Medication adherence typically refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication [
1]. The World Health Organisation defines medication adherence to long-term therapy as “the extent to which a person’s behaviour - taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider” [
2]. Accruing evidences show that inadequate medication compliance can cause alterations in benefit/risk ratios, resulting in reduced benefits, increased risks or both [
3,
4]. Medication non-adherence is significantly associated with adverse clinical outcomes and higher healthcare costs [
5].
Aromatase inhibitor and breast cancer risk and recurrence
Breast cancer is the leading type of cancer affecting women, and it was estimated that worldwide over 508,000 women died of this condition in 2011 [
6]. In Singapore, it is also the primary cause of death for women from 2011 to 2015 [
7]. Besides, a total of 9634 new cases of breast cancer were diagnosed in the same period, accounting for 29.1% of incident cancers in females and making it the most common cancer among women [
7].
Estrogen promotes the growth and survival of normal and cancerous breast epithelial cells by binding and activating the estrogen receptor (ER). The activated receptor in turn binds to gene promoters in the nucleus and activates many other genes responsible for cell division, inhibition of cell death, new blood vessel formation and protease activity [
8]. Thus, hormone therapy, which is a form of systemic therapy, is recommended for women with hormone receptor-positive breast cancer. Aromatase inhibitor (AI), a commonly prescribed hormonal therapy for early stage breast cancer, interferes with the body’s ability to produce estrogen from androgens by suppressing the aromatase enzyme activity. Research has shown that women treated with adjuvant hormone therapy for early-stage ER positive breast cancer gain at least 5 more years due to the treatment. However, it has been reported that patients could suffer from serious side effects of the hormone therapy [
9].
Key et al. demonstrated a significant association between breast cancer risk and circulating estrogens in postmenopausal women [
10]. Estrogen is the main stimulant in the development and growth of breast cancer, [
11] and higher endogenous estrogen level has been found to be associated with elevated breast cancer risk. Tamoxifen has been successfully used for treating ER positive breast cancer for the past three decades. More recently, AI has been demonstrated to provide a significant reduction in breast cancer recurrence in post-menopausal women [
4]. Following menopause, aromatase in fat and muscle may be responsible for much of the circulating estrogen. In highly estrogen-sensitive tissues such as the breast, uterus, vagina, bone, brain, heart and blood vessels, it provides local estrogen in an autocrine fashion. The aromatase gene promoter in breast tissue is less sensitive than the gene promoter in the ovary due to fluctuations in luteinising hormone but much more sensitive to increases in inflammatory cytokines, which increases with age. In particular, breast tissue inflammatory cytokines increase with proliferative breast disease and breast cancer [
8].
A prospective, multi-centre, non-interventional study reported significant improvements in long-term quality of life of postmenopausal Chinese patients with hormone-receptor-positive early-stage breast cancer after starting treatment with AI [
12]. A recent meta-analysis also showed the superiority of AI as an adjuvant hormonal therapy in improving the disease-free and overall survival of postmenopausal ER-positive breast cancer as compared to tamoxifen [
13]. In another clinical trial, researchers have suggested that improvement in overall survival (hazard ratio 0.78; 95% CI 0.62 to 0.98) was seen among premenopausal women with the use of exemestane plus ovarian suppression as compared to tamoxifen users [
14].
However, adverse events include hot flushes, vaginal dryness, loss of libido, fatigue, arthralgia, joint stiffness and loss of bone mineral density with subsequent increased risk of fracture [
8,
15]. Also, as the treatment of AI is long-term, medication adherence is an issue of concern, with a proportion of women stopping before completing the full treatment, while others not taking a daily tablet regularly [
16,
17]. Its adherence rate has been shown to decline over time from 78 to 86% in the first year, and reaching 62 to 79% by Year 3 [
17]. A recent nested case-control study showed that non-adherence to oral endocrine therapy was significantly associated with worse breast cancer survival (OR 4.07; 95% CI 3.27–5.06) [
18].
Intervention to improve medication adherence
Recent reviews have shown that although various behavioural, educational, integrated care and self-management risk communication interventions have been implemented to improve medication adherence, none of them have shown promising impact [
19,
20]. On the other hand, studies have suggested that reminder of any form, such as setting an alarm on a regular daily basis at home, or have family reminding the patient to take medication, have a positive influence on medication adherence in cancer patients [
19]. While healthcare institutions sometimes use short message service (SMS) to remind patients of follow-up clinic appointments, mobile technology is seldom implemented to monitor medication adherence until the recent decade [
21]. This is a feasible and acceptable form of managing medication which has a high participant satisfaction [
22]. Its use has been shown to improve medication adherence in cardiovascular disease, diabetes, HIV, oral contraception, asthma, as well as oncology patients with chronic conditions [
22,
23]. As mobile phone ownership continues to increase, there is a great potential to utilise this technology to overcome adherence barriers and optimise therapeutic effects [
24].
Barriers and facilitating factors influencing medication adherence
Malcolm et al. identified cost, side-effects, transportation, lack of reimbursement for the medication and inefficient patient-physician communication as barriers to medication adherence [
25]. Medication-taking behaviour has been shown to be influenced by a patient’s belief and his/her trust in the physician who prescribes the medication [
26]. Also, non-adherence to endocrine therapy might be due to patients’ response to the AI therapy and its associated side effects such as arthralgia [
27]. Besides, it has been shown that nonadherence to medications for chronic diseases prior to hormonal therapy was associated with more severe nonadherence to oral hormonal therapy in patients with breast cancer [
28] A cross-sectional study comprising mostly White women showed that survivors who perceived that their pain made taking AIs difficult or that the AI treatment lasted too long were likely to be non-adherent, as assessed by the Health Beliefs Scale Items and Scale Properties [
29]. In contrast, a systematic review showed that taking more medications at baseline, referral to an oncologist, and being diagnosed at earlier times were positively associated with adherence and/or persistence [
16]. Thus, in non-adherent patients, it is desirable to understand their attitude and perception towards medication taking.
Cancer treatment adherence plays a crucial role in optimising health outcomes while medication non-adherence is associated with decreased survival, higher recurrences and increased healthcare costs. Hsieh et al. reported that interruption and non-adherence to long-term adjuvant hormone therapy was associated with increased mortality in breast cancer women [
30]. Treatment non-adherence to adjuvant hormonal therapy was found to be associated with increased all-cause mortality amongst Asian breast cancer women. Moreover, a greater impact of non-adherence on mortality was especially found in the younger breast cancer population [
30].
Implementing innovative technology to tackle the problem of non-adherence and understanding its barriers will provide scientific evidence for clinical decision making and improve health outcomes. We thus propose to examine the effect of a computer automated SMS reminder in improving medication adherence amongst breast cancer women receiving oral AI therapy.
Study objectives
The primary objective is to evaluate whether SMS reminder improves medication adherence as compared to standard care (control) amongst breast cancer women who have been receiving adjuvant endocrine therapy for at least 1 year, and are continuing to receive adjuvant AI therapy for at least 1 more year.
The secondary objectives are to examine whether SMS reminder improves the inhibition of aromatisation process of patients receiving AI therapy. We postulate that at 1-year, there will be
Tertiary objectives include
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Assessing the impact of SMS reminder on the improvement in knowledge, attitude and behaviour towards medication compliance.
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Identifying barriers and facilitating factors for medication adherence.