Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases

Abstract

Objective: To assess the risks of breast cancer associated with different types and durations of hormone replacement therapy (HRT).

Design: Two nested case-control studies.

Setting: UK general practices contributing to QResearch or Clinical Practice Research Datalink (CPRD), linked to hospital, mortality, social deprivation, and cancer registry (QResearch only) data.

Participants: 98 611 women aged 50-79 with a primary diagnosis of breast cancer between 1998 and 2018, matched by age, general practice, and index date to 457 498 female controls.

Main outcome measures: Breast cancer diagnosis from general practice, mortality, hospital, or cancer registry records. Odds ratios for HRT types, adjusted for personal characteristics, smoking status, alcohol consumption, comorbidities, family history, and other prescribed drugs. Separate results from QResearch or CPRD were combined.

Results: Overall, 33 703 (34%) women with a diagnosis of breast cancer and 134 391 (31%) controls had used HRT prior to one year before the index date. Compared with never use, in recent users (<5 years) with long term use (≥5 years), oestrogen only therapy and combined oestrogen and progestogen therapy were both associated with increased risks of breast cancer (adjusted odds ratio 1.15 (95% confidence interval 1.09 to 1.21) and 1.79 (1.73 to 1.85), respectively). For combined progestogens, the increased risk was highest for norethisterone (1.88, 1.79 to 1.99) and lowest for dydrogesterone (1.24, 1.03 to 1.48). Past long term use of oestrogen only therapy and past short term (<5 years) use of oestrogen-progestogen were not associated with increased risk. The risk associated with past long term oestrogen-progestogen use, however, remained increased (1.16, 1.11 to 1.21). In recent oestrogen only users, between three (in younger women) and eight (in older women) extra cases per 10 000 women years would be expected, and in oestrogen-progestogen users between nine and 36 extra cases per 10 000 women years. For past oestrogen-progestogen users, the results would suggest between two and eight extra cases per 10 000 women years.

Conclusion: This study has produced new generalisable estimates of the increased risks of breast cancer associated with use of different hormone replacement preparations in the UK. The levels of risks varied between types of HRT, with higher risks for combined treatments and for longer duration of use.

Fig 1

Flow chart of included cases and controls

Fig 2

Recent and past use of oestrogen, oestrogen-progestogen, and tibolone in association with breast cancer risk. Odds ratios are with reference to never users and adjusted for smoking status, alcohol consumption, Townsend fifth (QResearch only), body mass index, ethnicity, history of other cancers, oophorectomy or hysterectomy, records of early and late menopause, menopausal symptoms, mammography or scans, family history, comorbidities, other drugs, and years of data. Cases are matched to controls by age, general practice, and index date

Fig 3

Recent and past use of different hormones in association with breast cancer risk. Odds ratios are with reference to never users and adjusted for smoking status, alcohol consumption, Townsend fifth (QResearch only), body mass index, ethnicity, history of other cancers, oophorectomy or hysterectomy, records of early and late menopause, menopausal symptoms, mammography or scans, family history, comorbidities, other drugs, and years of data. Cases are matched to controls by age, general practice, and index date

Fig 4

Adjusted odds ratios for different durations of recent and past exposures to hormone replacement therapies in association with breast cancer risk. Odds ratios are with reference to never users and adjusted for smoking status, alcohol consumption, Townsend fifth (QResearch only), body mass index, ethnicity, history of other cancers, oophorectomy or hysterectomy, records of early and late menopause, menopausal symptoms, mammography or scans, family history, comorbidities, other drugs, and years of data. Cases are matched to controls by age, general practice, and index date. Model includes fractional polynomial terms for recent use of oestrogen-progestogen (power 0.5), estradiol-norethisterone (power 0.5), past use of oestrogen-levonorgestrel (power 0.5), and linear terms (1) for all other exposures

Fig 5

Use of oestrogen only, oestrogen-progestogen, and tibolone in women of different ages in association with breast cancer risk. Odds ratios are with reference to never users and adjusted for smoking status, alcohol consumption, Townsend fifth (QResearch only), body mass index, ethnicity, history of other cancers, oophorectomy or hysterectomy, records of early and late menopause, menopausal symptoms, mammography or scans, family history, comorbidities, other drugs, and years of data. Cases are matched to controls by age, general practice, and index date

Fig 6

Use of oestrogen-only, oestrogen-progestogen, and tibolone in women of different body mass index in association with breast cancer risk. Odds ratios are with reference to never users and adjusted for smoking status, alcohol consumption, Townsend fifth (QResearch only), body mass index, ethnicity, history of other cancers, oophorectomy or hysterectomy, records of early and late menopause, menopausal symptoms, mammography or scans, family history, comorbidities, other drugs, and years of data. Cases are matched to controls by age, general practice, and index date

Fig 7

Incident breast cancer rate per 10 000 women years for women unexposed and exposed for different durations to different hormone replacement therapies by age range. Rates were estimated using rates in unexposed populations multiplied by adjusted odds ratios derived from subgroup analyses for different age categories (see fig 5)