Use of hormone replacement therapy and risk of breast cancer
Hormone replacement therapy (HRT) relieves adverse symptoms experienced by some women during menopause. Although treatments are helpful, they may be associated with increased risks of developing breast cancer.Evidence for increased risks among women using HRT is, however, mixed. Studies have differed in terms of age profiles, durations of follow-up and exposures to different HRT treatments. Many studies have investigated the different drugs only as a single class, and lack of evidence – particularly for progestogens – is noted in the 2015 National Institute of Health and Clinical Excellence guideline on menopause. Our large-scale, comprehensive study investigated breast cancer risks associated with all drug formulations commonly used in HRT treatments in the UK.
A nested case-control study based on the general female population used clinical records from UK general practices contributing to the QResearch database. 72,731 women aged between 40 and 79 had a primary breast cancer diagnosed between 1998 and 2018. These cases were matched by year of birth and general practice to 325,046 female controls alive at the time of case diagnosis (the index date). Women with previous breast cancer diagnoses were excluded. Exposure to HRT drugs was based on prescriptions before the index date, excluding the last year. Associations with duration and with gaps in exposure since last use were investigated. Conditional logistic regression was used to calculate odds ratios adjusted for smoking, ethnicity, body-mass index and co-morbidities associated with increased breast cancer risk or use of HRT.
21,195 (29%) cases and 86,825 (27%) controls had used HRT drugs in the relevant exposure period. 26% of exposed cases and 30% of exposed controls were prescribed oestrogen-only therapy and 74% and 70% respectively were prescribed a combined therapy. Overall compared to no use, there was no increased risk associated with exposures of less than one year of HRT use, but exposures over one year were associated with steadily increasing risks, reaching 35% (95% confidence interval 1.30 to 1.39) for 5 to 10 years of exposure. Oestrogen-only therapy (estradiol or conjugated equine oestrogen) was associated with a 1% (0.6% to 1.8%) increased risk per additional year of use. Each additional year of exposure to progestogens was associated with a 5% (4% to 6%) increased risk for levonorgestrel or norethisterone and 6% (5% to 7%) for medroxyprogesterone acetate. Two years after discontinuation, increased risks for oestrogens had disappeared, but the risks for progestogens remained significant.
In one of the largest-ever studies of breast cancer and HRT treatments, increasing exposures were associated with increased risks, mostly attributable to progestogen use. The findings should help doctors and patients in their choice of hormonal therapy, particularly for women already having increased breast cancer risk.