Sleep and endocrine therapy in breast cancer

Abstract

Sleep disturbances and insomnia are common among breast cancer survivors, and can have a significant effect on quality of life and numerous other significant outcomes. Among risks for sleep disturbance is the introduction of anti-estrogen endocrine therapies. The possible contributing factors to sleep disturbance in endocrine therapy are complex, and include pre-existing sleep disorders, the effects of chemotherapy and other treatments, and concurrent symptoms such as hot flashes. In addition, sleep disturbance in menopause, the natural downregulation of reproductive hormones in older age, is a common occurrence, and can offer a model for understanding the high prevalence of sleep problems in breast cancer survivors on endocrine therapy, as well as suggesting possible treatments such as behavioral interventions and pharmaceuticals. Altogether, significantly more research is needed to better understand and address sleep disturbance in breast cancer survivors on endocrine therapy in order to support quality of life and treatment adherence.

Introduction

Breast cancer is the most common cancer in women, affecting about one in eight American women.¹ Approximately 75% of breast cancer tumors are estrogen receptor positive, which means that standard adjuvant treatment recommendations will include 5-10 years of anti-estrogen endocrine therapy.^2,3 The most common endocrine therapies administered to breast cancer patients are effective at reducing breast cancer recurrence through downregulating the action of estrogen in the body, by either inhibiting the synthesis of estrogen (i.e., aromatase inhibitor) or acting as a selective estrogen receptor modulator (i.e., tamoxifen).⁴ Although effective at preventing cancer recurrence, these treatments can also have an impact on multiple systems regulated by circulating estrogens, resulting in several undesirable side effects that impact adherence. One common and significant side effect is sleep disturbance, ranging from mild symptoms to a more chronic insomnia disorder.^5–8 Comparied to 20% in the general population, sleep disturbance can be as high as 60% in breast cancer survivors on endocrine therapy.⁹ Both sleep disturbance and insomnia disorders are studied in breast cancer survivors and definitions can vary across studies, with the latter referring to the more severe diagnostic classification threshold. Importantly, the sleep disturbance often cannot be readily attributed to a single cause, but can stem from pre-diagnosis vulnerabilities and sleep disorders as well as sleep effects of primary cancer treatments and endocrine therapy in later survivorship – highlighting the complexity of this issue for breast cancer survivors and the care needed to attend to a range of possible contributing and exacerbating factors. Overall though, sleep disturbance among breast cancer survivors has a significant impact on quality of life and health, and is a major focus of survivorship research and care.^10,11

Aside from being a risk for non-adherence to endocrine therapy⁶, the downstream effects of sleep disturbance are serious concerns. Poor sleep can significantly reduce quality of life in breast cancer survivors, specifically increasing fatigue, a symptom many breast cancer survivors already struggle with.^10,11 Likewise, in cancer and non-cancer populations, sleep disturbances are linked with cognitive decline and dementia.^{12,13*,14*,15} Critically, several studies have linked poor sleep to reduced survival rates in women with breast cancer,^16,17 and the immunological toll of sleep disturbance is theorized to be a significant risk for cancer progression.¹⁸ This review will cover what is known about the impact of endocrine therapies on sleep disturbance in breast cancer survivors, identify possible mechanisms for the manifestation of these symptoms, review potential treatments, and highlight the several areas in need of targeted research.

Sleep problems in breast cancer survivors and the influence of endocrine therapies

In breast cancer survivors broadly, there is a high prevalence of insomnia symptoms, with estimates of over 60% of survivors reporting symptoms such as difficulty falling asleep, frequent nighttime awakenings, and early morning awakenings, with an inability to fall back to sleep.^19,20 Sleep disturbances have been reported during primary cancer treatments including direct side effects of the chemotherapy, radiation therapy, and surgery.²¹ Many patients report acute effects of these treatments, with some remediation after recovery, although the role of concurrent physical symptoms related to these treatments (e.g., hot flashes, pain) in the development of sustained sleep problems has also been raised.²¹ Others argue that new or ongoing mood disorders including anxiety and depression could be drivers of new onset sleep disturbances.²² As endocrine therapy is typically initiated after the completion of surgery, chemotherapy, and radiation treatments, breast cancer patients have often already experienced sleep disturbance by the time endocrine therapy is introduced. Thus, the issue of sleep disturbance in breast cancer survivors on endocrine therapy is a complex one that requires appreciating the dynamics of multiple factors including early, pre-cancer diagnosis vulnerability, the effect of cancer and cancer treatments, and then the direct and/or exacerbating effects of the influence of endocrine therapy, see Figure 1.

