Originally published as JCO Early Release 10.1200/JCO.2006.10.1022 on December 10 2007

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Predictors of Tamoxifen Discontinuation Among Older Women With Estrogen Receptor–Positive Breast Cancer

Cynthia Owusu, Diana S.M. Buist, Terry S. Field, Timothy L. Lash, Soe Soe Thwin, Ann M. Geiger, Virginia P. Quinn, Floyd Frost, Marianne Prout, Marianne Ulcickas Yood, Feifei Wei, Rebecca A. Silliman

From the Division of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, OH; Group Health Center for Health Studies, Seattle, WA; Meyers Primary Care Institute: Fallon Community Health Plan/Fallon Foundation/University of Massachusetts Medical School, Worcester; Boston University Medical Center, Boston, MA; Division of Public Health Sciences, Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Research and Evaluation, Kaiser Permanente Medical Care Program, Pasadena, CA; Lovelace Respiratory Research Institute, Albuquerque, NM; Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT; Josephine Ford Cancer Center, Henry Ford Health System, Detroit, MI; and HealthPartners Research Foundation, Minneapolis, MN

Corresponding author: Cynthia Owusu, MD, MSc, Case Western Reserve University, University Hospitals Health System Ireland Cancer Center-BHC 5055, 11100 Euclid Ave, Cleveland, OH 44106-5055; e-mail: cynthia.owusu{at}case.edu

	ABSTRACT

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Purpose Five years of adjuvant tamoxifen therapy for estrogen receptor (ER) –positive breast cancer is more effective than 2 years of use. However, information on tamoxifen discontinuation is scanty. We sought to identify predictors of tamoxifen discontinuation among older women with breast cancer.

Patients and Methods Within six health care delivery systems, we identified women 65 years old diagnosed with stage I to IIB ER-positive or indeterminant breast cancer between 1990 and 1994 who had filled a prescription for adjuvant tamoxifen. We observed them for 5 years after initial tamoxifen prescription. We used automated pharmacy records to validate tamoxifen prescription information abstracted from medical records. The primary end point was tamoxifen discontinuation, operationalized as ever discontinuing tamoxifen during 5 years of follow-up. We used Cox proportional hazards to identify predictors of tamoxifen discontinuation.

Results Of 961 women who were prescribed tamoxifen, 49% discontinued tamoxifen before the completion of 5 years. Discontinuers were more likely to be aged 75 to less than 80 years (v < 70 years; hazard ratio [HR] = 1.41; 95% CI, 1.06 to 1.87), be aged 80 years (HR = 2.02; 95% CI, 1.53 to 2.66), have an increase in Charlson Comorbidity Index at 3 years from diagnosis (HR = 1.52; 95% CI, 1.18 to 1.95), have an increase in the number of cardiopulmonary comorbidities at 3 years (HR = 1.75; 95% CI, 1.34 to 2.28), have indeterminant ER status (v ER-positive status; HR = 1.36; 95% CI, 1.00 to 1.85), and have received breast-conserving surgery (BCS) without radiotherapy (v mastectomy; HR = 1.62; 95% CI, 1.18 to 2.22).

Conclusion Attention to nonadherence among older women at risk of discontinuation, particularly those receiving BCS without radiotherapy, might improve breast cancer outcomes for these women.

	INTRODUCTION

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The National Comprehensive Cancer Network guidelines¹ recommend the use of adjuvant endocrine therapy in women with hormone receptor–positive breast cancer. Supporting these recommendations are results from the Early Breast Cancer Trialists' Collaborative Group²; the results demonstrated that use of adjuvant tamoxifen therapy over a 5-year period in women with estrogen receptor (ER)–positive disease resulted in a 41% reduction in the risk of recurrence and 31% reduction in annual mortality rate, regardless of age, and that 5 years was more effective than 2 years of adjuvant tamoxifen therapy.² It is clear that tamoxifen is beneficial in older women and offers a reasonable alternative to aromatase inhibitors, which have been slightly more effective in preventing breast cancer recurrences in adjuvant trials.

