pISSN 1738-6756   eISSN 2092-9900
Open Access, Peer-reviewed
    J Breast Cancer. 2023 Aug;26(4):309-333. English.
    Published online May 10, 2023.
    https://doi.org/10.4048/jbc.2023.26.e22
    © 2023 Korean Breast Cancer Society
    Original Article

    Investigation of Factors Affecting Adherence to Adjuvant Hormone Therapy in Early-Stage Breast Cancer Patients: A Comprehensive Systematic Review

    Seongwoo Yang,1 Seong Won Park,1 Soong June Bae,2 Sung Gwe Ahn,2 Joon Jeong,2 and Kyounghoon Park1
      • 1HERINGS, The Institute of Advanced Clinical & Biomedical Research, Seoul, Korea.
      • 2Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine/Institute for Breast Cancer Precision Medicine, Yonsei University College of Medicine, Seoul, Korea.
    • Correspondence to Kyounghoon Park. HERINGS, The Institute of Advanced Clinical & Biomedical Research, 560 Eonju-ro, Gangnam-gu, Seoul 06144, Korea. Email: khpark@heringsglobal.com
    Received November 16, 2022; Revised February 05, 2023; Accepted April 16, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Adherence and persistence to adjuvant hormone therapy (AHT) are seldom maintained among early-stage hormone receptor-positive breast cancer (BC) survivors, despite the significant clinical benefits of long-term AHT. As the factors influencing adherence to AHT remain unclear, this study aimed to comprehensively identify such factors and classify them into specific dimensions.

    Methods

    PubMed, Cochrane Library, Embase, PsycINFO, and CINAHL were searched for qualified articles. The search mainly focused on three components: early-stage (0–III) BC, oral AHT administration, and adherence to AHT, with keywords derived from MeSH and entry terms. The factors identified were then classified into six categories based on a modified WHO multidimensional model.

    Results

    Overall, 146 studies were included; the median sample size was 651 (range, 31–40,009), and the mean age of the population was 61.5 years (standard deviation, 8.3 years). Patient- and therapy-related factors were the most frequently investigated factors. Necessity/concern beliefs and self-efficacy among patient-related factors were consistently related to better adherence than depression. Although drug side effects and medication use cannot be modified easily, a refined prescription strategy for the initiation and switching of AHT is likely to increase adherence levels.

    Conclusion

    An effective psychological program that encourages positive views and beliefs about medication and management strategies for each therapy may be necessary to improve adherence to AHT. Social support and a sense of belonging can be enhanced through community participation and social media for better adherence to AHT. Patient-centered communication and appropriate recommendations by physicians may be attributable to better adherence outcomes. Findings from systematically organized factors that influence adherence to AHT may contribute to the establishment of intervention strategies to benefit patients with early-stage BC to achieve optimal health.

    Keywords
    Breast Neoplasms; Hormone Antagonists; Medication Adherence; Patient Compliance; Risk Factors

    INTRODUCTION

    Breast cancer (BC) is one of the most common cancer types and the leading cause of cancer-related deaths in women worldwide, according to Global Cancer Statistics 2020 [1]. The incidence rate of BC has increased, especially in countries with a high human development index, due to the higher prevalence of reproductive, hormonal, and lifestyle risk factors, as well as increased detection through mammographic screening [2]. A substantial number of BC cases are confirmed as hormone receptor-positive (HR+) [3, 4]. Therefore, adjuvant hormone therapy (AHT) or adjuvant endocrine therapy, including tamoxifen (a selective estrogen receptor modulator) and aromatase inhibitors (AIs), is prescribed for at least five years to reduce the risk of HR+ BC recurrence or mortality [5, 6, 7, 8, 9].

    Nonadherence or noncompliance is defined as the failure to take medications as prescribed, and nonpersistence or discontinuation is the termination of medication use before the prescribed duration [10]. Nonadherence and nonpersistence to AHT has increased among survivors with early-stage HR+ BC despite the significant clinical benefits of long-term AHT [11]. In previous studies, adherence to tamoxifen and AIs varied from 65% to 80% but declined to approximately 50% by the fourth or fifth year [12, 13, 14], which is similar to the discontinuation rate [15, 16]. This suggests that a considerable number of patients did not receive maximum benefits from their medication. Since nonadherence, measured by a medication possession ratio < 80%, and discontinuation of AHT are associated with an increase in all-cause mortality [17], identifying factors that promote or demote adherence to AHT is critical.

