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Cardiotoxicity and Cardiac Monitoring Among Chemotherapy-Treated Breast Cancer PatientsFree Access

Original Research

J Am Coll Cardiol Img, 11 (8) 1084–1093
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Graphical abstract

Abstract

Objectives:

This study sought to determine the rate of chemotherapy-related cardiotoxicity and to estimate adherence to recommendations for cardiac monitoring among breast cancer patients treated with chemotherapy.

Background:

Heart failure (HF) is a known complication associated with cancer therapies. Little is known regarding the rate of chemotherapy-related cardiotoxicity and adherence to recommendations for cardiac monitoring among chemotherapy-treated breast cancer patients.

Methods:

Patients >18 years of age with a diagnosis of nonmetastatic invasive breast cancer between 2009 and 2014, treated with chemotherapy within 6 months of their diagnosis, were identified in the Truven Health MarketScan (IBM Watson Health, Cambridge, Massachusetts) database. HF, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics, Cox proportional hazard regression, and logistic regression.

Results:

A total of 16,456 patients were included; the median age was 56 years old. Cardiotoxicity was identified in 4.2% of patients. Therapy with trastuzumab (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.72 to 2.36) and anthracyclines (HR: 1.53; 95% CI: 1.30 to 1.80), Deyo comorbidity scores (HR: 1.38; 95% CI: 1.15 to 1.66; HR: 2.47; 95% CI: 1.94 to 3.15 for scores of 1 and ≥2, respectively), hypertension (HR: 1.28, 95% CI: 1.09 to 1.51), and valve disease (HR: 1.93; 95% CI: 1.48 to 2.51) were associated with an increased risk of cardiotoxicity. Patients ≤35 years of age (HR: 0.37; 95% CI: 0.19 to 0.72) and 36 to 49 years of age (HR: 0.49; 95% CI: 0.38 to 0.62) were less likely to have cardiotoxicity than patients 65 years of age and older. Among 4,325 patients treated with trastuzumab, guideline-adherent cardiac monitoring was identified in 46.2% of patients. Therapies using anthracyclines (odds ratio [OR]: 1.58; 95% CI: 1.35 to 1.87), taxanes (OR: 1.63; 95% CI: 1.27 to 2.08), and radiation (OR: 1.22; 95% CI: 1.08 to 1.39) were associated with guideline-adherent monitoring.

Conclusions:

HF is an uncommon complication of breast cancer therapies. The risk was higher among patients treated with trastuzumab or anthracyclines and lower in younger patients. Cardiac monitoring among trastuzumab-treated patients should be a priority among high-risk patients and in the presence of comorbidities or other chemotherapies such as those using anthracyclines.

Introduction

After secondary malignancies, cardiovascular disease is the leading cause of morbidity and mortality among breast cancer survivors (1). These high rates are due in part to the cardiac toxicities of cancer therapies. Trastuzumab-based chemotherapy is the cornerstone of systemic therapy for patients with HER2-positive tumors (2). Trastuzumab is a monoclonal antibody with excellent tolerability, however, its use is associated with cardiotoxicity (2). Data from clinical trials suggest that trastuzumab cardiotoxicity rates range from 4.1% to 10% (3–6). Trastuzumab causes damage to the cardiac myocytes, which can lead to heart failure (HF) through a type II cardiotoxicity, characterized by its reversibility (2). Despite being reversible in patients who are recovering their cardiac function, to date, it is not possible to predict who will develop this complication; therefore, it is important to understand the incidence in the general population and identify at-risk patients.

