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Richard J Santen, Cynthia A Stuenkel, Susan R Davis, JoAnn V Pinkerton, Anne Gompel, Mary Ann Lumsden, Managing Menopausal Symptoms and Associated Clinical Issues in Breast Cancer Survivors, The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 10, 1 October 2017, Pages 3647–3661, https://doi.org/10.1210/jc.2017-01138
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Abstract
Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly.
Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies.
Symptoms and clinical problems associated with estrogen depletion—sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis—confront the estimated 9.3 million breast cancer survivors globally.
Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind–brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol.
Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential.
Early diagnosis and concomitant initiation of more effective cancer treatments have reduced the death rate from breast cancer by 38% from 1989 to 2014 (1, 2). The 5-year survival rate in developed countries is now 99% for patients with localized disease (3). Accordingly, the number of breast cancer survivors is increasing and has now reached 3.1 million in the United States and is estimated to be approximately 9.3 million worldwide (3, 4). Note that the incidence of new breast cancers worldwide in 2008 was 1.38 million with an estimate of approximately 9.3 million survivors. This estimate is based on the ratio of new cases to survivors in the United States (231,000 new cases/3.1 million survivors) reduced by an estimated factor of 0.5 to account for higher mortality outside of North America and Western Europe (3, 4). In Western countries, approximately 43% are ≥65 years old and approximately 25% are ≤50 years old at diagnosis. The numbers of survivors are increasing due to the reduction in disease specific death rates since 1989. Early detection in developed countries has enhanced the number of women free of lymph node metastases; the 5 year survival rate for these women is 99% in comparison with 84% if lymph nodes are positive (3).
A large proportion of women experience menopausal symptoms or clinical manifestations of estrogen deficiency during treatment of their breast cancer or after completion of therapy (5, 6). The specific symptoms and clinical challenges differ based on menopausal status prior to initiation of cancer treatment and therapeutic agents used. For example, premenopausal women treated with chemotherapy can develop ovarian insufficiency and severe menopausal symptoms as well as infertility resulting from toxic effects of chemotherapeutic agents on the ovary (7). Postmenopausal women treated with aromatase inhibitors (AIs) may experience arthralgia, accelerated bone loss, and an increased incidence of osteoporotic fractures as a result of markedly suppressed estrogen levels (i.e.,<2 pg/mL) (8–10). They may also experience a severe form of vulvovaginal atrophy (VVA) with significantly higher rates of vaginal dryness (16.3%) and dyspareunia (17.8%) compared with women taking tamoxifen (8.4% and 7.5%, respectively) (11–13).
The constellation of signs and symptoms related to estrogen deficiency has prompted a variety of studies of menopause management in breast cancer survivors (5, 7, 14–20). However, the lack of randomized placebo-controlled trials (RCTs) in this population has limited the evidence upon which to base therapeutic decisions. Consequently, written guidelines to address menopause management in women during and after treatment of breast cancer have not sufficiently focused on treatment of this subgroup of women. To address this gap, the writing group (C.A.S., S.R.D., A.G., M.A.L., J.V.P., and R.J.S.) of the Endocrine Society Guidelines on management of menopausal symptoms (13) was prompted to write a review focusing on current and future approaches to management of menopausal symptoms and sequelae in women after breast cancer.
The prevalence of estrogen-deficiency symptoms in women after breast cancer ranges from 79% to 95% (6, 21–27) and is higher than in women without breast cancer (6, 22). Survivors report more sleep disturbance (P < 0.01), difficulty concentrating (P < 0.01), muscular/joint pain (P < 0.01), crying (P < 0.01) and irritability (P < 0.01), and vasomotor symptoms (VMS; P < 0.01) (28). These differences may reflect the rapidity of the menopause transition and the magnitude of estrogen deficiency exacerbated by AI therapy. Illustrative data originate from a follow-up study of women with breast cancer no longer on therapy and 6 years on average after diagnosis (6).In the group of women ages 50 to 59, 72.8% reported VMS, and 80.8% sexual symptoms (6). The prevalence of these symptoms was lower in women younger than age 50 and older than 59 but the symptoms were still frequent (i.e., 50% to 60%) (6, 19). The authors reported that breast cancer survivors had significantly higher vasomotor domain (P ≤ 0.002) and sexual domain (P ≤ 0.004) scores than community controls (6), indicating more bothersome symptoms. Weight gain is also a common problem associated with breast cancer therapy (29).
