Management of Menopause in Breast Cancer Survivors

What is the Experience of Menopause in Women With Breast Cancer?

The median age of breast cancer diagnosis is 63 years; therefore most women experience natural menopause prior to starting their cancer journey. However, the number of premenopausal women diagnosed with breast cancer has increased over the past decade, and more than 12,000 women under age 40 years are diagnosed with invasive breast cancer each year in the United States. Young women who are premenopausal at diagnosis are at highest risk for disruptive menopausal symptoms and poorer quality of life secondary to cancer-directed therapy. However, it is also important to recognize that nearly all women who are treated for breast cancer will experience some form of menopausal symptoms. Postmenopausal women commonly experience an exacerbation of menopausal symptoms due to cancer-directed therapy.

This chapter will explore the ways in which menopausal symptoms can present and the best management strategies for them. It will also discuss associated disease states like depression, osteoporosis, and cardiovascular disease with special consideration for needs of breast cancer survivors.

Vasomotor Symptoms

Vasomotor symptoms, including hot flashes and night sweats, are experienced by most women during or after treatment for breast cancer. Symptoms are particularly common among women who have received therapies that abruptly precipitate a sudden and substantial decline in circulating estrogen, either through ovarian failure or a blockade of estrogen activity, such as alkylating agents, endocrine therapies, or ovarian function suppression. Hot flashes are a common reason for early endocrine therapy cessation, contributing to poorer breast cancer survival outcomes.

Providers likely underestimate the prevalence of hot flashes. While clinical trials report that 20% to 40% of women undergoing endocrine therapy experience vasomotor symptoms, population-based studies utilizing patient-based outcomes report a much higher incidence, with estimates as high as 80%. Women may also accept hot flashes as a necessary consequence of cancer-directed therapy, potentially leading to underreporting and undertreatment. It is important to recognize that individuals may describe their hot flashes in different ways, not only using somatic descriptors, such as feeling “warm” or “flushed,” but also with emotional or behavioral symptoms. For instance, patients with moderate hot flash symptoms might describe perspiration, clammy skin, or palpitations, while those with severe symptoms may describe profuse diaphoresis with anxiousness, panic, and disruption of sleep or usual activities. For hot flashes, symptom severity is not simply a product of frequency and duration of symptoms.

In the sections that follow, we review a variety of supportive care options for clinicians and patients to consider, ranging from a “watch and wait” approach to pharmacotherapy and complementary or alternative medicine.

Natural History of Hot Flashes and Physical Measures

Hot flash symptoms secondary to endocrine therapy typically increase over the first few months of treatment and then plateau in their severity and frequency. Hot flashes can sometimes improve with no specific intervention, but providers should counsel patients that symptoms may continue for years after their final menstrual period and even after completing cancer-directed therapies. For instance, one study followed 1683 patients with invasive breast cancer using an annual questionnaire assessing menopausal symptoms. Even at the completion of the recommended 5 years of adjuvant endocrine therapy, those who had received breast cancer therapies experienced significantly worse vasomotor symptoms than community controls. These data illustrate the natural history of hot flashes in breast cancer survivors and may help inform patient expectations.

Supportive care for hot flashes starts with education. Lifestyle-based recommendations include dressing in layers, using a fan, lowering room temperature, and avoiding hot flash triggers, such as caffeine, alcohol, tobacco, and spicy foods. Obesity is also a modifiable risk factor for hot flashes; even modest weight loss (as little as 5 kg) can significantly decrease hot flash scores. While exercise may help patients lose weight, a meta-analysis found the current level of evidence to be insufficient for recommending exercise as a stand-alone measure to reduce hot flashes.

Tincture of time and lifestyle modifications are reasonable first steps for most patients to relieve hot flashes, particularly among those with milder symptoms. Some breast cancer survivors will need additional treatment, and early pharmacotherapy should be considered for those who are experiencing troublesome physical, emotional, or behavioral consequences of vasomotor symptoms.

