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Breast Cancer

Cardiovascular Reserve and Risk Profile of Postmenopausal Women After Chemoendocrine Therapy for Hormone Receptor–Positive Operable Breast Cancer

^aDepartment of Surgery, Duke University Medical Center, Durham, North Carolina, USA; ^bCardiovascular Therapeutic Exercise Laboratory, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada; ^cDepartment of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

Key Words. Cardiovascular reserve • Cardiovascular risk profile • Early breast cancer • Adjuvant therapy

Correspondence: Lee W. Jones, Ph.D., Box 3624, Duke University Medical Center, Durham, North Carolina 27710, USA. Telephone: 919-668-6791; Fax: 919-684-8203; e-mail: lee.w.jones{at}duke.edu

Received January 9, 2007; accepted for publication July 27, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	Learning Objectives

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
After completing this course, the reader will be able to:

1. Discuss cardiorespiratory fitness and cardiac functional reserve in postmenopausal women treated with chemoendocrine therapy.
   
2. List the cardiovascular risk factors in this study that were found to be less favorable among patients than among controls.
   
3. Explain the significance of peak aerobic power as a predictor of cardiovascular disease.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
Purpose. To examine cardiovascular function and risk profile of postmenopausal women treated with chemoendocrine therapy (CET) for hormone receptor–positive operable breast cancer.

Methods. Forty-seven breast cancer patients and 11 age-matched healthy controls were studied. Participants performed a cardiopulmonary exercise test with expired gas analysis and impedance cardiography to assess peak aerobic power (VO_2peak) and cardiovascular function (stroke volume, cardiac output, cardiac power output, and cardiac reserve). Traditional (i.e., body mass index, lipid profile, and fasting insulin and glucose) and novel (i.e., C-reactive protein, brain natriuretic peptide) cardiovascular risk biochemical factors were also assessed.

Results. Breast cancer patients had significantly lower peak exercise stroke volume (68 ± 9 versus 76 ± 11 ml/beat), cardiac output (10.4 ± 1.5 versus 11.7 ± 2.4 l/minute), cardiac power output (3.0 ± 0.5 versus 3.5 ± 0.9 Watts), cardiac power output reserve (1.7 ± 0.6 versus 2.4 ± 0.8 Watts), and VO_2peak (1.3 ± 0.3 versus 1.6 ± 0.2 l·min^–1) than control subjects (p-values < .05). Patients with the greatest impairment in VO_2peak had the worse cardiovascular risk profile. Exploratory analyses revealed several differences in study outcomes between the 26 patients receiving hormonal therapy with tamoxifen (TAM) and the 21 patients receiving aromatase inhibitor (AI) therapy.

Conclusion. Breast cancer patients treated with adjuvant CET have a significantly and markedly lower cardiorespiratory fitness and cardiac functional reserve compared with age- and sex-matched controls. AI therapy may be associated with a more unfavorable cardiovascular risk profile than TAM. Prospective studies are required to further investigate the clinical value of these findings.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
Breast cancer is the most commonly diagnosed malignancy in American women with approximately 213,000 new cases expected in 2006. While breast cancer incidence increased by 0.2% per year between 1997 and 2000, mortality from breast cancer decreased 2.3% per year during this period. As a result, approximately 2.3 million American women are living with a prior history of breast cancer. One downside of these improved outcomes is that women with early-stage breast cancer are now surviving sufficiently long to be at risk for long-term adverse effects of breast cancer therapy.

