Comorbidities and Cardiovascular Disease Risk in Older Breast Cancer Survivors

Objective: To evaluate cardiovascular disease (CVD) risk factors in older breast cancer survivors compared with a group of women without breast cancer.

Study Design: The retrospective study included (1) women aged 65 or more years who were initially diagnosed with stage I or II breast cancer from 1990 to 1994 in 6 US health plans and who survived at least 5 years post-diagnosis (cases) and (2) a matched comparison group. They were followed for a maximum of 15 years.

Methods: Data sources included medical charts and electronic health records. Cases (n = 1361) were matched on age, health plan site, and enrollment year to women in the comparison group (n = 1361). Subjects were followed to the first CVD outcome, health plan disenrollment, death, or study end. We compared rates of CVD in these 2 groups and used Cox proportional hazard models to estimate the hazard ratio (HR), considering body mass index, smoking history, diabetes, and hypertension.

Results: The strongest predictors of CVD were smoking history (HR = 1.29; 95% confidence interval [CI], 1.15-1.46), diabetes (HR = 1.72; 95% CI, 1.48-1.99), and hypertension (HR = 1.48; 95% CI, 1.31-1.67) rather than breast cancer case-comparison status (HR = 0.97; 95% CI, 0.87-1.09).

Conclusion: Results suggest that long-term prognosis in breast cancer patients is affected by management of preexisting conditions. Assessment of comorbid conditions and effective management of diabetes and hypertension in older breast cancer survivors may lead to longer overall survival.

Am J Manag Care. 2014;20(1):86-92Our results suggest that older long-term breast cancer survivors (initially diagnosed with early-stage disease) have a cardiovascular disease (CVD) risk similar to that of otherwise healthy women of comparable ages.

• The established risk factors (very old age, smoking history, diabetes, and hypertension) were more predictive of CVD risk than breast cancer history status.

• Long-term prognosis in older breast cancer patients is affected by management of preexisting conditions, and these may be best managed by primary care providers.

• Management of comorbidities in survivors should not be different from that in the general population of older patients.

More than half of the 2.6 million breast cancer survivors living in the United States are over age 65 years,^1,2 and the fraction of older people with cancer is growing, partly attributable to the success of cancer screening and treatment. Consequently, the number of older cancer survivors at risk of developing other age-related conditions such as cardiovascular disease (CVD) is increasing. Many of these older breast cancer patients also have comorbid conditions or other CVD risk factors.³ Moreover, CVD is the leading cause of death in breast cancer survivors.⁴ As comorbidities impact prognosis and cardiovascular outcomes in breast cancer patients, the role of primary care physicians in the care of survivors is expanding to manage these preexisting conditions.

Despite CVD being the leading cause of morbidity in older breast cancer survivors, very few studies have examined CVD risk factors in such women, whether these factors differ from those in women in the general population, and the long-term impact of these risk factors on CVD outcomes.⁴ For example, prior studies on CVD risk in older cancer survivors were limited by cross-sectional designs; few included information on health status prior to cancer diagnosis; and even fewer included data from comparison subjects without a cancer history.^5-20 Given these limitations, it is unclear whether there is excess risk of CVD among breast cancer survivors.

Examining CVD risk poses a challenge, as long-term observation periods are required. Further, CVD is more common in older adults in general and especially in those who have established risk factors other than cancer treatments. Because few older breast cancer survivors are treated with chemotherapy,²¹ particularly those agents known to be cardiotoxic, examining the impact of comorbidities on CVD risk is crucial. Therefore, a well-characterized comparison group with long follow-up is essential to determine whether there truly is excess morbidity in older women treated for breast cancer.

The purpose of this investigation was to determine whether incident CVD was greater in a group of older breast cancer survivors versus a cancer-free comparison group, and if the excess risk could be attributed to differences in comorbid conditions. To this end, we compared incident CVD in the 2 groups over a 15-year follow-up period, incorporating baseline risk factors such as race/ethnicity, body mass index (BMI), smoking history, diabetes, and hypertension.

