Hormone combos, longer use carry highest increased risk

A large observational study from the U.K. confirmed the association between exposure to hormone replacement therapy (HRT) drugs and an increased risk of breast cancer; however, risk varied by length and type of treatment, with combination HRT drugs and longer treatment duration posing the greatest risk, researchers found.

HRT is used by millions of women to help relieve the symptoms of menopause, sometimes over extended lengths of time. But concerns over adverse events — particularly breast cancer — have led to a major decrease in HRT use in recent years, explained Yana Vinogradova, PhD, MSc, and Carol Coupland, PhD, MSc, of the University of Nottingham in Nottingham, U.K., and Julia Hippisley-Cox, MB, ChB, FRCP, DRCOG, FRCGP, of the University of Oxford in Oxford, U.K., in the BMJ. A major source of these concerns, they noted, was a 2019 meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer, which found higher than expected associations between HRT and breast cancer than had been suggested by earlier trials.

In order to provide a realistic picture of exposure to HRT component hormones among women in the U.K. and determine the associations between increased breast cancer risk and specific treatments, Vinogradova, Coupland, and Hippisley-Cox used data from electronic health records (EHR) from the two largest U.K. primary care databases to assess the differences in risks associated with the individual component hormones commonly used in HRT.

And, while they confirmed that HRT is linked to breast cancer risk, the association might not be as strong as the 2019 meta-analysis would suggest.

“This large observational study found that exposure to most HRT drugs is associated with an increased risk of breast cancer,” they found. “In comparison with a recent meta-analysis [by the Collaborative Group on hormonal Factors in Breast Cancer], however, our findings generally suggest lower increased risk associations between longer term HRT use and breast cancer, and we report a more noticeable decline in risks once HRT has stopped. Risk increases were mostly associated with estrogen-progestogen treatments, but small increases were also associated with estrogen only treatments.”

Moreover, the associations for all treatments depended on treatment duration, they added, “with no increased risks for less than one year of treatment but increasing risks for longer exposures to medroxyprogesterone, norethisterone, and levonorgestrel. Associations were more pronounced for older women and less noticeable for obese women.”

For their analysis, Vinogradova, Coupland, and Hippisley-Cox performed a nested case-control study, using data from the QResearch and Clinical Practice Research Datalink (CPRD) GOLD databases — as well as linked data from Hospital Episode Statistics (HES), Office for National Statistics (ONS) mortality data, and (QResearch only) cancer registry data — to identify two open cohorts of women ages 50-79 years registered with a general practice from Jan. 1, 1998 to Dec. 31, 2018. Women with previously diagnosed breast cancer or records of mastectomy at the cohort entry date and women with fewer than three years of medical records were excluded.

Two types of estrogen (conjugated equine estrogen and estradiol) and four types of progestogen (norethisterone acetate, levonorgestrel, medroxyprogesterone, and dydrogesterone) were included in the analysis, and duration of use was categorized as never (0 years), less than 1 year, 1-2 years, 3-4 years, 5-9 years, and 10 years or more.

Overall, the study authors identified 59,999 cases of breast cancer in QResearch and 38,612 cases in CPRD. Across both databases, 33,703 (34%) breast cancer cases and 142,391 (31%) controls had ever been exposed to HRT — of these, 8,860 (26%) cases and 42,799 (30%) controls were exposed to estrogen-only therapy, while 24,843 (74%) cases and 99,592 (70%) controls were exposed to combination estrogen-progestogen therapy.

“Compared with never use, in recent users (<5 years) with long-term use (≥5 years), estrogen only therapy and combined estrogen and progestogen therapy were both associated with increased risks of breast cancer (adjusted odds ratio 1.15 (95% confidence interval 1.09-1.21) and 1.79 (1.73-1.85), respectively),” the study authors reported. “For combined progestogens, the increased risk was highest for norethisterone (1.88, 1.79-1.99) and lowest for dydrogesterone (1.24, 1.03-1.48). Past long-term use of estrogen only therapy and past short term (<5 years) use of estrogen-progestogen were not associated with increased risk. The risk associated with past long-term estrogen-progestogen use, however, remained increased (1.16, 1.11-1.21).

“In recent estrogen only users, between three (in younger women) and eight (in older women) extra cases per 10,000 women years would be expected, and in estrogen-progestogen users between nine and 36 extra cases per 10,000 women years,” they added. “For past estrogen-progestogen users, the results would suggest between two and eight extra cases per 10,000 women years.”

They also found that associations between use of HRT and risk of breast cancer rapidly decreased with increasing years of discontinuation, with no significantly increased risk from two years after discontinuation for patients exposed to estrogen only, estradiol combined with norethisterone and dydrogesterone, and tibolone — “For medroxyprogesterone, the risk was reduced after two years but remained raised until after five years; for levonorgestrel until after 10 years,” they noted.

Vinogradova, Coupland, and Hippisley-Cox concluded that their analysis “provide some counterbalance” to the meta-analysis by the Collaborative Group on Hormonal Factors.

“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 wrote.

Some limitations of the study include missing, incomplete, or unreliable data for a small proportion of the study cohort, as well as a lack of data on established breast cancer risk factors among participants, past treatments, physical activity, and adherence to HRT. The study authors also noted questions for future research, including the difference in associations between HRT and breast cancer for different tumor types, as well as questions regarding breast cancer survival rates and all-cause mortality in women on HRT.

  1. A large observational study from the U.K. confirmed an association between HRT and an increased risk of breast cancer; however, breast cancer risk varied by hormone type and treatment duration, with longer treatment and combination estrogen-progestogen posing the greatest risk.

  2. Note that the study authors reported lower increased risk associations between long-term HRT and breast cancer than was reported in a 2019 meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer, as well as a more substantial decline in risk after discontinuation of HRT.

John McKenna, Associate Editor, BreakingMED™

Vinogradova, Coupland, and Hippisley-Cox declared support from the National Institute for Health Research School for Primary Care Research and by Cancer Research U.K. through the cancer research U.K. Oxford Centre; Hippisley-Cox is professor of clinical epidemiology at the University of Oxford and unpaid director of QResearch, and was a paid director of ClinRisk until 2019.

No other competing interests were disclosed.

Cat ID: 22

Topic ID: 78,22,22,39,691,192,925