Both locoregional radiotherapy and polychemotherapy have been associated with acute and long-term cardiac toxicity among breast cancer patients [1]. Several recent large-scale cohort studies have suggested that, while older radiation techniques are associated with a higher risk for cardiovascular disease (CVD), newer approaches that individualize the radiation field and minimize heart exposure may significantly reduce this risk [2–4]. However, prospective studies using sensitive imaging modalities identified cardiac perfusion defects in 50%–63% of women 6–24 months after receiving modern radiotherapy for left-sided breast cancer [5–7]. Radiation therapy has been shown to damage all aspects of the heart, including the myocardium, pericardium, valves, and coronary vessels [8]. Anthracycline-based adjuvant chemotherapy has now become the current standard for high-risk breast cancers because of its superior breast cancer efficacy over older regimens [9]. While randomized trials of anthracycline-containing chemotherapy have reported the incidence of symptomatic cardiac toxicity to be <5%, prospective studies closely monitoring cardiac function have reported that 20%–51% of patients demonstrate subclinical cardiac dysfunction [10–13]. Furthermore, the recent addition of adjuvant trastuzumab to the management of human epidermal growth factor receptor (HER)-2/neu–positive early breast cancer has increased clinical and subclinical cardiotoxicity rates, and drawn attention to the cardiac tolerability of adjuvant breast cancer therapy [14, 15].

While the adverse cardiac effects of radiation and polychemotherapy have been recognized for many years, traditional endocrine therapy (tamoxifen, oophorectomy) for women with hormone receptor–positive breast cancer has not been clearly associated with cardiovascular dysfunction. Seminal results from recent trials have demonstrated marked improvements in terms of both the disease-free and overall survival rates with aromatase inhibitors (AIs) used instead of or after 2–3 years or 5 years of the traditional endocrine therapy agent tamoxifen (TAM) [16–20]. Of relevance, TAM has been reported to have beneficial estrogenic agonist effects on lipid profiles [21], leading to fewer cardiac events among breast cancer patients [22, 23]. Thus, marked estrogen depletion in AI-treated patients had raised initial concerns about the potential cardiovascular effects of these agents. When compared with adjuvant tamoxifen therapy, AIs have generally been associated with numerically more ischemic cardiovascular events and a greater incidence of hypercholesterolemia [24].

Taken together, modern adjuvant therapy may substantially increase patients' risk for late-occurring CVD, which is becoming an increasingly important indicator of competing mortality in early breast cancer [25, 26]. Despite this risk, current cardiac monitoring techniques (e.g., echocardiography [ECG]) used in clinical trials and day-to-day clinical practice do not assess the subclinical pathophysiological changes that precede the development of overt CVD, nor do they assess the reserve capacity of the heart [27, 28]. Such information is of critical importance when fully evaluating the risk-to-benefit ratio of cancer therapy, and for identifying patients at high risk for late-occurring cardiovascular complications. Accordingly, we conducted a pilot study to comprehensively evaluate the cardiovascular function and risk profile of postmenopausal women treated with chemoendocrine therapy (CET) for hormone receptor–positive operable breast cancer. A prespecified objective was to explore for potential differences in study endpoints between women receiving an AI and those receiving TAM. We hypothesized that breast cancer patients would have worse cardiovascular function and a higher risk profile than age- and sex-matched controls.

	METHODS

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
Setting and Patients
The study was conducted at the Cardiovascular Therapeutic Exercise Laboratory, University of Alberta, and Cross Cancer Institute (CCI), Edmonton, Canada. Consecutive patients with histologically confirmed hormone receptor–positive early-stage breast cancer at the CCI were potentially eligible for this study. Additional inclusion criteria included: (a) completion of definitive surgery, chemotherapy, and/or radiotherapy; (b) no evidence of recurrent or metastatic disease; (c) age >18 years and <80 years; (d) Karnofsky performance status score 70%; (e) no recent documented cardiac or psychological disease; (f) no contraindications to a cardiopulmonary exercise test; (g) receipt of an AI or TAM for at least 6 months prior to study entry; and (h) primary-treating oncologist approval. Eleven postmenopausal, age-matched, healthy women were also recruited for comparison purposes. The Alberta Cancer Board and University of Alberta Ethical Review Boards each approved the study, and written informed consent was obtained from all participants prior to initiation of any study procedures.

Study Procedures
Using a cross-sectional design, potential participants were identified and screened for eligibility via medical chart review of patients scheduled to attend for follow-up of early breast cancer. After obtaining written informed consent, all participants were scheduled for a fasting blood draw and cardiopulmonary exercise test. The postmenopausal healthy subjects were recruited from a convenience sample of those staff at the CCI without a prior history of breast cancer.

