Hormone replacement therapy (HRT) in patients with breast cancer

• the prescription of HRT in patients with a history of breast cancer is controversial - seek expert advice before making a decision
  • up to 80% of breast tumours are oestrogen receptor-positive (1)
  • tamoxifen is invariably given to women with a history of oestrogen receptor-positive breast cancer - although tamoxifen does have some oestrogenic effects there are not the same beneficial effects seen with respect to lipid profile and bone density as occur with the use of HRT. It is light of this, that 'many oncologists therefore believe that in certain circumstances, such as severe menopausal symptoms, HRT can be prescribed for patients on tamoxifen who are being treated for breast cancer (2)'
    
    
• NICE state (2) :
  • regarding menopausal symptoms following management of early breast cancer:
    • discontinue hormone replacement therapy (HRT) in women who are diagnosed with breast cancer
    • HRT (including oestrogen/progestogen combination) should not be offered routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to women with severe menopausal symptoms and with whom the associated risks have been discussed
    • tibolone or progestogens are not recommended for women with menopausal symptoms who have breast cancer
    • the selective serotonin re-uptake inhibitor antidepressants paroxetine and fluoxetine may be offered to women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not to those taking tamoxifen (2,4)
    • clonidine, venlafaxine and gabapentin should only be offered to treat hot flushes in women with breast cancer after they have been fully informed of the significant side effects
    • soy (isoflavone), red clover, black cohosh, vitamin E and magnetic devices are not recommended for the treatment of menopausal symptoms in women with breast cancer
    • 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
      
• NICE in the menopause guidance state (4):
  • offer menopausal women with, or at high risk of, breast cancer:
    • information on all available treatment options
    • information that the SSRIs paroxetine and fluoxetine should not be offered to women with breast cancer who are taking tamoxifen
    • referral to a healthcare professional with expertise in menopause
      
      
• raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting
  • in postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment
  • evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels
  • in randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment
  • however, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them
  • '.. raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes...' (3)
    
    
• Danish Observational Cohort Study - to determine the association of use of hormonal treatment (VET and MHT) with the risk of breast cancer (BC) recurrence and mortality in a large population-based cohort of Danish postmenopausal women treated for early-stage estrogen receptor-positive (ER+) BC(5):
  • study of postmenopausal women with early breast cancer found neither vaginal oestrogen therapy nor menopausal hormone therapy was associated with an increased risk of recurrence or mortality overall; subgroup analysis suggested increased risk in those taking aromatase inhibitors
    • study included a total of 8461 women who had not received any menopause treatment prior to their cancer diagnosis, 1957 who went on to use vaginal oestrogen therapy (VET) and 133 who used menopausal hormone therapy (MHT)
    • with a median follow-up of 9.8 years for recurrence, the adjusted relative risk was 1.08 (95% CI 0.89 to 1.32) for VET overall, 1.39 (1.04 to 1.85) for VET in the subgroup receiving adjuvant aromatase inhibitors and 1.05 (0.62 to 1.78) for MHT
    • with a median follow up of 15.2 years for mortality, the adjusted RR was 0.78 (0.71 to 0.87) for VET and 0.94 (0.70 to 1.26) for MHT
    • the authors conclude there was no evidence that VET or oral HRT increased recurrence risk among patients treated with tamoxifen or those who did not receive adjuvant endocrine therapy
      • "..In postmenopausal women treated for early-stage estrogen receptor-positive (ER+) breast cancer (BC), use of VET or MHT was not associated with increased risk of recurrence or mortality. In patients treated with VET and adjuvant aromatase inhibitors (AIs), we observed an increased risk of recurrence but not mortality. This association was not observed among women who received tamoxifen or in those who did not receive adjuvant endocrine therapy. In the small subset receiving hormone replacement treatment, no increased risk of recurrence or mortality was observed. For early-stage BC patients receiving adjuvant AIs, vaginal estrogen therapy should be used with caution."

With respect to vasomotor symptoms (VMS) associated with menopause following treatment for hormone receptor positive breast cancer a review states (6):

• in post-menopausal women, switching from AI (aromatase inhibitors) to tamoxifen may reduce symptoms but should be carefully considered in cases of high-risk disease, in collaboration with an oncologist
• 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
  • note that fluoxetine and paroxetine interact with tamoxifen metabolism and the combination should be avoided
• there is evidence that short-term use of oxybutynin (2.5–5 mg) reduced VMS but further evidence needs to be gathered regarding long-term oxybutynin use
• neurokinin-3 receptor antagonists show promise for VMS reduction
• non-pharmacological measures include acupuncture and cognitive behavioural therapy (CBT)
• trial evidence 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

Reference:

1. Percentage of Hormone Receptor Positivity in Breast Cancer Provides Prognostic Value: A Single-Institute Study. J Clin Med Res. v.13(1); 2021 Jan
2. NICE (July 2018).Early and locally advanced breast cancer - diagnosis and treatment
3. Sismondi P et al. How to manage the menopause following therapy for breast cancer. is raloxifene a safe alternative? Eur J Cancer. 2000 Sep;36 Suppl 4:S74-6.
4. NICE (November 2015). Menopause: diagnosis and management
5. Cold S et al. Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study, JNCI: Journal of the National Cancer Institute, 2022;, djac112, https://doi.org/10.1093/jnci/djac112
6. McGrath S et al. Management of menopausal symptoms following treatment for hormone receptor positive breast cancer. BJGP 2025; 75 (759): 476-480.