The National Comprehensive Cancer Network recommends cardiac monitoring before initiating trastuzumab treatment and every 3 months while taking the treatment (i.e., at 3, 6, 9, and 12 months) (7). Cardiac monitoring is usually performed with an echocardiogram or with radionuclide ventriculography (multiple-gated acquisition [MUGA] scans) (8). There is little information about patterns of cardiac monitoring in breast cancer patients. In a previous work we found that, among 2,203 breast cancer patients older than 65 years of age, 64% received suboptimal cardiac monitoring during trastuzumab therapy (8). Thavendiranathan et al. (9) found that, although the absolute risk of cancer treatment-related cardiotoxicity was lower in younger patients, the relative risks of cancer treatment-related cardiotoxicity in older patients were similar to those in younger patients, indicating the need for surveillance of cardiac dysfunction in this young population, which has been typically considered to be at low risk for such events. To the best of our knowledge, there are no data from insurance claims for either the rates or the factors associated with cardiotoxicity and guideline-adherent cardiac monitoring in young American patients. In the large cohort of breast cancer patients in the present study, we estimated the rate and determinants of cardiotoxicity associated with the use of chemotherapy and trastuzumab-based chemotherapy. In addition, we calculated the rate of cardiac monitoring among trastuzumab-treated patients and describe the pattern of cardiac monitoring according to age.

Methods

Data source and data extraction

Female patients older than 18 years of age with nonmetastatic invasive breast cancer diagnosed between 2009 and 2014 were identified in the Truven Health MarketScan (IBM Watson Health, Cambridge, Massachusetts) database. This database includes de-identified patient-level health data from medical claims and prescription drug claims for insured employees, spouses, and their dependents throughout the United States. Data are from large employers, managed care organizations, hospitals, electronic medical record providers, and Medicare and Medicaid and are often used for health services research.

Patients were included if they had been treated with chemotherapy within the first 6 months after their diagnosis. Male breast cancer patients and patients with a history of HF or cancer were excluded from the study. Patients were followed from the date of their breast cancer diagnosis until they either died or lost insurance coverage. The last follow-up date was December 31, 2015.

Definitions

Cardiotoxicity was defined as an incident case of HF following a breast cancer diagnosis. HF after breast cancer diagnosis was identified using International Classification of Diseases version 9 (ICD-09) diagnosis codes 425, 428, and 785.51 in inpatient, facility, and outpatient claims, respectively. HF, therefore, denoted symptomatic and asymptomatic events, as data for symptoms were not available in the MarketScan database. Patients were noted as having HF if there was at least 1 claim in the inpatient file or at least 2 claims that were more than 30 days apart in the outpatient files.

Among patients treated with trastuzumab-based chemotherapy, we evaluated the rates of cardiac monitoring. Guideline-adherent cardiac monitoring was defined as a baseline cardiac evaluation performed within 4 months before the first dose of trastuzumab was administered and a subsequent follow-up cardiac evaluation performed at least every 4 months during trastuzumab therapy (8). Our group used this 4-month cutoff in previous work, and it was chosen to compensate for differences in scheduling, resources, or levels of accessibility to medical care (8). Baseline cardiac monitoring was defined as a test conducted before any trastuzumab dose. Follow-up cardiac monitoring was defined as monitoring every 4 months after initiating treatment. Methods for cardiac monitoring such as echocardiograms and MUGA scans were identified in the facility, outpatient, and inpatient claims by using Current Procedural Terminology (CPT) codes (e.g., CPT codes 93303–4, 99306–8, 99320–1, and 93325 for echocardiograms; and CPT codes 78414, 78433, 78451–4, 78472, 78478, and 78480 for MUGA scans). We also identified CPT codes 75557, 75559, 75561, 75563, and 75565 for cardiac magnetic resonance.

The Deyo comorbidity score was calculated from claims made within 6 months before diagnosis (10). Pre-existing conditions were identified by using ICD-9 codes 401 to 409 (excluding 402.11 and 402.91) for hypertension; 410 to 414 (excluding 414.1, 36.01, and 36.1) for coronary artery disease; 394 to 397 and 424 (excluding 424.9 and 35) for valve disease; and code 250 for diabetes. We used codes from the Healthcare Procedure Coding System to identify the chemotherapy drugs trastuzumab (J9355), anthracycline (J9000, J9001, J9010, J9178, and J9180), and taxanes (J9170, J9171, J9264, J9265).