Specific components of the problem
Both pre- and postmenopausal breast cancer survivors often experience moderate to severe VMS and sleep disturbances with related fatigue, mild depressive symptoms, and mood changes (26). Arthralgia, osteopenia, osteoporosis, and related fractures occur predominantly in postmenopausal women as does VVA and associated dyspareunia (11, 12, 28, 30, 31). Less common problems include weight gain, symptomatic osteoarthritis and intervertebral disk degeneration, degenerative skin changes, radiation- and chemotherapy-related cardiovascular disease, and reduced quality of life (11, 12).
Strategies for Management
Key principles are to determine (a) the severity of the signs and symptoms related to estrogen deficiency and (b) the degree of bother to the patient. This allows treatment to be individually tailored based on these assessments. For mild symptoms or maintenance of health, lifestyle modifications or over the counter options may be sufficient. Moderate or severe signs or symptoms usually require pharmacological management.
Lifestyle modifications
Amelioration of symptoms
Women with mild VMS frequently do not need pharmacotherapy but do benefit from lifestyle changes (32). Simple behavioral measures such as lowering of room temperature, using portable fans, dressing in layers that can be easily shed, avoiding triggers (such as spicy foods and stressful situations) and likely exercise, may help reduce the number of hot flashes (13, 32, 33). A Cochrane review provided supportive evidence that exercise results in a reduction in hot flashes but suggested that additional randomized trials are needed to resolve existing controversy (34). Whereas a recent RCT provided evidence that exercise training decreases hot flashes (35), a pooled analysis of six studies reported no benefit from aerobic exercise (36). Diet may modify the incidence of VMS (37). Loss of 10% or more of body weight, as part of a healthy dietary intervention may significantly reduce VMS (37). Use of nonpharmacologic agents such as soy, black cohosh, flaxseed, remifemin, equol in equol-producers, and vitamin E have been reported to be beneficial for VMS, primarily when mild (13, 38, 39). However, RCT evidence of efficacy is mostly lacking and safety has not been firmly established in any population, much less in women who have had breast cancer. Of potential concern are products that may have some degree of weak estrogenic actions.
Recent research emphasis has been on the development of nonpharmacologic therapies of VMS. Cognitive behavioral strategies which include stress management, relaxation, deep breathing, and yoga have been tested in clinical trials with varying results (12, 13, 33). Hypnosis appears to be promising based on recent randomized trials (40). Another approach, stellate ganglion block with a local anesthetic, provides improvement in hot flashes but has more potential risks (41). Acupuncture may be another effective procedure although sham acupuncture is also effective (20, 42, 43).
Overall health and survival benefit
Increased physical activity, weight reduction, and cessation of smoking and alcohol are important for breast cancer survivors based on evidence that these steps may provide objective benefit (44). Specifically, physical activity improves postmenopausal women’s balance, body composition, muscle strength, and bone health; improves mood (45); reduces cardiovascular risk (46, 47); and, potentially, reduces falls contributing to osteoporotic fractures (47). As obesity, independent of treatment, is associated with a poorer prognosis after breast cancer, including women with early disease, normalization of body weight is to be encouraged (48). Smoking cessation reduces mortality and improves quality of life (49). These lifestyle improvements may also benefit the metabolic syndrome (50). Adherence to a Mediterranean diet has been shown to decrease the incidence of breast cancer, particularly estrogen receptor negative cancer, and could reduce the incidence of second breast cancers (51).
