Breast Cancer
Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction ANTHONY F. YU,a NANDINI U. YADAV,a ANNE A. EATON,b BETTY Y. LUNG,a HOWARD T. THALER,b JENNIFER E. LIU,a CLIFFORD A. HUDIS,a CHAU T. DANG,a RICHARD M. STEINGARTa Departments of aMedicine and bBiostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Cardiotoxicity x Heart failure x Trastuzumab x Adjuvant chemotherapy x Breast cancer
ABSTRACT Background. Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatmentinduced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment.We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF. Methods. We retrospectively evaluated patients with HER2positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of $10% to below 55% or an absolute decrease of $16%. Logistic regression was used to determine the association
between candidate risk factors and treatment-induced cardiotoxicity. Results. Among 573 patients, 92 (16%) developed treatmentinduced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity—all were asymptomatic with LVEF of $50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%–63%), and none developed heart failure during follow-up. Risk factors associated with treatment-induced cardiotoxicity included age (p 5 .011), anthracycline chemotherapy (p 5 .002), and lower pretrastuzumab LVEF (p , .001). Conclusion. Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of $50%, continuous trastuzumab therapy appears to be safe. The Oncologist 2015;20:1105–1110
Implications for Practice: Cardiotoxicity is the most common reason for patients with HER2-positive breast cancer to receive an incomplete course of life-saving trastuzumab therapy. Data from this study suggest that continuous trastuzumab may be safe in patients with asymptomatic cardiotoxicity and left ventricular ejection fraction of $50%. Given the substantial oncologic benefit of trastuzumab, increasing efforts are needed to ensure that patients complete the full course of treatment without interruption. Current recommendations for trastuzumab interruption in patients who develop cardiotoxicity should be re-evaluated.
INTRODUCTION Trastuzumab (Herceptin; Genentech, South San Francisco, CA, https://www.gene.com) added to adjuvant chemotherapy has led to a substantial and sustained improvement in diseasefree survival and overall survival among women with early HER2-positive breast cancer [1–4]. However, this regimen is cardiotoxic and can cause asymptomatic declines in left ventricular ejection fraction (LVEF) or overt symptomatic heart failure. Thus, LVEF monitoring is recommended at baseline and every 3 months during treatment. Although the risk of heart failure during therapy is low, ranging from 1% to 4%, asymptomatic LVEF declines are more common, reported in 7%–19% of patients in clinical trials [2, 5, 6]. In clinical practice, rates of adverse cardiac events are considerably higher,
particularly among older patients who often have underlying cardiovascular disease or risk factors [7–10].These patients are not well represented in clinical trials. In pivotal clinical trials of trastuzumab in the adjuvant setting, trastuzumab was held or discontinued if LVEF failed to meet cardiac safety criteria [1, 5, 11]. As a result, asymptomatic LVEF decline has been reported as the most common reason for premature discontinuation of trastuzumab and can result in an incomplete course of therapy [6, 12]. The cardiac safety of continuing trastuzumab among patients with asymptomatic LVEF declines has not previously been investigated. Accordingly, we conducted a retrospective study among patients with HER2-positive early breast cancer to evaluate the incidence of
Correspondence: Anthony F. Yu, M.D., Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-7932; E-Mail: [email protected] Received March 24, 2015; accepted for publication June 8, 2015; published Online First on August 3, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0125
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asymptomatic LVEF decline or symptomatic heart failure during adjuvant trastuzumab therapy, with particular attention to the clinical course of patients who continued trastuzumab despite an asymptomatic LVEF decline. We also aimed to identify potential risk factors that may be predictive of significant LVEF decline.
PATIENTS AND METHODS Study Population Using the institutional medical records database at Memorial Sloan Kettering Cancer Center, all patients diagnosed with HER2-positive early breast cancer from January 2005 to October 2010 and treated with adjuvant trastuzumab were identified. Patients were eligible for the study if they had at least two LVEF assessments while undergoing breast cancer treatment, including a baseline LVEF performed prior to initiation of treatment. LVEF was assessed by either multigated acquisition scan (MUGA) or two-dimensional echocardiography. Patients participating in a clinical trial were excluded.
Baseline Characteristics For each patient, the following information was collected from the electronic medical record: age, body mass index, tumor characteristics, cancer treatment details, and baseline cardiovascular comorbidities (i.e., hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, smoking status). In addition, baseline treatment with a b blocker, angiotensinconverting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) prior to initiation of trastuzumab was determined. During and after treatment, the medical records were searched for a diagnosis of heart failure or the occurrence of signs or symptoms to suggest the presence of heart failure.
Cardiotoxicity Outcomes Most patients included in this study were treated with anthracycline chemotherapy followed by trastuzumab; therefore the term “treatment-induced cardiotoxicity” (TIC), rather than trastuzumab-induced cardiotoxicity, will be used.TIC was defined as an absolute decrease from baseline in LVEF of $16% or an absolute decrease in LVEF of $10% to below the institutional lower limit of normal (LLN) (defined as LVEF 5 55%) during trastuzumab therapy with or without symptoms of heart failure, as per prescribing information [13]. If a repeat LVEF assessment performed within 7 days showed recovery of LVEF, these changes were considered to reflect variability of measurements rather than TIC. Trastuzumab interruption, defined as an interruption of one or more doses, was at the discretion of the treating provider. Patients with symptomatic TIC were further classified by the New York Heart Association (NYHA) classification system. We determined whether patients were prescribed b blockers, ACE inhibitors, or ARBs after diagnosis of cardiotoxicity among those not already receiving these medications and whether patients were referred for cardiology consultation. When available, follow-up LVEF assessments were recorded to at least 12 months after the last dose of trastuzumab.
Statistical Analysis Descriptive statistics were used for patient characteristics. Continuous measures were summarized as median and interquartile range, whereas categorical measures were summarized as frequency and percent. Comparisons of LVEF at baseline and the time of TIC diagnosis between the interrupted versus continuous trastuzumab groups were made using unpaired Student’s t test. Dependent variables considered in univariate logistic regression for the TIC outcome included age, body mass index, preanthracycline LVEF, pretrastuzumab LVEF, hypertension, diabetes, hyperlipidemia, smoking, coronary artery disease, anthracycline treatment, and radiotherapy. All variables associated with TIC at a threshold of a p value less than .10 were included in the multivariable logistic regression model to determine the independent predictors of TIC. All statistical analysis was performed in GraphPad Prism 6 (GraphPad Software, Inc., La Jolla, CA, http://www.graphpad. com), SAS 9.2 (SAS Institute, Inc., Cary, NC, http://www.sas. com), and R 3.0.1 (R Foundation, Vienna, Austria, https://cran. r-project.org), and p values less than .05 were considered significant.
