Does Hormonal Replacement Therapy Increase Breast Cancer Risk?


Niki J. Agnantis, MD, Evangelos Paraskevaidis, MD and Dimitrios H.Roukos, MD
From the Departments of Pathology (NJA), Obstetrics and Gynecology (EP), and Surgery (DHR), Ioannina University School of Medicine, 45110 Ioannina, Greece, droukos@cc.uoi.gr

Millions of menopausal women globally -6 million in the U.S. alone have used since many years hormone replacement therapy (HRT). Now a national study[1] reveals that the combination estrogen-progestin regimen does more harm than benefit; HRT increased risks of breast cancer, heart attack, stroke and venous thromboembolic events, but decreased risk of colorectal cancer and fractures.

The study has been considered a triumph for evidence-based medicine and was abandoned in early July because after 5.2 years follow-up, the incidence of breast cancer was increased by 26% among women taking the drug in comparison with those who were taking a placebo. The researchers underscore that HRT has not one risk but several, and since they run concurrently they add up over time. Consequently, given the millions of women who have been on the regimen, it is likely-by conservative estimates-that many thousands of them have developed or will develop breast cancer or a life-threatening cardiovascular illness as a result.

If really HRT causes breast cancer, even only to a very small proportion of women -less than one-tenth of 1% per year,[1] indeed it is a triumph of epidemiological-based medical evidence to detect potential harms. However, the trial arises several important key questions: If there is a logical explanation for the increased risk for breast cancer -the relation of hormone levels and breast cancer is known - how can be explained the reduced risk for colorectal cancer in women taking hormone pills? Are both observations accidental or do they represent the reality? Do they need validation and confirmation by molecular-based studies? Should millions of women who used HRT be closely and intensively followed-up for early detection and prevention of breast cancer?

The study was funded by a National Institute of Health program called the Women's Health Initiative (WHI). It begun in 1993, it is the first study to put HRT through a placebo-controlled randomized clinical trial-the gold standard for the purpose-to examine its risks and benefits in healthy women. Originally it scheduled to continue well into 2005, but the trial was stopped because of the elevation in the breast cancer in women taking the hormone regimen.

The trial's 16,608 participants were healthy, active women who were 50 to 79 years old when they volunteered for the study and came from a wide variety of backgrounds and circumstances. The trial used hormone doses-0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone acetate per day-that are most frequently prescribed for this population.

The relative risk among women who received the drugs was elevated by 26% for breast cancer with 5 or years of use, but reduced by 37% for colorectal cancer compared with the placebo group. The trial confirms the adverse impact of the regimen on cardiovascular events, stroke and blood clots (thromboembolic events) in the legs and lungs and the benefits in reducing risk of fractures.

Looking at the absolute risks there were 8 more breast cancers for every 10,000 women on estrogen and progestin for a year (38 cases per 10,000 women taking HRT, compared with 30 cases per 10,000 women not taking hormones), but 6 fewer colon cancers. There were also 33 more heart, stroke and thromboembolic events but 5 fewer hip fractures per 10,000 women each year. However, the study was stopped because the serious adverse health events caused by HRT would outnumber those it prevented.

The women who joined the estrogen-progestin trial will no longer be taki ng their study pills, but the WHI will continue to follow them.

The critical question that arises this trial is whether HRT provides a diverged effect enhancing breast carcinogenesis and inhibiting colorectal cancer development. Molecular pathway-based confirmation of epidemiological observational findings is the best way to assess treatment effects. However, particularly if we consider both the very small differences between treatment and placebo groups in this trial and that many other genetic and environmental factors influence tumorigenesis of both cancer sites it is extremely hard to establish this effect of estrogen-progestin regimen on breast and colorectal cancer.

Although the association of circulating hormone levels and breast cancer cell proliferation has been recognised3 and this also supported by the reduced risk of breast cancer among BRCA1/BRCA2-mutation carriers after prophylactic oophorectomy,[4,5] the underlying mechanisms are poorly understood. Generally, hormonal manipulation may affect breast carcinogenesis and under this aspect the finding of WHI trial is not completely surprising but there is long way to establish this effect. Similarly, the beneficial effect of HRT on reducing of colorectal cancer risk is questionable for the same reasons. Notably, this observation is supported by a latest meta-analysis[2] of 18 observational studies that showed a 20% reduction in colon cancer incidence among women who had ever used HRT (RR, 0.80; 95% CI, 0.74-0.86).

To sum up, the findings of this randomized placebo-controlled clinical trial suggest that an evidence-based decision-making about hormone replacement therapy should balance risks and benefits in each individual postmenopausal woman. But the interpretation of the observations on the effect of this drug on breast and colon

References
1. 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 Jul 17;288(3):321-33.
2. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002 Aug 21;288(7):872-81.
3. Elisaf M., Roukos DH, Briasoulis E, Paraskevaidis E, Agnantis NJ, Kappas AM. Comparing recent advances in gastric and breast cancer. Gastric Breast Cancer 2002; 1(3): 59-64.
4. Roukos DH, Kappas AM. Risks and benefits of risk-reducing surgery in inherited breast and gastric cancer susceptibility. Gastric Breast Cancer 2002; 1(3): 65-67.
5. Roukos DH, Agnantis NJ, Paraskevaidis E, Kappas AM. Challenges in surgical preventive decision for BRCA1/BRCA2-mutation carriers. Gastric Breast Cancer 2002; 1(3): 68-70.