Hormone Replacement Therapy Linked to Ovarian Cancer

Hormone Replacement Therapy Linked to Ovarian Cancer

News Author: Allison Gandey
CME Author: Laurie Barclay, MD

Release Date: April 24, 2007

April 24, 2007 -- The Million Women Study, a trial in the United Kingdom of postmenopausal women, has found that those receiving hormone replacement therapy (HRT) were, on average, 20% more likely to develop and die from ovarian cancer than women who never received therapy. Authors of the report, published in the April 19 Early Online Publication issue of The Lancet, say that since 1991, HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from this malignancy in the United Kingdom alone.

"The effect of HRT on ovarian cancer should not be viewed in isolation," write the study collaborators, led by Valerie Beral from the Cancer Research UK's Epidemiology Unit in Oxford, England, "especially since use of HRT also affects the risk of breast and endometrial cancer. In total, ovarian, endometrial, and breast cancer account for 39% of all cancers registered in women in the UK." The total incidence of these 3 cancers in the study population is 63% higher in current users of HRT than in never users.

As previously reported by Medscape, a study by Ravdin and colleagues published in the April 19 issue of The New England Journal of Medicine shows a dramatic fall in breast cancer incidence that perfectly mirrors the decline in HRT use in the United States.

During an interview, the study's senior author Donald A. Berry, PhD, from the University of Texas MD Anderson Cancer Center in Houston, called it a "precipitous drop" in breast cancer incidence that started immediately after the announcement of the Women's Health Initiative results questioning the safety of the drugs. He said he was surprised by the findings. "But when I realized that stopping a cancer's fuel could slow its growth, it seemed quite reasonable," he noted.

Commenting on the 2 important findings, Ahmedin Jemal, PhD, an epidemiologist at the American Cancer Society who has studied in this area, told Medscape these results make sense. "We know that estrogen-positive cancers tend to increase when HRT is used," he said. "It would therefore not be surprising if the drugs were playing a role in ovarian as well as breast cancer."

In the current study assessing ovarian cancer risk in the United Kingdom, researchers looked at 948,576 postmenopausal women who did not have previous cancer or bilateral oophorectomy. They were observed for an average of 5.3 years for incident ovarian cancer and 6.9 years for death. Information on HRT use was obtained at recruitment and updated where possible. The women's socioeconomic status, reproductive history, previous use of oral contraceptives, body mass index, and alcohol and tobacco consumption reportedly did not alter the effect of HRT on their risk of developing ovarian cancer.

Menopause Society Says Study Will Cause Unnecessary Distress

But not everyone is concerned about the findings. Responding to the current study in a news release, the International Menopause Society raised a number of criticisms of the work. "Following the previous analysis of the Million Women Study on breast and endometrial cancers, there were many reservations concerning the methodology and these are still pertinent," the International Menopause Society wrote. "Most epidemiologists would consider that a relative risk of 1.2 is of minimal clinical significance, but will inevitably reach statistical significance with very large numbers. Risk is far better reported in absolute numbers rather than relative risk or percentage. The absolute risk for ovarian cancer in the study was only 1 extra case per 2500 women after 5 years and mortality was 1 per 3300 over 5 years."

The International Menopause Society added, "Such manipulation of data can only cause unnecessary distress to the many women who are benefiting from HRT." The group pointed out that no increase in risk was recorded in women using HRT for less than 5 years and past users had the same risk as never users.

In an accompanying comment published in The Lancet, Steven A. Narod from the Women's College Research Institute in Toronto, Ontario, writes, "A relative risk of 1.2 might be thought of as small, but enormous numbers of women have been exposed. In the Million Women Study alone, half a million women had taken HRT."

He notes, "Because current use was found to be the main risk factor, the number of new cases attributable to HRT should be a function of the number of women who are taking the drug at any given time." The editorialist points out that use of HRT has declined greatly in the United Kingdom and elsewhere since the report of the Women's Health Initiative. "With these new data on ovarian cancer, we expect the use of HRT to fall further," he writes. "We hope that the number of women dying of ovarian cancer will decline as well."

Commenting on the current study, Robert Rebar, MD, executive director of the American Society for Reproductive Medicine, told reporters, "Although long-term use of estrogen appears to increase the risk of ovarian cancer, women should be reassured that short-term use for symptomatic treatment at or near the menopause is unlikely to increase the risk of ovarian cancer appreciably." He said these data, taken together with findings from the Women's Health Initiative, provide reassurance all-in-all that short-term use of estrogen is not harmful to symptomatic women.