Another lifestyle modification is to optimize vitamin D levels so as to maintain bone health (52). A Cochrane meta-analysis (53) concluded that supplementation of vitamin D and calcium in older patients reduces fracture risk [odds ratio = 0.89; 95% confidence interval (CI), 0.80 to 0.99]. An Institute of Medicine (IOM) report (54, 55) stated that raising low levels to normal is beneficial, whereas no benefits accrue from increasing Vitamin D levels above 50 ng/mL. Disagreement exists as to what levels constitute vitamin D deficiency. As defined by the IOM, deficiency represents a level below which rickets or osteomalacia occurs, namely <10 to 20 ng/mL (25 to 50 nmol/L), and normal levels are 20 ng/mL and above (56). The Endocrine Society Guidelines consider deficiency to be <20 ng/mL, insufficiency to be 20 to 29 ng/mL, and normal to be ≥30 ng/mL (57). The IOM suggests daily supplementation of vitamin D with 600 IU for women <70 years and 800 IU for those older. Although vitamin D intoxication is rare unless supplementation exceeds 10,000 IU daily, a recent detailed IOM report suggests that levels above 50 ng/mL may be associated with cardiac toxicity (56). Selected recent data suggest that levels of vitamin D may correlate with overall survival (58). Calcium supplementation is currently controversial, but postmenopausal women need 1200 mg of calcium, ideally from diet, to maintain bone health during menopausal transition.
General advice
All breast cancer survivors should be advised to modify their lifestyles to include smoking cessation, losing weight (if indicated), limiting or avoiding alcohol, maintaining adequate levels of vitamin D and calcium, eating a healthy diet, and participating in regular physical activity (59).
Management of moderate or severe signs and symptoms
VMS
Hot flashes and night sweats have been categorized as mildly, moderately, or severely bothersome depending on presence of sweating or disruption of usual activity (32). Previous opinion held that hot flashes resolve within 5 to 10 years after menopause onset in most women. However, recent data suggest that this symptom can continue for 15 years or more in as many as 33% of women with natural menopause (60). Women taking tamoxifen may experience severe flushing, which leads to stopping the treatment. Although the most effective treatment of moderate to severe VMS is the use of menopausal hormone therapy (MHT) (12, 13), clinical guidelines consider this approach contraindicated in women with a history of breast cancer based on existing but limited RCT evidence. Early meta-analyses based on observational data reported this approach to reduce breast cancer recurrence in breast cancer survivors (61). Later, more critical assessments have suggested that selection bias may have confounded this conclusion (62). Specifically women thought to be cured of breast cancer were likely selected to receive MHT, and the women felt to harbor residual tumors were not. Accordingly, the recurrence rate in the women receiving MHT appeared to be reduced compared with the placebo group.
To address the “wellness bias,” three RCTs compared MHT to placebo in breast cancer survivors (63–66). Two of the trials [Hormonal Replacement After Breast Cancer–Is it Safe? (HABITS) and Stockholm] compared estrogen with or without a progestogen and were conducted in Stockholm. The trials differed with respect to the progestogen used, primarily norethisterone in HABITS Trial and medroxyprogesterone acetate in the Stockholm Trial. The HABITS Trial with 898 women, reported an increased hazard ratio (HR) for breast cancer recurrence of 2.2 (95% CI, 1.0 to 5.1) for those using MHT, whereas the other, the Stockholm trial with 844 women, reported no increased risk (HR = 0.82; 95% CI, 0.35 to 1.9) (63–65). Differences in the trials included continued use of tamoxifen and stage or histology or receptor status of the preexisting breast cancer. Prior to completion of these studies, the decision was made to combine the data, resulting in an overall HR of 1.8 (95% CI, 1.03 to 3.10) (64). The third trial evaluated tibolone, 2.5mg/day, and also reported an increased risk of breast cancer recurrence (HR = 1.40; 95% CI, 1.14 to 1.70). The results might have been influenced by the inclusion of women taking AIs in the study, as tibolone can exert estrogenic effects (66). These three trials, though not definitive, have led the majority of guideline committees to consider MHT to be contraindicated in breast cancer survivors (13, 66–68).