Statistical methods

Descriptive statistics were used to determine the rate of cardiotoxicity and the rate of guideline-adherent cardiac monitoring. The chi-square or Wilcoxon test was used to compare demographic and clinical features of patients who did and did not experience these outcomes of interest. A time-dependent Cox regression model was used to evaluate the risk of cardiotoxicity in our entire cohort (N = 16,456). Trastuzumab was the only time-dependent variable and was defined as any use following breast cancer diagnosis. Other variables in the model included age (groups ≤35, 36 to 49, 50 to 64, and 65+ years of age), year of breast cancer diagnosis (2009, 2010, 2011, 2012, 2013, and 2014), and use of trastuzumab, anthracyclines, taxanes, and radiation; Deyo comorbidity score; hypertension, valve disease, insurance (Preferred Provider Organization [PPO], Health Maintenance Organization [HMO], and other), and geographical region (northeast, north central, south, west, and unknown). Results are expressed in hazard ratios (HRs) and 95% confidence interval (CI). A sensitivity analysis using only inpatient claims as a proxy for severity was performed to calculate the rate of cardiotoxicity. We used a previously described method to incorporate a time-dependent variable in a Kaplan-Meier curve (11). In simple terms, this method updates the cohort at all event times and splits survival time according to covariate status. Comparisons were made using the log-rank test.

A logistic regression model was used to determine the odds of receiving guideline-adherent cardiac monitoring among the 4,325 trastuzumab-treated patients. Variables in the model included age, year of diagnosis, anthracyclines, taxanes, radiation, Deyo comorbidity score, hypertension, valve disease, insurance, and region. Results are expressed as odds ratios (ORs) and 95% CI. We also compared rates of guideline-adherent cardiac monitoring according to age group at baseline and at follow-up among the patients who had been treated with trastuzumab.

Statistical analyses were performed using SAS version 9.4 software (Cary, North Carolina). The research was reviewed by the institutional review board of the University of Texas MD Anderson Cancer Center and was exempt under the codes of regulations.

Results

A total of 16,456 patients were included in this study. The median age was 56 years old. Among the patients, 4,325 received trastuzumab-based chemotherapy.

Cardiotoxicity

In our cohort, 692 patients (4.2%) developed HF after chemotherapy. The median time to event was 8 months. Patient characteristics according to cardiotoxicity are listed in Table 1. Among patients treated with trastuzumab, the rate was 8.3% compared to 2.7% for those who were not treated with trastuzumab (p < 0.001). In comparison, the rates for anthracycline users versus non-anthracycline users were 4.6% versus 4.0%, respectively (p = 0.048). From the sensitivity analysis, using only inpatient claims, we found that the rates for cardiotoxicity were the same for trastuzumab users and nonusers at 1.7% (p ≤ 0.001) (Online Table 1).

Table 1. Patient Characteristics According to Cardiotoxicity Among Patients 18 to ≥80 Years of Age With Breast Cancer (N = 16,456)

TotalYesp Value
All patients16,456692 (4.2)<0.001
Age, yrs<0.001
≤354269 (2.1)
36–494,116121 (2.9)
50–648,914314 (3.5)
65+3,000248 (8.3)
Year of diagnosis0.166
20093,324162 (4.9)
20103,186134 (4.2)
20113,256136 (4.2)
20122,54698 (3.8)
20132,432105 (4.3)
20141,71257 (3.3)
Any trastuzumab use after diagnosis<0.001
No12,131322 (2.7)
Yes4,325360 (8.3)
Anthracyclines0.048
No10,870433 (4.0)
Yes5,586259 (4.6)
Taxanes<0.001
No1,62196 (5.9)
Yes14,835596 (4.0)
Radiation0.968
No5,481230 (4.2)
Yes10,975462 (4.2)
Deyo comorbidity score<0.001
012,680436 (3.4)
13,023168 (5.6)
2+75388 (11.7)
Hypertension<0.001
No10,522350 (3.3)
Yes5,934342 (5.8)
Diabetes<0.001
No14,475546 (3.8)
Yes1,981146 (7.4)
Coronary artery disease<0.001
No15,816615 (3.9)
Yes64077 (12.0)
Valve disease<0.001
No15,824628 (4.0)
Yes63264 (10.1)
Insurance0.001
PPO9,608361 (3.8)
HMO2,10392 (4.4)
Other4,745239 (5.0)
Region0.003
North Central3,963193 (4.9)
Northeast2,779140 (5.0)
South6,507234 (3.6)
Unknown28910 (3.5)
West2,918115 (3.9)

Values are N or n (%).

