medwireNews: UK researchers have provided updated estimates of the risks for breast cancer associated with the use of various hormone replacement therapy (HRT) preparations.
The study confirms the overall increased risk with HRT use, but suggests “generally lower increased risks for combined HRT treatments and […] more pronounced declines in risk once HRT has stopped” compared with a recent meta-analysis of 24 observational studies, say Yana Vinogradova, from the University of Nottingham, and colleagues.
“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 write in The BMJ.
The team drew on two UK primary care databases – QResearch and Clinical Practice Research Datalink GOLD – to identify 98,611 women aged 50–79 years with a diagnosis of breast cancer between 1998 and 2018, and matched them by age, primary care practice, and index date to 457,498 women without breast cancer. The rate of HRT use, based on prescriptions data, prior to a year before the index date was 34% and 31% in the groups with and without breast cancer, respectively.
Overall, ever use of HRT was associated with a significantly elevated risk for breast cancer compared with no use, at an odds ratio (OR) of 1.21 after adjustment for a raft of confounders including lifestyle factors, comorbidities, family history, and use of other drugs.
The increased risk appeared to be driven primarily by use of combined estrogen–progestogen therapy (OR=1.26), with only “a small increased risk” with the use of estrogen-only therapy (OR=1.06), say the study authors, adding that “[t]he risks associated with HRT increased with duration of use.”
They note that the findings were similar for women who had only used HRT recently (within 5 years of the index date), “but the risks were consistently higher and more pronounced, particularly for oestrogen-progestogen therapy.” For instance, the ORs for breast cancer risk relative to no use ranged from 1.09 for less than 1 year of estrogen-only HRT to 1.17 for at least 10 years of use, while the ORs for estrogen–progestogen preparations ranged from 1.11 to 2.05.
Among past users (≥5 years before the index date), the association between HRT and breast cancer risk was only significant for estrogen–progestogen use for 1–2, 3–4, and 5–9 years, with ORs of 1.05, 1.08, and 1.17, respectively, versus no use.
Analysis by hormone type showed that recent use of conjugated equine estrogen or estradiol for at least 5 years was associated with a significantly increased risk for breast cancer relative to no use (ORs=1.11 and 1.15, respectively).
But again the risk appeared to be greater with the use of estrogen–progestogen combinations, with recent use of at least 5 years of formulations comprising norethisterone and medroxyprogesterone conferring the highest risk (OR=1.88 and 1.87, respectively). By contrast, using dydrogesterone-containing preparations for 5 years or more conferred a lower increased risk, at an OR of 1.24.
There was no significant association between breast cancer risk and past use of either estrogen-only formulation, or combinations containing medroxyprogesterone or dydrogesterone, but use of combinations with levonorgestrel or norethisterone for 1 year or more significantly increased the risk, with ORs ranging from 1.05 for 1–4 years of norethisterone to 1.24 for at least 5 years of levonorgestrel.
Vinogradova et al also estimated the excess numbers relative to never users across different age groups, finding that the number of excess cases per 10,000 women–years among recent, short-term (1–5 years) users of estrogen-only HRT was three, four, and eight for women aged 50–59, 60–69, and 70–79 years, respectively.
For estrogen–progestogen treatment, the corresponding numbers of excess cases per 10,000 women–years in the different age groups were nine, 15, and 19 for recent, short-term users, and were 15, 26, and 36 for recent, long-term (≥5 years) users.
Commenting on the results to the press, Michael Jones (The Institute of Cancer Research, London, UK) said that the study is “very large” and therefore “the strong statistical associations are unlikely to be due to chance.”
He cautioned, however, that “no one study should be considered in isolation.”
Jones continued: “Even though some risks were found to be slightly smaller than those reported in another meta-analysis […] published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
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