Older women are less likely to receive a tamoxifen prescription.³ Among women who do receive a prescription for tamoxifen therapy, nonadherence can further reduce the expected preventive and curative benefits. Information about tamoxifen discontinuation is sparse, ranging from 23% to 40% in clinical trial settings^4-6 and from 15% to 50% in clinical practice.^7-10

Members of our research team have previously examined tamoxifen discontinuation in a cohort of older women with ER-positive breast cancer using self-reported tamoxifen information.¹⁰ The study presented here expands on previous work by examining the pattern and predictors of adjuvant tamoxifen discontinuation over a 5-year period among a cohort of older women with ER-positive breast cancer using tamoxifen information from medical record review and with negligible loss to follow-up.

	PATIENTS AND METHODS

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We have previously described the study design and data collection methods,¹¹ which were approved by institutional review boards at the coordinating center and enrollment sites and were conducted in accord with an assurance filed with and approved by the Department of Health and Human Services; all sites had a waiver of consent.

Study Design and Setting
Briefly, the Breast Cancer Treatment Effectiveness in Older Women (BOW) study¹¹ is a 10-year prospective cohort study of older women with early-stage breast cancer who were enrolled in six geographically diverse health care delivery systems that are members of the Cancer Research Network. The six health care delivery systems that participated in this study include Group Health, Seattle, WA; Kaiser Permanente, Pasadena, CA; Lovelace, Albuquerque, NM; Henry Ford Health System, Detroit, MI; HealthPartners, Minneapolis, MN; and Fallon Community Health Plan, Worcester, MA.

Study Population
Potentially eligible women for the Breast Cancer Treatment Effectiveness in Older Women study (N = 1,859) had to be aged 65 years, newly diagnosed with histologically confirmed American Joint Committee on Cancer TNM stage¹² I to IIB unilateral breast cancer between January 1, 1990 and December 31, 1994, and enrolled in their health plans for at least 12 months before and after diagnosis, unless they died within the first year of diagnosis. We limited the cohort for this tamoxifen discontinuation study (n = 961) to women with ER-positive or indeterminant receptor tumors, who had received primary surgical therapy, had evidence in their medical record of receiving at least one tamoxifen prescription with identifiable dates in their medical records corresponding to when tamoxifen therapy was first initiated and discontinued, and had not discontinued tamoxifen as a result of death (Fig 1). Excluded patients (11%), compared with included patients, were more likely to be 80 years old (31% v 17%, respectively; P < .0001), to have Charlson Comorbidity Index scores 2 (9% v 4%, respectively; P < .0001), to have negative/unassessed nodal status (78% v 65%, respectively; P = .005), not to have received chemotherapy (98% v 93%, respectively; P = .02), and to have received breast-conserving surgery (BCS) without radiotherapy (18% v 8%, respectively; P = .002).

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Flow diagram of study population. (*) Breast Cancer Treatment Effectiveness in Older Women. ER, estrogen receptor.

Abstractors recorded dates of initial tamoxifen prescription and discontinuation. For patients who took tamoxifen intermittently, all dates when tamoxifen was stopped and restarted were recorded. Abstractors recorded reasons for discontinuation as documented by treating physicians and classified reasons as a result of end of a physician's recommended duration of treatment, adverse effects (cerebrovascular disease, thromboembolic disease, endometrial cancer, hot flashes, or other), financial constraints, or other/unknown. Information on adverse effects was not collected on women who completed treatment.

Dependent Analytic Variable: Discontinuation of Adjuvant Tamoxifen
Tamoxifen discontinuation was operationalized as ever discontinuing tamoxifen for more than 60 days^13,14 during the 5 years after initial tamoxifen prescription. We limited follow-up to the first of the following: first tamoxifen discontinuation for longer than 60 days or completion of 5 years of tamoxifen from the time of initial tamoxifen prescription. We censored women who received more than 5 years of tamoxifen at 5 years because the recommended duration of adjuvant tamoxifen therapy in the late 1990s was 5 years.¹⁵ Never discontinuers include women who had medical record documentation that they had discontinued tamoxifen as a result of completion of their physician's recommended duration of tamoxifen therapy (n = 441; median duration of tamoxifen therapy, 60.0 months; interquartile range, 58.6 to 60.0 months) and women who did not have any medical record documentation that they had completed their physician's duration of treatment but received at least 5 years of adjuvant tamoxifen without an interruption (n = 48) or with an interruption for 60 days (n = 30). Discontinuers include women who did not belong to any of the groups described earlier and who received tamoxifen for less than 5 years before their first discontinuation without interruption (n = 391) or with interruption for more than 60 days (n = 51). The median duration of tamoxifen use was 60.0 months (interquartile range, 58.4 to 60.0 months) in the never-discontinued group and 23.0 months (interquartile range, 8.0 to 40.1 months) in the ever-discontinued group. Additionally, we created two subgroups of discontinuers, defined as women who discontinued tamoxifen within 12 months (early discontinuers) or after 12 months (late discontinuers) of initial tamoxifen prescription.