HMO = health maintenance organization; PPO = preferred provider organization.

∗ p < 0.05.

Figure 1 contains the Kaplan-Meier curve for time to HF. Kaplan-Meier plots used trastuzumab as a time-dependent variable. Patients treated with anthracyclines and trastuzumab were at highest risk, followed by patients who received trastuzumab-based chemotherapy. The lowest risk was seen among patients treated with anthracyclines and those who received chemotherapy with regimens not containing trastuzumab or anthracyclines. Cardiotoxicity was identified in 2.1% of patients ≤35 years of age (n = 426), 2.9% of patients 36 to 49 years of age (n = 4,116), 3.5% of patients 50 to 64 years of age (n = 8,914), and 8.3% of patients 65+ years of age (n = 3,000). Table 2 contains the complete univariate and multivariate Cox regression models. After we adjusted for potential confounders, we found trastuzumab-treated patients (HR: 2.01; 95% CI: 1.72 to 2.36) and those treated with anthracycline-containing regimens (HR: 1.53; 95% CI: 1.30 to 1.80) were more likely to develop HF. Using the 65+ age group as a reference, our analysis showed all other age groups had a lower risk of HF, with patients ≤35 years of age having the lowest risk (HR: 0.37; 95% CI: 0.19 to 0.75). Other variables that were associated with an increased risk of HF included comorbidities (HR: 1.38; 95% CI: 1.15 to 1.66; HR: 2.47; 95% CI: 1.94 to 3.15 for Deyo scores of 1 and ≥2, respectively), hypertension (HR: 1.28, 95 CI% 1.09 to 1.51), and valve disease (HR: 1.93; 95% CI: 1.48 to 2.51). Online Table 2 contains the same models for determining the risk of cardiotoxicity, using only inpatient claims.

Figure 1.
Figure 1.

Kaplan-Meier Survival Plots for HF-free Survival for Patients With Breast Cancer by Incorporating Trastuzumab Use as a Time-Dependent Variable

(Left) Stratified by trastuzumab use. (Right) Stratified by trastuzumab and anthracycline use. AT = anthracycline and trastuzumab; A_noT = anthracycline and no trastuzumab; T_noA = trastuzumab and no anthracycline; noAT = no anthracycline or trastuzumab.

Table 2. Cox Regression Model Using Trastuzumab as a Time-Dependent Variable to Evaluate the Risk of Cardiotoxicity Among Breast Cancer Patients Whose Condition Was Diagnosed Between 2009 and 2014 (N = 16,456)

Crude HR (95% CI)Adjusted HR (95% CI)
Age, yrs
65+RefRef
≤350.09(0.01–0.66)0.37(0.19–0.72)
36–490.38(0.26–0.55)0.49(0.38–0.62)
50–640.49(0.38–0.63)0.52(0.44–0.63)
Year of diagnosis
2009RefRef
20101.02(0.75–1.39)0.91(0.72–1.15)
20111.04(0.75–1.44)1.03(0.82–1.30)
20120.99(0.69–1.43)0.98(0.76–1.27)
20130.93(0.61–1.40)1.16(0.90–1.50)
20141.13(0.71–1.80)0.98(0.72–1.33)
Trastuzumab
NoRefRef
Yes1.83(1.57–2.13)2.01(1.72–2.36)
Anthracyclines
NoRefRef
Yes1.74(1.39–2.16)1.53(1.30–1.80)
Taxanes
NoRefRef
Yes0.70(0.53–0.94)0.81(0.65–1.01)
Radiation
NoRefRef
Yes0.79(0.63–0.99)0.95(0.81–1.11)
Deyo comorbidity score
0RefRef
11.50(1.11–2.02)1.38(1.15–1.66)
2+3.04(2.08–4.45)2.47(1.94–3.15)
Hypertension
NoRefRef
Yes1.63(1.28–2.08)1.28(1.09–1.51)
Valve disease
NoRefRef
Yes2.05(1.45–2.90)1.93(1.48–2.51)
Insurance
PPORefRef
HMO1.09(0.78–1.53)1.12(0.89–1.41)
Other1.23(0.97–1.56)1.09(0.92–1.29)
Region
NortheastRefRef
North Central1.25(0.88–1.76)0.90(0.72–1.12)
South1.13(0.81–1.57)0.72(0.58–0.89)
Unknown1.65(0.74–3.68)0.74(0.39–1.42)
West0.99(0.66–1.50)0.82(0.64–1.05)