The study was funded by Cancer Research UK, the NHS Breast Screening Programme, and the Medical Research Council.

Lancet. Published online April 19, 2007.
Clinical Context

In the United Kingdom, ovarian cancer is the fourth most common cancer in women, with 6700 new cases and 4600 deaths from ovarian cancer every year. Studies of the association between use of HRT and later risk of developing ovarian cancer are inconclusive, with some showing a significantly increased risk for fatal and incident ovarian cancer in users of HRT, but with most lacking statistical power.

The current study used a large cohort of women in the United Kingdom (Million Women Study), in which about half the postmenopausal women had used HRT, to evaluate the effect of HRT on women's risk of developing and dying from ovarian cancer.
Study Highlights

* During 1996 - 2001, 1.3 million women invited for breast cancer screening completed the first study questionnaire concerning social, demographic, lifestyle, and other factors, including HRT use (ever, current, and past use; age at first and last use; total duration of use; and the name and duration of the proprietary preparation last used).
* Participants were 948,576 postmenopausal women (average age, 57.2 years) enrolled in the Million Women Study who did not have previous cancer or bilateral oophorectomy. About 3 years after recruitment, a second questionnaire was sent to update information on use of HRT and other factors, and 64% responded.
* Exclusion criteria were any type of cancer except nonmelanoma skin cancer before recruitment, bilateral oophorectomy, not postmenopausal at the time of last contact, or use of HRT or hysterectomy status unknown.
* Average follow-up (5 million woman-years) was 5.3 years for incident ovarian cancer and 6.9 years for death.
* Relative risks (RRs) for ovarian cancer were stratified by age and hysterectomy status and adjusted for area of residence, socioeconomic status, time since menopause, parity, body mass index, alcohol consumption, and oral contraceptive use.
* At the time of last contact, 473,894 women (50%) had ever used HRT; 287,143 women (30%) were current users; and 186,751 (20%) were past users. Demographic, social, health, and lifestyle characteristics of these 3 groups were not significantly different, except that never users were less likely than past and current users to have had a hysterectomy (13%, 20%, and 29%, respectively) and to have used oral contraceptives (47%, 63%, and 66%, respectively).
* Among current users of HRT at the time of last contact, 85,931 (30%) were using estrogen-only HRT, 169,273 (59%) were using estrogen-progestagen combinations, and 31,939 (11%) were using other or unknown preparations.
* During follow-up via the National Health Service Central Registers, there were 2273 incident ovarian cancers reported and 1591 related deaths.
* Compared with never users of HRT, current users were more likely to develop and die from ovarian cancer (RR for incident disease, 1.20; 95% confidence interval [CI], 1.09 - 1.32; P = .0002; and RR for death, 1.23; 95% CI, 1.09 - 1.38; P = .0006). Of malignant ovarian cancers, 95% were epithelial.
* For current HRT users, incidence of ovarian cancer increased with increasing duration of use (estimated duration of use of HRT at time of diagnosis, 7.7 years). However, type of HRT used, its constituents, or mode of administration did not significantly affect incidence.
* Risks associated with HRT varied significantly according to tumor histology (P < .0001). In women with epithelial tumors, RR for current vs never use of HRT was greater for serous (1.53; 95% CI, 1.31 - 1.79) than for mucinous (0.72; 95% CI, 0.52 - 1.00), endometrioid (1.05; 95% CI, 0.77 - 1.43), or clear cell histology (0.77; 95% CI, 0.48 - 1.23).
* Past users of HRT were not at increased risk for ovarian cancer (RR for incident disease, 0.98; 95% CI, 0.88 - 1.11; and RR for fatal disease, 0.97; 95% CI, 0.84 - 1.11).
* During 5 years, standardized incidence rates for ovarian cancer per 1000 were 2.6 (95% CI, 2.4 - 2.9) in current users of HRT, vs 2.2 (95% CI, 2.1 - 2.3) in never users of HRT. This was equivalent to 1 extra ovarian cancer in about 2500 users. Death rates were 1.6 (95% CI, 1.4 - 1.8) and 1.3 (95% CI, 1.2 - 1.4) per 1000, respectively, or 1 extra ovarian cancer death in about 3300 users.

Pearls for Practice

* In the Million Women Study, current users of HRT were at a 20% increased risk for incident ovarian cancer. Since 1991, use of HRT has resulted in about 1300 additional ovarian cancers in the United Kingdom.
* In the Million Women Study, current users of HRT were at a 23% increased risk for death from ovarian cancer. Since 1991, about 1000 additional deaths from this malignancy in the United Kingdom are attributed to use of HRT.

Medscape.com