adherence research Introduction Breast cancer is the most common cancer diagnosis among women in the United States,

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1 Psychosocial factors in adjuvant hormone therapy for breast cancer: An emerging context for adherence research Introduction Breast cancer is the most common cancer diagnosis among women in the United States, comprising nearly one-third of new female cancer diagnoses and 41% of female survivors [1, 2]. Nearly three-quarters of breast cancer diagnoses involve cancer cells that express receptors for estrogen and/or progesterone, and are considered hormone receptor positive [3]. The successful use of hormone therapy as an adjuvant treatment in these patients has contributed to the improved five-year cause-specific breast cancer survival rates [4]. Adjuvant hormone therapy begins after primary treatment (i.e., surgery, chemotherapy, radiation) is complete, and is typically conceptualized as prolonged self-management of a chronic illness through daily oral medication intake. Tamoxifen, a medication that prevents estrogen from binding to cancer cells, has been prescribed in premenopausal and postmenopausal patients for more than two decades [5]. A five-year course of adjuvant tamoxifen reduces breast cancer mortality by one-third through 15 years post-diagnosis and reduces recurrence rates by an average of 39% through 10 years postdiagnosis, compared to no tamoxifen use [6]. Aromatase inhibitors (AIs) are a newer class of medications that reduce estrogen levels by inhibiting an enzyme responsible for estrogen production; they are primarily used in treating postmenopausal women. Use of AIs as primary adjuvant treatment or in sequence with (before or after) tamoxifen reduces risk of recurrence and improves recurrence-free survival compared to five years of tamoxifen use alone [5, 7]. Notably, survival is poorer and recurrence risk is greater when hormone therapy is discontinued before completion of five years of treatment and when adherence to the daily 1

2 treatment regimen is sub-optimal (less than 80% of daily doses taken), and periodically poor adherence is a predictor of premature discontinuation [5, 6, 8, 9]. Unfortunately, only 41-72% of patients in clinical practice settings are considered adherent, and adherence declines over the five-year course of treatment (from 79.6% to 68.3% in year one and five, respectively) [10, 11]. These adherence rates are supplemented by data regarding patients premature discontinuation, or treatment non-persistence. In clinical practice settings, 31-73% of patients fail to complete the recommended five-year course, with premature discontinuation increasing over time (from 13.6% to 40.9% in year one and five, respectively) [10, 11]. The Present Review A non-negligible number of breast cancer survivors do not take hormone therapy as prescribed, despite the associations of these medications with optimal health outcomes. However, a systematic understanding of the correlates of non-adherence and early discontinuation is lacking, and the critical need for identification of these factors has been recognized [10, 12]. To date, no published review has considered the potential influences of psychosocial or behavioral variables on adjuvant hormone therapy adherence. Among other chronic illness patient populations, psychosocial factors have been both positively and negatively associated with medical regimen adherence. For example, depressed patients have been found to be three times more likely to be non-adherent to medical recommendations than non-depressed patients in a meta-analytic review, and non-adherence may be a behavioral mediator of the relationship between depression and worse medical outcomes [17]. Social support and cognitive factors (e.g., self-efficacy, perceived control, and intentions) predict behavior and adherence independently and within comprehensive models of health behavior engagement [18, 19]. 2

3 Increasingly, the interactions between patients and their health care providers are being considered for their impact on patient adherence [20]. Among cancer survivors, both inter- and intrapersonal factors are believed to influence well-being and may affect regimen adherence in systematic and clinically important ways. Ten to 25% of breast cancer survivors reportedly experience clinically significant depressed mood, 15.2% report chronic psychological distress throughout the illness trajectory, and 15.2% report distress uniquely in the post-treatment survivorship phase [21, 22]. Survivors taking adjuvant hormone therapy have reported significantly more emotional concerns and greater likelihood of experiencing fear of recurrence and emotional distress, compared to breast cancer survivors not taking hormone therapy [23]. Moreover, survivors may experience changes in their social support networks and interactions with medical providers as primary treatment subsides. Despite the apparent importance of these psychosocial factors in breast cancer survivors daily lives, as well as the documented relationships between some of these variables and regimen adherence in other medical populations, it remains unclear how psychosocial factors impact breast cancer survivors adherence [10]. The current review aims to evaluate the associations between psychosocial factors and breast cancer survivors adherence to adjuvant hormone therapy. Psychosocial factors could represent risk factors for medication non-adherence and premature discontinuation of therapy. A more comprehensive understanding of the role of psychosocial variables as potential risk factors for medication non-adherence is a warranted initial step toward improving patient adherence and long-term medical outcomes in the ever-growing breast cancer survivor population. Methods 3