We conducted a validation of tamoxifen discontinuation dates from medical records with automated pharmacy records among a subset of our patients (n = 466) who were members of five of the six integrated health care delivery systems. Medical and pharmacy record discontinuation dates differed by a median of 27 days (interquartile range, –11 to 71 days).

Independent Analytic Variables
Sociodemographic characteristics. We categorized women into age groups of 65 to less than 70, 70 to less than 75, 75 to less than 80, and 80 years of age. We classified race/ethnicity as non-Hispanic white, Hispanic, African American, and other.

Comorbidity. We ascertained from medical records each woman's comorbidities 1 year before and 3 years after initial breast cancer diagnosis and used this information to calculate the Charlson Comorbidity Index.¹⁶ The Charlson Comorbidity Index was chosen for its validity in breast cancer research.¹⁶ We created a change variable defined as an increase in Charlson Comorbidity Index from the year before diagnosis to 3 years after diagnosis to examine the relationship between increasing number of comorbidities and tamoxifen discontinuation. We also examined change in cardiopulmonary comorbidities from the same time interval to explore the relationship between comorbidities that had a potential for reducing life expectancy (eg, myocardial infarction, congestive heart failure, cerebrovascular accident, peripheral vascular disease, and chronic obstructive airways disease) and tamoxifen discontinuation.

Tumor characteristics. We categorized tumor size as 0.5 cm, more than 0.5 cm to 1 cm, more than 1 cm to 2 cm, more than 2 cm to 5 cm, or more than 5 cm; lymph node status as positive or negative/unassessed; histologic grade as well differentiated, moderately differentiated, poorly differentiated, or not determined; and ER and progesterone receptor status as positive or indeterminant.

Breast cancer treatment variables. We categorized primary therapy as receipt of mastectomy, BCS with radiotherapy, or BCS without radiotherapy. Patients were dichotomized according to whether or not they had received adjuvant chemotherapy.

Data Analysis
We used life-table analysis to calculate the proportion of patients who had discontinued tamoxifen by midyear for each year of follow-up and tabulated the reasons for tamoxifen discontinuation for each year of follow-up. To examine associations between categoric variables, the ² test or Fisher's exact test, when appropriate, was used. We calculated the proportions of patients who ever discontinued tamoxifen within the categories of the independent variables and estimated the univariate hazard ratios (HRs) and 95% CIs using Cox proportional hazards. We developed our multivariable model by first including variables that were significant predictors of tamoxifen discontinuation at P < .10 on univariate analysis. Our final multivariable model included variables that remained significant at P < .05. Interaction terms between significant predictors of tamoxifen discontinuation were explored.

We modeled change in comorbidity as time-dependent covariates within multivariable Cox proportional hazards models. These models included Charlson Comorbidity Index at baseline in addition to other variables in our final model. We limited these analyses to patients who had not discontinued tamoxifen by the end of year 3 (n = 631) to ensure that tamoxifen discontinuation did not precede a change in comorbidity at 3 years. Patients who were excluded from these analyses were more likely to be 80 years old (24% v 14% of included patients; P = .002) and to have received BCS without radiotherapy (13% v 6% of included patients; P = .0004). All analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Patient Baseline Characteristics
Of 961 women with ER-positive or indeterminant breast cancer who were prescribed tamoxifen, approximately one fifth were 80 years old (Table 1). The cohort was predominantly white (81%), more than half (71%) had no comorbidities at diagnosis, and most had tumors that were 2 cm in size (69%), no nodal involvement/unassessed nodes (65%), and well/moderately differentiated tumors (55%). Eight percent of the cohort received BCS without radiotherapy.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Proportion of older women with breast cancer who never discontinued tamoxifen over a 5-year follow-up period (life-table analysis).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Secular trend of tamoxifen discontinuation among 442 older women with estrogen receptor–positive/indeterminant breast cancer who discontinued tamoxifen over a 5-year follow-up period.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Secular trend of reasons for tamoxifen discontinuation among 442 older women with estrogen receptor–positive/indeterminant breast cancer who discontinued tamoxifen over a 5-year follow-up period.