RESULTS Study Population A total of 573 patients with HER2-positive early breast cancer were included in this study. Baseline characteristics are shown in Table 1. Median age at breast cancer diagnosis was 50 years (range, 26–81 years). Of the total 573 patients, 467 (82%) were treated with adjuvant anthracycline chemotherapy (median doxorubicin equivalent dose, 240 mg/m2; range, 60–360 mg/m2), followed by initiation of trastuzumab 2 weeks later. The median cumulative trastuzumab dose was 106 mg/kg (range, 6–134 mg/kg). Many patients had underlying cardiovascular risk factors, including 153 (27%) with hypertension, 125 (22%) with hyperlipidemia, 40 (7%) with diabetes mellitus, and 216 (38%) with smoking history. History of coronary artery disease was present in only 9 (2%) patients (Table 2). No patient had a history of heart failure. A total of 126 patients (22%) were being treated with a b-blocker, ACE inhibitor, or ARB at baseline prior to initiation of breast cancer treatment. After completion of anthracycline chemotherapy, 2 patients developed an absolute decline in LVEF of $16% and were not included in the TIC group—trastuzumab was initiated in both patients with no further LVEF decline, heart failure events, or interruption of treatment.
Treatment-Induced Cardiotoxicity Of the total 573 patients, 92 (16.1%) developed TIC: 24 (26%) during the first quarter of therapy, 26 (28%) during the second quarter of therapy, 23 (25%) during the third quarter of therapy, and 19 (21%) during or after the fourth quarter of therapy. Of patients with TIC, 74 (12.5%) had an asymptomatic LVEF decline, 8 (1.4%) had symptoms suggestive of NYHA class I–II heart failure, and 10 (1.7%) had NYHA class III–IV heart failure. The median LVEF at the time of TIC diagnosis was 49% (range, 10%–63%). Overall, 59 of 92 (64%) patients with TIC were referred to a cardiologist for evaluation. Of 92 patients with TIC, 27 (29%) were already being treated with a b blocker, ACE
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Table 1. Demographics and treatment characteristics Characteristic
Entire cohort (n = 573)
Age (years) Body mass index (kg/m2) Histologic type Ductal Lobular Other Tumor size (cm) Histologically positive nodes Estrogen receptor status Positive Negative Progesterone receptor status Positive Negative Histologic grade Poorly differentiated Moderately differentiated Well differentiated Other Surgery type Mastectomy Breast conserving Radiation therapy Chemotherapy regimen Anthracyclines (any) Doxorubicin equivalent dose, median (range) Anthracycline, cyclophosphamide, paclitaxel, trastuzumab Anthracycline, cyclophosphamide, trastuzumab 5-Fluorouracil, epirubicin, cyclophosphamide, trastuzumab Cyclophosphamide, methotrexate, 5-fluorouracil, trastuzumab Taxotere, carboplatin, trastuzumab Docetaxel, cyclophosphamide, trastuzumab Paclitaxel, trastuzumab Trastuzumab (single agent) Trastuzumab dose (mg/kg)
50 (43–58) 26.0 (23.0–29.9) 555 (96.9) 14 (2.4) 4 (0.7) 1.8 (1.1–2.6) 1 (0–34) 371 (64.7) 202 (35.2) 292 (51.0) 281 (49.0) 479 (83.6) 77 (13.4) 2 (0.3) 15 (2.6) 349 (61.0) 224 (39.0) 353 (61.6) 467 (81.5) 240 (60–360) 449 (78.3) 17 (3.0) 1 (0.2) 18 (3.1) 12 (2.1) 6 (1.0) 59 (10.3) 11 (1.9) 106 (102–110)
The data are presented as medians (interquartile range) for continuous variables, and n (%) for categorical variables.
inhibitor, or ARB prior to initiation of trastuzumab. Among the remaining 65 patients, 25 were prescribed a new b blocker, ACE inhibitor, or ARB after the diagnosis of TIC was made.
Risk Factors for Treatment-Induced Cardiotoxicity On univariate analysis, risk factors associated with TIC with p , .10 included age (p 5 .051), diabetes (p 5 .045), treatment with adjuvant anthracycline chemotherapy (p 5 .011), baseline treatment with cardiac medications (p 5 .052), and pretrastuzumab LVEF (p , .0001) (Table 2).We also considered
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preanthracycline LVEF and change in LVEF after anthracycline treatment (i.e., preanthracycline LVEF – pretrastuzumab LVEF) as covariates but found that pretrastuzumab LVEF had the strongest association with cardiotoxicity. In a multivariable model, baseline treatment with cardiac medications had p . .10 and was eliminated. On multivariable logistic regression analysis, TIC was associated with age (p 5 .011), anthracycline treatment (p 5 .002), and pretrastuzumab LVEF (p , .001) (Table 3).
Trastuzumab Interruption for Treatment-Induced Cardiotoxicity Trastuzumab was interrupted in 57 of 92 (62%) patients with TIC. Overall, 8 patients missed only one trastuzumab treatment, and 49 patients missed 2 or more treatments. A followup LVEF was obtained at least 3 months after the diagnosis of TIC in 45 of 57 patients, and 15 had a LVEF less than 55% (range, 35%–54%). Trastuzumab was reinitiated for 27 of 57 (47%) patients who had an improvement in LVEF after a median interruption period of 64 days. At the time of trastuzumab rechallenge, 17 of 27 patients were treated with a b-blocker, ACE-I, or ARB. A recurrent decline in LVEF occurred in 5 patients, leading to a second interruption of therapy. LVEF failed to recover to $55% in 2 patients, with last follow-up LVEF of 50% and 52%, respectively. In 31 of 92 (34%) patients with TIC, trastuzumab was completed without interruption: LVEF declined by $10% from baseline to below 55% in 22 patients and by $16% in 9 patients during the course of treatment. At the time of TIC diagnosis, LVEF ranged from 50% to 63%. None developed symptoms of heart failure despite continuous trastuzumab treatment. A follow-up LVEF was obtained at least 3 months after the diagnosis of TIC in 18 of 31 patients, and only 4 had a LVEF of less than 55% (range 53%–54%). TIC patients who received uninterrupted trastuzumab were younger (median age 49 years vs. 56 years, p 5 .01) and had a higher LVEF at baseline (median 69% [range, 61%–83%] vs. 64% [range 46%–78%], p 5 .0001) and at TIC diagnosis (median 53% [range 50%–63%] vs. 45% [range 10%–57%], p 5 .0001) compared with the TIC group with interruption (Fig. 1). Cardiovascular risk factors including hypertension, diabetes, hyperlipidemia, and coronary artery disease were not significantly different between the two groups. In 4 of 92 patients, TIC was detected after completion (range, 3–65 days) of trastuzumab therapy.
