History

The straightforward reply to the preceding question posed in the title is yes. But to do so without delving into the details of the answer would be an oversimplification and be doing a great disservice to the vast amount of research that has given us the answer today.

Hormone replacement therapy (HRT) is commonly prescribed as either unopposed oestrogen or combined with synthetic progesterone or progestogen (combined HRT). Combined HRT has traditionally been favoured over unopposed oestrogen therapy in women with an intact uterus due to the increased risk of endometrial cancer in the latter.

Prior to 2000, HRT was seen as a panacea to the many effects of aging in postmenopausal women. It improved vasomotor and urogenital symptoms and just as importantly, it was also frequently prescribed for its anti-osteoporotic activity as well as its supposed cardioprotective and reduced overall mortality benefit.

However, endogenous hormones are strongly implicated in the pathogenesis of breast cancer with its risk increased by early age at menarche and late menopause. In the 1990’s, evidence of HRT’s breast cancer promoting effect was already accumulating[1] but the paucity of large prospective randomized control trials and the net benefit of its overall health effects were generally felt to outweigh this potential harm by proponents of HRT use.

This dogma took an abrupt reversal early this decade when randomized trials of HRT in secondary prevention of vascular events unexpectedly failed to demonstrate any protective effects[2,3,4,5,6] and several large prospective studies also established the link between HRT and breast cancer. Two of the seminal studies that have contributed to this paradigm shift that will be discussed here are the Women’s Health Initiative (WHI) Study and the Million Women Study (MWS).

Combined HRT

Women’s Health Initiative (WHI) Study

The WHI Oestrogen + Progestin Study[7] was a large randomized trial of combined HRT versus placebo in postmenopausal women. The study was terminated prematurely in 2002 when the risks of breast cancer and heart disease were found to be increased in the HRT arm after a median follow-up of 5.2 years.

For 10,000 women taking the drug for a year, this translated to 7 additional coronary events, 8 more invasive breast cancers, 8 more strokes, 8 more pulmonary emboli, but 6 fewer colorectal cancers and 5 fewer hip fractures.

The incidence of abnormal mammograms started to increase by the second year and the adverse effects of increased breast cancer risk surfaced after four years of treatment. In addition, the breast cancer diagnosed also tend to be larger and at a more advanced stage.[8] Due to the competing reduction in mortality from other events, there was no effect seen on the overall risk of cancer, death from cancer, or death from any other cause.

Million Women Study (MWS)

Following the WHI study came the publication of the MWS in 2003.[9]This large prospective observational cohort study revealed that postmenopausal women taking combined HRT were twice as likely to develop breast cancer as non-users.

In absolute terms, for every 1,000 women taking combined HRT, this translated to an additional 6 and 19 breast cancer cases after 5 and 10 years of treatment respectively.  The findings appeared to vary little between specific types, doses or route of administration of combined HRT.

The increase in breast cancer risk emerged after HRT has been taken for 1–2 years, but increased with longer duration of HRT use. Once HRT is stopped the risk begins to subside, and within 5 years the risk is within the level of never users of HRT.

Unlike the WHI study, the MWS also showed that the use of HRT not only increased the incidence of breast cancer but also the rate of breast cancer mortality.

Oestrogen only HRT

Million Women Study (MWS)

The oestrogen only group of the MWS also showed an elevated risk of breast cancer compared to non-users, albeit mush less than that of the combined HRT. For every 1,000 women aged 50-65 taking oestrogen only HRT, one would see an additional 2 and 5 breast cancer cases after 5 and 10 years of treatment respectively.

WHI Study

The WHI Oestrogen-Alone Study recently published its findings of the estrogen only study arm.[10] The study was closed early due to increased risk of strokes in women taking HRT although no effect was seen on cardiovascular disease (the primary endpoint).

In contrast to the observational MWS, no increase in breast cancer risk was seen for at least seven years after starting oestrogen alone HRT. In fact, there was a non-statistically significant trend towards a lowered risk of breast cancer (hazard ratio 0·77; 95% CI 0·59-1·01) among users compared to placebo.

Although this finding appears to be discordant from that of the MWS, one must bear in mind that the WHI study is a randomized trial while the MWS is an observational study. Indeed, the WHI findings are in keeping with results from the recently updated observational Nurses’ Health Study that showed a significant breast cancer risk only after 15 years of exposure to oestrogen only HRT.[11]

Post 2001

The negative publicity surrounding the effects of HRT use led to a sharp fall in its prescription globally and epidemiological data have since also shown a corresponding reduction in breast cancer incidence after 2001. This finding has been demonstrated both in the U.S. as well as in Europe, lending further credence to the association between HRT use and breast cancer.[12,13]

Conclusion

In summary, there is now compelling evidence supporting an association between HRT use and breast cancer from retrospective data, prospective epidemiological studies and randomized control trials.

 

Dr Raymond Ng
Associate Consultant
Department of Medical Oncology
National Cancer Centre Singapore

References

1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.
2. HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.
3. Viscoli CM, Brass LM, Kernan WN, et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-9.
4. ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:2001-8.
5. DM Herrington, DM Reboussin and KB Brosnihan et al., Effects of estrogen replacement on the progression of coronary artery atherosclerosis, N Engl J Med 2000; 343:522-9.
6. DD Waters, EL Alderman and J Hsia et al., Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial, JAMA 2002; 288:2432-40.
7. 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;288:321-33.
8. WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-53.
9. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27.
10. 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;291:1701-12.
11. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-32.
12. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007;356:1670-4.
13. Katalinic A, Rawal R: Decline in breast cancer incidence after decrease in utilisation of hormone replacement therapy. Breast Cancer Res Treat [epub ahead of print April 24, 2007]