Pharmacologic Treatment Options

For those who find lifestyle modification insufficient, pharmacotherapy can be considered. Menopausal hormone replacement therapy (MHT) with exogenous estrogen +/− progesterone is widely considered to be the most effective intervention for hot flashes. It can be expected to decrease hot flash severity and frequency by up to 75%. However, MHT theoretically opposes the beneficial effects of endocrine therapies and ovarian function suppression in women with hormone receptor–positive cancers. Therefore, consensus guidelines recommend avoiding MHT for women at high or intermediate risk of breast cancer, including those who have a history of breast cancer. However, the data regarding breast cancer risks with MHT are mixed. Recently, in an updated analysis from a Women’s Health Initiative study, an increase in primary breast cancer incidence was observed among women receiving combined estrogen/progesterone therapy after age 50 years, whereas women receiving estrogen alone experienced a lower frequency of breast cancer, suggesting that estrogen after 50 years of age may provide protective effects from breast cancer (though estrogen supplementation increases uterine cancer risk, except in post-hysterectomy patients). Among women with a history of breast cancer, hormonal replacement was reported to increase risk for recurrence at a median follow-up of 2.1 years in the Hormonal Replacement Therapy After Breast Cancer Trial (HABITS). In contrast, the results of another (Stockholm) trial, which also evaluated breast cancer recurrence after hormonal therapy, did not reveal an association between menopausal hormone therapy and breast cancer recurrence over a median follow-up of 4.1 years. These trials were limited by significant heterogeneity in hormonal therapy preparations. For now, guidelines continue to recommend avoiding MHT in those with a history of breast cancer. Therefore, alternative, nonestrogenic therapies for hot flashes should be considered. If MHT is prescribed to a woman with a history of breast cancer, the patient should be made aware of potential risks and informed of alternative treatment options before starting a time-limited trial of MHT.

In the next section, we will review the growing number of medications that have been shown to improve vasomotor symptoms, with large, randomized controlled trials (RCTs) supporting their use. Readers may note the heterogeneous patient populations included in the various trials, with some patients entering menopause naturally and others because of breast cancer treatments. Nonestrogenic therapies can be prescribed agnostic to the cause of hot flashes, and most seem to be equally effective regardless of the etiology of vasomotor symptoms.

There are few prospective studies comparing efficacy amongst the various drug classes. Most of these medications were not developed with the intent of treating hot flashes, but rather they were later noted to have the fortuitous side effect of decreasing hot flash frequency. So, when a provider is considering which drug to try first, comorbidities and potential side effects factor prominently in decision-making. If a breast cancer survivor also has mood or anxiety symptoms, it makes most sense to start with an antidepressant. If she has competing neuropathic pain or symptoms that are more prominent at night, it might be best to start with a gabapentinoid. If she has urinary symptoms from overactive bladder, oxybutynin is an appealing first choice. When there are no comorbidities to guide agent selection, the limited available evidence would suggest starting with an antidepressant and then trying a second medication if the first drug does not work as well as the patient desires.

Alternatives to Estrogen-Based Therapy for Management of Vasomotor Symptoms

Antidepressants

A number of antidepressants have demonstrated efficacy in treating hot flashes. Commonly used selective serotonin reuptake inhibitor (SSRIs) and serotonin and norepinephrine reuptake inhibitor (SNRIs) for vasomotor symptoms include venlafaxine, desvenlafaxine, citalopram, escitalopram, and paroxetine.

The practice of treating hot flashes with venlafaxine gained traction following the publication of a pilot study in 1998, which reported that 4 weeks of treatment with low-dose venlafaxine (12.5 mg twice daily) reduced hot flash scores by 55% among women with a history of breast cancer and men receiving androgen deprivation therapy. A subsequent placebo-controlled trial evaluated the efficacy of venlafaxine at three different doses (37.5, 75, and 150 mg daily) versus placebo. All three doses were better than placebo for reducing hot flashes, but 75 mg daily seemed to be the best dose when balancing efficacy and toxicity concerns. Venlafaxine dosed at 75 mg daily reduced median hot flash scores by 61% from baseline. At higher doses than 75 mg daily, there was no greater reduction in hot flash scores, and patients reported more side effects, including mouth dryness, anorexia, nausea, and constipation. Desvenlafaxine, an active metabolite of venlafaxine, also functions as an SNRI. Cross-trial comparisons of randomized, placebo-controlled trials suggest that there is a similar reduction in hot flashes with use of desvenlafaxine and venlafaxine. The side effect profiles of venlafaxine and desvenlafaxine are similar, but desvenlafaxine has fewer drug-drug interactions. Patients starting these medications should be alerted to potential for a withdrawal syndrome upon discontinuation, including dizziness, nausea, and irritability; these symptoms may be severe, so doses should be tapered down slowly before cessation.

After seeing the promise of SNRIs in treating hot flashes, researchers began studying newer generations of SSRIs, which have fewer anticholinergic side effects, such as dry mouth, constipation, and sedation. In a single-arm pilot study, citalopram at a dose of 20 mg daily improved hot flash frequency by 58% and hot flash score by 64% from baseline. In the subsequent phase III trial, citalopram at doses of 10, 20, and 30 mg daily were compared to placebo. All three doses of citalopram improved hot flash scores to a similar degree (reduction by approximately 50% from baseline to week 6), but the 20 mg dose was noted to reduce hot flash–related daily interference, as well as anxiety symptoms. Those in the 20-mg arm noted a significantly lower detrimental impact of hot flashes on work, sleep, mood, concentration, and quality of life. For these reasons, if citalopram is used for hot flashes, it is recommended to start at a dose of 10 mg daily for a week and then increase to 20 mg daily to potentially accrue additional benefits, provided the medication is well tolerated. Side effects were minimal with infrequent reports of grade 3 sedation (3 of 132 patients) and insomnia (only 1). Sexual concerns trended higher in those receiving citalopram but were not statistically different from placebo. Overall, women receiving citalopram reported less overall distress from their hot flashes and more satisfaction with their hot flash control. Citalopram has also been studied in women with hot flashes refractory to venlafaxine. In this population, citalopram was seen to improve baseline hot flash scores by 53% after 4 weeks of treatment. This study suggests there may be value to rotating antidepressants if the first drug does not work.