DISCUSSION Cardiotoxicity associated with anthracycline and trastuzumab, as well as other cancer therapies, remains an area of concern. However, the sustained clinical benefit of trastuzumab in patients with early HER2-positive breast cancer is striking, with 40% and 37% reductions in disease-free and overall survival events, respectively, achieved by the addition of trastuzumab to chemotherapy with a median follow-up of 8.4 years in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and N9831 [3]. A similar but less robust outcome with sequential trastuzumab after chemotherapy completion was reported after an 8-year follow-up in the Herceptin Adjuvant (HERA) study [14]. Because of this significant improvement in clinical outcome, there has been an increasing effort to ensure that all patients who are ©AlphaMed Press 2015
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Table 2. Risk factors associated with cardiotoxicity Characteristic Age (years) Mean Median Hypertension Smokingb Diabetes Hyperlipidemia Coronary artery disease Cardioprotective medicationc BB ACE-I/ARB Adjuvant anthracycline Pretrastuzumab LVEFd Mean Median #55% 56%–65% .65%
All (n 5 573)
Patients without TIC (n 5 481)
Patients with TIC (n 5 92)
51 6 11.0 50 (43–58) 153 (26.7) 216 (37.7) 40 (7.0) 125 (21.8) 9 (1.6) 126 (22.0) 53 (9.2) 90 (15.7) 467 (81.5)
51 6 11.2 50 (43–58) 126 (26.2) 185 (38.5) 29 (6.0) 103 (21.4) 7 (1.5) 99 (20.6) 38 (7.9) 73 (15.2) 383 (79.6)
53.2 6 9.9 55 (47–60) 27 (29.3) 31 (33.7) 11 (12.0) 22 (23.9) 2 (2.2) 27 (29.3) 15 (16.3) 17 (18.5) 84 (91.0)
66.0 6 6.4 67 (62–70)
66.7 6 6.1 67 (63–70)
61.8 6 6.4 62 (59–66)
OR (95% CI)a
p valuea
1.22 (0.99, 1.49) (per 10 year increase)
.051
1.17 (0.72, 1.92) 0.81 (0.51, 1.30) 2.12 (1.02, 4.41) 1.15 (0.68, 1.95) 1.51 (0.31, 7.36) 1.64 (1.00, 2.71)
.531 .388 .045 .595 .613 .052
2.69 (1.26, 5.73)
.011 ,.0001
3.38 (1.55, 7.39) 2.71 (1.67, 4.39) Reference
The data are presented as means 6 SD or median (interquartile range) for continuous variables, and n (%) for categorical variables. a Logistic regression OR and p value testing the association between the characteristic and TIC. b Current or prior smoking history. c Treatment with BB, ACE-I, or ARB prior to beginning breast cancer treatment. d Pre-anthracycline LVEF was used for 82 patients because of unavailability of pre-trastuzumab LVEF. Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; CI, confidence interval; LVEF, left ventricular ejection fraction; OR, odds ratio; TIC, treatment-induced cardiotoxicity.
Table 3. Multivariable logistic regression model for cardiotoxicity Factor
OR (95% CI)
p value
Age (per 10-year increase) Diabetes Anthracycline Pretrastuzumab LVEF (categorical) #55% 56–65% .65%
1.36 (1.07, 1.72) 2.05 (0.93, 4.55) 3.66 (1.61, 8.30)
.011 .077 .002 ,.001
3.07 (1.37, 6.85) 2.60 (1.59, 4.26) Reference
Abbreviations: CI, confidence interval; OR, odds ratio; LVEF, left ventricular ejection fraction.
likely to benefit from trastuzumab can complete the full recommended course of therapy without treatment interruption. In the current study of clinical practice,TIC occurred in 16% of patients, defined in most by an asymptomatic decline in LVEF. Trastuzumab was continued uninterrupted in approximately one third of these patients.The nadir LVEF was $50% in all these patients (range, 50%–63%), and none developed heart failure despite continuous trastuzumab. Although trastuzumab interruption is recommended in the package insert for patients who develop a significant decline in LVEF during therapy [13], the data from the current analysis suggest that continuing trastuzumab may be safe among a subset of asymptomatic patients with nadir LVEF of $50%. Long-term follow-up is needed to monitor for the late occurrence of
worsening LVEF or heart failure in patients continuing trastuzumab despite an asymptomatic decline in LVEF, particularly given the increased incidence of heart failure and cardiomyopathy that was observed by Bowles et al. several years after completion of treatment [15]. The SAFE-HEART trial (NCT01904903) will provide additional prospective data to define the safety parameters of trastuzumab therapy among patients with a further reduction of LVEF to less than 50%. Variations in the definition of normal LVEF likely explain the inconsistent practice of trastuzumab interruption observed in this study. For example, in both the NSABP B-31 and Breast Cancer International Research Group006 trials,trastuzumab was held if LVEF declined by 10–15 absolute percentage points from baseline to below the lower limit of normal or $16 absolute percentage points from baseline, and the lower limit of normal was at the discretion of the institution [1, 5]. In contrast, in the HERA study trastuzumab was interrupted or discontinued if LVEF declined by $10 absolute percentage points from baseline to below 50% [11], and the most recent recommendations by the American Society of Echocardiography have defined normal LVEF to range from 53% to 73% [16]. Further research is needed to determine the predictive value of serial cardiac assessments that incorporate new cardiac imaging technology (i.e., threedimensional or speckle tracking echocardiography) on the risk of clinical cardiac endpoints and to clearly define threshold values below which trastuzumab should be interrupted. Consistent with prior reports, the current study demonstrates that the risk of cardiotoxicity increases with age, prior anthracycline chemotherapy administration, and lower
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Figure 1. Histograms of patients meeting criteria for treatment-induced cardiotoxicity, with and without trastuzumab interruption. (A, B): Baseline LVEF in the group with trastuzumab interruption (A) and the group without trastuzumab interruption (B). (C, D): Nadir LVEF at time of cardiotoxicity diagnosis in the group with trastuzumab interruption (C) and the group without trastuzumab interruption (D). (E, F): Follow-up LVEF (at least 3 months after cardiotoxicity diagnosis) in the group with trastuzumab interruption (E) and the group without trastuzumab interruption (F). p, p , .0001 for baseline LVEF in trastuzumab interruption versus no interruption group; pp, p , .0001 for nadir LVEF in trastuzumab interruption versus no interruption group. Abbreviation: LVEF, left ventricular ejection fraction.