CI = confidence interval; HR = hazard ratio; other abbreviations as in Table 1.

Cardiac monitoring

Of the 4,325 patients treated with trastuzumab-based chemotherapy, 73.5% (n = 3,181) underwent cardiac monitoring at baseline. Although there are no guidelines for conducting cardiac monitoring with cardiac magnetic resonance, we identified 15 of 4,325 trastuzumab-treated patients (0.3%) who had this test performed during their treatment. Guideline-adherent cardiac monitoring was identified in 46.2% or 1,997 patients (n = 4,325). Table 3 shows patient characteristics according to recommended cardiac monitoring. Anthracyclines, taxanes, radiation, and region were associated with guideline-adherent cardiac monitoring. In the adjusted model (Table 4), patients who received a diagnosis more recently (e.g., 2013 compared to 2009 [OR: 1.29; 95% CI: 1.05 to 1.60], or 2014 compared with 2009 [OR: 1.40; 95% CI: 1.11 to 1.76]); those treated with anthracyclines (OR: 1.58; 95% CI: 1.35 to 1.87), taxanes (OR: 1.63; 95% CI: 1.27 to 2.08), and radiation (OR: 1.22; 95% CI: 1.08 to 1.39); and those who had insurance other than HMO or PPO (OR: 1.16; 95% CI: 1.01 to 1.34 for other vs. PPO) had higher odds of receiving guideline-adherent cardiac monitoring. Patients who lived in the western region were less likely to receive guideline-adherent cardiac monitoring (OR: 0.78; 95% CI: 0.63 to 0.96) than those from the northeast.

Table 3. Trastuzumab Users Only: Patient Characteristics According to Recommended Cardiac Monitoring Among Trastuzumab-Treated Breast Cancer Patients (N = 4,325)

TotalYesp Value
All patients4,3251,997 (46.2)<0.001
Heart Failure<0.001
No3,9651,789 (45.1)
Yes360208 (57.8)
Age, yrs0.457
≤3511245 (40.2)
36–491,019485 (47.6)
50–642,3811,097 (46.1)
65+813370 (45.5)
Year of diagnosis0.166
2009733339 (46.2)
2010816350 (42.9)
2011801341 (42.6)
2012652319 (48.9)
2013710375 (52.8)
2014512273 (53.3)
Anthracyclines<0.001
No3,5741,579 (44.2)
Yes751418 (55.7)
Taxanes<0.001
No327114 (34.9)
Yes3,9981,883 (47.1)
Radiation0.002
No1,631703 (43.1)
Yes2,6941,294 (48.0)
Deyo comorbidity score0.959
03,3831,559 (46.1)
1738342 (46.3)
2+20496 (47.1)
Hypertension0.471
No2,8041,306 (46.6)
Yes1,521691 (45.4)
Diabetes0.320
No3,8491,767 (45.9)
Yes476230 (48.3)
Coronary artery disease0.595
No4,1591,917 (46.1)
Yes16680 (48.2)
Valve Disease0.737
No4,1471,917 (46.2)
Yes17880 (44.9)
Insurance0.113
PPO2,5381,141 (45.0)
HMO484224 (46.3)
Other1,303632 (48.5)
Region0.005
North Central1,049508 (48.4)
Northeast740363 (49.1)
South1,676769 (45.9)
Unknown7337 (50.7)
West787320 (40.7)

Values are N or n (%).

