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Summary

The preventive management of breast cancer often involves endocrine targeted treatments including tamoxifen and aromatase inhibitors. These have shown to lead to fewer diagnosis of estrogen receptor-positive breast cancers but have not consistently demonstrated reduced mortality related to breast cancer. The following paper to be commented is a review of the evidence of different treatments to reduce risk of future breast cancer [1]. A meta-analysis of four randomised prevention trials has shown that tamoxifen reduced the 10 year cumulative incidence of invasive breast cancers by 33% [2]. However, there was no beneficial effect on mortality demonstrated. Interventions such as magnetic resonance imaging screening and risk reduction bilateral mastectomy have shown to be effective interventions. Despite this, in the Women’s Health Initiative (WHI) randomized, controlled trial, ER-positive, PR-negative cancers were statistically significantly reduced in the group given conjugated equine estrogen and also deaths from breast cancer were reduced by 40% [3]. This finding has not been demonstrated for any other pharmacological intervention. This information needs to be widely disseminated to clinicians.

Commentary

Although hormone replacement therapy (HRT) has been used for women for over 70 years, there are still many disagreements among clinicians and academics about its clinical value and safety. This has resulted in only the minority of menopausal women receiving HRT which results in risks to their future health. The publication of the preliminary results of the WHI in the medical and lay press lead to many inaccurate claims being made about HRT risks [3]. The fact that the relative risk of breast cancer in women taking any type of HRT was not statistically significant still resulted in some of the WHI investigators and others subsequently messaging that HRT increased breast cancer risk [4]. A subsequent publication of the WHI study, where breast cancer risk was appropriately adjusted for confounding variables, showed that there was no significant increased risk, but this was not given publicity [5]. For the past two decades, healthcare professionals have been avoiding prescribing estrogen to women for fear of breast cancer which has not been based on good quality evidence. The WHI excluded women with prior breast cancer and then serial mammograms were undertaken and all breast cancer outcomes were measured. Mortality information was available on more than 98% of women in the study in the estrogen-alone trial in postmenopausal women with prior hysterectomy.

The WHI trial commenced in 1993, and 5,310 and 5,429 women, respectively, were randomly assigned to conjugated estrogen therapy (ET, 0.625 mg), or a placebo. The trial was terminated after an average of 6.8 years of follow-up, apparently on safety grounds, but not on the recommendation of the Data and Safety Monitoring Board [6]. The evidence from this study that ET without an added progestogen does not increase the risk of breast cancer is statistically robust [7]. However, there have been different reports regarding the outcomes in women who took estrogen only HRT. In an ‘intention-to-treat’ analysis, the hazard ratio (HR) for invasive breast cancer was 0.77 (95% CI 0.59–1.01), and “this comparison narrowly missed statistical significance (p = 0.06)”. The authors commented that “the trend toward a reduction in breast cancer incidence was unanticipated and … opposite to that observed in the WHI [E+P] trial” [8]. Another report concluded that with more prolonged follow up, the decreased risk of breast cancer persisted [9]. The publication of the WHI study, where breast cancer risk was appropriately adjusted for confounding variables, actually showed that there was a significantly lower risk of breast cancer (hazard ratio 0.79, 95% CI 0.65-0.97) in women who took estrogen only HRT for 7 years compared to women who had taken placebo [9].

To the extent that detection bias may have been present, its effect would have been to underestimate the magnitude of the observed reduction in the risk of breast cancer among ET recipients [7]. Estrogens have shown anti-proliferative and pro-apoptotic effects [10,11]. Estrogens can also be metabolised to carcinoprotective metabolites [12]. These mechanisms could even be considered as a rationale for the treatment of breast cancer [13,14].

There is still so much misinformation and misreporting in the medical and lay press regarding perceived risks of taking HRT that benefits such as breast cancer reduction are often over looked or ignored. As the benefits of taking HRT far outweigh any risks, women should be reassured and its use should not be restricted, even in women with an increased risk of developing breast cancer.

Dr. Louise Newson, BSc (Hons), MBChB (Hons), MRCP FRCGP
Newson Health Research and Education

References

  1. Chlebowski RT, Aragaki AK, Pan K. Breast Cancer Prevention: Time for Change. JCO Oncol Pract 2021:17:709-14.
    https://ascopubs.org/doi/full/10.1200/op.21.00343
  2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771-84.
    https://pubmed.ncbi.nlm.nih.gov/21802721/
  3. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
    https://pubmed.ncbi.nlm.nih.gov/12117397/
  4. 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(10204):1159-1168.
    https://pubmed.ncbi.nlm.nih.gov/31474332/
  5. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55(2):103-15.
    https://pubmed.ncbi.nlm.nih.gov/16815651/
  6. Langer RD. The evidence base for HRT: what can we believe? Climacteric. 2017;20(2):91-96.
    https://pubmed.ncbi.nlm.nih.gov/28281363/
  7. Shapiro S, Farmer RDT, Mueck A, Helen Seaman H, Stevenson JC. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Fam Plann Reprod Health Care. 2011;37(4):225–230.
    https://pubmed.ncbi.nlm.nih.gov/21642263/
  8. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-12.
    https://pubmed.ncbi.nlm.nih.gov/15082697/
  9. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305–1314.
    https://pubmed.ncbi.nlm.nih.gov/21467283/
  10. Lewis-Wambi JS, Jordan VC. Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res. 2009;11(3):206.
    https://pubmed.ncbi.nlm.nih.gov/19519952/
  11. Maximov P, Sengupta S, Lewis-Wambi JS, Kim HR, Curpan RF, Jordan VC. The conformation of the estrogen receptor directs estrogen-induced apoptosis in breast cancer: a hypothesis. Horm Mol Biol Clin Invest. 2011;5(1):27–34.
    https://pubmed.ncbi.nlm.nih.gov/21660224/
  12. Munster PN, Carpenter JT. Estradiol in breast cancer treatment: reviving the past. JAMA. 2009;302(7):797–798.
    https://pubmed.ncbi.nlm.nih.gov/19690316/
  13. Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009;302(7):774–780.
    https://pubmed.ncbi.nlm.nih.gov/19690310/
  14. Mueck AO, Seeger H. 2-Methoxyestradiol – biology and mechanism of action. Steroids. 2010;75(10):625–631.
    https://pubmed.ncbi.nlm.nih.gov/20214913/

 


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