Outcome Assessments

Peak Aerobic Power and Exercise Cardiovascular Function
The incremental exercise test (15-Watt increments every 2 minutes) was performed on an electronically braked cycle ergometer (Ergoline, Ergoselect 100, Bitz, Germany) during which time expired gas analysis data were collected (TrueOne® 2400 Metabolic Measurement System; Parvomedics Inc., Salt Lake City, UT) according to the American Thoracic Society guidelines [29]. Resting and exercise cardiac output were assessed using impedance cardiography (Minnesota Impedance Cardiograph, model 304B; Surcom Inc., Minneapolis, MN) and a three-lead ECG. A phonocardiogram (Hewlett Packard, model 21050A; Hewlett Packard, Palo Alto, CA) was integrated with the impedance cardiograph to identify the first and second heart sounds in order to landmark respective B and X points of dZ/dt waveforms for determination of left ventricular ejection time. Impedance cardiography was used to calculate stroke volume during 7-second sampling periods at the end of each minute using Bernstein's equation [30]. Blood pressure (cuff sphygmomanometer), heart rate, stroke volume, cardiac output, and cardiac power output (cardiac output x mean arterial pressure) were obtained at the end of each exercise stage.

Body Composition
Body composition was assessed through body weight, body mass index (BMI), and waist and hip circumference. Body weight was assessed in a hospital gown to the nearest 0.1 kg. Waist circumference was measured to the nearest 0.1 cm at the narrowest point between the hips and chest in a standing position.

Biochemical CVD Risk Factors
The following CVD risk factors were analyzed: lipid profile (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglyceride), fasting insulin and glucose, C-reactive protein (C-RP), and plasma concentration of brain natriuretic peptide (BNP). All assays were performed at the University of Alberta Hospital in one batch and in duplicate against known standards.

Statistical Analysis
The initial analysis provided descriptive information on the demographic and clinical treatment characteristics of participants. To examine differences between breast cancer patients and healthy controls in study endpoints we used a one-way analysis of variance (ANOVA) for means comparisons and Pearson ² tests for proportion comparisons. We also used a one-way ANOVA and Pearson ² tests to explore differences between breast cancer patients receiving an AI and those receiving TAM on study endpoints. Linear regression analysis was used to determine the univariate association between peak aerobic power (VO_2peak) and individual CVD risk factors. Data are presented as mean ± standard deviation. All statistical tests were two-sided and significance was prespecified for p < .05. No adjustment was made for multiple tests.

	RESULTS

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
A total of 172 postmenopausal, hormone receptor–positive operable breast cancer patients were screened for eligibility. Of these, 155 (155/172 = 90.1%) met inclusion criteria and 47 agreed to participate (47/155 = 30.3%). The reason for noneligibility was that these women had not received endocrine therapy for the minimum specified period of time (6 months) (n = 17). Reasons for nonparticipation were: (a) medical reasons as decided by the patient or investigator (n = 15), (b) time commitment concerns (n = 31), (c) issues related to geography or transportation to study center (n = 20), and (d) disinterest in study participation (n = 42). There were no differences between participants and nonparticipants on any medical characteristic.

	PARTICIPANT CHARACTERISTICS

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
Participant characteristics are shown in Table 1. The patients' mean age and weight were 59 ± 7 years and 76 ± 7 kg. The mean number of months since diagnosis and since chemotherapy completion were 38 ± 19 months and 34 ± 18. Forty-seven percent were diagnosed with T1 disease and 72% underwent a mastectomy. Ninety-eight percent received locoregional radiotherapy (mean, 4,657 ± 244 Gy), with 60% receiving left-sided therapy; all patients received chemotherapy and 60% received an anthracycline. The mean resting left ventricular ejection fraction (LVEF) determined by a multigated acquisition (MUGA) scan during chemotherapy was 64% ± 19%. In healthy control subjects, the mean age and weight were 56 ± 5 years and 72 ± 16 kg. Eight patients (8/47 = 17%) were taking cardiovascular medications (e.g., antihypertensives, cholesterol-lowering medications). One participant in the control group was taking a cardiovascular medication (1/11 = 9%). All subjects were free from documented CVD at study entry.