4 Studies were identified through systematic searches conducted in PsycINFO and PubMed of all publication years until February 1, Our search strategy utilized combinations of the following terms: adherence, compliance, tamoxifen, aromatase inhibitor, hormone therapy, and endocrine therapy. The advanced search functions of the databases were used to restrict the search terms to appearing in the abstract in PsycINFO and the title/abstract in PubMed. For inclusion in the review, the study was required to: a) examine adult breast cancer survivors (diagnosed at age 18 or older) who initiated tamoxifen or an AI, b) include at least one psychosocial variable (defined below), c) include at least one hormone therapy outcome measure (adherence to daily pill regimen, interruptions in treatment, and/or persistence/discontinuation), d) use quantitative analyses to examine the statistical relationship between the psychosocial variable/s and hormone therapy outcome/s and e) be published in English in a peer-reviewed journal. To allow for a comprehensive review, the term psychosocial was broadly defined and included: interpersonal factors (e.g., social support, relationship factors, and patient-provider interactions) and intrapersonal factors (e.g., mental health factors, quality of life, and beliefs about illness, medication, and recurrence). Outcomes of adherence-promoting interventions, dissertations, book chapters, review papers, and conference abstracts were excluded. Fourteen studies were identified that met criteria for inclusion in the review (see Figure 1 for additional details regarding study selection process). Results Interpersonal factors Among Chinese male breast cancer patients, low social support (instrumental and emotional combined) was associated with decreased patient-reported tamoxifen adherence across the five-year course of therapy (adjusted hazard ratio (HR) = 2.45, 95% Confidence Interval (CI) 4

5 , p=.005) [9]. Among younger (< age 40), pre-menopausal French breast cancer patients, low emotional, but not instrumental, social support was associated with premature tamoxifen discontinuation (adjusted HR = 2.1, 95% CI , p=.006) [8]. Additional analyses of pharmacy refill data from this cohort assessed treatment interruptions of two or more consecutive months without a dispensed prescription. Lower general provision of social support was associated with increased likelihood of treatment interruptions during both the first 16 months of tamoxifen treatment (adjusted odds ratio (OR) = 3.7, 95% CI , p=.03) and the following year (adjusted OR = 3.13, 95% CI , p=.04) [15]. Various aspects of patients interactions with their medical providers and the associations of these factors with hormone therapy adherence and persistence were assessed. The degree to which oncologists communication after diagnosis was patient-centered was positively associated with AI and tamoxifen persistence at three years post-diagnosis [16]. At this time, 94% of patients who experienced the highest degree of patient-centered communication and 59% of patients who reported the lowest degree of patient-centered communication persisted with hormone treatment (adjusted OR = 1.22, p=0.006) [16]. Specific discussion of the need for hormone therapy treatment, however, was not associated with treatment persistence [16]. In another study, patients baseline perceptions of their providers abilities to offer information, discuss treatment options, and individually tailor treatments, as well as the degree to which providers actually were a source of helpful information regarding breast cancer and its treatment, did not predict tamoxifen persistence [13]. Although receipt of an insufficient amount of information regarding hormone therapy was not associated with treatment interruptions, receipt of poor quality (non-understandable) information did predict such interruptions (adjusted OR = 0.26, 95% CI , p = 0.01) [15]. Moreover, specifically feeling poorly informed about 5

6 treatment side effects was associated with an increased likelihood of discontinuation, even after statistical adjustment for side effect intensity (p=0.002) [30]. One study reported that patients who perceived less support from their providers were more likely to discontinue treatment (p=0.005) [30], however, other research indicated that patients ratings of their providers technical and interpersonal care were not associated with discontinuation [13]. In addition to medical providers behavior, patients perceptions of their own role in health care interactions may relate to treatment adherence. Higher perceived self-efficacy in encounters with medical providers predicted ongoing hormone use at three years post-diagnosis, with 91% of patients with high self-efficacy and 72% of patients with low self-efficacy during medical encounters persisting with treatment (adjusted OR = 1.04, p=0.04) [16]. However, another study reported that patients perceptions of their abilities to communicate with their providers were not associated with treatment discontinuation [13]. Although patients vary in the degree to which they wish to participate in their health care encounters, a lack of opportunity to ask questions at time of diagnosis was associated with interruptions in hormone use over a year later (adjusted OR = 0.27, 95% CI , p=0.007) [15]. Moreover, the degree to which patients participate in the decision-making surrounding a given treatment may impact their adherence and persistence. Although patients who felt they had a less than adequate role in hormone treatment decision-making had increased odds of discontinuation four years postdiagnosis (p=0.0049) [30], patients degree of participation in the decision to initiate hormone therapy was not associated with interruptions in tamoxifen treatment [15] or with three-year AI persistence [26]. Interestingly, patients who made the decision to initiate tamoxifen treatment independently were more likely to discontinue treatment compared to patients who left the 6