Abbreviations as in Table 1.

∗ p < 0.05.

Table 4. Trastuzumab Users Only: Logistic Regression Model Evaluating the Odds of Recommended Cardiac Monitoring Among Breast Cancer Patients Treated with Trastuzumab (N = 4,325)

Crude OR (95% CI)Adjusted OR (95% CI)
Age, yrs
65+RefRef
≤350.80(0.54–1.20)0.73(0.48–1.11)
36–491.09(0.90–1.31)1.02(0.83–1.26)
50–641.02(0.87–1.20)0.98(0.83–1.16)
Year of diagnosis
2009RefRef
20100.87(0.72–1.06)0.86(0.71–1.06)
20110.88(0.72–1.07)0.88(0.72–1.08)
20121.12(0.91–1.39)1.14(0.92–1.42)
20131.33(1.09–1.64)1.29(1.05–1.60)
20141.37(1.09–1.71)1.40(1.11–1.76)
Anthracyclines
NoRefRef
Yes1.59(1.35–1.86)1.58(1.35–1.87)
Taxanes
NoRefRef
Yes1.66(1.31–2.11)1.63(1.27–2.08)
Radiation
NoRefRef
Yes1.22(1.08–1.38)1.22(1.08–1.39)
Deyo comorbidity score
0RefRef
11.01(0.86–1.19)1.03(0.87–1.21)
2+1.04(0.78–1.38)1.06(0.79–1.42)
Hypertension
NoRefRef
Yes0.95(0.84–1.08)0.92(0.80–1.05)
Valve disease
NoRefRef
Yes0.95(0.70–1.28)0.96(0.70–1.30)
Insurance
PPORefRef
HMO1.05(0.87–1.28)1.09(0.89–1.34)
Other1.15(1.01–1.32)1.16(1.01–1.34)
Region
NortheastRefRef
North Central0.98(0.81–1.18)1.01(0.83–1.23)
South0.88(0.74–1.05)0.93(0.78–1.11)
Unknown1.07(0.66–1.73)1.22(0.74–2.01)
West0.71(0.58–0.87)0.78(0.63–0.96)

OR = odds ratio; other abbreviations as in Tables 1 and 2.

HF was more frequently identified among patients undergoing recommended cardiac monitoring (10.4% compared with 6.5%, respectively; p < 0.001), suggesting that, as more patients are screened, more patients are likely to be found having HF. When we evaluated only inpatient claims, we observed that the rates of HF were 2.0% among those whose treatment adhered to cardiac monitoring guidelines and 1.5% for those whose treatment did not (p = 0.210).

In Figure 2, we illustrate whether the rates of cardiac monitoring differed according to age and compared the rates of recommended cardiac monitoring. Overall, rates were similar at baseline and at follow-up for all age groups: 79.5% of patients ≤35 years of age received cardiac monitoring at baseline compared to 86.1% of patients 65+ years of age. At follow-up, among patients ≤35 years of age, 40.2% received the recommended cardiac monitoring compared to patients 65+ years of age, of whom 45.5% had received the recommended cardiac monitoring. Patients ≤35 years of age had the lowest rate of recommended cardiac monitoring, and the highest rate was seen in patients 36 to 49 years of age.

Figure 2.
Figure 2.

Rate of Cardiac Monitoring and Recommended Cardiac Monitoring by Age Group

The percentage of cardiac monitoring at baseline (before trastuzumab treatment), at follow-up, and the overall rate of recommended cardiac monitoring by age group in trastuzumab-treated breast cancer patients (n = 4,325).

Discussion

In this large cohort of breast cancer patients, we observed that 8.3% of the trastuzumab-treated patients developed cardiotoxicity compared to 2.7% among those not treated with trastuzumab. Among patients who received trastuzumab, guideline-adherent cardiac monitoring was identified in 46.2% of patients.

