A history of breast cancer is a common reason for referral to the complex menopause clinic and constitutes a large proportion of the cases we see. Breast cancer, and sex hormone sensitive cancers such as endometrial cancer and some types of ovarian cancers, are considered contraindications to the use of hormone replacement therapy (HRT). We also see patients who have a confirmed gene mutation which increases their risk of breast and ovarian cancers such as BRCA1, BRCA2 and BRIP1. 

Breast cancer is the most common female cancer after non-melanoma skin cancer in Ireland. It is estimated that one in seven women living in Ireland will develop breast cancer in their lifetime. The term breast cancer is heterogeneous encompassing many different types of breast cancer and is inclusive of premalignant or stage 0 cancers such as ductal carcinoma in situ ( DCIS) or lobular carcinoma in situ ( LCIS). Important characteristics to consider include the size, grade, stage, axillary node status and hormone receptor (HR) status. 

With the advancements that have occurred in the earlier detection and treatment of breast cancer, survival rates have improved considerably. This means there is an increase in women with a history of breast cancer who experience menopause – either naturally or induced. Therefore, it is important that we can help women navigate this process and have an awareness of the individual factors that can sometimes make this more challenging. 

Some of the challenging reasons include that cancer treatment in itself can induce a severe and sudden menopause in some instances. Adjuvant endocrine medications used to reduce the risk of recurrence can cause menopausal symptoms by virtue of their mechanism of action. However, HRT which is considered the most effective method of alleviating menopausal symptoms is generally considered contraindicated after a history of breast cancer.

After treatment for early stage non-metastatic breast cancer, many women will go on to have a natural menopause in the future, particularly if they didn’t require chemotherapy as part of their treatment protocol. However, for others, treatment can induce menopause which can be either temporary or permanent. This can be secondary to medications such as gonadotropin releasing hormone (GnRH) analogues which induce a temporary menopause, chemotherapy which can induce a temporary or permanent menopause, or surgery in the form of a bilateral salpingo-oophorectomy (BSO) which is immediate and permanent. GnRH analogues or a BSO may be recommended to premenopausal women with hormone sensitive breast cancer, alongside adjuvant endocrine therapies if their cancer is of a higher stage or they are considered to be at higher risk of recurrence.

Some women, therefore, will go on to develop premature ovarian insufficiency (POI) or early menopause if under the age of 40 and 45 respectively on diagnosis. In addition to the fertility and psychological implications, POI is associated with an increased risk of cardiovascular disease, osteoporosis, cognitive symptoms and Parkinson’s disease, which is particularly relevant when HRT isn’t recommended as a treatment option. Having an awareness of heart, bone and brain health is extremely important to maximise lifestyle factors in this context.

Adjuvant endocrine therapies used for hormone sensitive breast cancers can cause side-effects which can be particularly challenging for many women. Tamoxifen is a selective estrogen receptor modulator (SERM) which works by blocking the effects of oestrogen on breast tissue and has an oestrogen agonist effect on other areas of the body such as the endometrium. Vasomotor symptoms (VMS) such as hot flushes and night sweats are particularly common, along with other troublesome symptoms such as a vaginal discharge.

Aromatase inhibitors (AIs) work by inhibiting the conversion of androgens to oestrogen within adipose tissue by inhibiting the enzyme aromatase. They can have pronounced anti-oestrogen effects which can manifest as menopausal symptoms such as joint pains, vaginal symptoms, reduced libido, VMS, and cognitive symptoms such as brain fog or reduced concentration.

Multimodal management of menopause symptoms

Within the context of a complex menopause clinic, the aim is to manage menopause symptoms effectively to improve the quality of life of our patients. 

A multimodal approach is particularly useful in settings where HRT is considered contraindicated, that is using different treatment modalities to maximise impact.¹ This can include:

• Lifestyle interventions or modifications
• Psychological therapies such as cognitive behavioural therapies or psychosexual counselling
• Complementary therapies such as acupuncture
• Non-hormonal moisturisers and lubricants
• Pelvic physiotherapy
• Prescribed non-hormonal medications. 

Spending time discussing multimodal therapy is important so patients will understand the benefit of using different approaches.