Other nonhormonal pharmacological treatments of moderate to severe hot flashes that exhibit substantial efficacy are available. RCTs demonstrate the efficacy of the selective serotonin reuptake inhibitor (serotonin and norepinephrine reuptake inhibitor class of agents, transdermal nitroglycerin (69), and of gabapentin and pregabalin (Fig. 1) (36, 70–74). In general, these agents result in an overall 70% to 80% reduction in hot flash number and severity. However, on average, approximately 30% of the reduction is due to placebo effects (Fig. 1) (75). From the patient’s point of view, overall efficacy (including both drug and placebo effect) is the most important factor with respect to reduction of hot flash severity, sleep disruption, elevation in mood (76), and improvement in quality of life. Substantial clinical experience has been gained by the numerous trials of Charles Loprinzi and colleagues (15, 71, 77) in breast cancer survivors. The first recommendation from this group is to try low-dose antidepressants in women with moderate to severe hot flashes. Women taking tamoxifen should avoid potent CYP2D6 inhibitors as these agents reduce the levels of an active metabolite, endoxifene (73). Higher CYP2D6 inhibitory potency is found with paroxetine and fluoxetine (avoid), weak to moderate with citalopram, and relatively low (better choice) with venlafaxine, desvenlafaxine, escitalopram, gabapentin, and pregabalin (78–82).
Nighttime VMS may be associated with a greater risk of minor depression, fatigue, and mood changes than those occurring during the daytime (83). On this basis, the first step in management is to ascertain whether the symptoms occur predominantly at night as the pattern of hot flash presentation can inform the specific therapy to be chosen. For night time VMS or sleep disruption, a single dose of gabapentin given 1 hour before sleep is associated with a reduction in night time hot flashes and a soporific effect on initiating sleep. The short half-life of this agent yields fewer side effects upon awakening. Clinical experience has shown that the gabapentin dose must be individually determined and ranges from 100 mg to 1200 mg given as a single dose 1 hour before bedtime. A formal dose escalation protocol in each patient determines the appropriate dose. For VMS occurring both during the day and night, an additional morning dose of gabapentin can be added.
For women with predominantly daytime hot flashes, the serotonin and norepinephrine reuptake inhibitor class of agents has been shown to be effective. In the United States, only one agent, paroxetine salt 7.5 mg, is approved by the Food and Drug Administration (FDA) for treatment of VMS, but others in this class are also effective (Fig. 1) and have been shown to be successful for symptom relief in breast cancer survivors (15, 71, 73, 84). Another agent, clonidine, is somewhat effective, and can be a second line agent. Because of side effects with oral preparations, the long-acting transdermal therapy system preparation of clonidine is preferable, with titration of dose depending on symptom relief and effect on blood pressure. With each of these approaches, approximately half of these women experience at least a 50% decrease in hot flash score [see Table 2 from reference (77)].
In patients refractory to the above agents, intramuscular medroxyprogesterone acetate, 500 mg at 4- to 5-month intervals, has been suggested by the Mayo Clinic group to be as effective as estrogen therapy (77). Because this agent has been shown to be an effective therapy for hormone dependent breast cancer (85–87), these investigators consider it safe for breast cancer survivors. However, this conclusion is controversial because of concerns about the proliferative effects of a progestogen on occult breast cancer cells. Until more safety data are available, this agent is generally not recommended. An important side effect of medroxyprogesterone acetate is the weight gain occurring from its glucocorticoid actions. Micronized progesterone 300 mg nightly also significantly decreases VMS and improves sleep when compared with placebo (88). Notably, observational studies in healthy postmenopausal women have suggested a lesser effect of progesterone/estrogen combinations on breast cancer risk compared with synthetic progestogen/estrogen combinations (89–93), but these findings have not been confirmed in RCTs, and no data are available in women with breast cancer.
A key question is whether MHT might be prescribed to breast cancer survivors refractory to the agents mentioned previously. A multidisciplinary conference (94) recommended that MHT can be used in the lowest effective dose but only after obtaining full, written informed consent from the patient with attention to all potential risks and benefits (94). The Endocrine Society’s 2015 guidelines also allow for individual women to accept a degree of risk that might otherwise be considered to outweigh the benefits of MHT (13). The guideline states, “A fully informed patient should be empowered to make a decision that best balances individual QOL benefits against potential health risks” (13).
