Management of menopausal symptoms following treatment for hormone receptor positive breast cancer

Introduction

Approximately 700 000 women are alive in the UK following a breast cancer diagnosis. The majority will have had hormone receptor positive cancer, receiving endocrine therapy (ET), which minimises oestrogen uptake in cancer cells, either via oestrogen receptor modulation (tamoxifen), ovarian suppression (gonadotropin-releasing hormone agonists in pre-menopausal women), or inhibition of peripheral conversion of androgens to oestrogen (aromatase inhibitors [AIs]). Oestrogen deprivation-related side effects are akin to menopausal symptoms, and can be burdensome, especially arthralgia, vasomotor symptoms, and genitourinary syndrome. Up to 30% of patients prematurely discontinue endocrine therapy within 2 years because of toxicities, which can negatively impact recurrence rates. ^1,2 As a result, a Working Party on Symptom Management was established by the National Cancer Research Institute Breast Clinical Studies Group in 2013, to promote and develop research into this topic.

Following management of early breast cancer, patients may be discharged to Stratified Follow-Up programmes. While a pathway will usually be in place to manage ongoing toxicities, many women initially present to primary care who may lack the necessary specialised expertise to help these women. This article provides succinct information for primary care teams regarding the frequency and effects of such symptoms, and guides management. We focus on arthralgia, vasomotor symptoms, and genitourinary syndrome of the menopause (summarised in Table 1), with Table 2 listing additional common side effects. We also recommend consulting the British Menopause Society Consensus Statement for more in-depth guidance. ³

Table 1. Summary of supportive management options for menopausal symptoms following treatment for hormone receptor positive breast cancer.

Arthralgia	Vasomotor symptoms	Genitourinary syndrome
Simple analgesia Light exercise and weight loss Duloxetinea Acupuncture and relaxation techniques Nutritional supplementation, for example, omega-3 fatty acids, glucosamine, high- dose vitamin D2 AI switch	Lifestyle changes Portable fans Layered clothing Cotton or linen fabrics Alcohol and caffeine avoidance Weight loss Exercise Non-pharmacological interventions Cognitive behavioural therapy (CBT) Acupuncture Pharmacological interventionsb Citalopram 10 mg o.d. Venlafaxine 37.5–75 mg o.d. Gabapentin 300 mg t.d.s. Pregabalin 75–150 mg b.d. Clonidine 0.1 mg o.d.	Smoking cessation Vaginal lubricants (as required) Regular use of vaginal moisturisers Low-dose vaginal oestrogenc Vaginal dehydroepiandrosterone (DHEA)d

^aData remains limited for these interventions. ^bPharmacological interventions have rapid onset. If ineffective at 4 weeks, other options should be considered. ^cCaution in those taking AIs. ^dGiven limited data on risks, patients require appropriate counselling.

AI = aromatase inhibitor; b.d. = twice a day; t.d.s. = three times a day; o.d. = once a day;

Table 2. Additional endocrine therapy-related side effects.

System	Symptom/sign	Endocrine therapy	Incidence	Management techniques
Neurological	Cognitive impairment Mood disturbance	Tamoxifen Aromatase inhibitors	Unclear	Rehabilitation, for example, CBT Change tamoxifen brand
Skeletal	Osteoporotic fracture	Aromatase Inhibitors Ovarian suppression	10–20%	Lifestyle modification, for example, diet, weight-bearing exercise, reduced alcohol, smoking cessation Baseline DEXA; repeat as recommended 11 Calcium/vitamin D Bisphosphonates Denosumab
Cardiovascular	Venous thromboembolism	Tamoxifen	5.4%	Lifestyle modification, for example, smoking cessation, exercise
Ocular	Cataracts Corneal deposits Retinal deposits	Tamoxifen	3.2% 0.3% <1%	Surveillance Ophthalmology referral if concerned
Hepatic	Fatty liver disease	Tamoxifen Aromatase inhibitors	25–37%	Surveillance
Gynaecological	Endometrial cancer	Tamoxifen	2.5%	Women with non-menstrual bleeding should be referred to gynaecology for investigation
Other	Hair thinning/alopecia	Tamoxifen Aromatase inhibitors	4.4–15%

CBT = cognitive behavioural therapy. DEXA = dual-energy X-ray absorptiometry.

Arthralgia

Arthralgia due to AIs is a common ET-related side-effect, occurring in up to half of women on therapy. ⁴ Younger age and prior taxane-based (docetaxel/paclitaxel) chemotherapy are additional risk factors. Patients experience morning stiffness and pain, often in multiple joints, with a median time to onset of 1.6 months (range: weeks to 10 months). Oestrogen deprivation alongside activation of inflammatory pathways are probable causes, and symptoms may persist throughout AI therapy. Symptoms can be improved in varying degrees by simple analgesia, light exercise, and weight loss, which should be encouraged as initial measures. Women may benefit from duloxetine, acupuncture, and relaxation techniques, though there is no clear benefit of one approach over another. ⁵ The evidence base for nutritional supplementation, for example, omega-3 fatty acids, glucosamine, and high-dose vitamin D₂, is limited.

Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), demonstrated significant reductions in average joint pain score when given to AI-treated women with arthralgia. ⁶ By 12 weeks, the score was significantly lower for patients on duloxetine compared with placebo, with additional improvement in joint stiffness and function; side effects resulted in high discontinuation rates.

The effects of acupuncture were highlighted in patients receiving 12 sessions over 6 weeks, followed by one session weekly for 6 weeks, versus sham-acupuncture or wait-list control, that is, no intervention. ⁷ True acupuncture resulted in statistically significant reductions in joint pain at 6 weeks compared with baseline, measured by the BPI-WP score.

Switching to an alternative AI may improve symptoms, allowing patients to maintain treatment; ⁸ letrozole and anastrozole, both non-steroidal AIs, can be considered interchangeable, whereas a switch to the steroidal AI exemestane should be with oncological input. Of note, AI-induced arthralgia generally improves or resolves within 2 weeks of stopping AI therapy.

Vasomotor symptoms

Vasomotor symptoms (VMS), that is, hot flushes, are commonly experienced during natural menopause, but are generally more pronounced and prolonged in association with ETs, especially following rapid onset of menopause induced by chemotherapy or ovarian suppression. VMS usually persist throughout treatment, although severity may reduce over time. ⁹ In post-menopausal women, switching from AI to tamoxifen may reduce symptoms but should be carefully considered in cases of high-risk disease, in collaboration with an oncologist.

Simple measures such as portable fans, layered clothing, and avoidance of alcohol and caffeine may improve symptoms somewhat. Trials demonstrate reduced VMS with selective serotonin reuptake inhibitors (SSRIs) and SNRIs versus placebo, as well as clonidine and gabapentin treatment, but compliance is often poor due to side effects. ¹⁰ Of note, fluoxetine and paroxetine interact with tamoxifen metabolism and the combination should be avoided. Randomised trials demonstrate little advantage from products such as soy, red clover, black cohosh, and vitamin E over placebo; many contain phytoestrogens, which may increase risk of disease recurrence. ¹¹ A recent trial found that a 6-week course of oxybutynin (2.5–5 mg) reduced VMS, although patients did report anti-cholinergic side effects. The commonest side effect, dry mouth, was experienced by 33% of patients on 5 mg and 21% of patients on 2.5 mg of oxybutynin. Further evidence needs to be gathered regarding long-term oxybutynin use. ¹²

Neurokinin-3 receptor antagonists show promise for VMS reduction. The SKYLIGHT 1 trial found that fezolinetant, a neurokinin-3 antagonist, improved both the frequency and severity of VMS at both doses studied (30 mg and 45 mg) compared with a placebo after 4 weeks and 12 weeks, with efficacy being demonstrated within 1 week of taking fezolinetant. This effect persisted during the extended phase of the trial, which studied patients’ VMS until 52 weeks of treatment. The commonest adverse effects included headache and hyperglycaemia. ¹³ Fezolinetant’s safety and efficacy will be tested on patients with breast cancer receiving ET in the HIGHLIGHT 1 study with results expected in August 2027.

Non-pharmacological measures include acupuncture, which may reduce the frequency and intensity of VMS, with sustained effects up to 6 months. ¹⁴ Cognitive behavioural therapy (CBT) is also effective, possibly via altered perception. Self-managed internet-based and therapist-guided CBT, including pyscho-education, behaviour monitoring, and cognitive restructuring, reduced the perceived impact of VMS, and improved sleep quality, with results persisting to 24 weeks. ¹⁵ The UK-led MENOS4 trial also evaluated a 26-week-long specialist nurse-led CBT course, reporting a 46% reduction in the mean ‘hot flushes and night sweats’ problem rating score versus 15% reduction in those receiving standard care. Sleep, anxiety, and depression all improved significantly. ¹⁶

Systemic hormone replacement therapy (HRT) is widely avoided in patients with a prior history of breast cancer. The HABITS trial demonstrated a 3.7-fold increase in breast cancer events with HRT (median follow-up 2.1 years). ¹⁷ These findings were not replicated in the Stockholm study, however, although this may relate to differences in progesterone exposure and tamoxifen use. ¹⁸ Tibolone, a compound with oestrogenic, progestogen, and androgenic properties, was trialled as an alternative to HRT; however, the trial was prematurely stopped because of significant increases in breast cancer recurrence in the tibolone cohort. ¹⁹ Although HRT is the most effective therapy for VMS, significant concerns remain about its use after a breast cancer diagnosis. The National Institute for Health and Care Excellence UK breast cancer guideline (NG101) states that HRT should only be offered to women with a history of breast cancer in exceptional circumstances and that the risks and benefits must be fully discussed, with oncologist input. ¹¹

Genitourinary syndrome of the menopause (GSM)

During the peri-/post-menopausal period, reduced circulating oestrogen can result in thinning of the vaginal wall, with associated dryness and pruritus. Medications that mimic or induce menopause can result in similar changes, often with more rapid effect. The incidence of GSM may be as high as 70% in women receiving ET, with almost 50% reporting low sexual interest, leading around 20% to consider stopping treatment, yet few seek help for their symptoms. ²⁰

Symptoms occur as a result of vaginal wall thinning and reduced lubrication, with itching, pain, and bleeding, increased urinary frequency and incontinence. This may affect a woman’s relationship, sexual satisfaction, and self-esteem. ²¹ These symptoms may have a profound effect on quality of life and are often progressive, hence there may be a need for long-term proactive management.

