Association of breast cancer with hormone replacement therapy varies by regimen
A recent British study found differences in breast cancer risk by duration, recency, and specific formulation of hormone replacement therapy, although any use of hormones was associated with higher cancer risk than never use.
Both estrogen-only and combined estrogen and progestogen therapy were associated with increased risks of breast cancer, but the risk was higher with the latter, according to a large new study.
Researchers conducted a nested, case-control study using a database of U.K. general practices linked to hospital, mortality, social deprivation, and cancer registry data. A total of 98,611 women ages 50 to 79 years with a primary diagnosis of breast cancer between 1998 and 2018 were matched to 457,498 controls.
Breast cancer risk was analyzed according to hormone replacement therapy (HRT) regimen, whether estrogen only or combined estrogen and progestogen. Use was categorized as recent (within 1 to 5 years), past (5 or more years before), short term (<5 years), or long term (≥5 years). Odds ratios were calculated for HRT regimens, adjusted for personal characteristics, smoking status, alcohol consumption, comorbidities, family history, and other prescribed drugs. Results were published Oct. 28 by The BMJ.
Overall, 33,703 (34%) women with a diagnosis of breast cancer and 134,391 (31%) controls had used HRT at least a year before the study's index date. Compared to no use of HRT, any exposure was associated with an increased risk of breast cancer (adjusted odds ratio [OR], 1.21; 95% CI, 1.19 to 1.23), but the increased risk was mostly attributable to estrogen-progestogen therapy (OR, 1.26; 95% CI, 1.24 to 1.29). Estrogen-only therapy carried a much smaller increased risk (OR, 1.06; 95% CI, 1.03 to 1.10).
The risks associated with HRT increased with duration of use. Compared with never users, risks were increased in recent, long-term users of both estrogen-only therapy (OR, 1.15; 95% CI, 1.09 to 1.21) and combined estrogen and progestogen therapy (OR, 1.79; 95% CI, 1.73 to 1.85]). Past long-term estrogen-progestogen use was also associated with increased risk (OR, 1.16; 95% CI, 1.11 to 1.21). Past long-term use of estrogen-only therapy and past short-term use of estrogen-progestogen were not associated with increased risk.
Of the combined progestogens, the increased risk was highest for norethisterone (OR, 1.88; 95% CI, 1.79 to 1.99) and lowest for dydrogesterone (OR, 1.24; 95% CI, 1.03 to 1.48). Norethisterone, levonorgestrel, and medroxyprogesterone were associated with similar risks. No risk differences were found between low and high doses of estrogens or between different application methods for estradiol, norethisterone, or levonorgestrel.
The researchers said this study confirms that exposure to most HRT drugs is associated with an increased risk of breast cancer but generally suggests lower increased risk associations between longer-term HRT use and breast cancer than other recent research, as well as more pronounced declines in risk once HRT has stopped. The study also showed that risk varies between types of HRT, with the lowest risks associated with some of the most rarely used drugs, dydrogesterone and tibolone, the authors noted.
“Our results add more evidence to the existing knowledge base and should help doctors and women to identify the most appropriate HRT formulation and treatment regimen, and provide more consistently derived information for women's health experts, healthcare researchers, and treatment policy professionals,” they concluded.