Vulvovaginal atrophy (VVA)
This common condition is a consequence of estrogen deficiency. Symptoms of VVA include vaginal dryness, irritation, itching, infection, discomfort, and painful sex (dyspareunia). Dyspareunia, in turn, leads to diminished sexual desire, arousal difficulties, and relationship problems. Up to 25% to 50% of postmenopausal women, particularly those on AIs, have VVA; thus, many women with breast cancer are profoundly affected by this problem (25). Dyspareunia interferes with sexual intimacy and disrupts the quality of life and successful partnerships in women with VVA. With the growing awareness of quality-of-life issues in cancer survivors in general, the issue of VVA has been increasingly emphasized as a major problem. VVA has been recently included under the broader term genitourinary syndrome of menopause, which also includes urinary symptoms (urgency, dysuria, and recurrent urinary tract infections) (31, 95).
For mild symptoms, regular use of vaginal moisturizers may be effective in combination with lubricants proximate to intercourse. (Moisturizers are used continuously, but not at the time of intercourse, as they may be irritating.) Differences between lubricants used acutely prior to intercourse and vaginal moisturizers used chronically to improve vaginal pH and moisture should be emphasized to patients. There are many types of moisturizers and lubricants available, including preservative free if needed. For more severe symptoms, the measures described previously are not sufficiently effective. A logical approach is to consider low-dose vaginal estrogen therapy. However, high-sensitivity mass spectrometry assays have demonstrated that all vaginal estrogen preparations result in a minor degree of systemic absorption but not exceeding normal postmenopausal levels (96). Whether a very small increase in estradiol exposure will stimulate quiescent, occult breast cancer cells or contribute to the development of a breast cancer is not known. Preclinical data have shown that long-term estrogen deprivation can result in a state of estradiol hypersensitivity, to both proliferation and apoptosis (97), but it is not clear which effect would predominate.
Low-dose vaginal estrogen in women taking the antiestrogens tamoxifen or raloxifene might be theoretically safer than in women not receiving these agents because of blockade of some possible effects of systemic estrogen absorption (98). Three studies (observational and case controlled) have examined the impact of vaginal estrogen administration in breast cancer survivors, and the results are reassuring, at least when vaginal estrogen is administered concurrently with tamoxifen (98–100). These studies, however, do not provide robust evidence regarding the safety of vaginal estrogens in breast cancer survivors taking AIs, the efficacy of which is due to markedly suppressed estrogen levels (101). One observational study of breast cancer survivors using tamoxifen or an AI, however, found no increased breast cancer recurrence risk with low-dose vaginal estrogen (7.5 μg vaginal ring or 10-μg tablet) during a 3.5-year mean follow-up (98). In general, the use of low-dose vaginal estrogen in breast cancer survivors has been discouraged, particularly in those receiving AIs (13, 68). If recommended following consultation with the attending oncologist, one should use the lowest effective dose of vaginal estrogen as recommended by American College of Obstetricians and Gynecologists (102), American Cancer Society/American Society of Clinical Oncology (68), the Endocrine Society (13), and North American Menopause Society (95).
The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene can exert mildly estrogenic effects on vaginal tissue. In the Anastrozole, Tamoxifen, Alone or in Combination Trial, 11.4% of women treated with tamoxifen reported vaginal discharge compared with 2.8% treated with an AI (103). In a chemoprevention trial comparing the effects of tamoxifen and raloxifene, vaginal discharge was reported more commonly by women taking tamoxifen than raloxifene (104, 105). Ospemiphene, an oral SERM, has been approved in Europe and North America for the treatment of dyspareunia secondary to VVA in healthy postmenopausal women. Comprehensive studies of ospemiphene demonstrated an improvement in vaginal maturation index and relief of most VVA symptoms, as well as improvement in measures of sexual wellbeing (106, 107). Safety evaluation showed a negligible estrogen effect on the uterus, and preclinical data suggested a predominantly antiestrogen effect on breast cancer growth (106, 107). Current FDA labeling in the United States recommends against use of ospemiphene in women with a history of breast cancer, until results from an adequately powered RCT of its effect on the breast are available.
