An additional 1,000 women may have died from ovarian cancer linked to hormone therapy during a 15-year period in the United Kingdom, according to results from an enormous, but controversial, epidemiologic study.
After 6.5 million woman-years of follow-up, investigators for the Million Women Study concluded that those taking HT were 20% more likely to develop and die from ovarian cancer than those who had never taken it, but that the risk for women who quit taking HT returned to baseline by 5 years (Lancet 2007 [Epub doi:10.1016/S0140–6736(07)60534–0]).
Hormone therapy accounted for one extra case of ovarian cancer and one extra death per 2,500 users over a 5-year period, wrote Dr. Valerie Beral, lead author for the Million Women Study Collaboration. “If this association is causal, the use of HT since 1991 has resulted in roughly 1,300 extra cases of ovarian cancer and 1,000 extra deaths from the malignancy in the U.K.,” the investigators wrote.
From 1991 to 2001, the study—the largest epidemiologic study of its kind—enrolled 1.3 million women aged 50–64 years. All had been invited to the National Health Service Breast Screening Programme and completed an initial survey about social, demographic, and lifestyle factors, including the use of HT. About 3 years after recruitment, the women received a second questionnaire to secure updated information on HT.
Other researchers have questioned the MWS results since its first publication in 2003, saying that its methodologic problems make its conclusions difficult to interpret or accept.
The MWS ovarian cancer analysis included 948,576 women: 474,682 had never used HT, 186,751 were past users, and 287,143 were current users. The subjects' mean age at last follow-up was 57 years; 56% had used oral contraceptives, and 20% were current smokers.
The women were followed for an average of 5 years to determine ovarian cancer incidence. During that time, 2,273 such cancers were reported to the national registry. Current users were 20% more likely than never-users to develop the cancer—a significant difference. There was no difference in incidence between never-users and past users.
Current users had been taking HT for an average of 8 years at the time of diagnosis, and incidence increased with the duration of HT. Women who had taken hormones for 10 or more years were at a 30% increased risk for disease, compared with never-users.
But the risk of developing ovarian cancer dropped rapidly after ceasing HT. Compared with women who had never used HT, the relative risk for ovarian cancer was 1.01 for women who had been off HT less than 5 years and 0.95 for those who were off HT 5 or more years.
There were no significant differences in the risks between HT preparations (different estrogenic and progestogenic components; oral or transdermal; or between preparations with progestagens). Likewise, the researchers wrote, there were no significant associations with any demographic factor. Adjusting for age, socioeconomic status, body mass index, physical activity, or alcohol and tobacco use did not alter the relative risk for current users by more than 2%.
HT users who had undergone hysterectomy did have a significantly increased risk, compared with those who had not, but the researchers said that was probably because they had been taking HT longer.
The women were followed for an average of 7 years to determine ovarian cancer mortality. During this time, 1,591 deaths were attributed to ovarian cancer. Women who were current users of HT at their last follow-up were 23% more likely to die from the disease than never-users. Past users were at no significantly increased risk of death.
Again, there were no significant differences in risk after the researchers adjusted for demographic characteristics. There were also no significant differences in the risk of death between the different preparations of HT or the mode of administration.
The standardized ovarian cancer incidence rate was 2.2/1,000 women per 5 years among never-users and 2.6/1,000 women per 5 years in current users. The standardized mortality rate was 1.3 deaths/1,000 women per 5 years among never-users and 1.6/1,000 women per 5 years in current users.
But these numbers cannot be viewed in isolation, wrote the authors, whose study has previously examined the incidence of breast and endometrial cancers in these women. “Ovarian, endometrial, and breast cancer account for 39% of all cancers registered in women in the United Kingdom. The total incidence of these three cancers in the study population is 63% higher in current users of HT than in never-users. Thus, when ovarian, endometrial, and breast cancer are taken together, use of HT results in a material increase in the incidence of these common cancers.”