METHODSDesign, Setting, and Subjects

We identified women 65 years or older who were diagnosed with early-stage breast cancer (American Joint Commission on Cancer TNM stage I, IIA, or IIB) from January 1, 1990, through December 31, 1994, who survived at least 5 years after the initial breast cancer diagnosis. We selected 5-year survivors because this time period is most often used as a benchmark to define recovery.¹⁹ These women were participants in the BOWI study.²¹ Briefly, the BOWI multisite cohort study is a 10-year longitudinal study focusing on the effectiveness of treatment for breast cancer. Women in the BOWI cohort were identified through Cancer Research Network (CRN) managed care systems: Group Health Cooperative, Seattle, Washington; Kaiser Permanente, Southern California;

Lovelace Health System, New Mexico; Henry Ford Hospital and Health System, Detroit, Michigan; Health Partners, Minnesota; and Fallon Community Health Plan, Massachusetts. ²¹ These CRN sites were selected to achieve diversity in geography, system size, and patient populations.

The BOWII study extended data collection through 5 additional years of follow-up on the BOWI cohort and added a comparison group. The eligible BOWII case group for this analysis consisted of 1361 five-year breast cancer survivors. Comparison women were selected from the source population of each health plan. Comparisons included women who were cancer free at the time of the case’s year of diagnosis, and frequency matched (1:1) on age, health plan site, and enrollment year. These potential confounders were selected as matching variables because they are strongly associated either with survival or with treatments. To be eligible, comparison women also had to survive 5 years after enrollment into the study cohort. The final cohort consisted of 2722 women (1361 matched pairs). Women were followed from 5 years after the index date (breast cancer diagnosis date or matched enrollment date) until first CVD event, disenrollment from the health plan, loss to clinical follow-up, death, or completion of 15 years of follow-up (up to December 31, 2009), whichever occurred first. The protocol for this study was reviewed and approved by the institutional review board at each participating CRN site.

Data Source

Data on CVD outcomes, demographics, comorbidities, and other covariates were ascertained primarily from the women’s medical records and were supplemented with electronic health records. Standardized medical record reviews were conducted at each site by trained medical record abstractors. A detailed description of the data collection system and the training procedures implemented to standardize data collection across sites has been published elsewhere.²² Mortality data (date of death and whether the cause was related to breast cancer) were collected using the National Death Index. We used mortality information for censoring in the analysis.

Data Elements

Cardiovascular Outcomes. Study outcomes included the following CVD events and were examined as a single binary composite outcome (presence or absence of any event): myocardial infarction, congestive heart failure, coronary artery disease, arrhythmias, and cerebrovascular disease. The CVD events were identified by the first occurrence of a diagnosis in the women’s medical charts during the study follow-up period. Women with a diagnosis for multiple events on the same day were assigned a single outcome using a priority scale based on importance per the recommendation of one of the study clinicians (RAS): (1) myocardial infarction, (2) coronary artery disease, (3) cerebrovascular disease, (4) arrhythmia, and (5) congestive heart failure.²³

Demographics and Cardiovascular Disease Risk Factors. We gathered information on date of birth, race, and ethnicity. We also collected information on diabetes, hypertension, smoking status, and BMI for both groups. Information closest to time of entry into the cohort was used in the analyses.

Statistical Analyses

Differences in demographic characteristics and CVD risk factors between case and comparison women were first examined by comparing frequency distributions (P values were based on x² or Fisher exact tests). Cox proportional hazards models were used to estimate the hazard ratio (HR) of the association of CVD composite outcome with case-comparison status. Because we examined only the first CVD outcome (and not multiple occurrences), and as this model is the standard approach for analyzing cohort data, we used the Cox model.