Effect of Time-Dependent Comorbidity on Tamoxifen Discontinuation
Of the 631 women who did not discontinue tamoxifen within 3 years after initial breast cancer diagnosis, 14% had a change in Charlson Comorbidity Index, and 8% had a change in number of cardiopulmonary comorbidities by the third year of follow-up. Both a change in Charlson Comorbidity Index from the year before diagnosis to 3 years after initial diagnosis (HR = 1.52; 95% CI, 1.18 to 2.00) and an increase in cardiopulmonary comorbidities during the same time interval (HR = 1.75; 95% CI, 1.34 to 2.28) were associated with tamoxifen discontinuation during the succeeding years.

	DISCUSSION

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In this study of older women with early-stage ER-positive breast cancer from six geographically diverse health care delivery systems, we found that 49% of women discontinued tamoxifen before completion of their recommended 5 years. Older age, increasing comorbidities, indeterminate ER status, and receipt of BCS without radiotherapy were associated with tamoxifen discontinuation.

Information on tamoxifen adherence is limited.^8-10,17,18 Our observed tamoxifen discontinuation rate over the course of 5 years is consistent with two studies that have examined tamoxifen adherence over the long term in the community setting. The first study examined tamoxifen adherence among female breast cancer patients enrolled in New Jersey's Medicaid or Pharmaceutical Assistance to the Aged and Disabled Programs between 1990 and 1996⁸ and observed progressively worse adherence with each passing year, with approximately 50% of women being nonadherent by the end of the fourth year of follow-up. Most nonadherence occurred within the first year of follow-up. Our results are consistent with this pattern. The second study examined tamoxifen discontinuation in a cohort of older women treated in a mix of academic and community settings¹⁰ and observed a tamoxifen discontinuation rate of 31% by the end of the fifth year of follow-up. This lower tamoxifen discontinuation rate may be an underestimation as a result of the reliance on self-report of tamoxifen adherence. These rates of tamoxifen discontinuation are high and should be of concern to practicing oncologists and primary care physicians.

The relationship between tamoxifen discontinuation and older age has been demonstrated in other studies.^8,17,18 Adherence to medications may be negatively impacted by multiple comorbidities,^19,20 polypharmacy,²¹ cognitive impairment,²² lack of financial resources, and/or insurance or drug benefits,²³ all of which are prevalent in older patients and offer a plausible explanation for the association between older age and tamoxifen discontinuation.

Previous studies of tamoxifen adherence^8-10 and our study do not show any relationship between comorbidity burden at diagnosis and tamoxifen adherence. However, the association between increasing comorbidities and tamoxifen discontinuation raises a number of interesting hypotheses. Plausible explanations for increasing comorbidities in this cohort include adverse effects of tamoxifen or a surveillance bias among tamoxifen users. However, the current study is unable to test either hypothesis because this would require a comparison between a cohort of tamoxifen users and nonusers. Regardless of reason for increasing comorbidities, the association between increasing comorbidities and tamoxifen discontinuation is consistent with existing literature.^10,24 Monane et al²⁴ demonstrated that, in the presence of multiple comorbidities and polypharmacy, elderly patients were more likely to be nonadherent to antihypertensives. Lash et al¹⁰ demonstrated that, although women with more prescriptions at breast cancer diagnosis were less likely to discontinue tamoxifen, they were more likely to discontinue tamoxifen if the number of prescriptions increased over time. This may reflect the perception that future life expectancy will be impacted more by new and developing comorbidities than by adherence to medications for existing conditions.²⁵

Partridge et al⁸ showed that receipt of mastectomy in lieu of BCS was directly associated with tamoxifen nonadherence. Our finding that women who received BCS without radiotherapy were the patients additionally at risk for tamoxifen discontinuation is particularly concerning because receipt of BCS without radiotherapy is associated with increased local recurrence.^26,27 Coupled with premature discontinuation of adjuvant endocrine therapy, this may result in earlier recurrences and, ultimately, increased breast cancer mortality. This has implications for the latest National Comprehensive Cancer Network guidelines,²⁸ which allows for the use of BCS without radiotherapy plus tamoxifen or an aromatase inhibitor in women age 70 years or older with ER-positive, node-negative breast cancer. A favorable outcome with this treatment approach can only be achieved if older women are adherent to prescribed oral endocrine therapies.