pretrastuzumab LVEF [17–19]. An association between other conventional cardiac risk factors and TIC was also not apparent. However, other studies have reported conflicting data on the risk factors for cardiotoxicity, and this underscores the limitation of retrospective analyses [20–22].There remains a growing interest in identifying risk factors for TIC to develop a personalized assessment tool (i.e., risk score) to estimate the risk of TIC with adjuvant trastuzumab therapy. Romond et al. [17] developed a cardiac risk score using age and baseline LVEF to predict the probability of cardiac death or heart failure in the NSABP B-31 trial. Using the Surveillance, Epidemiology, and End Results Medicare database, Ezaz et al. [23] proposed a seven-factor risk score to stratify the risk of heart failure or cardiomyopathy, including the following variables: adjuvant therapy, age, coronary artery disease, atrial fibrillation/flutter, diabetes, hypertension, and renal failure. This type of risk score could provide several clinical benefits. For example, patients with high risk scores may be the most likely to benefit from aggressive management of cardiac risk factors and/or use of prophylactic cardioprotective medications prior to initiation of treatment. Conversely, the frequency of serial cardiac monitoring might be safely reduced among low-risk patients; however, the definition of “low risk” needs further clarification. Many questions regarding the optimal management of TIC remain unanswered. These include whether trastuzumab interruption or discontinuation is necessary in patients who develop asymptomatic LVEF decline to ,50%, what cardiac medications, if any, are most effective for the treatment of TIC, and which patients should be referred to a cardiologist. In the current study, most patients with LVEF decline were asymptomatic and thus fall into the category of stage B heart failure.
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Evidence for the management of stage B heart failure to prevent adverse left ventricular remodeling or progression to more advanced stages of heart failure has mainly been derived from studies of patients with ischemic cardiomyopathy and reduced LVEF of ,40% [24–29]. There are limited data on the role of b blockers and ACE inhibitors or the optimal dose of these medications in the management of patients with LVEF declines as a consequence of cancer therapy [30, 31]. Several studies are ongoing to evaluate the utility of cardioprotective medications for prevention of TIC (NCT 01009918 and NCT01434134), and this approach may be increasingly relevant because follow-up studies suggest that LVEF decline may persist long term despite completion of trastuzumab [5, 17, 32]. The current study has several limitations. LVEF assessments were performed with either echocardiography or MUGA, and the frequency and location of testing in the clinical practice setting was at the discretion of the treating provider. The definition of TIC in the current study was based on prescribing information from the package insert [13]. A repeat LVEF assessment was not routinely performed prior to trastuzumab interruption to confirm that an observed LVEF decline was due to cardiotoxicity rather than measurement variability, nor was an evaluation for alternative etiologies of reduced LVEF. There was significant heterogeneity in the type and dose of cardiac medications (i.e.,b-blockers, ACE inhibitors, orARBs)prescribed and varying indications for the use of these medications in patients prior to beginning breast cancer treatment. The decision to start cardiac medications after the diagnosis of TIC was also at the discretion of the treating provider. Finally, given the small number of patients who continued trastuzumab after TIC, there is insufficient information to accurately estimate the incidence of cardiac safety endpoints. ©AlphaMed Press 2015
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CONCLUSION This study showed that TIC occurred in 92 of 573 (16%) patients, and most received an anthracycline before trastuzumab. In patients who developed TIC with a normal LVEF or one just below the LLN, continuing trastuzumab without interruption appears to be safe. However, we recommend that the cardiac status of these patients continue to be closely monitored. Given the life-saving benefit of anti-HER2 therapy, efforts should be made to avoid unnecessary interruption or discontinuation of treatment.
AUTHOR CONTRIBUTIONS Conception/Design: Anthony F. Yu, Clifford A. Hudis, Chau T. Dang, Richard M. Steingart
Provision of study material or patients: Anthony F.Yu, Clifford A. Hudis, Chau T. Dang Collection and/or assembly of data: Anthony F. Yu, Nandini U. Yadav, Betty Y. Lung Data analysis and interpretation: Anthony F. Yu, Anne A. Eaton, Howard T. Thaler, Jennifer E. Liu, Chau T. Dang, Richard M. Steingart Manuscript writing: Anthony F. Yu, Anne A. Eaton, Chau T. Dang, Richard M. Steingart Final approval of manuscript: Anthony F. Yu, Clifford A. Hudis, Chau T. Dang, Richard M. Steingart
DISCLOSURES Chau T. Dang: Roche/Genentech, GlaxoSmithKline (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
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19. Guarneri V, Lenihan DJ, Valero V et al. Longterm cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center experience. J Clin Oncol 2006;24:4107–4115.
30. Cardinale D, Colombo A, Lamantia G et al. Anthracycline-induced cardiomyopathy: Clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010;55:213–220.
20. Farolfi A, Melegari E, Aquilina M et al. Trastuzumab-induced cardiotoxicity in early breast cancer patients: A retrospective study of possible risk and protective factors. Heart 2013;99:634–639.
31. Cardinale D, Colombo A, Torrisi R et al. Trastuzumab-induced cardiotoxicity: Clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910–3916.
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32. Telli ML, Hunt SA, Carlson RW et al. Trastuzumab-related cardiotoxicity: Calling into question the concept of reversibility. J Clin Oncol 2007;25:3525–3533.