We tested the proportional hazards assumption using Schoenfeld residuals.²⁵ The subjects’ entry into the analysis corresponded to 5 years after the initial breast cancer diagnosis for the cases and matched enrollment date for the comparisons. We examined the association with 2 models: a parsimonious model adjusted for the matching factors, age, and site, and another model that included hypertension, diabetes, smoking history, BMI, and race/ethnicity. Life table analysis was used to compare CVD incidence by case-comparison status.

RESULTS

Demographic characteristics, comorbidities, and CVD risk factors for cases and comparisons are displayed in Table 1. Although the majority of women in both groups were white non-Hispanic (81.9% and 84.3% for cases and comparisons, respectively), the race/ethnicity distribution was similar in both groups (P = .34). Case patients were more likely to be obese (BMI >30 kg/m², P = .01) and have hypertension (P = .005) than comparison women. There were no significant differences observed in smoking history and diabetes between the 2 groups.

Table 2 displays follow-up characteristics of the case and comparison groups. The mean follow-up time among cases was 5.0 years (1828 days) after entry into the cohort compared with 5.3 years (1942 days) among comparisons. Nearly 20% of women in both groups completed 15 years of follow-up (17.4% and 19.7% for cases and comparisons, respectively). Nearly half of the women in both groups experienced a CVD event during the follow-up period, with a slightly higher proportion of comparisons experiencing a CVD event (47.7%) than cases (45.3%). The fraction of deaths was nearly 2- greater in cases (21.7%) than in comparisons (12.1%). As expected, there was a greater risk of death due to breast cancer among cases. Nearly one-third died of breast cancer in the case group (97/295) versus 1% in the comparison group (2/165).

Of the 2722 total women in the entire cohort, 1266 (46.5%) experienced a CVD event. Of the 1266 women, 740 experienced 1 of the 5 CVD events constituting the composite outcome and 526 experienced 2 or more CVD events during follow-up (data not shown). Table 3 shows the incidence of first CVD event during the follow-up period (maximum 10 years) for the composite outcome as well as the individual conditions. No overall differences were found with the composite CVD outcome (P = .40) nor with the individual outcomes in terms of risk. The rates of the composite CVD outcome and the individual outcomes were also similar in cases and comparisons (83.3/1000 person-years vs 82.90/1000 person years, respectively). We also examined the risk of CVD in the 2 groups over time. The life table curves for CVD events by case-comparison status showed no difference in overall survival probabilities between the 2 groups (data not shown).

Table 4 presents the adjusted HR for the association between CVD and case-comparison status. Multivariable models were initially adjusted for matching factors (model 1 included age at diagnosis and health plan site). Cases were no more likely to experience a CVD event than comparisons (HR = 1.00; 95% confidence interval [CI], 0.90-1.12). In model 2, we further examined race/ethnicity, BMI, smoking history, diabetes, and hypertension. Interestingly, the strongest predictors of CVD were smoking history, diabetes, and hypertension rather than breast cancer case-comparison status (HR = 0.97; 95% CI, 0.87-1.09). For example, smoking history increased CVD risk by nearly 30% (HR = 1.29; 95% CI, 1.15-1.46). Women with diabetes were 72% more likely to develop CVD (HR = 1.72; 95% CI, 1.48-1.99), and those with hypertension were 48% more likely to develop CVD after accounting for case-comparison status (HR = 1.48; 95% CI, 1.31-1.67). Also, white women were 50% (HR = 1.51; 95% CI, 1.28-1.77) more likely to develop CVD than minority women. As expected, CVD risk increased with older age (P for trend <.10). We did not find a trend with BMI categories, possibly due to missing values. We repeated the Cox regression analysis excluding the 121 survivors exposed to chemotherapy (and their matched comparisons). As the subset results were similar, we reported the HRs of the full cohort.

DISCUSSION

Our goal was to determine whether older cancer survivors are at increased risk of CVD events compared with the general population. In this population-based study of more than 2700 breast cancer survivors 65 years and older and age-matched comparison women, we found that the risk of CVD was similar in the 2 groups. The incidences of the composite CVD outcome were the same, as were the incidences of the individual conditions.

