Swedish Study Finds Increased Risk of Breast Cancer With Progestin-Containing HRT

SAN ANTONIO—A large Swedish cohort study of hormone replacement therapy (HRT) use and breast cancer suggests that women on progestin-containing regimens are three times more likely to develop breast cancer than are women who have never used HRT. Estrogen-only preparations, in contrast, did not appreciably increase the risk, said Hakan Olsson, MD, professor of oncology, University Hospital, Lund, at the 25th Annual San Antonio Breast Cancer Symposium (abstract 34).

The cohort consisted of 30,000 women age 25 to 65 who were first interviewed through a structured questionnaire between 1990 and 1992. The women were all Swedish born, with no evidence of any type of cancer at the time. The questionnaire addressed health issues such as hormonal and reproductive factors, family history, constitutional factors, alcohol and smoking history, and sun exposure.

Recall of hormone exposure was facilitated through use of color charts of the name and time period when various types of hormone preparations had been used. Dr. Olsson said his group has almost complete follow-up of the cohort, which now constitutes 298,649 person-years.

At the 2001 follow-up, 556 breast cancers had been diagnosed, compared with an expected 508. The peak exposure to HRT in the cohort occurred at age 54, at which time about 30% of the women had used hormone replacement, Dr. Olsson said. He noted that overall risk of cancer (all types) was not increased, indicating that the increased risk of breast and endometrial cancers was being balanced by a decreased risk of some other types of cancer, such as colon cancer and smoking-related cancers.

The researchers reported their initial results in 2001 (Br J Cancer 85:674-677, 2001). "In our first results, overall HRT use gave an 80% increased risk of breast cancer after 4 years of use," Dr. Olsson said. "This risk was independent of other risk factors, and it disappeared after the woman had stopped HRT for 5 years."

He noted that there was no synergy between HRT use and family history of breast cancer—both were independent risk factors. Moreover, previous users of oral contraceptives did not have a higher risk of breast cancer when they took HRT.

In their second study, the researchers analyzed breast cancer risk by type of HRT. Dr. Olsson noted that several previous studies of the issue had found a higher risk among women who had taken a combination of estrogen and progestin than among those who had taken estrogen alone. However, the studies were not consistent in determining whether the type of combined therapy—combined continuous therapy or combined sequential therapy—made a difference. His group attempted to address this issue by looking at all types of HRT.

"In multivariate analysis, we found a very high risk of breast cancer in the combined situation, both for combined sequential therapy and combined continuous therapy, which showed the highest risk of all after 4 years of use," he said.

Progestin-only use was also associated with a high risk of breast cancer. The use of estradiol-only components did not increase breast cancer risk. "Estriol use was associated with a slightly increased risk of breast cancer, but the difference was not statistically significant," he said.

The hazard ratios for less than 4 years’ use and 4 or more years of use, respectively, were: combined sequential regimens, 2.53 and 2.23 (both significant); combined continuous regimens, 1.37 and 4.60 (significant); progestins only, 0.52 and 3.74 (significant); estradiol only, 1.11 and 0.35; and estriol, 1.26 and 1.89.

When the progestin-containing regimens were considered together, women taking a progestin were three times more likely to develop breast cancer after 4 years of use than were women who had never used HRT (hazard ratio, 1.8 for less than 4 years and 3.0 for 4 or more years). Estrogen-only therapy did not increase breast cancer incidence (hazard ratio, 0.8 for less than 4 years and 1.2 for 4 or more years) (see Table)

"What does this translate to? We think that all the progestin-containing components increase breast cancer risk, while the estrogen-only components do not," Dr. Olsson said. "What that means for 50-year-old women is that after 10 years of follow-up, 2% of never-users would develop breast cancer, 2% to 3% of those taking estrogen-only preparations for at least 4 years would develop breast cancer—not a significant increase—and 7% of progestin-users would develop breast cancer." He added that this would mean that among women age 45 and older, 9% of all breast cancers in southern Sweden are related to HRT use.

The researchers concluded that there is a very high risk of breast cancer in users of progestin-containing regimens, and that estrogen-only preparations do not appreciably increase the risk. The full study has been published in Cancer (97:1387-1392, 2003).