    Several systematic reviews have been conducted to resolve these issues and find compelling reasons for nonadherence to AHT. After the first study was conducted [18], subsequent reviews have discussed this topic from different perspectives. While some studies focused on potentially modifiable risk factors for nonadherence to AHT, such as psychosocial factors, including depression, beliefs, and behaviors related to medication [19, 20, 21], others mainly concentrated on interventions to improve endocrine therapy (ET) adherence [11, 22, 23, 24]. A qualitative approach to review-related articles can improve our understanding based on theories and in-depth interviews with patients with BC [25, 26]. The most recent systematic reviews focused only on patients who fully completed their therapy as prescribed [27]. Despite these contributions, hidden factors associated with adherence might have been ignored as they limited the scope of the review. Furthermore, inconsistent inclusion and exclusion criteria for article selection, as well as specific aims of the studies, prevented the complete review of eligible articles related to adherence to AHT.

    Therefore, the present systematic review aimed to exhaustively identify diverse factors that could affect adherence to AHT and classify all such factors into specific dimensions. Additionally, we summarized and compared the traits of the study population according to certain categories, such as type of AHT and adherence outcome.

    METHODS

    Search strategy

    This study was conducted according to the standards described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [28], and the protocol was registered with PROSPERO (ID: CRD42021266621). The search dates were limited to studies from Jan 1998 to July 2021 because the Early Breast Cancer Trialists’ Collaborative Group concluded in a 1998 review that tamoxifen reduced the risk of BC recurrence. The following databases were included in the search: PubMed, Cochrane Library, Embase, PsycINFO, and CINAHL complete. The search was performed to encompass three main components: early-stage (0–III) BC (and < 1% of stage IV), oral AHT administration, and adherence to AHT. Keywords for the search strategy were derived from MeSH and the entry terms listed in Supplementary Data 1. Non-peer-reviewed articles and grey literature were excluded. After screening the reference lists of eligible studies, six additional articles were included.

    Study selection

    The inclusion and exclusion criteria for study selection are presented in Table 1. After duplicates were removed, two authors (SY and SP) independently screened the titles and abstracts of all articles. The full texts of the screened articles were reviewed for final inclusion by the two authors. Any disagreements were resolved through discussion or by a third reviewer (KP).

    Table 1
    Inclusion and exclusion criteria for study selection

    Data extraction

    Data extraction was conducted by one author (SY) using the following predefined variables: first author, year, country, study design, length of follow-up, sample size, mean or median age of the population, eligibility criteria, type of AHT, details of factors, outcome variable, definition of the outcome, results of the outcome, and method of measuring the outcome. As each study had distinct characteristics and aims, it was difficult for the number of eligibility criteria to be consistent. The pooled mean ages and standard deviations (SDs) were calculated based on the reported mean ages and sample sizes, if available. The outcome variables also varied by study; thus, we borrowed six different adherence outcomes from each study: nonadherence, nonpersistence, discontinuation, interruption, and intentional and unintentional nonadherence. The means and SDs of each nonadherence outcome were calculated if the reported outcomes were available.

    Adherence to AHT

    We classified the factors that affect adherence to AHT into five dimensions according to the evidence synthesis of medication adherence from a review study [29]. This review used a modified WHO multidimensional model for drug adherence [30], to specifically target adult patients with chronic physical diseases. In addition, we included one separate category because of newly introduced methods for improving adherence using mobile devices or patient-reported outcome scores. Therefore, our final classification model was equipped with six dimensions: patient-related, therapy-related, socioeconomic, healthcare system/healthcare provider (HCP)-related, disease-related, and mobile healthcare-related factors. We also verified whether the association between each factor and adherence outcomes was consistent.