A recent FDA-approved (i.e., November 2016) therapy for dyspareunia secondary to VVA is intravaginal dehydroepiandrosterone (DHEA). This therapy has not yet been approved beyond the United States. Nightly vaginal application of a 6.5-mg DHEA ovule has been shown to significantly improve vaginal cell maturation indices and the most bothersome symptoms of VVA. As DHEA can be enzymatically converted into both estrogen and androgens locally, this therapy theoretically provides a nonsystemic hormonal approach. Carefully conducted studies with highly sensitive and specific mass spectrometry assays suggest a slight but statistically significant increase in plasma estradiol and testosterone (108). Intravaginal DHEA has not been tested in breast cancer survivors; thus, there is a warning about its use due to lack of testing.
A small double-blind RCT of women without breast cancer has shown that intravaginal testosterone may be efficacious when compared with a placebo and vaginal estrogen in terms of subjective and objective VVA measures (109). A preliminary noncontrolled trial suggested that intravaginal testosterone may provide an effective treatment option for women with breast cancer taking an AI and experiencing symptoms of atrophic vaginitis (110). Further data on safety and efficacy are needed before this approach is recommended.
An additional approach to treatment of VVA includes laser reduction of the vaginal mucosal lining using a fractional CO2 laser (111). Although FDA approved for use on soft tissues, the specific indication for laser treatment of VVA is not included (112). The American College of Obstetricians and Gynecologists currently recommends against this procedure due to lack of safety and efficacy data (112). Although results appear promising in a number of observational studies, including one in women with breast cancer (113, 114), no RCTs have compared this approach with sham treatment, and its efficacy and safety therefore remain unclear (113).
Depressive symptoms and mood changes
The relationship between menopause, VMS, and depressive symptoms and mood changes has been well established (115). Major depression should be identified and treated with specific pharmacologic agents and/or cognitive behavioral therapy. Recent experimental data support the concept that mild depressive symptoms and fatigue may in part result from sleep disruption with frequent awakening at night due to hot flashes (83, 116). Further data are needed to confirm this conclusion in women with breast cancer.
Cognition
Menopause appears to be associated with subtle changes in cognitive function, notably, delayed verbal memory (117). Sleep disruption may contribute, as sleep is important for the encoding and consolidation of memory (118). However, evidence that exogenous estrogen therapy improves cognitive function within the first few years after menopause is lacking except for those with early surgical menopause (119, 120). Lower testosterone levels, as seen with age, surgical menopause, or chemotherapy, have been implicated in cognition (121). As breast cancer survivors experience chemotherapy-induced “chemo brain” and sex-steroid deficiency related effects, further understanding and possible treatments of cognitive problems remain key goals at the present time.
Osteopenia, osteoporosis, and fractures
Endocrine therapy for hormone dependent breast cancer impedes either estrogen synthesis or its action. Surgical oophorectomy or chemotherapy-induced ovarian insufficiency in premenopausal women reduce estrogen levels and accelerate the rate of bone resorption, as does tamoxifen in this population (11). On this mechanistic basis, an increased rate of osteopenia or osteoporosis and fracture has been reported (11). In postmenopausal women with breast cancer, AIs have become first-line therapy in preference to tamoxifen. The substantial reduction of estradiol levels to subpicogram concentrations (i.e., 0.05 to 0.6 pg/mL) (8, 10) markedly contributes to bone resorption. Quantitative data demonstrate a rapid and substantial increase in markers of bone resorption such as N-terminal telopeptide or C-telopeptide and a subsequent reduction in bone density with AIs (Fig. 2) (11, 122, 123). These effects are not sufficiently counteracted by a reflex rise in bone formation, demonstrated by measurements of osteocalcin and other markers. Accordingly, there is a net decrease in bone density and an increase in fracture rate. As recent data demonstrate the greater efficacy of 10 years vs 5 years of therapy with the AIs, this problem will become increasingly severe in the future (124). Interestingly, tamoxifen acts as a weak estrogen on bone in postmenopausal women and, as a SERM, increases bone density. On this mechanistic basis, tamoxifen is associated with fewer fractures than use of AIs (11, 125, 126).