Very few studies have compared CVD risk factors and outcomes of cancer survivors with those of a general population of women to determine whether there truly is an excess risk among cancer survivors. Our results were consistent with the few studies that have included a comparison group. For example, a Dutch study examined more than 4000 breast cancer survivors and compared their CVD incidence with that of a general female population, and determined that radiation to the breast alone did not increase CVD risk.²⁶ Similar to our present study, breast cancer survivors followed in Ontario, Canada, also did not have an increased risk of myocardial infarction compared with age-matched women from the general population (other CVD outcomes were not studied).²⁷ However, in these 2 studies, comorbid conditions were not examined. The remaining studies examined CVD outcomes within a group of breast cancer survivors and focused on cancer treatments, whereas our aim was to examine risk factors common to both groups. Further, few of these studies included a cancer-free comparison group and, again, did not examine the impact of comorbid conditions or lacked information on lifestyle factors (smoking history, BMI).^10,11,26,27

Our study has a number of strengths. A major advantage of this study is that data elements were mainly obtained from medical record reviews, not solely from electronic clinical data.²⁰ We carefully identified a group of comparison women (without breast cancer) to determine whether there truly was excess CVD morbidity in the cancer case group. In addition, mean follow-up time was similar in both groups, thereby reducing the potential for selection bias. Importantly, the case and comparison groups were followed a maximum of 15 years; manifestation of CVD requires more than a decade of follow-up.

Certain limitations of this study must be considered. Although we captured low-density lipoprotein (LDL) cholesterol and glycated hemoglobin (A1C) levels from health plan laboratory databases, very few women had these values (overall, about 70% of women had missing LDL levels and 85% had missing A1C levels; data not shown). Therefore, we did not include these variables in the analyses. However, the percentage of missing values was nondifferential (71% of the cases had missing LDL cholesterol levels vs 67% of comparisons; 83% of cases had missing A1C levels vs 85% of comparisons), so any bias resulting from this exclusion was likely to be minimal. Similarly, many women were missing BMI, but again, the percentage of missing values was nondifferential (roughly 20% in both groups). In addition, all women in this study were selected from integrated healthcare delivery systems, so their experiences may not reflect those of others in the general population. However, we selected a nationally representative group of health plans, and the race/ethnic distribution of these subjects was similar to the source population at each health plan.

Because our main objective was to examine factors common to both cases and comparisons, and because very few breast cancer patients in our study underwent chemotherapy (121 of 1361 cases), we did not examine the impact of chemotherapy within the cancer case group. In a sensitivity analysis, when we excluded breast cancer survivors exposed to chemotherapy, the results were similar to those with the full cohort. In general, as older breast cancer survivors are less likely to receive chemotherapy, our results are still generalizable to a broader group of older breast cancer survivors.²¹ However, our results may only be generalizable to breast cancer survivors cared for in other integrated healthcare delivery systems. For similar reasons, we did not examine the impact of aromatase inhibitors in the breast cancer survivor group. Few survivors used such drugs (98 of 1361 cases), as the majority were diagnosed before the availability of aromatase inhibitors in the mid 2000s. However, given the long latency of CVD (which may be 10 or more years), we were able to capitalize on the long observation period in this study (maximum of 15 years postdiagnosis).²⁷ Before risk/benefit ratios can be determined, data on the long-term toxicity profiles of aromatase inhibitors need to be available, and these data are still pending. In addition, while a few studies suggest that aromatase inhibitors may slightly increase cardiotoxicity,^28,29 tamoxifen may be cardioprotective.^30,31 Therefore, given that nearly 900 of the 1361 breast cancer patients used tamoxifen, it is possible that the lack of difference in CVD outcomes between cases and comparisons could be partially attributed to the cardioprotective effect of tamoxifen.