    Quality assessment

    To assess the quality of the studies that represented the four types of study design, the quality assessment tool was adopted from Toivonen et al. [21] based on recommendations from Sanderson et al. [31] and was revised according to the following: 1) whether the adherence outcome of the study was clearly defined with measurable standards; 2) whether the measured adherence outcome was apparently reported; 3) whether the factors influencing the outcome were clearly identifiable; 4) whether the inclusion and exclusion criteria were clearly stated with at least two components in the Methods section; and 5) whether confounders were statistically adjusted. Assessment of selection bias was omitted because of lack of information. One author (SY) checked the quality of all the studies, and another author (KP) confirmed a random subset of 10% of the articles.

    RESULTS

    From the five selected databases, 4,640 articles were retrieved, and 3,433 articles remained after removing duplicates. Screening of the titles and abstracts left 592 articles that were subjected to full-text review. Finally, 146 articles were included in this review (Figure 1). Owing to the heterogeneity of the study population, definitions of the outcome, and type of analysis, a meta-analysis was not deemed suitable.

    Figure 1
    Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram representing the selection of studies in the systematic review.

    Study characteristics

    The characteristics of all the studies are summarized into three categories: region, study design, and outcome measurement (Table 2). The mean/median sample size was 3,740/651 (range, 31–40,009), and the mean age of the population was 61.5 years (range, 35.7–77.5; SD 8.3). Most studies were conducted in North America (n = 80, 54.8%) and Europe (n = 45, 30.8%) as prospective (n = 40, 27.4%) or retrospective (n = 55, 37.7%) studies. The measured outcomes were mainly from self-reports (n = 60, 41.1%) and secure medical or pharmacy records (n = 74, 50.7%). While some studies targeted postmenopausal women (n = 26, 17.8%), both AIs and tamoxifen were predominantly used to measure adherence (n = 99, 67.8%), and adherence and nonadherence were the most frequently used outcome (n = 94, 64.4%). Further details of the study characteristics, including eligibility criteria, type of AHT, factors associated with the outcome, and results of the outcome are provided in Supplementary Table 1.

    Table 2
    Characteristics of study population by category

    Adherence outcomes

    While more than half of the studies (n = 84, 57.5%) used adherence or nonadherence as an outcome variable, other studies yielded diverse adherence outcomes, such as compliance (n = 10), persistence (n = 15), discontinuation (n = 30), interruption (n = 2), or intentional and unintentional nonadherence (n = 5). Some studies (n = 20) employed two outcome measures: adherence and persistence. Despite the use of different measures, the mean nonadherence rate was 26.4% (range, 2.6–83.8%; SD, 16.6%) (Figure 2). Higher nonadherence was reported in randomized controlled trials (34.5%), self-reported outcome measures (30.0%), and AI use (32.8%).

    Figure 2
    Percentages of nonadherence outcomes from included studies (n = 146). The means and standard deviations were calculated for each reported nonadherence outcome.
    RCT = randomized controlled trial; AI = aromatase inhibitor.

    Quality assessment

    Ninety-one percent of the selected studies clearly defined the adherence outcome using a measurable standard, and 96% of the studies reported the measured outcome (Table 3). While influencing factors were identified in 99% of the studies, the inclusion/exclusion criteria and statistical adjustment for confounders (or randomization) were lower (90% and 66%, respectively). The details of the assessment results for each study are presented in Supplementary Table 2.

    Table 3
    Summary of quality assessment

    Factors influencing adherence to AHT

    The number of articles on each factor and their relationship with adherence to AHT classified into six dimensions were indicated with positive (+) and negative (-) directions if they were all consistent (Figure 3). Factors that had both positive and negative associations with adherence outcomes were considered inconclusive and indicated with a question mark (?). The systematic process for classifying all factors using specific criteria is depicted in Supplementary Figure 1. The results for each dimension are also presented.

    Figure 3
    Factors influencing adjuvant hormone therapy adherence. Direction shows whether each factor significantly has a positive (+), negative (−), or inconclusive (?) association with adjuvant hormone therapy adherence. Blue (+) or red (−) color text represents a consistent direction of the results from all the included studies. Every count represents one study by factor.
    Hx = history; BMI = body mass index; AHT = adjuvant hormone therapy; HCP = healthcare provider; GI = gastrointestinal; AI = aromatase inhibitor; TAM = tamoxifen; HT = hormone therapy; SSRI = selective serotonin reuptake inhibitor; BC = breast cancer; BCS = breast-conserving surgery; SMS = short message service.