Figure 1:

Theoretical Model of Factors Related to Sleep Disturbance in Breast Cancer Survivors

Careful tracking of symptoms might yield new insights into the role of endocrine therapy at initiating or exacerbating sleep disturbances. Although much work remains to be done, as many of the major clinical trials of endocrine therapy have not specifically reported on sleep as an adverse effect, limiting full understanding of the rates of these symptoms,^23–25 several trials have begun reporting sleep disturbances as an adverse effect of treatment. The multi-center SOLE trial investigating continuous versus intermittent treatment with an aromatase inhibitor in over four thousand breast cancer patients did report on insomnia symptoms, which was one of the highest adverse effects reported during study duration in approximately 40% of the sample.²⁶ In a quality of life sub-study of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial, higher levels of sleep disturbance were observed among those taking an aromatase inhibitor compared to tamoxifen.²⁷ Notably, there were even higher levels of sleep problems observed in the more carefully assessed subgroup in this sub-study than were reported among adverse events in the larger trial, highlighting the care that may be required for capturing these symptoms.²⁸ Despite inconsistent assessment across major trials, there is general clinical concern that endocrine therapies do adversely impact sleep, with high rates reported by patients. ^6,7

Possible Mechanisms

There are a few potential mechanisms by which endocrine therapy might contribute to sleep disturbances. Sleep disturbance is a prominent symptom associated with the menopausal transition²⁹. Therefore, we turn to menopause as a potential model; despite the limited attention to insomnia as a potential adverse effect to endocrine therapy treatment, it is reasonable to explore potential mechanisms related to inhibiting estrogen function. There is evidence suggesting a direct neurobiological link between circulating estrodiol and sleep, that estradiol contributes to circadian rhythms,^30* while melatonin may inhibit estrogen signaling pathway^31,32. Pre-clinical and clinical studies have revealed estrogen receptors on the suprachiastmatic nucleus of the hypothalamus, a critical brain nucleus for regulating circadian rhythms.³³ Melatonin, the primary hormone responsible for regulating sleep-wake cycles, has been shown to decrease around the menopausal transition in women.³⁴ Indeed, electroencephalography studies show cortical activity patterns during sleep are altered in peri and post-menopausal women with greater beta power indicating more nocturnal arousal³⁵ and a shift to less slow-wave sleep and more wakefulness^36* in the later menopausal transition. Difficulties in maintaining sleep is a common complaint, and these data are consistent with the hypothesis that changes in hormonal milieu may increase neural arousal during sleep. An inhibition of estrogen via anti-estrogen endocrine therapies could thus prevent normal circadian release of melatonin, alter brain regulation of circadian drive for sleep timing and maintenance.

Concurrent symptoms commonly reported on endocrine therapy may also contribute to sleep disturbance. Vasomotor symptoms (i.e., hot flashes) are among the most common adverse effects associated with endocrine therapies.² These disruptive episodes can occur at any time of day, and in menopausal women have been found to be a significant contributor to sleep problems. ^37,38 Hot flashes during the night are common causes of nocturnal awakenings ³⁹, and are associated with a rise in sympathetic and a withdrawal of parasympathetic nervous system activity that increases heart rate and alters brain alertness^40,41, potentially interfering with a return to sleep. Improving patient regulation of their responses to arousal may prove to be a key intervention target, although more research is needed. In addition, other common side effects of endocrine treatments include arthralgia and mood changes, such as depression and anxiety.^42,43* These symptoms are also common in menopause, and have been studied for their unique contribution to disrupted sleep.^44,45. Little is known about the effects of these symptoms on sleep in breast cancer survivors taking endocrine therapies, however.

It is important to note that the pharmacokinetics of the SERM Tamoxifen are are still under active investigation. Tamoxifen has different affinities for estrogen receptor types (E₂ vs E₁), and may behave differenty depending on tissue type and endogenous local estrogen levels.^46,47 Overall, considerably more research and attention is needed to better understand and potentially address the nature of sleep disturbances and unique effects of specific endocrine therapies after breast cancer.