Lifestyle factors 

Lifestyle factors are explored to see whether behavioural changes can be made in relation to diet, exercise, sleep, stress, alcohol and smoking if these are highlighted during the course of the consultation. The benefits of a Mediterranean style diet and regular exercise are discussed.

Psychological therapies 

Psychological therapies, particularly cognitive behavioural therapy (CBT) has been shown to reduce the impact of menopausal symptoms and improve quality of life.² This can be self-directed via reading, online resources or apps, or delivered via trained practitioners. Other forms of psychological therapies such as general counselling and mindfulness may be useful. Psychosexual counselling can be helpful for sexual dysfunction which is affecting quality of life, particularly when concomitant factors have been addressed and treated such as genitourinary syndrome of menopause (GSM).

Complementary therapies 

Complementary therapies such as acupuncture have been studied in breast cancer patients with a systematic review and meta-analysis of randomised controlled trials (RCTs) by Zhang et al³ showing an improvement in patient-reported outcomes in areas such as fatigue, joint pains, vasomotor symptoms with acknowledgement that more rigorous, well-designed, and larger RCTs are required to confirm results. Paraphernalia such as portable fans can also be useful for VMS, alongside cooling creams and sprays, and the use of blankets rather than duvets.

Prescribed non-hormonal oral medications 

Prescribed non-hormonal oral medications are medications that are mainly licenced for other conditions but have been shown to improve some types of menopausal symptoms in some women. They mainly work via a neurotransmitter modulator effect in the brain. The medications with most evidence of efficacy, particularly when it comes to vasomotor symptoms, include selective serotonin and noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), gabapentin and oxybutynin.⁴ The SSRIs, paroxetine and fluoxetine, which have a potent inhibitory effect on the CYP2D6 enzyme which converts tamoxifen to its active metabolite, should not be used alongside tamoxifen as it can reduce its efficacy. Like all medications, side-effects can occur and these can limit their use. 

In practice, we try to tailor the use of prescribed non-hormonal medications to the presence of concomitant symptoms that might also benefit, such as mood symptoms in the case of SNRIs and SSRIs, sleep with gabapentin, and overactive bladder with oxybutynin. 

The neurokinin 3 antagonist, fezolinetant, has just been licensed for the treatment of menopausal vasomotor symptoms in Ireland and has shown improvement in VMS in clinical trials. However, women with a history of breast cancer were excluded from these trials. As it is a new medication with no long-term safety data, we are reserving its use at present to patients with VMS which haven’t responded to other prescribed non-hormonal options. 

Non-hormonal vaginal moisturisers and lubricants

GSM is a chronic, progressive, vulvovaginal, sexual and lower urinary tract condition caused by the decline and loss of oestrogen. It causes thinning of the vaginal epithelium, loss of tissue elasticity and changes in the vaginal microbiome leading to symptoms such as vaginal dryness, dyspareunia, vaginal discharge, overactive bladder, and recurrent urinary tract infections. Direct questioning in relation to the presence of GSM symptoms is always done, along with determining whether there is any negative impact on sexual function. The screening questionnaire is also helpful in opening this important conversation. 

Non-hormonal vaginal moisturisers and lubricants are considered first-line treatment for GSM symptoms in women with a history of a hormone sensitive cancer. There are many different types and brands. 

Local vaginal estrogen (LVE) 

Local vaginal estrogen (LVE) may be considered a second-line option for hormone sensitive cancers if symptoms persist, which they will in many cases. A discussion of the evidence is necessary, including its limitations.^5,6,7  LVE is very effective at treating GSM and is superior to systemic HRT in this context. It acts locally in the vagina and surrounding structures such as the pelvic floor musculature and bladder. Other than for the potential at the initiation of treatment for a small increase in serum oestradiol levels if the vaginal mucosa is very atrophied and thin, levels otherwise remain in the postmenopausal range once treatment is established and vaginal atrophy has improved. 