    Patient-related factors

    In total, 110 studies reported that patient-related factors were associated with adherence to AHT. Negative associations with depression were the most repeated and consistent, followed by smoking/substance use and poor personal beliefs. Some studies reported a positive [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58] and others reported a negative association with age [15, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78]. Extreme age categories (younger or older) were negatively associated with adherence to AHT in a few studies [13, 79, 80, 81, 82, 83, 84, 85]. Some factors, such as preexisting conditions or comorbidities [12, 13, 15, 36, 37, 39, 45, 46, 49, 52, 59, 60, 63, 64, 66, 68, 73, 76, 77, 79, 80, 81, 83, 85, 86, 87, 88] and higher body mass index [51, 73, 89], were associated both positively and negatively with adherence. Depression and anxiety were both negatively associated with adherence [10, 39, 52, 62, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99]; however, one study on anxiety suggested a positive relationship between anxiety and adherence [95]. A family history of breast or ovarian cancer [80, 100], frailty [61], pain [42, 46, 101, 102], poor sleep quality [103, 104], smoking/substance use [54, 66, 85, 105, 106], lower cognitive function [48, 55, 61, 67, 90, 94, 107], concern belief [32, 46, 105, 108, 109, 110], strong belief in the risk of recurrence [47], negative decisional balance [111, 112, 113], and poor personal belief [114] were negatively associated with adherence to AHT. In contrast, better quality of life [115, 116, 117, 118], positive necessity [10, 44, 97, 119, 120, 121], positive belief/attitude about AHT [42, 87, 115, 122], greater internal locus of control [96], high confidence in decision [123], perceived self-efficacy [57, 81, 88, 124], trust in HCP [74, 125], and adequate information or knowledge [16, 67, 74] and satisfaction [115] were positively related to AHT adherence as well as calculated patient reported outcomes (PRO) scores [42]. Furthermore, few studies have reported that perceptions of information [126], health literacy [127], religious events [128], sexual problems, menopausal symptoms, and health comorbidities [129] were not significantly associated with AHT adherence.

    Therapy-related factors

    A total of 92 studies identified therapy-related factors affecting adherence to AHT, and drug side effects was a dominant factor in this dimension [32, 43, 48, 50, 54, 57, 70, 71, 73, 78, 88, 90, 91, 93, 97, 98, 99, 102, 104, 109, 114, 116, 117, 120, 122, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141], followed by the type of AHT and administration of other adjuvant chemotherapy. Most of these were negatively associated with adherence; however, vaginal dryness and hair thinning/loss were positively associated with the continuation of therapy [130]. The association between hot flashes or night sweats and adherence was inconsistent [71, 99, 131, 137, 138, 141]. Although the type of AHT also accounted for a substantial portion [37, 44, 59, 61, 62, 63, 64, 67, 75, 77, 82, 85, 86, 94, 101, 121, 140, 142, 143], whether tamoxifen or AIs discouraged patients from adhering to the prescription was controversial. Unlike taking both tamoxifen and AIs [13] or initiation with AIs [61, 85], the use of exemestane or letrozole was negatively associated with adherence to AHT [42, 52, 63, 91]. Patients did not adhere to AHT as prescribed if it was switched to another type (e.g., tamoxifen to an AI) in most studies [10, 35, 36, 52, 56, 75, 80, 86, 117] except one [82]. In addition, the duration of HT [13, 40, 78, 113], medications other than AHT or polypharmacy [12, 49, 59, 65, 72, 75, 111, 113, 122, 144], refill synchronization [13, 48, 145], and hormone replacement therapy [54, 77, 80, 137] were either positively or negatively associated with adherence. Taking specific types of medications was associated with adherence [63, 77, 80, 143, 144, 146]; however, the results were inconclusive. Receiving chemotherapy positively affected adherence in most studies [13, 35, 38, 60, 61, 62, 74, 77, 86, 134, 147, 148] with few exceptions [41, 58, 64, 111]. In contrast, receiving radiotherapy consistently showed positive association with adherence to AHT [13, 105, 136, 149]. However, non-significant results have been reported for chemotherapy [150], radiotherapy [150], and their side effects [151].