Smoking is associated with accelerated vaginal atrophy, therefore smoking cessation is encouraged. Women should avoid fragranced soaps, lotions, or feminine hygiene products, as these can promote dryness of the vulvo-vaginal tissues. In women who are sexually active, regular intercourse can improve vaginal atrophy secondary to increased blood flow to the genital area.

Non-hormonal topical preparations are a popular first-line management option (Table 3). ²² Vaginal lubricants can provide short-term lubrication, especially during sexual intercourse. Vaginal moisturisers are designed to coat the vaginal surface and deliver moisture, restore elasticity, and ensure a balanced osmolality and pH level as similar as possible to natural vaginal secretions. The effects may last up to 72 hours after application, therefore the products should be applied regularly (2–3 times per week) whether or not sexual activity is planned, yet it may take up to 30 days for the patient to really notice symptomatic benefit. During sexual activity, lubricants and moisturisers can be used together to minimise dyspareunia. Although these products have proven benefit in relieving symptoms, GSM symptoms may persist despite regular use, or only abate for a short period, so women may seek alternative approaches.

Table 3. Vaginal preparations for genitourinary syndrome of the menopause.

Preparation	Sub-type	Examples	Comments
Vaginal lubricant (short-term use)	Water based	Sylk® Sensilube® Pjur Med Natural Glide® Yes WB®	Usual first-line option Minimal local irritation/mucosal reaction
	Oil based	Yes OB®	Not compatible with barrier contraception methods
	Silicone based	Pjur Med Silicone Premium Glide®	Have an oily texture Longer acting Compatible with barrier contraception
Vaginal moisturiser (longer-term use)		Replens® Hyalofemme® Yes VM®	Effects may last up to 72 hours Apply regularly 2–3 times per week, irrespective of sexual activity
Vaginal oestrogen	Low-dose pessary (10 mcg) cream (1 mg) cream (0.1 mg)	Vagifem® Ovestin® (0.1%) Estriol (0.01%)	Consider monitoring for systemic oestrogen absorption
Vaginal ring		Estring®	Slowly releases oestrogen over a 3-month period

In women without prior breast cancer, vaginal oestrogens are recommended for moderate-to-severe GSM. While some studies have demonstrated potential for systemic absorption of topical oestrogens, particularly with higher-dose preparations, most show only transient or no increase in circulating oestrogen levels. ^22,23 Vaginal oestrogens have been trialled in the form of creams, tablets, and vaginal ring, but findings are limited by small sample size, and have often assessed circulating oestrogen levels only. ²⁴ Current data have not demonstrated increased mortality related to vaginal oestrogen treatment; however, a retrospective study of Danish patients with breast cancer showed an increased risk of recurrence in those taking an AI and vaginal oestrogen in a subgroup analysis. ²⁵ This remains an area of debate, with several limitations of this study being noted. Given these limitations, together with changes to breast cancer management since the study period, guidelines have not changed to limit use of vaginal oestrogens, and the 2021 American College of Obstetricians and Gynecologists and 2018 American Society of Clinical Oncology guidelines do accept that low-dose vaginal oestrogen may be necessary in those unresponsive to non-hormonal therapies, after discussion of the risks and benefits. ^22,26 Vaginal oestrogens may pose less risk for breast cancer recurrence in those taking tamoxifen, an oestrogen receptor modulator. For women on AIs experiencing GSM refractory to non-hormonal preparations, a short-term switch to tamoxifen and vaginal oestrogen-based products may be advocated, with the intention of changing back to an AI in time following oncologist approval. If this is not an option, then the decision to commence low-dose vaginal oestrogen for those on AIs must be a shared decision between the patient, their oncologist, and their gynaecologist.

Discussion

This article should enhance the medical professional’s understanding and management of common side effects related to ET for hormone-positive breast cancer. Optimal proactive management of symptoms is important, as they can dramatically affect patients’ quality of life, and, if poorly managed, may lead to discontinuation of potentially curative treatments resulting in reduced survival. A variety of pharmacological and non-pharmacological approaches, without exogenous hormone, may improve menopausal symptoms, depending on the issues and a patient’s preference. Nevertheless, if patients continue to struggle despite the aforementioned options, then a change of endocrine therapy can be considered. A multidisciplinary approach may be warranted, including input from the patient, primary care physician, oncologist, and gynaecologist, to ensure a consideration of the risks and benefits, particularly in higher-risk women.

Provenance

Freely submitted; not externally peer reviewed.

Competing interests

The authors have declared no competing interests.