While there is good quality evidence to show LVE does not increase the risk of breast cancer in women without breast cancer,² there is limited evidence looking at whether it increases the risk of recurrence of breast cancer in woman who use it after a history of breast cancer. A large-scale cohort study in England and Wales showed no increase in mortality.⁸ A systematic review of RCTs looked at whether the use of LVE and SERMs in breast cancer survivors increased the risk of recurrence. While none of the studies had this as a primary end-point, it did not find any increase.⁹

An evaluation of the limited observational studies looking at the end-point of breast cancer recurrence with LVE use has not shown an increased risk of recurrence when LVE is used alone or alongside tamoxifen but there has been conflicting results with aromatase inhibitors. A nested case control study using the UK General Practice Database looking at LVE use after hormone sensitive breast cancer showed no increased risk of recurrence with concomitant adjuvant endocrine therapy,which included AIs over a 10-year period.¹⁰ Whereas a Danish cohort study looking at LVE use after early stage hormone sensitive breast cancer in women who received either no adjuvant therapy, or adjuvant endocrine therapy, showed no increased risk of recurrence but subgroup analysis showed a small increased risk with AIs only (RR 1.39).¹¹

The majority opinion of the St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023 was that LVE can be used alongside AIs when non-hormonal methods are not effective.⁷

In practice, we do prescribe LVE when required alongside AIs, and correspond with the oncology team to ensure they are aware and in agreement.

HRT on a case by case basis 

Finally, there will be women who have ongoing severe symptoms who have tried a multitude of different treatment options where we consider HRT on a case by case basis in consultation with their oncology team. A lower threshold for its use is considered in HR-negative breast cancer.

HRT is still considered contraindicated as a first-line treatment for menopausal symptoms in breast cancer and menopause clinical guidelines whereby non-hormonal options are recommended in the first instance.^2,5,7,12 These guidelines don’t differentiate between hormone sensitive and hormone receptor negative breast cancer in this stipulation. However, logically, a history of previous hormone sensitive breast cancer would be suggestive of carrying the most risk when it comes to the possibility of HRT precipitating a recurrence.

The BMS Consensus Statement states it may be incorrect to assume HRT is risk free in women with hormone receptor negative cancer as it may be associated with a small risk of a hormone receptor positive recurrence in the same breast, or a new hormone sensitive breast cancer in the opposite breast. The change in receptor status from hormone negative to positive was found to be 8% in one retrospective Swedish study with a sample size of 486 women.¹³ Therefore there are theoretical concerns that HRT could cause a proliferative effect if there was a change in hormone receptor status from negative to positive in an occult micrometastasis. 

In scrutiny of the literature, there is one prospective study where the majority of participants had a history of hormone receptor negative breast cancer, which showed no evidence of increased risk of recurrence using HRT but it had a small sample size.¹⁴ A meta-analysis looking at the effects of HRT usage in women with a history of breast cancer which studied the type of breast cancer as a subgroup analysis, showed a small risk of recurrence with hormone receptor negative breast cancer (HR 1.19) which was less than that seen with hormone sensitive breast cancer and this was not statistically significant.¹⁵ This same meta-analysis showed a recurrence HR of 1.8 for hormone sensitive breast cancer which was statistically significant. 

Despite this, there are still limitations of the available evidence which can make counselling and the assessment of risk difficult. There is a paucity of studies looking at HRT use after DCIS and LCIS, and the majority of the RCTs used older types of synthetic progestogens rather than micronised progesterone, which observational studies suggest is of lesser risk for the development of breast cancer and is usually our first choice progestogen in women with risk factors for breast cancer and after a history of breast cancer.

Conclusion

Our aim is to manage menopausal symptoms effectively while minimising any potential risks to cancer recurrence or progression, with shared decision making and informed consent. All our cases are individualised and we aim for an overall holistic approach. 

References

1. Donohoe F, O’Meara Y, Roberts A et al. Multimodal, technology-assisted intervention for the management of menopause after cancer improves cancer-related quality of life – Results from the Menopause after Cancer (Mac) Study. Cancers 2024; 16:1127. doi: 10.3390/cancers16061127
2. NICE guideline [NG23]: Menopause: diagnosis and management, 2015 (updated 2019). www.nice.org.uk/guidance/ng23
3. Zhang H, Hu J, Meng R, Liu F, Xu F, Huang M. A systematic review and meta-analysis comparing the diagnostic capability of automated breast ultrasound and contrast-enhanced ultrasound in breast cancer. Front Oncol 2024; 13:1305545. doi: 10.3389/fonc.2023.1305545
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