    Socioeconomic factors

    In total, 50 articles were related to socioeconomic factors. Among these, social, familial, and emotional support were the only factors that had a consistently positive association with adherence [16, 50, 71, 74, 89, 92, 96, 98, 112, 123, 140, 152]. Employment status [32, 47, 49, 50, 56, 59, 82], education level [32, 56, 77, 100, 107, 114, 134, 153], and financial [10, 64, 134, 141] and marital status [13, 33, 40, 56, 64, 74, 77, 81, 107, 148, 154, 155] were both positively and negatively associated with adherence to AHT. However, most studies have confirmed that Black people and ethnic minority groups are less adherent to AHT than Caucasians or Asians [13, 15, 37, 40, 46, 47, 53, 61, 64, 68, 69, 83, 100, 108, 156, 157], with the exception of a few studies [66, 142].

    Health care system/HCP-related factors

    A total of 28 articles examined the relationship between the healthcare system or HCP-related factors with AHT adherence. Insurance and co-payment were the most common factors. Patients who received subsidies [158] and underwent mammography screening [159] were more adherent to AHT; however, high co-payment [34, 68] or out-of-pocket costs decreased adherence [35, 36, 52, 64, 84, 160]. While having health insurance encouraged patients to adhere [48, 82, 88, 134, 136], being signed for Medicare or Medicaid had an inverse effect [68, 69, 81, 157, 161]. Additional care (i.e., gynecological care) [39, 45, 62, 149], follow-up with oncologists [58, 162], consultation [131, 147], patient-centered communication [88, 140], and good relationships with HCPs [10, 114] were all positively associated with adherence to AHT.

    Disease-related factors

    Eighteen studies identified a relationship between BC traits and adherence to AHT. Early-stage [58, 61, 66, 75, 131] and advanced stage of BC [66, 73, 74, 77, 139, 163] were related to adherence; however, the results were controversial. Lymph node involvement was both positively and negatively associated with adherence [15, 71, 77, 111, 134, 163, 164]; however, larger tumor size [136, 155] and human epidermal growth factor receptor 2-positive tumors [77] were positively associated with adherence to AHT.

    Interventions to improve AHT adherence

    A total of eight articles introduced interventions to improve adherence to AHT, ranging from conventional reminders to mHealth approaches. Mobile apps with reminders [165] and short message service (SMS) reminders [166] were positively associated with adherence to AHT. However, educational materials for patients [167, 168, 169], patient support programs [170], and other types of reminders [171, 172] were not significantly associated with AHT adherence.

    DISCUSSION

    Although previous reviews encompassed diverse factors, this comprehensive review included a greater number of studies examining a wider range of factors that may influence adherence to AHT, which is crucial for patients with early-stage BC. The present review also categorized the factors into six dimensions based on the conceptualization of a previous study [29] to help us understand their origin. Moreover, this review attempted a simple but intuitive approach to explain the complexity of the numerous factors by confirming those that had a consistent effect on adherence to AHT.

    Patient-related factors were most frequently mentioned in the included studies. Depression is a known patient-related determinant of nonadherence to ET, and our results were consistent with those of previous studies [10, 20, 121]. Although the association between adherence and anxiety was equivocal, only one study reported a positive association between menopausal anxiety and better adherence, with an absolute difference by period [95]. Other psychosocial factors should also be considered important for improving adherence because they can be modified with clinical or social interventions. Specifically, positive views, beliefs about medication, concerns about side effects, and self-efficacy in medication management may play key roles in supporting patients’ medication behaviors [173, 174]. Therefore, effective psychological programs should be developed and implemented for discharged patients with BC. A better quality of life can be used as a mediator for the improvement of adherence; therefore, factors influencing the quality of life or well-being of patients with BC should be considered.