7 decision solely to their provider or who made the decision with input from their medical provider (p=0.018) [30]. Intrapersonal factors Global QOL was not associated with self-reported adherence [9], treatment interruptions [15], or discontinuation [8, 13]. Cancer-specific QOL was also not associated with discontinuation at two years [14] or five years [12] after treatment initiation. General emotional well-being was not associated with patient-reported adherence [29] or discontinuation [13], nor did baseline general mental health predict treatment discontinuation at two years [14] or five years [12] after hormone initiation. Similarly, breast cancer-specific emotional health was not associated with discontinuation [13]. Level of depressive symptoms did not predict hormone discontinuation [8, 26] or significant interruptions in treatment [15]. Medical chart documentation of a depression diagnosis, however, was associated with reduced likelihood of treatment discontinuation in two retrospective database analyses combining tamoxifen and AI patients (adjusted HR=0.92, 95% CI , p=.002; adjusted OR=1.57, 95% CI , p<.001) [24, 25], yet not associated with discontinuation in a third database analysis focusing exclusively on tamoxifen patients [28]. Reduction in depressed mood and reduction in anxiety between one and two years following medication initiation were independently associated with adherence (> 80% of daily pill intake; depression: Z=-2.4, p=.01; anxiety: Z=-2.2, p=.03) [27]. No relationship was found between temporal changes in irritability and adherence. In another study, however, an analogous reduction in fear of cancer recurrence was associated with subsequent interruptions in treatment (adjusted OR=2.89, 95% CI , p=.03) [15]. These interruptions of two or more months signify poor adherence and persistence. Receipt of psychological help since diagnosis and use of 7

8 psychotropic medication (anti-depressants, hypnotics, or sedatives) were not associated with such treatment interruptions [15]. A decisional balance variable, created by subtracting perceived risks of tamoxifen use from perceived benefits, was utilized in two studies [12 and 14] to assess patients beliefs about tamoxifen use. Patients who had neutral or negative decisional balance scores at baseline, reflecting the perception that the risks of tamoxifen use are similar to or greater than the benefits, were three times more likely to discontinue tamoxifen use at the two-year follow-up compared to women with positive decisional balance scores, who believed that the benefits of use outweighed the risks (OR = 3.0, 95% CI ) [14]. After the full five-year follow-up period, women with positive baseline decisional balance scores and those whose attitudes toward tamoxifen became more positive over time (a positive change in decisional balance score) were less likely to discontinue tamoxifen treatment (HR for a 10-point higher score= 0.93, 95% CI ; HR for a 10-point positive change = 0.93, 95% CI ) [12]. Similarly, in a cross-sectional study, lower perceived necessity of tamoxifen use predicted non-adherence (p=.026) [29]. Discussion The relationships between psychosocial factors and breast cancer survivors adherence to adjuvant hormone therapy are complex and at times inconsistent (see Table 1 for a summary). Interpersonal factors reviewed included social support and patient-provider interactions. Low social support was reliably associated with decreased adherence, increased likelihood of treatment interruptions of more than two months, and increased likelihood of premature treatment discontinuation. Aspects of poor patient-provider communication, low degree of provider support, inadequate patient opportunity to ask questions and make decisions, and low patient self-efficacy in interactions impacted persistence with hormone therapy years later. 8

9 Overall, more collaborative and supportive patient-provider interactions were associated with positive adherence outcomes. These findings highlight the enduring importance of meeting patients unique needs for information, decision-making, and support, and extend the possibility that changing providers interactions with patients could improve adherence. Intrapersonal factors reviewed included various measures of mental health and patient beliefs about tamoxifen use. Global and cancer-specific QOL and well-being were unrelated to adjuvant hormone therapy adherence or treatment persistence. Depression was primarily associated with adherence outcomes when categorical diagnoses, rather than continuous symptom measures, were utilized. However, conflicting results concerning depression and hormone therapy adherence preclude an understanding of these relationships. A diagnosis of depression was both not associated with persistence and, contrary to what has been reported in other patient populations, predictive of improved persistence. Alternatively, a reduction in depressive symptoms across time (i.e., experiencing less depression) was also associated with improved daily regimen adherence. An analogous reduction in fear of recurrence, however, predicted poorer adherence through its association with significant interruption in treatment. Women who are depressed may ruminate about their cancer, and thus experience greater fear of recurrence and sustained adherence. Results consistently indicated that patients beliefs about tamoxifen use, including perceived risks, benefits, and necessity, were associated with adherence and persistence. Patients who do not perceive tamoxifen to be beneficial may choose to use it irregularly or discontinue use to reduce the impact of the perceived costs of taking the medication [29]. If these risk and benefit perceptions are inaccurate, updating patients knowledge has the potential to greatly impact adherence outcomes. These beliefs represent an important potentially modifiable factor to consider. 9