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Continuous Trastuzumab Therapy in Breast Cancer Patients With Asymptomatic Left Ventricular Dysfunction ANTHONY F. YU,a NANDINI U. YADAV,a ANNE A. EATON,b BETTY Y. LUNG,a HOWARD T. THALER,b JENNIFER E. LIU,a CLIFFORD A. HUDIS,a CHAU T. DANG,a RICHARD M. STEINGARTa Departments of aMedicine and bBiostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Cardiotoxicity x Heart failure x Trastuzumab x Adjuvant chemotherapy x Breast cancer
ABSTRACT Background. Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However, trastuzumab interruption is recommended for patients who develop treatmentinduced cardiotoxicity (i.e., decline in left ventricular ejection fraction [LVEF], with or without symptoms) and can lead to an incomplete course of treatment.We studied the cardiac safety of continuous trastuzumab therapy among patients with asymptomatic declines in LVEF. Methods. We retrospectively evaluated patients with HER2positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity was defined by an absolute decrease in LVEF of $10% to below 55% or an absolute decrease of $16%. Logistic regression was used to determine the association
between candidate risk factors and treatment-induced cardiotoxicity. Results. Among 573 patients, 92 (16%) developed treatmentinduced cardiotoxicity. Trastuzumab was continued without interruption in 31 of 92 patients with treatment-induced cardiotoxicity—all were asymptomatic with LVEF of $50% at cardiotoxicity diagnosis with median LVEF of 53% (range, 50%–63%), and none developed heart failure during follow-up. Risk factors associated with treatment-induced cardiotoxicity included age (p 5 .011), anthracycline chemotherapy (p 5 .002), and lower pretrastuzumab LVEF (p , .001). Conclusion. Among patients who develop asymptomatic treatment-induced cardiotoxicity with LVEF of $50%, continuous trastuzumab therapy appears to be safe. The Oncologist 2015;20:1105–1110
Implications for Practice: Cardiotoxicity is the most common reason for patients with HER2-positive breast cancer to receive an incomplete course of life-saving trastuzumab therapy. Data from this study suggest that continuous trastuzumab may be safe in patients with asymptomatic cardiotoxicity and left ventricular ejection fraction of $50%. Given the substantial oncologic benefit of trastuzumab, increasing efforts are needed to ensure that patients complete the full course of treatment without interruption. Current recommendations for trastuzumab interruption in patients who develop cardiotoxicity should be re-evaluated.
INTRODUCTION Trastuzumab (Herceptin; Genentech, South San Francisco, CA, https://www.gene.com) added to adjuvant chemotherapy has led to a substantial and sustained improvement in diseasefree survival and overall survival among women with early HER2-positive breast cancer [1–4]. However, this regimen is cardiotoxic and can cause asymptomatic declines in left ventricular ejection fraction (LVEF) or overt symptomatic heart failure. Thus, LVEF monitoring is recommended at baseline and every 3 months during treatment. Although the risk of heart failure during therapy is low, ranging from 1% to 4%, asymptomatic LVEF declines are more common, reported in 7%–19% of patients in clinical trials [2, 5, 6]. In clinical practice, rates of adverse cardiac events are considerably higher,
particularly among older patients who often have underlying cardiovascular disease or risk factors [7–10].These patients are not well represented in clinical trials. In pivotal clinical trials of trastuzumab in the adjuvant setting, trastuzumab was held or discontinued if LVEF failed to meet cardiac safety criteria [1, 5, 11]. As a result, asymptomatic LVEF decline has been reported as the most common reason for premature discontinuation of trastuzumab and can result in an incomplete course of therapy [6, 12]. The cardiac safety of continuing trastuzumab among patients with asymptomatic LVEF declines has not previously been investigated. Accordingly, we conducted a retrospective study among patients with HER2-positive early breast cancer to evaluate the incidence of
Correspondence: Anthony F. Yu, M.D., Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-7932; E-Mail: [email protected] Received March 24, 2015; accepted for publication June 8, 2015; published Online First on August 3, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0125
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asymptomatic LVEF decline or symptomatic heart failure during adjuvant trastuzumab therapy, with particular attention to the clinical course of patients who continued trastuzumab despite an asymptomatic LVEF decline. We also aimed to identify potential risk factors that may be predictive of significant LVEF decline.
PATIENTS AND METHODS Study Population Using the institutional medical records database at Memorial Sloan Kettering Cancer Center, all patients diagnosed with HER2-positive early breast cancer from January 2005 to October 2010 and treated with adjuvant trastuzumab were identified. Patients were eligible for the study if they had at least two LVEF assessments while undergoing breast cancer treatment, including a baseline LVEF performed prior to initiation of treatment. LVEF was assessed by either multigated acquisition scan (MUGA) or two-dimensional echocardiography. Patients participating in a clinical trial were excluded.
Baseline Characteristics For each patient, the following information was collected from the electronic medical record: age, body mass index, tumor characteristics, cancer treatment details, and baseline cardiovascular comorbidities (i.e., hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, smoking status). In addition, baseline treatment with a b blocker, angiotensinconverting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB) prior to initiation of trastuzumab was determined. During and after treatment, the medical records were searched for a diagnosis of heart failure or the occurrence of signs or symptoms to suggest the presence of heart failure.
Cardiotoxicity Outcomes Most patients included in this study were treated with anthracycline chemotherapy followed by trastuzumab; therefore the term “treatment-induced cardiotoxicity” (TIC), rather than trastuzumab-induced cardiotoxicity, will be used.TIC was defined as an absolute decrease from baseline in LVEF of $16% or an absolute decrease in LVEF of $10% to below the institutional lower limit of normal (LLN) (defined as LVEF 5 55%) during trastuzumab therapy with or without symptoms of heart failure, as per prescribing information [13]. If a repeat LVEF assessment performed within 7 days showed recovery of LVEF, these changes were considered to reflect variability of measurements rather than TIC. Trastuzumab interruption, defined as an interruption of one or more doses, was at the discretion of the treating provider. Patients with symptomatic TIC were further classified by the New York Heart Association (NYHA) classification system. We determined whether patients were prescribed b blockers, ACE inhibitors, or ARBs after diagnosis of cardiotoxicity among those not already receiving these medications and whether patients were referred for cardiology consultation. When available, follow-up LVEF assessments were recorded to at least 12 months after the last dose of trastuzumab.
