Review of the evidence for breast cancer risk and HRT

The British Menopause Society (BMS), International Menopause Society (IMS), European Menopause and Andropause Society (EMAS), Royal College of Obstetricians and Gynaecologists (RCOG) and Australasian Menopause Society (AMS) have issued clarification of the evidence on the risk of breast cancer with menopausal hormone therapy (MHT) in response to the recommendations of the European Medicines Agency (EMA) - the central European drug regulatory body - Pharmacovigilance Risk Assessment Committee on 11-14 May 2020 that followed on from a meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) published in the Lancet on 30 August 2019.

This advice is summarised below:

Interpretation of the evidence on the risk of breast cancer with MHT

• the findings from the CGHFBC meta-analysis are in keeping with the NICE guidance 2015 analysis of the observational data on the risk of breast cancer and MHT
• the findings from the CGHFBC meta-analysis should be explained to women when discussing the benefits and risks of MHT. However, discussions on the risk of breast cancer with MHT should also include the findings from the WHI placebo-controlled randomized trials and the large E3N observational studies, which reported on the risk of breast cancer risk in users of micronized progesterone and dydrogesterone compared with other progestogens. Neither of the latter two studies was included in the CGHFBC meta-analysis
• the recently published WHI data showed a significant decrease in the risk of diagnosis of breast cancer with estrogen-only MHT and a significant reduction in breast cancer mortality compared with placebo
  • women who took combined estrogen and progestogen MHT had an increased risk of breast cancer compared to placebo, in keeping with NICE guidance conclusions, but showed no significant difference in breast cancer mortality compared with placebo
• the E3N observational studies suggested a lower breast cancer risk in users of micronized progesterone and dydrogesterone compared to users of other progestogens
• the joint statement highlights that "
  • " Recommendations on the risk of breast cancer with MHT should take into consideration the findings from the WHI randomized trials and the observational data on micronized progesterone and dydrogesterone from the E3N study as well as those from the CGHFBC meta-analysis

Informed consent:

• risk of breast cancer should be considered in the context of the overall benefits and risks associated with MHT intake including menopausal symptom control, improved quality of life and the long-term impact on bone and cardiovascular health. The decision whether to take MHT, the dose of MHT and the duration of its use should be made on an individualized basis after discussing the benefits and risks with women to help them make an informed choice about their health and care.

MHT and breast cancer risk - The CGHFBC meta-analysis

There are a number of limitations in the methodology of the CGHFBC meta-analysis that need to be considered when interpreting the data. These include the following (1):

• 1. Some of the studies included in the CGHFBC meta-analysis had methodological limitations
  • a key example of this is that one of the main studies contributing to the meta-analysis, the Million Women Study, had a significantly increased risk of breast cancer at 4 months from commencement of recruitment (RR 1.19; 95% CI 1.09 to 1.30 for users of estrogen-only and RR 1.41; 95% CI 1.31 to 1.52 for users of combined MHT). It is highly unlikely that breast cancer would develop within 4 months from recruitment and this would, therefore, suggest that a significant proportion of women had undetected breast cancer at the time of entry into the study; this should be considered when interpreting the findings from the CGHFBC meta-analysis
    
    
  • 2. The CGHFBC meta-analysis only included a very small number of women on micronized progesterone and it appears that the large observational data from the French E3N study which suggested that micronized progesterone is likely to be associated with a lower risk of invasive breast cancer compared to that noted with other progestogens were not considered in the meta-analysis
    
    
  • 3. The CGHFBC meta-analysis did not report on breast cancer mortality
    • long-term follow up of the WHI RCT up to 13 years showed no significant difference in breast cancer mortality or all-cause mortality with MHT compared with placebo
    • WHO and Eurostat data showed a decline in European breast cancer mortality over the last three decades in women of all ages. This steady decline pre-dated by over a decade, the sustained worldwide fall in MHT prescribing following publication of WHI and the Million Women Study in the early 2000s. The reduction is likely to be related to treatment improvements and earlier diagnosis, including the impact of screening and is less likely to be related to the changing patterns in MHT use
    • the WHI long-term randomized clinical trials, published in JAMA 2020, reported a significant reduction in breast cancer mortality with estrogen-only MHT and no significant difference in breast cancer mortality in women who took combined estrogen and progestogen MHT compared with placebo

"We believe that the findings from the CGHFBC meta-analysis should be explained to women when discussing the benefits and risks of MHT. However, discussions on the risk of breast cancer with MHT should also include the findings from the WHI placebo-controlled randomized trials and the large E3N observational studies, which reported on the risk of breast cancer risk in users of micronized progesterone and dydrogesterone compared with other progestogens. Neither of the latter two studies was included in the CGHFBC meta-analysis. (1)"

Reference:

• BMS, IMS, EMAS, RCOG and AMS Joint Statement on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020
• Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394:1159-68. doi: 10.1016/S0140-6736(19)31709-X 31474332.
• Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369–80. doi: 10.1001/jama.2020.9482
• Fournier A, Mesrine S, Dossus L, et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Research and Treatment 2014;145(2):535–43