Overall, our results suggest that older long-term, early-stage breast cancer survivors have a risk of CVD similar to that of otherwise healthy women of comparable ages. The established risk factors (very old age, smoking history, diabetes, and hypertension) were more predictive of CVD risk than breast cancer history status. For long-term survivors, comorbid conditions are a greater health threat than the initial cancer.³² This study demonstrates that long-term prognosis in older breast cancer patients is affected by management of preexisting conditions, and these may be best managed by primary care providers.³³ Our results also suggest that management of comorbidities in survivors should not be different from that in the general population of older patients. The transfer of cancer survivorship care to primary care settings is a challenge; however, careful attention to follow-up care of other chronic diseases in survivors may best be facilitated in coordinated healthcare systems. Author Affiliations: From Kaiser Permanente (RH, CA, VQ), Pasadena, CA; Boston Medical Center, (RAS), Boston, MA; Boston University, School of Public Health (MP, ST), Boston, MA; Wake Forest School of Medicine (AMG), Winston-Salem, NC; Group Health Research Institute (AK), Seattle, WA; VA-Healthcare System (ST), Boston, MA; Henry Ford Health Systems (MEUY), Detroit, MI.

Funding Source: Research reported in this publication was supported by the National Cancer Institute, National Institutes of Health, under award numbers R01CA093772 (RAS), R01CA136743 (RH), and U19CA079689 (EW).

Author Disclosures: Dr Haque reports that she has received grants from California Breast Cancer Research Program. The other authors (MP, AMG, AK, SST, CA, RAS, VQ, MUY) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (RH, SST, RAS, MUY); acquisition of data (RH, AK, VQ, MUY); analysis and nterpretation of data (RH, SST, RAS, MUY); drafting of the manuscript (RH, SST, RAS, and MUY); critical revision of the manuscript for important intellectual content (RH, SST, RAS, MUY); statistical analysis (RH, SST); provision of study materials or patients (RH, AK, VQ, MUY); obtaining funding (RAS); administrative, technical, or logistic support (RH, CA, RAS, VQ); and supervision (RH, RAS).

Address correspondence to: Reina Haque, PhD, MPH, Kaiser Permanente Southern California, Department of Research & Evaluation, 100 South Los Robles Ave, 2nd Floor, Pasadena, CA 91101. E-mail: reina.haque@kp.org.1. McCaskill-Stevens W, Abrams JS. Comorbidities in the aging breast cancer population: are current assessments leading to improved outcomes? J Natl Cancer Inst. 2011;103(14):1072-1073.

2. Parry C, Kent EE, Mariotto AB, Alfano CM, Rowland JH. Cancer survivors: a booming population. Cancer Epidemiol Biomarkers Prev. 2011;20(10):1996-2005.

3. Patnaik JL, Byers T, Diguiseppi C, Denberg TD, Dabelea D. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst. 2011;103(14):1101-1111.

4. Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 2011;13(3):R64.

5. Roychoudhuri R, Robinson D, Putcha V, Cuzick J, Darby S, Møller H. Increased cardiovascular mortality more than fifteen years after radiotherapy for breast cancer: a population-based study. BMC Cancer. 2007;7:9.

6. Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol. 2007;25(21): 3031-3037.

7. Jagsi R, Griffith KA, Koelling T, Roberts R, Pierce LJ. Stroke rates and risk factors in patients treated with radiation therapy for early-stage breast cancer. J Clin Oncol. 2006;24(18):2779-2785.

8. Nilsson G, Holmberg L, Garmo H, Terent A, Blomqvist C. Radiation to supraclavicular and internal mammary lymph nodes in breast cancer increases the risk of stroke. Br J Cancer. 2009;100(5):811-816.

9. Nilsson G, Holmberg L, Garmo H, Terent A, Blomqvist C. Increased incidence of stroke in women with breast cancer. Eur J Cancer. 2005;41(3):423-429.