Statistical Analysis Descriptive statistics were used for patient characteristics. Continuous measures were summarized as median and interquartile range, whereas categorical measures were summarized as frequency and percent. Comparisons of LVEF at baseline and the time of TIC diagnosis between the interrupted versus continuous trastuzumab groups were made using unpaired Student’s t test. Dependent variables considered in univariate logistic regression for the TIC outcome included age, body mass index, preanthracycline LVEF, pretrastuzumab LVEF, hypertension, diabetes, hyperlipidemia, smoking, coronary artery disease, anthracycline treatment, and radiotherapy. All variables associated with TIC at a threshold of a p value less than .10 were included in the multivariable logistic regression model to determine the independent predictors of TIC. All statistical analysis was performed in GraphPad Prism 6 (GraphPad Software, Inc., La Jolla, CA, http://www.graphpad. com), SAS 9.2 (SAS Institute, Inc., Cary, NC, http://www.sas. com), and R 3.0.1 (R Foundation, Vienna, Austria, https://cran. r-project.org), and p values less than .05 were considered significant.
RESULTS Study Population A total of 573 patients with HER2-positive early breast cancer were included in this study. Baseline characteristics are shown in Table 1. Median age at breast cancer diagnosis was 50 years (range, 26–81 years). Of the total 573 patients, 467 (82%) were treated with adjuvant anthracycline chemotherapy (median doxorubicin equivalent dose, 240 mg/m2; range, 60–360 mg/m2), followed by initiation of trastuzumab 2 weeks later. The median cumulative trastuzumab dose was 106 mg/kg (range, 6–134 mg/kg). Many patients had underlying cardiovascular risk factors, including 153 (27%) with hypertension, 125 (22%) with hyperlipidemia, 40 (7%) with diabetes mellitus, and 216 (38%) with smoking history. History of coronary artery disease was present in only 9 (2%) patients (Table 2). No patient had a history of heart failure. A total of 126 patients (22%) were being treated with a b-blocker, ACE inhibitor, or ARB at baseline prior to initiation of breast cancer treatment. After completion of anthracycline chemotherapy, 2 patients developed an absolute decline in LVEF of $16% and were not included in the TIC group—trastuzumab was initiated in both patients with no further LVEF decline, heart failure events, or interruption of treatment.
Treatment-Induced Cardiotoxicity Of the total 573 patients, 92 (16.1%) developed TIC: 24 (26%) during the first quarter of therapy, 26 (28%) during the second quarter of therapy, 23 (25%) during the third quarter of therapy, and 19 (21%) during or after the fourth quarter of therapy. Of patients with TIC, 74 (12.5%) had an asymptomatic LVEF decline, 8 (1.4%) had symptoms suggestive of NYHA class I–II heart failure, and 10 (1.7%) had NYHA class III–IV heart failure. The median LVEF at the time of TIC diagnosis was 49% (range, 10%–63%). Overall, 59 of 92 (64%) patients with TIC were referred to a cardiologist for evaluation. Of 92 patients with TIC, 27 (29%) were already being treated with a b blocker, ACE
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Table 1. Demographics and treatment characteristics Characteristic
Entire cohort (n = 573)
Age (years) Body mass index (kg/m2) Histologic type Ductal Lobular Other Tumor size (cm) Histologically positive nodes Estrogen receptor status Positive Negative Progesterone receptor status Positive Negative Histologic grade Poorly differentiated Moderately differentiated Well differentiated Other Surgery type Mastectomy Breast conserving Radiation therapy Chemotherapy regimen Anthracyclines (any) Doxorubicin equivalent dose, median (range) Anthracycline, cyclophosphamide, paclitaxel, trastuzumab Anthracycline, cyclophosphamide, trastuzumab 5-Fluorouracil, epirubicin, cyclophosphamide, trastuzumab Cyclophosphamide, methotrexate, 5-fluorouracil, trastuzumab Taxotere, carboplatin, trastuzumab Docetaxel, cyclophosphamide, trastuzumab Paclitaxel, trastuzumab Trastuzumab (single agent) Trastuzumab dose (mg/kg)
50 (43–58) 26.0 (23.0–29.9) 555 (96.9) 14 (2.4) 4 (0.7) 1.8 (1.1–2.6) 1 (0–34) 371 (64.7) 202 (35.2) 292 (51.0) 281 (49.0) 479 (83.6) 77 (13.4) 2 (0.3) 15 (2.6) 349 (61.0) 224 (39.0) 353 (61.6) 467 (81.5) 240 (60–360) 449 (78.3) 17 (3.0) 1 (0.2) 18 (3.1) 12 (2.1) 6 (1.0) 59 (10.3) 11 (1.9) 106 (102–110)
The data are presented as medians (interquartile range) for continuous variables, and n (%) for categorical variables.
inhibitor, or ARB prior to initiation of trastuzumab. Among the remaining 65 patients, 25 were prescribed a new b blocker, ACE inhibitor, or ARB after the diagnosis of TIC was made.
Risk Factors for Treatment-Induced Cardiotoxicity On univariate analysis, risk factors associated with TIC with p , .10 included age (p 5 .051), diabetes (p 5 .045), treatment with adjuvant anthracycline chemotherapy (p 5 .011), baseline treatment with cardiac medications (p 5 .052), and pretrastuzumab LVEF (p , .0001) (Table 2).We also considered
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preanthracycline LVEF and change in LVEF after anthracycline treatment (i.e., preanthracycline LVEF – pretrastuzumab LVEF) as covariates but found that pretrastuzumab LVEF had the strongest association with cardiotoxicity. In a multivariable model, baseline treatment with cardiac medications had p . .10 and was eliminated. On multivariable logistic regression analysis, TIC was associated with age (p 5 .011), anthracycline treatment (p 5 .002), and pretrastuzumab LVEF (p , .001) (Table 3).