Potential Treatments

Although the symptoms of endocrine therapy may interfere with maintenance of sleep, several intervention modalities may reduce patients’ experience of sustained wakefulness that is characteristic of insomnia. Some of these interventions have been studied specifically in breast cancer survivors on endocrine therapy, but most include all breast cancer survivors with ~70% taking endocrine therapy. While some of the trials were restricted to women who met clinical criteria for an insomnia disorder, the majority did not and instead report on perceived sleep quality outcomes as a secondary endpoint in breast cancer survivors whose primary symptom complaint was hot flashes or fatigue.

For women with hot flashes, results of these trials show efficacy on sleep quality over placebo for pharmacologic interventions including serotonergic agents (paroxetine⁴⁶, venlafaxine⁴⁷), gabapentin⁴⁸, the alpha-adrenergic agonist clonidine⁴⁷, and the weak estrogenic and androgenic steroid tibolone⁴⁷. Further trials in women with hot flashes show additional benefit of gabapentin⁵² over vitamin E in improving sleep quality, and additional benefit of the combination of venlafaxine and the partial GABA agonist zolpidem⁵³ over venlafaxine alone when sleep disturbance was required for eligibility in addition to hot flashes. Over-the-counter complementary agents shown to be effective in improving sleep quality in survivors with hot flashes include St. John’s wort⁵⁴ and black cohosh⁵⁵ has shown preliminarily to be helpful in open-label studies. Melatonin⁵⁶ has been shown to be more effective than placebo in survivors who were not taking endocrine therapy and who did not have any sleep complaints; we are not aware of studies looking at the efficacy of melatonin in breast cancer survivors on endocrine therapy. More recently, open label trials of stellate ganglion blockade have benefit for sleep quality in survivors with vasomotor symtpoms, via indirectly effecting norepinephrine levels in the brain, which modulate body temperature.⁵⁷

Trials of mind-body interventions in breast cancer survivors have shown benefit for sleep quality for exercise^58,59, yoga, mindfulness meditation^60,61, Tai Chi⁶², acupressure⁶³ (relaxing, not stimulating), acupuncture^64,65, and hypnosis⁶⁶ when compared to usual care, waitlist control, or sham interventions.

Cognitive behavioral therapy for insomnia (CBTi) has been widely studied in healthy and cancer patients with insomnia. In breast cancer survivors, multiple trials have shown efficacy of CBT in reducing insomnia symptoms when compared with usual care⁶⁷, wait list control⁶⁸, or placebo (in a 3-arm trial involving co-therapy with armodafinil)⁶⁹. Similarly, internet-based CBTi^70* has been demonstrated as effective for insomnia in this population, highlighting the relative accessibility of this highly effective behavioral intervention when local CBTi providers are not available. In addition to CBTi, menopause symptom directed CBT⁷¹ improves sleep quality among other menopause symptoms in breast cancer survivors.

Although the symptoms of endocrine therapy may interfere with maintenance of sleep, several intervention modalities may reduce patients’ experience of sustained wakefulness that is characteristic of insomnia. These interventions target the specific mechanisms that inhibit the return to sleep in patients with frequent awakenings. By enhancing the patient’s confidence and ability to return to sleep, overall reductions in wake after sleep onset and extension of overall sleep duration can be obtained.

Conclusion

Sleep disturbance is a significant concern for women initiating endocrine therapy for breast cancer. The direct and indirect effects of downregulating estrogen function in women is a primary focus of studies across several clinical issues, and underscores the pervasive and multisystem organization of a woman’s hormonal milieu. This complexity is reflected in the cluster of symptoms associated with endocrine therapy treatment, and requires a broad frame to appreciate these dynamics. Since sleep disturbance similarly emerges as a pivotal issue across a number of outcomes, including non-adherence to these longstanding daily therapies, which can already be ~30-70% in clinical samples⁷². The examination of sleep problems during endocrine therapy presents as highly dynamic and complex and remains essential to address for the health of women on these treatments.

There is clearly a signal from patients that endocrine therapy impacts sleep, and an equal response from clinical and research communities is needed. Systematic evaluation of insomnia symptoms across clinical and research settings is essential to get a foothold in understanding these problems and how best to intervene. Given the complexity of these issues, evidence-based treatments for this population specifically is essential and currently lacking. The rapid rate of breast cancer treatment development must be accompanied by supportive care efforts including addressing insomnia, and offering these patients optimal chances for survival including the best possible quality of life.