10. Patt DA, Goodwin JS, Kuo YF, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol. 2005;23(30):7475-7482.

11. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97(6):419-424.

12. Doyle JJ, Neugut AI, Jacobson JS, et al. Radiation therapy, cardiac risk factors, and cardiac toxicity in early-stage breast cancer patients. Int J Radiat Oncol Biol Phys. 2007;68(1):82-93.

13. Jagsi R, Griffith KA, Koelling T, Roberts R, Pierce LJ. Rates of myocardial infarction and coronary artery disease and risk factors in patients treated with radiation therapy for early-stage breast cancer. Cancer. 2007;109(4):650-657.

14. Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6(8):557-565.

15. Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: current knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76(3):656-665.

16. Correa CR, Darby SC. Cardiac disease and second lung cancer after radiotherapy for breast cancer. Eur J Cancer. 2009;45(suppl 1):420-421.

17. Taylor CW, McGale P, Darby SC. Cardiac risks of breast-cancer radiotherapy: a contemporary view. Clin Oncol (R Coll Radiol). 2006;18(3): 236-246.

18. Taylor CW, Brønnum D, Darby SC, et al. Cardiac dose estimates from Danish and Swedish breast cancer radiotherapy during 1977- 2001. Radiother Oncol. 2011;100(2):176-183.

19. Sweeney C, Schmitz KH, Lazovich D, Virnig BA, Wallace RB, Folsom AR. Functional limitations in elderly female cancer survivors. J Natl Cancer Inst. 2006;98(8):521-529.

20. Oeffinger KC, Van Leeuwen FE, Hodgson DC. Methods to assess adverse health-related outcomes in cancer survivors. Cancer Epidemiol Biomarkers Prev. 2011;20(10):2022-2034.

21. Enger SM, Thwin SS, Buist DS, et al. Breast cancer treatment of older women in integrated health care settings. J Clin Oncol. 2006;24(27): 4377-4383.

22. Avila CC, Quinn VP, Geiger AM, Kerby TJ, St Charles M, Clough-Gorr KM. Webinar Training: an acceptable, feasible and effective approach for multi-site medical record abstraction: the BOWII experience. BMC Res Notes. 2011;4:430.

23. Haque R, Yood MU, Geiger AM, et al. Long-term safety of radiotherapy and breast cancer laterality in older survivors. Cancer Epidemiol Biomarkers Prev. 2011;20(10):2120-2126.

24. Breslow NE, Day NE. Statistical methods in cancer research. Volume II—the design and analysis of cohort studies. IARC Sci Publ. 1987;(82):1-406.

25. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika. 1982;69(1):239-241.

26. Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 2007;99(5):365-375.

27. Vallis KA, Pintilie M, Chong N, et al. Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol. 2002;20(4):1036-1042.

28. Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 2011;103(17): 1299-1309.

29. Cuppone F, Bria E, Verma S, et al. Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early stage breast cancer? meta-analysis of randomized trials. Cancer 2008;112(2):260-267.

30. Chlebowski RT, Cuzick J, Amakye D, et al. Clinical perspectives on the utility of aromatase inhibitors for the adjuvant treatment of breast cancer. Breast. 2009;(suppl 2):S1-S11.

31. Visvanathan K, Chlebowski RT, Hurley P, et al; American Society of Clinical Oncology. American Society of Clinical Oncology 2008 clinical practice guideline: update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27(19):3235-3258.

32. Grunfeld E. Cancer survivorship: a challenge for primary care physicians. Br J Gen Pract. 2005; 55(519):741-742.

33. Hong S, Nekhlyudov L, Didwania A, Olopade O, Ganschow P. Cancer survivorship care: exploring the role of the general internist. J Gen Intern Med. 2009;24(suppl 2):S495-S500.

34. Cancer Research Network. http://www.crn.cancer.org. Accessed January 1, 2012.

Download PDF: Comorbidities and Cardiovascular Disease Risk in Older Breast Cancer Survivors