Minimal trauma fractures are common after a breast cancer diagnosis, with nonpathological rib fracture the most commonly reported fracture (30). In a 6-year follow-up study of 1683 women after a diagnosis of breast cancer, minimal trauma fracture was not associated with radiotherapy, chemotherapy, treatment with an AI, or bilateral oophorectomy (30).
Several additional approaches have been developed to prevent osteoporosis and fractures in AI treated patients or in women after breast cancer with osteoporosis. Algorithms to guide decisions whether to use pharmacologic agents or life style changes have been developed (Fig. 3) (11, 122). Prophylactic or treatment agents include oral and parenteral bisphosphonates and denosumab (127). Both are effective but associated with serious but uncommon (rare) toxicity such as osteonecrosis of the jaw (estimated by expert consensus to occur at rates of 1 in 10,000 and 1 in 100,000 person-years) and atypical femoral fractures (estimated at 3.2 to 50 cases/100,000 person-years) (127). The disproportionate concern about these toxicities by the public has led to a 50% reduction in utilization by patients who are candidates for these agents.
Published reviews have recommended such agents in all breast cancer survivors with osteoporosis and selective use depending on other risk factors in those with osteopenia (11, 122).The algorithm in Fig. 3 provides a roadmap for selection of which patients to treat with pharmacologic agents during therapy with tamoxifen, AI, or gonadotropin-releasing hormone agonist. Effects of these agents beyond the bone may also be important in breast cancer survivors. Recent studies have shown that intravenous zoledronic acid and denosumab are associated with a decrease in breast cancer recurrence in postmenopausal but not premenopausal women (128). For zoledronic acid, this represented a 34% relative risk reduction of disease recurrence and for denosumab 19% (129, 130). Zoledronic acid also was associated with a 19% relative risk of death (128, 129).
Cardiovascular disease
With aging, the incidence of coronary artery disease, myocardial infarction, and acute coronary syndrome increase, as does coronary plaque. Incomplete data address the increased rate of cardiovascular disease in premenopausal women aged <45 years undergoing chemotherapy-induced premature menopause. Both chemotherapy (anthracycline, trastuzumab, and AIs) and radiation therapy (especially to the left breast and axilla) can contribute to development of ischemic coronary heart disease, valvular injury, pericardial injury, and cardiomyopathy (131, 132). Statins are effective therapy in those with increased cardiovascular risk factors and represent a reasonable approach in breast cancer survivors (131). Emphasis on cessation of smoking, maintenance of a healthy body weight, nutritious dietary pattern, regular exercise, and aggressive treatment of traditional risk factors such as hypertension and glucose intolerance also represent appropriate approaches (13, 33, 68).
Emerging Approaches for Unmet Needs in Breast Cancer Survivors
SERMs
As VVA and the osteopenia/osteoporosis/fracture complex are common in breast cancer survivors, an approach targeting both conditions would be useful. A major goal of pharmaceutical development has been to create SERMs with three separate actions: (1) prevention of breast cancer, (2) decrease of bone resorption and prevention of fractures, and (3) improvement in the symptoms of VVA. Most SERMs increase VMS, but not enough to cause discontinuation. Although tamoxifen and raloxifene prevent breast cancer, these two agents have not been shown to exert sufficient vaginal effects to treat VVA. Ospemiphene objectively improves VVA by increasing vaginal maturation indices and reducing the most bothersome symptoms (106, 107), and preclinical studies suggest a neutral effect on breast. No clinical data yet exist to demonstrate breast cancer prevention and reduction of bone resorption. With respect to lasofoxifene (an unapproved SERM), the Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene studies indicate prevention of breast cancer and fractures, reduction of bone resorption, and improvement of VVA, suggesting that this agent shows promise for breast cancer survivors. As breast cancer survivors experience a 0.5 to 1.0% rate of contralateral breast cancer per year, an agent blocking growth of these lesions when too small to be detected clinically would be useful (133). Of note, VTE rates were higher with lasofoxifene than other SERMs, but this agent also significantly reduced both stroke and MI (134). Lasofoxifene will be starting phase 2 trials for treatment of locally advanced and metastatic breast cancer.
