is currently unknown.Unfortunately, Seicean et al4 do not specify the mean dose or type of β-blockers used in their study population. Furthermore, they do not delineate the reduction in HF with β-blockers by type of chemotherapeutic exposure (trastuzumab versus anthracycline). It is conceivable that the low rates of anthracycline-mediated cardiotoxicity observed in this study might reflect the protective effect of β-blockade. Conversely, the high incidence of cardiomyopathy in trastuzumab-treated patients might demonstrate that β-blockers do not offer the same protection with trastuzumab as they do with anthracyclines.Ongoing Trials of β-Blockade in Trastuzumab-Induced CardiomyopathyThe ability of β-adrenergic blockade to prevent trastuzumab-induced cardiomyopathy is currently being addressed in randomized clinical trials. Specifically, the Multidisciplinary Approach to Novel Therapies in Cardiology-Oncology Research Trial (MANTICORE 101—Breast) is evaluating the effect of concomitant bisoprolol, perindopril, or placebo on magnetic resonance imaging indices of LV remodeling patients with HER2+ early stage breast cancer.26 Another study being conducted in collaboration with the National Cancer Institute isalso evaluating the effect of concomitant carvedilol, lisinopril, or placebo on LV ejection fraction at 52 weeks in 468 women with HER2+ breast cancer (NCT01009918). Additional trials evaluating the effect of concomitant metoprolol in patients receiving anthracyclines or trastuzumab for breast cancer are also currently underway (NCT01434134, NCT00806390). Unfortunately, none of these studies are designed to compare different types of β-blockers, nor are they powered to detect a difference in symptomatic HF with these medications.Making the Case for Prevention Rather than CureCardiac toxicity as a result of cancer therapy is now being recognized as a significant problem of increasing proportions. Timely detection of asymptomatic LV dysfunction and institution of standard HF therapies, such as angiotensin-converting enzyme inhibitor and β-blockers, have been shown to attenuate, and sometimes reverse, this cardiac dysfunction.13,27 Even in these instances, the duration of treatment with HF medications remains uncertain. Furthermore, rechallenge with potentially life-saving cancer medications can sometimes results in recurrent and permanent LV dysfunction.13 Although it is well known that cardiac toxicity can manifest many years after anthracycline exposure,28 trials of trastuzumab are relatively recent with limited cardiac follow-up. A recent analysis of the SEER database suggests that the incidence of trastuzumab-induced cardiomyopathy also increases with time from treatment.12 However, despite the increased risk in anthracycline- and trastuzumab-exposed patients, the optimal screening strategy remains unclear. Studies have shown that elevations in serum troponin during chemotherapy might identify patients at risk for acute cardiotoxicity,13,29 but the use of biomarkers to predict delayed toxicity remains unclear. Childhood cancer survivorship guidelines30 recommend periodic life-long surveillance for asymptomatic LV dysfunction, but this may not be practical or cost-effective. On the contrary, waiting for symptomatic HF to initiate treatment might confer a prognosis worse than that with breast cancer for many survivors. Therefore, strategies that limit the development of cardiotoxicity in the first place seem most desirable (Figure).Download figureDownload PowerPointFigure. Management of chemotherapy-induced cardiomyopathy. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; BNP, brain natriuretic peptide; and LVEF, left ventricular ejection fraction.Strategies for Prevention of Anthracycline- and Trastuzumab-Induced CardiotoxicityCurrent strategies to prevent cardiac toxicity include limiting the cumulative anthracycline dose, prolonging infusion times to limit peak serum concentrations of anthracyclines, using liposomal formulations of anthracyclines, administering anthracyclines and trastuzumab sequentially rather than concurrently, and using nonanthracycline-based chemotherapy regimens for the treatment of HER2+ breast cancer.6,31 However, despite these attempts, cardiotoxicity remains prevalent. The iron chelator, dexrazoxane, is the only drug currently approved to prevent anthracycline-induced cardiomyopathy. However, its use in clinical practice is limited by concerns of myelosuppression and reduced tumor response rates.32 In a small single-center prospective study, angiotensin-converting-enzyme inhibitor have been shown to prevent a decline in LV ejection fraction and cardiac events in cancer patients treated with high-dose anthracyclines.29 The concurrent use of statins may also limit anthracycline-induced systolic dysfunction and HF.33,34 The current study adds β-adrenergic antagonists to this list of promising agents.In summary, the cardiotoxicity associated with anthracyclines and trastuzumab is a prevalent and growing problem. In addition to worsening cardiac prognosis, cardiotoxicity often limits patients' treatment options in the event of cancer relapse or lack of adequate response to initial chemotherapy. Therefore finding agents that limit cardiotoxicity without diminishing the antineoplastic activity of chemotherapeutic agents is critical. The current study suggests that β-blockers may be cardioprotective in patients treated with anthracycline or trastuzumab chemotherapy.4 Further prospective studies are needed to evaluate the efficacy of specific β-blockers for preventing chemotherapy-induced cardiotoxicity, while balancing their effects on underlying tumor biology.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Anju Nohria, MD, Cardio-Oncology Program, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA. E-mail [email protected]References1. American Cancer Society. Cancer Facts & Figures 2013.Atlanta: American Cancer Society; 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013. Accessed March 4, 2013.Google Scholar2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. 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Olorundare O, Adeneye A, Akinsola A, Ajayi A, Agede O, Soyemi S, Mgbehoma A, Okoye I, Albrecht R, Ntambi J and Crooks P (2021) Therapeutic Potentials of Selected Antihypertensive Agents and Their Fixed-Dose Combinations Against Trastuzumab-Mediated Cardiotoxicity, Frontiers in Pharmacology, 10.3389/fphar.2020.610331, 11 Dong J and Chen H (2018) Cardiotoxicity of Anticancer Therapeutics, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2018.00009, 5 May 2013Vol 6, Issue 3 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.113.000267PMID: 23694770 Originally publishedMay 1, 2013 KeywordsEditorialsanthracyclinestrastuzumabPDF download Advertisement SubjectsCongenital Heart Disease
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