	CARDIOVASCULAR FUNCTION AND RISK FACTORS

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

View larger version (16K): [in this window] [in a new window]   Figure 1. Temporal changes in heart rate (beats/minute) (A), stroke volume (ml/beat) (B), and cardiac output (l/minute) (C) in breast cancer patients (n = 47) and controls (n = 11).

	DISCUSSION

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
The principal finding of this investigation was that breast cancer patients treated with adjuvant CET have a significantly and markedly lower VO_2peak secondary to impairments in cardiac reserve. A second important finding was that patients with the greatest impairment in VO_2peak had the worse CVD risk profile.

In the present study, breast cancer patients' VO_2peak was 17.9 ml·kg^–1·min^–1, or 24% below that of age- and sex-matched healthy control subjects. The low VO_2peak observed in the present study is consistent with reports in Hodgkin's disease survivors treated with chest radiation [31] and our prior work among 26 early-stage patients treated with adjuvant taxane- and anthracycline-containing chemotherapy and/or trastuzumab [32]. In this study, the VO_2peak was 36% below that of age- and sex-matched healthy control subjects [32]. The low aerobic capacity observed in this study has a number of potentially important clinical implications. First, low VO_2peak has been recognized as a strong, independent predictor of CVD and all-cause mortality in both diseased and healthy populations [33–37]. For example, Gulati and colleagues reported that exercise capacity was the strongest predictor of mortality among 5,000 asymptomatic women. Specifically, with every one metabolic equivalent (3.5 ml·kg^–1·min^–1) increase in exercise capacity, the risk for death was reduced by 17% [33]. Moreover, Paterson et al. [35] demonstrated that a minimum VO_2peak of 15 ml·kg^–1·min^–1 in women was necessary for independent living. In our study, 13 patients (28%) were below this minimum level, compared with no subjects (0%) in the healthy control group. Finally, the low VO_2peak of the patients is even more striking given that the control participants, on average, were also 15% below population-based, age-predicted fitness for sedentary women [38]. The moderate-to-strong univariate associations between VO_2peak and BMI and biochemical CVD risk factors (i.e., glucose, insulin, C-RP) confirm the central importance of this parameter in determining the overall CVD risk profile of breast cancer patients. Given this, interventions demonstrated to augment cardiorespiratory fitness (e.g., exercise training) may have clinical benefit for operable breast cancer patients.

While this study replicates our prior work confirming low VO_2peak in operable breast cancer patients [32], to our knowledge, this is the first study to examine the mechanisms of exercise limitation in this clinical population. Our results indicate that impaired VO_2peak may be secondary to a lower stroke volume and cardiac output at peak exercise, thus resulting in a concomitant reduction in oxygen delivery to the active skeletal muscles. Stroke volume is determined by three factors: heart rate, myocardial contractility, and loading (i.e., preload and afterload). In the present study, we found no differences between patients and controls in peak heart rate and afterload (i.e., systemic vascular resistance), suggesting that impaired left ventricular preload or contractility is likely responsible for the low stroke volume observed in breast cancer patients. This finding corroborates prior work suggesting that anthracycline-containing chemotherapy and radiotherapy are associated with diastolic dysfunction and reduced myocardial contractility in cancer populations [39–41]. Moreover, although the present study was conducted a mean of 3 years following chemotherapy cessation, cardiac functional reserve was significantly impaired, compared with healthy controls, suggesting that left ventricular function may not fully recover following completion of chemotherapy and/or radiotherapy. Clearly, this study was designed to determine the mechanisms responsible for the cardiac and cardiovascular impairment observed in this study. As such, impairment could be the result of adjuvant therapy (direct effects) or deconditioning from insufficient physical activity (indirect effects). It is our position that both significantly contribute to the observed impairment [42].