Tissue-Selective Estrogen Complex Therapy
The concept of combining a SERM with an estrogen to create a tissue-selective estrogen complex (TSEC) has been studied intensively in the past decade, and one TSEC, pairing 0.45 mg oral conjugated equine estrogen with 20 mg bazedoxifene, has been approved in the United States and Canada and by the European Union (135–142). In a series of studies (141, 142), this combination improves hot flashes, reduces bone resorption, and exerts no stimulatory effects on the uterus, though highly effective for VMS and VVA (143). In 2-year clinical trials, the effect on breast tenderness and breast density was the same as placebo (144, 145) with no increase in breast cancer cases, but further testing is needed. Preclinical studies demonstrate that this TSEC blocks the growth of three separate breast tumor models (MCF-7 xenografts, N-nitrosomethylurea-induced tumors, and estrogen induced ACI tumors in rats) (146–148). Confirmation of breast antitumor effects in women would support the use of this TSEC in breast cancer survivors.
Miscellaneous agents
Recent data suggest that the kisspeptin, neurokinin B, and dynorphin neurons in the arcuate nucleus of the hypothalamus—particularly, neurokinin B—mediate hot flashes (149). On this basis, two randomized controlled trials have evaluated the effects of oral neurokinin B receptor antagonists on hot flashes (76, 150, 151). Both agents (MLE 4901 and fezolinetant) reduced hot flash frequency and severity by 40% to 50% over placebo in postmenopausal women, with negligible side effects (150, 151). As these inhibitors act on specific hot-flash-mediating pathways, they show promise as effective, nonhormonal agents to treat hot flashes. The pregnancy-associated natural estrogen, estetrol, is undergoing clinical trials in postmenopausal women as a candidate for hormone therapy. A rationale for use of this agent is that estetrol did not stimulate the hormone dependent 7,12-dimethylbenz[a]anthracene tumors in rats and could potentially be safe for use in breast cancer survivors (152–158).
Conclusions
Lifestyle optimization may improve estrogen-deficiency symptoms, improve quality of life, and possibly improve prognosis. Smoking cessation, losing weight (if indicated), limiting or avoiding alcohol, maintaining adequate levels of vitamin D and calcium, eating a healthy diet, and participating in regular physical activity are suggested for all women with prior breast cancer. Nonpharmacologic therapies for VMS such as cognitive behavioral therapy, hypnosis, and acupuncture may be helpful as may vaginal lubricants and moisturizers. For women with more severe symptoms or signs of estrogen deficiency, pharmacologic agents are available to relieve VMS and VVA and to prevent and treat fractures. Therapy must be individualized based on each woman’s needs and goals for therapy. Several emerging approaches such as SERMs, TSECs, estetrol, and neurokinin B inhibitors show promise as useful agents to expand options for symptom relief with less breast cancer risk but have not yet been tested in women with prior breast cancer.
Abbreviations
- AI
aromatase inhibitor
- CI
confidence interval
- DHEA
dehydroepiandrosterone
- FDA
Food and Drug Administration
- HR
hazard ratio
- IOM
Institute of Medicine
- MHT
menopausal hormone therapy
- RCT
randomized placebo-controlled trial
- SERM
selective estrogen receptor modulator
- TSEC
tissue-selective estrogen complex
- VMS
vasomotor symptoms
- VVA
vulvovaginal atrophy.
Acknowledgments
Financial Support: R.J.S. received research funding from Panterhei Bioscience, J.V.P. received research funding from Therapeutics, MD. S.R.D. received research funding from Lawley Pharmaceuticals and honoraria from Abbott, Besins Health Care, and Pfizer Pharmaceuticals.
Disclosure Summary: A.G., M.A.L., and C.A.S. have no conflicts to disclose.
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