Escitalopram provides more potent inhibition of serotonin reuptake in vitro and when studied among healthy women with menopausal hot flashes, 55% of women receiving escitalopram (10–20 mg daily) had a 50% reduction in hot flash frequency as compared to 36% of those receiving placebo. With discontinuation of treatment, hot flashes increased in those receiving escitalopram but not placebo. Though women experienced only a modest reduction in the number of hot flashes per day (1.4 fewer hot flashes), 70% of women reported satisfaction with escitalopram. Tolerability was high, and there were no differences in adverse events as compared to placebo. The benefits of escitalopram for hot flashes have been reported in multiple smaller trials enrolling women with breast cancer as well.

Paroxetine is the only SSRI or SNRI that currently has US Food and Drug Administration approval for the treatment of hot flashes. At a low dose of 10 mg daily, it also has also been shown to improve sleep for women with hot flashes. However, drug-drug interactions are important to consider when using paroxetine. As paroxetine is a potent inhibitor of cytochrome P450 2D6 (CYP2D6), which converts tamoxifen to its active metabolite, endoxifen, it decreases plasma concentrations of endoxifen, theoretically reducing tamoxifen’s efficacy for breast cancer risk reduction and reduction in risk of recurrence. Therefore, paroxetine is not the preferred choice for women receiving tamoxifen.

Though several SSRIs and SNRIs improve hot flashes, not all reduce symptoms to a similar extent. For instance, multiple trials have shown that sertraline inconsistently outperforms placebo. Similarly, fluoxetine may slightly improve hot flash scores, but the effect size is modest at best ; fluoxetine was less likely than other SSRIs to improve hot flashes in a mixed treatment comparison analysis of SSRIs and pooled patient data from clinical trials. Given the limited evidence supporting sertraline or fluoxetine for hot flashes, alternative antidepressants are recommended.

Before discussing other pharmacotherapies, the antidepressant classes warrant some additional comments. First, the trials mentioned earlier demonstrate that SSRIs and SNRIs improve hot flashes much more quickly (within days) than they improve anxiety or mood symptoms, and often they may improve hot flashes at lower doses than are required for psychiatric indications. Using these agents at their lowest effective dose may help reduce unwanted side effects. Furthermore, most trials compare antidepressant to placebo rather than making head-to-head comparisons of the SSRIs/SNRIs. Thus there is a paucity of data to inform our understanding of possible efficacy differences between specific medications in these classes.

Gabapentinoids

In 2005 an RCT evaluated gabapentin for the treatment of hot flashes in women with breast cancer. A dose of 300 mg daily was no better than placebo, but a daily dose of 900 mg (300 mg three times daily) reduced hot flash frequency and severity by nearly 50%. Several other placebo-controlled trials also support the use of gabapentin at a similar dose. Taking any medication three times daily can be burdensome, and so pregabalin, which has a similar mechanism of action but is dosed twice daily, may be more appealing to patients. Pregabalin 75 mg twice daily outperformed placebo in suppressing hot flashes. Nearly 70% of trial participants who received pregabalin were satisfied with their hot flash control; perhaps even more importantly, approximately 60% of participants found the treatment to be beneficial for hot flashes and were not bothered by side effects. Toxicities of gabapentinoids include somnolence, dizziness, fatigue, and other neurologic complaints.

The efficacy of antidepressants and gabapentinoids in the treatment of vasomotor symptoms appears to be similar; however, women who have received both tend to prefer the antidepressant. In a crossover study, breast cancer survivors received both a 4-week trial of venlafaxine and a 4-week trial of gabapentin (separated by a washout period); the majority of participants preferred venlafaxine (68% vs. 32%) despite the fact that each medication reduced hot flashes to a similar extent. Though over two-thirds of women preferred the antidepressants, this trial also highlights that a subset of women preferred gabapentin. For those with hot flashes still refractory to antidepressants, transition to gabapentin reduces hot flash scores by 60%. The antidepressant can then be discontinued, as dual therapy with gabapentin and antidepressant offers no benefit over gabapentin alone.

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