    The therapy-related dimension was the second most common topic among the articles in our review, owing to drug side effects. Several side effects of ET potentially threaten the quality of life, and these were mainly responsible for numerous undesirable symptoms that led patients to be less adherent to AHT [175]. Vasomotor problems, such as hot flashes, night sweats, and cold sweats, led patients with early and metastatic BC to forget or deliberately choose not to take their medication [176, 177, 178]. Our results showed that hot flashes were positively associated with adherence in two studies [71, 137], but the reason for this was not identified. Unlike tamoxifen, AIs are mainly used after menopause; therefore, their side effects may vary. Hence, management strategies for each therapy should be considered because more vaginal discharge was observed after tamoxifen use, while vaginal dryness and loss of libido were common after the use of any AIs. Additionally, arthralgia and joint pain should be closely monitored, particularly in elderly patients with osteoarthritis. The association between the initial treatment with AIs and the level of adherence was ambiguous because exemestane or letrozole decreased adherence [52, 63], unlike other types of AIs [85]. Since frequent switching of the type of AHT may discourage patients from adherence, decisions on switching to ET should be made carefully from the onset. The use of other medications, specifically selective serotonin reuptake inhibitors for depression, analgesics, hypnotics, and gastrointestinal drugs, was associated with lower adherence to AHT. These might act as confounders because most of them were prescribed for treatment-related side effects, which is a major reason for discontinuing AHT [15, 93, 179]. Thus, further studies investigating the association between prescription of symptom-relieving drugs and discontinuation are needed.

    According to several previous studies on reported side effects, there was a discordance in the frequency and severity of side effects reported between physicians and patients [175]. Certain side effects, including hormone-related side effects such as hot flashes, night sweats, and fatigue, were underreported by doctors, and their severity was underestimated [180]. Therefore, guidelines or a consensus for conducting adherence studies should be established to reduce heterogeneity and standardize reporting between studies. Furthermore, multi-method approaches, including both self-reported and objective measurements, could alleviate measurement errors and help us understand the tendency of AHT use in patients with BC, as suggested by a previous review article [21].

    Among socioeconomic factors, social, familial, and emotional support were consistently associated with adherence, confirming the results of previous reviews [18, 19, 21, 24, 99]. Thus, medical staff should consider informing patients of the importance of community participation or encouraging them to use a mobile application or social media to form their own support network. Social media use is positively related to online self-presentation, which is a significant predictor of both social support and a sense of belonging [181]. Although Black people were less likely to adhere to AHT, as suggested by our results, it was difficult to conclude that racial differences were solely responsible for these results. A previous review found that both race/ethnicity and socioeconomic status were associated with ET use in most settings [182]. However, some studies have found that race/ethnicity and socioeconomic status were independent predictors of BC outcomes [183, 184]. Thus, this may require deeper exploration, and an integrated interpretation of diverse social determinants may be needed for a better understanding.

    Our results showed that the healthcare system is a crucial factor in maintaining adherence to AHT. However, most factors were related to medication costs and insurance, which seldom change unless government policies endorse a decision. Therefore, compelling evidence should be accumulated to persuade politicians to encourage this movement. While encouragement to participate in mammography screening was positively associated with adherence to AHT [159], the underlying reason needs to be investigated. HCPs also contributed to better adherence outcomes. Although assigned care or consultations may be limited in a real healthcare setting, some qualitative approaches, such as patient-centered communication and appropriate recommendations by a physician, could be viable. A previous study suggested that ET use, sharing decisions, support for side effects, and other related concerns should be managed through communication between healthcare systems and individual providers, and this might partly resolve racial outcome disparities [185].

    A previous review concluded that mHealth interventions improved medication adherence in patients with cardiovascular disease, although the magnitude of benefit was not consistently large [186]. In addition, a recent study showed that mHealth apps have the potential to support the adherence of BC patients by improving app quality and circulating information about available apps. However, this effect was minimal, possibly owing to the incomplete implementation of the newly introduced interventions [187]. The studies classified as intervention-related factors in our review may bolster this evidence.

    Some studies had categorized nonadherence as intentional or unintentional [32, 46, 47, 57, 108]. While intentional nonadherence is associated with various perceptual factors such as beliefs and side effects, unintentional nonadherence occurs because of memory lapses or lack of self-management capacity [188]. According to the results of our study, unintentional nonadherence was higher in every subset, suggesting that reminding patients to take medications and improving self-management were key to enhancing adherence to AHT. This expanded approach enabled us to distinguish nonadherence factors and offer suitable interventions.