Although our study represents one of the few large studies to have examined tamoxifen adherence in the community setting, our results must be considered with the following caveats. First, existing literature has shown that tamoxifen adverse effects^9,10,18,29 are related to tamoxifen discontinuation. Because we collected adverse effects data only on the subcohort of women who discontinued tamoxifen, we were unable to determine the association between tamoxifen adverse effects and tamoxifen discontinuation. Second, our outcome measure, tamoxifen discontinuation, was ascertained from medical records. This method relies on patient self-report of adherence and consistent documentation by medical providers in medical records, and therefore, it is unlikely that it will capture all periods of intermittent discontinuation. However, the consistency of our tamoxifen prescription information from medical records with automated pharmacy records and the consistency of our results with other studies that have used rates of refilling of tamoxifen prescriptions to ascertain tamoxifen adherence^8,17 lend support to the validity of our results. Rates of pharmacy dispensing in a closed pharmacy system have been shown to be a more accurate method of assessing adherence.^30,31 Third, although we examined reasons for tamoxifen discontinuation, the majority remains unknown because of our reliance on medical records. Studies specifically designed to examine reasons for tamoxifen discontinuation will be useful to inform the debate regarding the appropriate design of interventions to reduce nonadherence. Last, our results may not be generalizable to other populations of older women with breast cancer who do not have access to health care.

Barriers to adherence are multifaceted and include patient, provider, and health care system factors. In this study, not only were older patients more likely to discontinue tamoxifen, but older age was also associated with two of the independent predictors of tamoxifen discontinuation, notably indeterminate receptor status and BCS without radiotherapy. Failure to determine hormonal receptor status is an indicator of poor quality cancer care,³² which raises the issue of the quality of cancer care being provided to older cancer patients. With the current shift to the development of oral cancer therapies and the longer survival times³³ that require long-term daily medications, adherence is becoming an important issue in oncology care. System redesign, collaborative care with primary care providers, electronic health records, and the use of other professionals to assist in patient education are among the strategies that will be required to tackle this challenging problem.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Timothy L. Lash, Marianne Prout, Rebbecca A. Silliman

Provision of study materials or patients: Diana S.M. Buist, Terry S. Field, Virginia P. Quinn, Floyd Frost, Marianne Ulcickas Yood, Rebbecca A. Silliman

Collection and assembly of data: Diana S.M. Buist, Soe Soe Thwin, Ann M. Geiger, Floyd Frost, Marianne Ulcickas Yood, Feifei Wei, Rebbecca A. Silliman

Data analysis and interpretation: Cynthia Owusu, Terry S. Field, Timothy L. Lash, Soe Soe Thwin, Ann M. Geiger, Marianne Prout, Rebbecca A. Silliman

Manuscript writing: Cynthia Owusu, Diana S.M. Buist, Terry S. Field, Timothy L. Lash, Ann M. Geiger, Virginia P. Quinn, Marianne Prout, Marianne Ulcickas Yood, Feifei Wei, Rebbecca A. Silliman

Final approval of manuscript: Cynthia Owusu, Diana S.M. Buist, Terry S. Field, Timothy L. Lash, Ann M. Geiger, Virginia P. Quinn, Floyd Frost, Marianne Prout, Marianne Ulcickas Yood, Feifei Wei, Rebbecca A. Silliman

	NOTES

 
published online ahead of print at www.jco.org on December 10, 2007.

Supported by Grant Nos. K05 CA92395, CA093772, and CA093772-04S1 from the National Cancer Institute and by an American Society of Clinical Oncology Foundation Young Investigator Award.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 22, 2006; accepted June 8, 2007.

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