To the best of our knowledge, this study is the first of its kind to estimate cardiotoxicity rates and cardiac monitoring in American women with breast cancer using the MarketScan database, including both younger and older women. Reports have focused primarily on older women, who have higher rates of HF than those reported in clinical trials (12). Our study focused particularly on young women, who tend to have fewer comorbidities and, likely, are relatively like the patients included in the pivotal trastuzumab clinical trials (13–15). Thavendiranathan et al. (9) noted that, compared to older breast cancer patients, younger breast cancer patients have a longer life expectancy and may receive more aggressive chemotherapy. Thus, this is a critical group for analysis with regard to cardiotoxicity and cardiac monitoring.

Our calculated rate of cardiotoxicity was within the range of those reported in clinical trials. As expected, with increasing age, there was a consistent increase in the risk of cardiotoxicity. Deyo comorbidity score, hypertension, and valve disease were all associated with an increased risk of HF. This observation is in line with our previous findings. We reported that comorbidities were associated with increased risk of cardiotoxicity among older breast cancer patients (16). In addition, we quantified the risk of cardiotoxicity associated with other cancer therapies. Use of anthracycline and trastuzumab was associated with a higher risk of HF. This finding is consistent with the fact that anthracycline and trastuzumab use is associated with an increased risk of HF compared to no chemotherapy (17). Interestingly, taxanes were protective in our study, although the mechanisms for this observation are not clear, and although clinical trial data have not shown this observation, it has been reported that combination treatments with taxanes may be less cardiotoxic, and that modern adjuvant regimens of taxanes apparently do not increase anthracycline cardiotoxicity (18). We observed that radiation therapy had no association with risk of HF. Although some investigators have suggested that left chest wall radiation therapy increases the risk of a cardiac event, we were not able to test this association because we cannot reliably identify laterality in this dataset (19).

A limitation of claims-based research is that we cannot identify the exact cause of HF. In addition, data on ventricular ejection fraction was not available. It is possible that our estimates include events associated with causes other than cancer therapy; however, if this occurred, the misclassification would have been nondifferential, affecting potentially all the patients in the cohort and not biasing the direction of the estimate. We performed a sensitivity analysis evaluating exclusively inpatient claims as a marker for severity. The rates of HF requiring hospitalization were the same for those who received trastuzumab and those who did not. In addition, the inpatient HF estimates were much lower than those we observed in the original analyses that listed both inpatient and outpatient claims, suggesting that most trastuzumab-related HF is diagnosed and treated in the outpatient setting.

We previously reported that among Medicare beneficiaries (older than 65 years of age) treated with trastuzumab-based chemotherapy, 36% received recommended cardiac monitoring (8). In our current work, including in a younger patient population, we found that 46.2% of all trastuzumab-treated breast cancer patients received recommended cardiac monitoring. Furthermore, as expected, we found that younger breast cancer patients were less likely to receive cardiac monitoring during trastuzumab treatment than older patients. We must note, however, that our sensitivity analysis using inpatient claims allowed us to determine that the HF identified using cardiac monitoring was not severe enough to require hospitalization and was likely asymptomatic. The clinical implications of the diagnosis of asymptomatic HF are hard to determine and are beyond the scope of this study.

Across all age groups, baseline rates of cardiac monitoring were higher than at follow-up. Similarly, in a study conducted in Australia, 37.7% of patients received cardiac assessment pre-treatment, and then only 26.4% received it both before and during therapy (20). The high cardiac monitoring rates at baseline, as opposed to follow-up, are likely due to the tendency for cardiotoxicity to appear in the first 3 months of treatment (13,21). Other factors may include a lack of awareness of cardiac monitoring and a perceived lack of clinical relevance or need among physicians.

Our results also captured an interesting time trend, as a more recent diagnosis was associated with increased odds of receiving the guideline-adherent cardiac monitoring. In a 2007 study by Subar et al. (22), among 585 American breast cancer patients under 65 years of age, only 15.9% received the full cardiac assessment. Our rate is higher, which may reflect an increased awareness of cardiotoxicity and an improved dissemination of the cardiac monitoring guidelines.