Trastuzumab Interruption for Treatment-Induced Cardiotoxicity Trastuzumab was interrupted in 57 of 92 (62%) patients with TIC. Overall, 8 patients missed only one trastuzumab treatment, and 49 patients missed 2 or more treatments. A followup LVEF was obtained at least 3 months after the diagnosis of TIC in 45 of 57 patients, and 15 had a LVEF less than 55% (range, 35%–54%). Trastuzumab was reinitiated for 27 of 57 (47%) patients who had an improvement in LVEF after a median interruption period of 64 days. At the time of trastuzumab rechallenge, 17 of 27 patients were treated with a b-blocker, ACE-I, or ARB. A recurrent decline in LVEF occurred in 5 patients, leading to a second interruption of therapy. LVEF failed to recover to $55% in 2 patients, with last follow-up LVEF of 50% and 52%, respectively. In 31 of 92 (34%) patients with TIC, trastuzumab was completed without interruption: LVEF declined by $10% from baseline to below 55% in 22 patients and by $16% in 9 patients during the course of treatment. At the time of TIC diagnosis, LVEF ranged from 50% to 63%. None developed symptoms of heart failure despite continuous trastuzumab treatment. A follow-up LVEF was obtained at least 3 months after the diagnosis of TIC in 18 of 31 patients, and only 4 had a LVEF of less than 55% (range 53%–54%). TIC patients who received uninterrupted trastuzumab were younger (median age 49 years vs. 56 years, p 5 .01) and had a higher LVEF at baseline (median 69% [range, 61%–83%] vs. 64% [range 46%–78%], p 5 .0001) and at TIC diagnosis (median 53% [range 50%–63%] vs. 45% [range 10%–57%], p 5 .0001) compared with the TIC group with interruption (Fig. 1). Cardiovascular risk factors including hypertension, diabetes, hyperlipidemia, and coronary artery disease were not significantly different between the two groups. In 4 of 92 patients, TIC was detected after completion (range, 3–65 days) of trastuzumab therapy.
DISCUSSION Cardiotoxicity associated with anthracycline and trastuzumab, as well as other cancer therapies, remains an area of concern. However, the sustained clinical benefit of trastuzumab in patients with early HER2-positive breast cancer is striking, with 40% and 37% reductions in disease-free and overall survival events, respectively, achieved by the addition of trastuzumab to chemotherapy with a median follow-up of 8.4 years in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and N9831 [3]. A similar but less robust outcome with sequential trastuzumab after chemotherapy completion was reported after an 8-year follow-up in the Herceptin Adjuvant (HERA) study [14]. Because of this significant improvement in clinical outcome, there has been an increasing effort to ensure that all patients who are ©AlphaMed Press 2015
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Table 2. Risk factors associated with cardiotoxicity Characteristic Age (years) Mean Median Hypertension Smokingb Diabetes Hyperlipidemia Coronary artery disease Cardioprotective medicationc BB ACE-I/ARB Adjuvant anthracycline Pretrastuzumab LVEFd Mean Median #55% 56%–65% .65%
All (n 5 573)
Patients without TIC (n 5 481)
Patients with TIC (n 5 92)
51 6 11.0 50 (43–58) 153 (26.7) 216 (37.7) 40 (7.0) 125 (21.8) 9 (1.6) 126 (22.0) 53 (9.2) 90 (15.7) 467 (81.5)
51 6 11.2 50 (43–58) 126 (26.2) 185 (38.5) 29 (6.0) 103 (21.4) 7 (1.5) 99 (20.6) 38 (7.9) 73 (15.2) 383 (79.6)
53.2 6 9.9 55 (47–60) 27 (29.3) 31 (33.7) 11 (12.0) 22 (23.9) 2 (2.2) 27 (29.3) 15 (16.3) 17 (18.5) 84 (91.0)
66.0 6 6.4 67 (62–70)
66.7 6 6.1 67 (63–70)
61.8 6 6.4 62 (59–66)
OR (95% CI)a
p valuea
1.22 (0.99, 1.49) (per 10 year increase)
.051
1.17 (0.72, 1.92) 0.81 (0.51, 1.30) 2.12 (1.02, 4.41) 1.15 (0.68, 1.95) 1.51 (0.31, 7.36) 1.64 (1.00, 2.71)
.531 .388 .045 .595 .613 .052
2.69 (1.26, 5.73)
.011 ,.0001
3.38 (1.55, 7.39) 2.71 (1.67, 4.39) Reference
The data are presented as means 6 SD or median (interquartile range) for continuous variables, and n (%) for categorical variables. a Logistic regression OR and p value testing the association between the characteristic and TIC. b Current or prior smoking history. c Treatment with BB, ACE-I, or ARB prior to beginning breast cancer treatment. d Pre-anthracycline LVEF was used for 82 patients because of unavailability of pre-trastuzumab LVEF. Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, b blocker; CI, confidence interval; LVEF, left ventricular ejection fraction; OR, odds ratio; TIC, treatment-induced cardiotoxicity.
Table 3. Multivariable logistic regression model for cardiotoxicity Factor
OR (95% CI)
p value
Age (per 10-year increase) Diabetes Anthracycline Pretrastuzumab LVEF (categorical) #55% 56–65% .65%
1.36 (1.07, 1.72) 2.05 (0.93, 4.55) 3.66 (1.61, 8.30)
.011 .077 .002 ,.001
3.07 (1.37, 6.85) 2.60 (1.59, 4.26) Reference
Abbreviations: CI, confidence interval; OR, odds ratio; LVEF, left ventricular ejection fraction.
