Use of estrogen-alone hormone replacement therapy (HRT) after oophorectomy does not increase the risk of BRCA 1-associated breast cancer, although this may not be the case for progesterone-continuing HRT, researchers say.
Dr. Steven Narod of Women’s College Hospital in Toronto and colleagues prospectively investigated the association between HRT use and BRCA1-associated breast cancer in 872 BRCA1 mutation carriers (mean age 43.4) from 80 centers in 17 countries.
All participants underwent prophylactic bilateral oophorectomy after enrollment and completed a questionnaire every 2 years with detailed information on HRT use (43% of participants), menstruation status, and whether breast cancer had been diagnosed. Mean follow-up was 7.6 years.
Among HRT users, 69% used estrogen alone, 18% used estrogen and progesterone, 11% used progesterone alone, and 21% used another formulation. Mean duration of HRT use was 3.9 years.
As reported online April 19 in JAMA Oncology, 92 (10.6%) incident breast cancers were diagnosed, and the annual breast cancer risk was 1.4%. Among women who developed breast cancer, a mean of 4.5 years elapsed between the date of oophorectomy and a breast cancer diagnosis.
Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer (HR, 0.97 for ever use of any type of HRT vs no use).
However, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12%, compared with 22% among women who used estrogen plus progesterone.
For each year of use of estrogen-containing HRT (either alone or in combination with progesterone), there was a significant 8% reduction in breast cancer risk (HR, 0.92), but not for progesterone-containing HRT.
Further, in women who had an oophorectomy before age 45, each year of estrogen-containing HRT use was associated with a significant 18% reduction in breast cancer risk; however, each year of progesterone-containing HRT was associated with a nonsignificant 14% increase in risk.
No association between HRT use and breast cancer was detected among women who had an oophorectomy after age 45.
"We think that doctors should avoid giving progesterone-containing hormones to women with BRCA1 or BRCA2 mutations," Dr. Narod told Reuters Health. "Better to give estrogen alone."
"There is a theoretical risk of endometrial cancer but we have not seen this," he said by email. "The risk of breast cancer with progesterone is not that large but is substantial, (whereas) estrogen alone seems to be safe."
"Women should consider having a hysterectomy at the time of oophorectomy if they want to avoid the risk of endometrial cancer altogether," he advised.
Dr. Eloise Chapman-Davis, a gynecologic oncologist at NewYork-Presbyterian and Weill Cornell Medicine in New York City told Reuters Health, "I currently take care of many young women with BRCA mutations and feel very comfortable with offering HRT after oophorectomy in patients without a diagnosis of cancer."
"This study confirms previous published studies that have reported no increase in breast cancer risk in BRCA patients," she said by email, "but this is the first study to look at this in a prospective fashion, making these findings even more credible."
"The (suggestion) that combination therapy with progesterone and estrogen may be less safe than estrogen alone needs to be evaluated further, before recommending that all women have a hysterectomy to avoid using progesterone as a part of HRT," she said.
"Since the study period spanned 22 years, there have been newer forms of progesterone hormone delivery devices that are routinely used in the US but (were) not accounted for in this study," she noted.
For example, she said, "IUDs are a type of delivery system that is known to deliver progesterone locally to the uterus with overall lower absorption into the blood stream. Addressing route of progesterone administration and overall systemic levels of progesterone should be further studied, as they may influence the overall conclusions."
"They also excluded all women with bilateral mastectomies, which is an important fact to highlight," Dr. Chapman-Davis continued. "Many women with BRCA1 mutations have such a high rate of bilateral breast cancer development that they may opt for proceeding with both prophylactic mastectomy as well as oophorectomy."
"This group of women has already substantially decreased their risk of developing breast cancer," she noted, "and the differential findings attributed to addition of progesterone may not apply."
—Marilynn Larkin
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