    Straightforward interpretation of the results was challenging because each study measured adherence differently. However, this could indicate the tendency and importance of each adherence measure. Although nonadherence was higher in randomized controlled trials, self-reported outcome measures, use of AIs, discontinuation, and interruption of AHT were higher in prospective and retrospective studies, outcomes from secured records, and tamoxifen use. A previous study reported that the odds of discontinuation of tamoxifen use were higher than those of AIs [130]. However, this countertrend might have originated from the definition of adherence outcome measurements. Adherence refers to the entire process from drug prescription to the end of a prescription. Persistence refers to the duration between initiation and the last dose preceding discontinuation [189]. Therefore, the definition of adherence needs to be clarified and properly used in future studies because most of the included studies have defined adherence differently.

    Furthermore, it is important to define which factors should be considered modifiable. Most modifiable factors were arbitrarily set by the authors according to their requirements. A previous study argued that nonmodifiable risk factors for BC include age, sex, genetic factors, family history of BC, history of previous BC, proliferative breast disease, whereas modifiable factors include menstrual and reproductive factors, radiation exposure, hormone replacement therapy, alcohol consumption, a high-fat diet, and environmental factors [190]. However, this classification was limited and could not be directly applied to risk factors for medication adherence. Therefore, a clear definition of adherence and modifiable factors should be discussed in future studies. Furthermore, according to our quality assessment, descriptions of inclusion/exclusion criteria and statistical adjustment for confounders were relatively less considered, which might be attributable to different study designs and a large gap in the quality of the studies. Thus, these need to be secured for valid evidence synthesis.

    This study has some limitations. First, although each mean adherence outcome was calculated, quantitative synthesis of evidence was not performed because of the difficulty in merging the results of all articles due to the heterogeneity of the included studies. Hence, different measurements should be noted when interpreting the means and SDs of the adherence outcomes in this study. Second, the duration of AHT could not be considered as a measure of adherence outcomes because of the different study designs and study periods. Although adherence to AHT generally decreases over time, the exploration of factors associated with nonadherence to AHT at each time point may be discussed in future studies. Finally, we were unable to identify interactions between the factors. For instance, comorbidities and medication use may be highly correlated; however, the strength of their interactions was not covered in this study. Future studies should consider how similar factors interact with each other to elucidate the complex mechanisms with a more accurate definition and measures for medication adherence.

    This review examined the characteristics of adherence to AHT and the intertwined factors that should be considered to improve adherence. To improve adherence to AHT, an effective psychological program to encourage positive views and beliefs about medication may be introduced, and management strategies should be considered for each therapy because side effects vary depending on the type of AHT. Community participation or the utilization of social media to form one’s own support network can provide social support and a sense of belonging, which are positively associated with better adherence to AHT. Patient-centered communication and appropriate recommendations by physicians may also contribute to better adherence outcomes. Furthermore, this study suggests that findings from systematically organized factors that influence adherence to AHT may contribute to the establishment of intervention strategies to benefit patients with early-stage BC to achieve optimal health as well as coherence in future research.

    SUPPLEMENTARY MATERIALS

    Supplementary Data 1

    Search strategies for each database

    Click here to view.(33K, doc)

    Supplementary Table 1

    Details of the study characteristics of included articles

    Click here to view.(158K, xls)

    Supplementary Table 2

    Assessment of study quality

    Click here to view.(61K, xls)

    Supplementary Figure 1

    The systematic process for classification of all factors with specific criteria.

    Click here to view.(1M, ppt)

    Notes

    Conflict of Interest:The authors declare that they have no competing interests.

    Author Contributions:

    • Conceptualization: Yang S, Park K.

    • Data curation: Yang S, Park SW.

    • Formal analysis: Yang S.

    • Investigation: Park K.

    • Methodology: Yang S, Park K.

    • Project administration: Park K.

    • Supervision: Park K.

    • Visualization: Yang S.

    • Writing - original draft: Yang S.

    • Writing - review & editing: Bae SJ, Ahn SG, Jeong J, Park K.

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    MeSH Terms
    Breast Neoplasms*
    Breast*
    Community Participation
    Depression
    Drug-Related Side Effects and Adverse Reactions
    Hormone Antagonists
    Humans
    Medication Adherence
    Patient Compliance
    Prescriptions
    Program
    Risk Factors
    Sample Size
    Social Media
    Survivors
    Systematic Review*
    Metrics
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