10 Nearly two-thirds of the included studies were published in 2012 or later, suggesting that empirical interest in this topic is rapidly growing. Consideration of psychosocial factors from the outset of study conceptualization would allow for more rigorous and prospective measurement of the variables. Doing so would enable further delineation of the potentially dynamic relationships between psychosocial factors and hormone therapy adherence across time, and ultimately improve our ability to best serve this growing patient population s unique medical and psychosocial needs. Such analyses could provide information about the timing of psychosocial factors influence, which consequently could identify relevant periods for intervention. Future research should also strive to include analyses of non-linear, mediating, and moderating relationships, as well as control for side effects and quality of life. With an ever-increasing population of breast cancer survivors who are living for decades after their cancer treatment, attention to the relationships between psychosocial factors and adjuvant hormone therapy adherence is relevant and important. These results highlight the importance of considering individual patients preferences and medical and psychosocial characteristics when addressing medication adherence. Furthermore, they suggest that the associations between psychosocial factors and breast cancer survivors adherence to long-term hormone therapies differ from relationships observed in other chronic illness populations. Consequently, an understanding of adherence and adherence-promoting interventions based upon other populations may require adaptation for the unique illness context of breast cancer. 10

11 Identification Records identified through database searching (n=622) Screening Records remaining after duplicates removed (n=506) Records remaining after title and abstract reviewed (n=222) Eligibility Included Full-text articles assessed for eligibility (n=222) Articles included for review (n=14) Full-Text Articles Excluded, with reasons (n=208) Patient population: 29 Language: 22 Type of article: 18 Review: 18 Intervention: 6 Outcome variable: 62 Psychosocial variable: 53 Figure 1. Summary of Study Selection. 11

12 Table 1. Summary of Psychosocial Factors Associated With Adherence Outcomes Psychosocial Factor Low social support Poorer Adherence (i.e., increased discontinuation, poorer daily adherence, or significant interruptions) [8, 9, 15] Better Adherence (i.e., reduced discontinuation, better daily adherence, or lack of interruptions) No Effect Quality of life [8, 9, 12, 13, 14, 15] Depressive symptoms [8, 15, 26] Depression diagnosis [24, 25] [28] General mental health, well-being, utilization of psychological [12, 13, 14, 15, 29] services Improvement in mood (reduction in depression, anxiety, [15] [27] [27] fear of recurrence, irritability) Negative beliefs about hormone use [12, 14, 25] Limited patient involvement in treatment decisionmaking Poor quality of information provision by medical providers Poor patient-provider communication or provider support [15, 16, 30] [13, 15, 26] [15, 30] [15, 16] [16, 30] [13] 12

13 References Note: Where available, only the digital object identifier (doi) is used to reference a publication. Full references are available upon request. 1. American Cancer Society. Breast cancer facts & figures, Atlanta: American Cancer Society; American Cancer Society. Cancer treatment and survivorship facts & figures Atlanta: American Cancer Society; Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to J Clin Oncol. 2003;21: Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353: Haque R, et al. (2012). doi: /cam4.37; /cam EBCTCG, et al. (2011). doi: /S (11) Burstein HJ, et al. (2010). doi: /JCO Huiart L, et al. (2012). doi: /j.ejca Xu S, et al. (2012). doi: /s z 10. Murphy CC, et al. (2012). doi: /s Huiart L, et al. (2013). doi: /s Lash TL, et al. (2006). doi: /s Demissie S, Silliman RA, Lash TL. Adjuvant tamoxifen: Predictors of use, side effects, and discontinuation in older women. J Clin Oncol. 2001;19: Fink AK, et al. (2004). doi: /JCO Cluze C, et al. (2012). doi: /annonc/mdr Liu Y, et al. (2012). doi: /s DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: Meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160: DiMatteo RM. (2004). doi: / Christensen, A. J. Patient adherence to medical treatment regimens: Bridging the gap between behavioral science and biomedicine. New Haven: Yale University Press; Christensen AJ, et al. (2010). doi: /s Fann JR, et al. (2008). doi: /j.genhosppsych Henselmans I, et al. (2010). doi: /a van Londen GJ, et al. (2013). doi: /s y 24. Hadji P, et al. (2013). doi: /s Kostev K, Waehlert L, Jockwig A, Jockwig B, Hadji P. Physicians influence on breast cancer patient compliance. GMS Ger Med Sci. 2014;12:Doc03 ( ). 26. Huiart L, et al. (2013). doi: /journal.pone Kyvernitakis I, et al. (2013). doi: / Kostev K, et al. (2013). doi: /CP Grunfeld EA, et al. (2005). doi: /j.pec Kahn KL, et al. (2007). doi: /01.mlr f 13