From a clinical perspective, our results suggest that standard resting cardiac imaging modalities (e.g., ECG, MUGA) used in day-to-day oncology clinical practice and clinical trials may be of limited value and only allow for detection of therapy-associated cardiac dysfunction when significant dysfunction has already occurred [27, 28]. For example, Tan [43] demonstrated that peak cardiac power output measured during dobutamine stress was a better predictor of mortality than resting LVEF in individuals with moderate-to-severe heart failure. Accordingly, cardiac stress procedures achieved via exercise or pharmacologic techniques (e.g., dobutamine) that incorporate noninvasive assessments of cardiac reserve function may allow for early subclinical detection of cardiac abnormalities, which, in turn, may improve patient management [28].

The specific contributions to and impact of the direct (therapy effects) and indirect (secondary lifestyle changes) effects of adjuvant therapy on impaired cardiorespiratory fitness and cardiac reserve function remain to be elucidated. Each breast cancer adjuvant therapy (i.e., radiation, chemotherapy, trastuzumab, and endocrine therapy) is associated with unique cardiac effects [1]. As such (and depending on the individual treatment plan), the patient is subjected to a series of sequential or concurrent cardiac and vascular "insults" that deplete the compensatory abilities of the cardiovascular reserve. Of equal importance, these pathophysiologic events often occur in the context of therapy-associated lifestyle changes secondary to therapy (e.g., physical inactivity, weight gain) [44–46] that further predispose to cardiovascular damage. Adequately powered prospective studies using sensitive methods of subclinical cardiovascular injury are required to fully understand the pathogenesis and contribution of direct and indirect effects to late-occurring CVD in operable breast cancer.

Finally, an exploratory aim of this study was to examine the potential differences between patients receiving an AI and those receiving TAM. In concordance with reported data from recent adjuvant trials [24], our results indicate that AI therapy may be associated with a more unfavorable CVD risk profile than TAM. In fact, patients receiving an AI had a more unfavorable profile on several established (i.e., lipid profile) and novel (i.e., insulin, glucose, C-RP) CVD risk factors. Clearly, these findings must be viewed cautiously given that this study was not designed nor adequately powered to definitively examine the potential differential effects of endocrine therapy agents on CVD risk. In addition, whether these potential differences reflect direct AI-induced cardiovascular injury or simply the withdrawal of the cardioprotective effects of TAM remains to be determined, and future studies are warranted.

This study does have several limitations. Two obvious limitations are the relatively small sample size and cross-sectional study design. To adequately investigate the impact of adjuvant breast cancer therapy on cardiovascular health, large prospective studies are required. As demonstrated, women undergoing adjuvant therapy for early-stage breast are at high risk for late-occurring cardiovascular injury. As such, it is important for future studies to appropriately monitor patient exercise response (i.e., 12-lead ECG, pulse oximetry, and blood pressure) to detect any undiagnosed myocardial injury or ischemic disease [29, 47]. Finally, although our healthy control subjects were at a relatively high risk for late-occurring CVD, women who receive surgery only for premalignant breast cancer (i.e., ductal carcinoma in situ) may be a more appropriate comparison group to investigate the cardiovascular effects of adjuvant therapy. In summary, breast cancer patients treated with adjuvant CET have a significantly and markedly lower cardiorespiratory fitness and cardiac functional reserve than age- and sex-matched controls. Prospective studies are required to further investigate these findings.

	ACKNOWLEDGMENTS

Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 
This paper was presented in part at the 29th Annual Meeting of the San Antonio Breast Cancer Symposium, December 2006.

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Top Learning Objectives Abstract Introduction Methods Results Participant Characteristics Cardiovascular Function and Risk... Discussion Acknowledgments References

 

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jones, L. W. Articles by Mackey, J. R. Search for Related Content PubMed PubMed Citation Articles by Jones, L. W. Articles by Mackey, J. R.