likely to benefit from trastuzumab can complete the full recommended course of therapy without treatment interruption. In the current study of clinical practice,TIC occurred in 16% of patients, defined in most by an asymptomatic decline in LVEF. Trastuzumab was continued uninterrupted in approximately one third of these patients.The nadir LVEF was $50% in all these patients (range, 50%–63%), and none developed heart failure despite continuous trastuzumab. Although trastuzumab interruption is recommended in the package insert for patients who develop a significant decline in LVEF during therapy [13], the data from the current analysis suggest that continuing trastuzumab may be safe among a subset of asymptomatic patients with nadir LVEF of $50%. Long-term follow-up is needed to monitor for the late occurrence of
worsening LVEF or heart failure in patients continuing trastuzumab despite an asymptomatic decline in LVEF, particularly given the increased incidence of heart failure and cardiomyopathy that was observed by Bowles et al. several years after completion of treatment [15]. The SAFE-HEART trial (NCT01904903) will provide additional prospective data to define the safety parameters of trastuzumab therapy among patients with a further reduction of LVEF to less than 50%. Variations in the definition of normal LVEF likely explain the inconsistent practice of trastuzumab interruption observed in this study. For example, in both the NSABP B-31 and Breast Cancer International Research Group006 trials,trastuzumab was held if LVEF declined by 10–15 absolute percentage points from baseline to below the lower limit of normal or $16 absolute percentage points from baseline, and the lower limit of normal was at the discretion of the institution [1, 5]. In contrast, in the HERA study trastuzumab was interrupted or discontinued if LVEF declined by $10 absolute percentage points from baseline to below 50% [11], and the most recent recommendations by the American Society of Echocardiography have defined normal LVEF to range from 53% to 73% [16]. Further research is needed to determine the predictive value of serial cardiac assessments that incorporate new cardiac imaging technology (i.e., threedimensional or speckle tracking echocardiography) on the risk of clinical cardiac endpoints and to clearly define threshold values below which trastuzumab should be interrupted. Consistent with prior reports, the current study demonstrates that the risk of cardiotoxicity increases with age, prior anthracycline chemotherapy administration, and lower
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Figure 1. Histograms of patients meeting criteria for treatment-induced cardiotoxicity, with and without trastuzumab interruption. (A, B): Baseline LVEF in the group with trastuzumab interruption (A) and the group without trastuzumab interruption (B). (C, D): Nadir LVEF at time of cardiotoxicity diagnosis in the group with trastuzumab interruption (C) and the group without trastuzumab interruption (D). (E, F): Follow-up LVEF (at least 3 months after cardiotoxicity diagnosis) in the group with trastuzumab interruption (E) and the group without trastuzumab interruption (F). p, p , .0001 for baseline LVEF in trastuzumab interruption versus no interruption group; pp, p , .0001 for nadir LVEF in trastuzumab interruption versus no interruption group. Abbreviation: LVEF, left ventricular ejection fraction.
pretrastuzumab LVEF [17–19]. An association between other conventional cardiac risk factors and TIC was also not apparent. However, other studies have reported conflicting data on the risk factors for cardiotoxicity, and this underscores the limitation of retrospective analyses [20–22].There remains a growing interest in identifying risk factors for TIC to develop a personalized assessment tool (i.e., risk score) to estimate the risk of TIC with adjuvant trastuzumab therapy. Romond et al. [17] developed a cardiac risk score using age and baseline LVEF to predict the probability of cardiac death or heart failure in the NSABP B-31 trial. Using the Surveillance, Epidemiology, and End Results Medicare database, Ezaz et al. [23] proposed a seven-factor risk score to stratify the risk of heart failure or cardiomyopathy, including the following variables: adjuvant therapy, age, coronary artery disease, atrial fibrillation/flutter, diabetes, hypertension, and renal failure. This type of risk score could provide several clinical benefits. For example, patients with high risk scores may be the most likely to benefit from aggressive management of cardiac risk factors and/or use of prophylactic cardioprotective medications prior to initiation of treatment. Conversely, the frequency of serial cardiac monitoring might be safely reduced among low-risk patients; however, the definition of “low risk” needs further clarification. Many questions regarding the optimal management of TIC remain unanswered. These include whether trastuzumab interruption or discontinuation is necessary in patients who develop asymptomatic LVEF decline to ,50%, what cardiac medications, if any, are most effective for the treatment of TIC, and which patients should be referred to a cardiologist. In the current study, most patients with LVEF decline were asymptomatic and thus fall into the category of stage B heart failure.
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Evidence for the management of stage B heart failure to prevent adverse left ventricular remodeling or progression to more advanced stages of heart failure has mainly been derived from studies of patients with ischemic cardiomyopathy and reduced LVEF of ,40% [24–29]. There are limited data on the role of b blockers and ACE inhibitors or the optimal dose of these medications in the management of patients with LVEF declines as a consequence of cancer therapy [30, 31]. Several studies are ongoing to evaluate the utility of cardioprotective medications for prevention of TIC (NCT 01009918 and NCT01434134), and this approach may be increasingly relevant because follow-up studies suggest that LVEF decline may persist long term despite completion of trastuzumab [5, 17, 32]. The current study has several limitations. LVEF assessments were performed with either echocardiography or MUGA, and the frequency and location of testing in the clinical practice setting was at the discretion of the treating provider. The definition of TIC in the current study was based on prescribing information from the package insert [13]. A repeat LVEF assessment was not routinely performed prior to trastuzumab interruption to confirm that an observed LVEF decline was due to cardiotoxicity rather than measurement variability, nor was an evaluation for alternative etiologies of reduced LVEF. There was significant heterogeneity in the type and dose of cardiac medications (i.e.,b-blockers, ACE inhibitors, orARBs)prescribed and varying indications for the use of these medications in patients prior to beginning breast cancer treatment. The decision to start cardiac medications after the diagnosis of TIC was also at the discretion of the treating provider. Finally, given the small number of patients who continued trastuzumab after TIC, there is insufficient information to accurately estimate the incidence of cardiac safety endpoints. ©AlphaMed Press 2015
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CONCLUSION This study showed that TIC occurred in 92 of 573 (16%) patients, and most received an anthracycline before trastuzumab. In patients who developed TIC with a normal LVEF or one just below the LLN, continuing trastuzumab without interruption appears to be safe. However, we recommend that the cardiac status of these patients continue to be closely monitored. Given the life-saving benefit of anti-HER2 therapy, efforts should be made to avoid unnecessary interruption or discontinuation of treatment.
AUTHOR CONTRIBUTIONS Conception/Design: Anthony F. Yu, Clifford A. Hudis, Chau T. Dang, Richard M. Steingart
Provision of study material or patients: Anthony F.Yu, Clifford A. Hudis, Chau T. Dang Collection and/or assembly of data: Anthony F. Yu, Nandini U. Yadav, Betty Y. Lung Data analysis and interpretation: Anthony F. Yu, Anne A. Eaton, Howard T. Thaler, Jennifer E. Liu, Chau T. Dang, Richard M. Steingart Manuscript writing: Anthony F. Yu, Anne A. Eaton, Chau T. Dang, Richard M. Steingart Final approval of manuscript: Anthony F. Yu, Clifford A. Hudis, Chau T. Dang, Richard M. Steingart
DISCLOSURES Chau T. Dang: Roche/Genentech, GlaxoSmithKline (RF). The other authors indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board
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