Comorbidity score, hypertension, and valve disease were not associated with increased odds of recommended cardiac monitoring. This is in line with our previous findings, where the administration of anthracyclines was associated with recommended cardiac monitoring but comorbidities were not (8). Consistently, Lu et al. (20) observed in a cohort of 3,418 patients with HER2-positive metastatic breast cancer that trastuzumab, taxanes, anthracyclines, and older age predicted cardiac assessment. Subar et al. (22) also reported that prior anthracycline treatment and duration of trastuzumab therapy were associated with increased odds of receiving cardiac monitoring.

Study limitations

Our study is unique. In this large cohort, we examined time and geographic trends, insurance information, and a variety of comorbidities and cancer therapies. However, our study is subject to the limitations of claims-based research. Our cohort includes only patients with private insurance, which could limit generalizability. Because older women are more likely to be insured by Medicare, they may be underrepresented in this study. We were also unable to examine how these outcomes may have differed by cancer stage, race and ethnicity, and by rural or urban settings. Overtesting for cardiotoxicity and the impact of lifestyle factors, such as smoking or obesity, may also have been areas of interest, but we were unable to evaluate them (15,23,24). The low rates of cardiac monitoring in women could have many possible explanations. They could reflect a low perceived need on the part of physicians, instead of unawareness of the guidelines. In our previous findings, physician-level characteristics had more influence on adherence to cardiac monitoring recommendations than patient-level characteristics (8). The database used for this project did not allow us to examine this association. We must remember that, although cardiac monitoring is recommended in different guidelines, such recommendations are not based on category 1 data, and the timing recommended and the intervals of testing are arbitrary (25). In examining the rates of both cardiac monitoring and cardiotoxicity, we could begin to address the controversial issue of whether cardiac monitoring is warranted in young breast cancer patients (25,26).

Our study demonstrates that cancer treatment history and comorbidities are important risk factors for cardiotoxicity. Biomarkers may be promising and cost effective in the prediction of cardiotoxicity compared to cardiac monitoring (2,27). The number of cancer survivors is expected to increase over time, and we will continue to see patients develop treatment-related cardiotoxicity. Thus, more research, evidence-based guidelines, and tools for prediction of cancer treatment-related cardiotoxicity are needed.

Perspectives

COMPETENCY IN SYSTEMS-BASED PRACTICE: This study could have implications in the use of cardiac monitoring in breast cancer patients. Our results suggest a low adherence to guidelines for cardiac monitoring, as well as a time trend such that adherence is increasing over time. It is important to examine the reasons for the lack of adherence to cardiac monitoring. Our findings can begin to address the need for quality improvement in the cardiovascular care for cancer patients, as well as the evaluation of the cost effectiveness for cardiac monitoring.

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: This study provides important information about the rates of cardiac toxicities associated with cancer therapies outside of a clinical trial. In a large patient population, we identified cardiotoxicity rates according to regimen and age, thus providing practicing clinicians important information that should be considered during treatment planning and counseling. Our data also add to the understanding of the risk factors associated with HF in this patient population and, thus, can help identify patients at higher risk who may benefit from cardiac monitoring.

TRANSLATIONAL OUTLOOK 1: Because cancer therapies are associated with rare but clinically relevant cardiac toxicities, we should continue to look for a more cost-effective way of detecting cardiotoxicity, with the understanding that the primary objective is not only to identify toxicities but to improve outcomes.

TRANSLATIONAL OUTLOOK 2: Guideline-adherent monitoring may be potentially a marker of quality cancer care that may lead to improved cardiovascular health in cancer patients. Additional research is needed to understand the reasons for the low rates of adherence to cardiac monitoring guidelines.

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Abbrevations and Acronyms

HF

heart failure

MUGA

multiple-gated acquisition

Footnotes

Supported by National Cancer Institute Cancer Center grant 2P30 CA016672 to MD Anderson Cancer Center, and Cancer Prevention and Research Institute of Texas grant RP160674. Drs. Chavez-MacGregor and Giordano are supported by Susan G. Komen Breast Cancer Foundation grants SAC150061 and SAC110053. Dr. Chavez-MacGregor has served as a consultant for Pfizer and Roche. All other authors have reported that they have no industrial relationships relevant to the contents of this paper to disclose.