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Hormone replacement therapy and risk of breast cancer: case-control study

Status

Completed

Title

Hormone replacement therapy and risk of breast cancer: case-control study using QResearch

What were the objectives of the study?

Hormone replacement therapy (HRT) can be of significant benefit to women who suffer severe symptoms during menopause. This is the stage in every woman’s life when hormone production in the ovaries slows down and her periods stop. Up to 80% of women experience some unpleasant symptoms such as hot flushes, night sweats, mood changes or memory and concentration losses. Osteoporosis is also associated with menopause and, for a small proportion of women, symptoms can be disabling and affect their quality of life.

HRT treatments involve one or more of a class of hormonal drugs, with an oestrogen as the key component and a progestogen normally added to protect the womb. As with all drug treatments, HRT has side effects and an increase in risk of breast cancer is one these. The current National Institute for Health and Care Excellence (NICE) guideline notes, however, that evidence of the risks for the different hormones used is lacking. The most recent major study was a 2019 meta-analysis, published in the Lancet, which summarised information from a variety of different studies worldwide and reported higher than expected risks.

Our purpose was to conduct the largest single study ever undertaken in a single healthcare environment and to include all available information on HRT use and other risk factors. Through this original research, we aimed to provide comprehensive, detailed and accurate estimates of the risks for different HRT treatment formulations.

How was the research done?

The study used the two largest UK primary care databases, which between them cover 2000 English general practices. Both contain anonymised, routinely-collected information from doctors and have links to associated hospital patient records. Over the 20-year period between 1998 and 2018, we identified all women aged from 50 to 79 with a diagnosis for breast cancer, matching each by age and general practice to controls without any breast cancer diagnosis. We then compared the HRT prescription records of all women who developed breast cancer with those for women who did not, taking into account when, and for how long, users had been exposed. To ensure that our results correctly reflected the effects of the HRT treatments alone, we also took into account all available information on relevant health conditions and patient characteristics, which might have affected the risk of developing breast cancer. To investigate the relative safety of different treatments, we included all HRT treatments, looking at the formulation of each (the oestrogen and progesterone used) and the method of use (tablets, patches or creams).

Chief Investigator

Yana Vinogradova

Lead Applicant Organisation Name

Sponsor

University of Oxford

Location of research

University of Oxford and University of Nottingham

Date on which research approved

01-Apr-2018

Project reference ID

Q107 and OX11

Generic ethics approval reference

18/EM/0400

Are all data accessed are in anonymised form?

Yes

Brief summary of the dataset to be released (including any sensitive data)

Women aged 40-79 registered during the study period (1998-2017) with a diagnosis of breast cancer each matched to 5 controls by age, practice and calendar time.
GP data includes diagnoses, risk factors and medication relevant to breast cancer.
Hospital, mortality and cancer registry data includes diagnoses and operations relevant to breast cancer (eg mastectomy; hysterectomy).

What were the main findings?

Women who were diagnosed with breast cancer were more likely to have used or be using HRT. The increase in breast cancer risk was relatively much higher for combined oestrogen-progestogen treatments than for oestrogen-only treatments. Increased breast cancer risk was also duration-dependent, rising over the period of use, but more gradually for lower risk-increase treatments than for higher ones. The levels of increased risk diminished after discontinuation, disappearing eventually for oestrogen-only users and for short-term users of combined treatments. However, small increased risks persisted for longer-term users of combined treatments. Also for combined treatments, the level of increased risk depended on the progestogen used, with dydrogesterone confirmed by our study as the one associated with the lowest and least persistent increased risk of breast cancer.

Overall, our study did not confirm the unexpected increase in risks reported by the Lancet study, but provided a more detailed picture for women of different ages. Older women were found to be at greater increased risk of breast cancer from HRT than younger women, particularly while still using it and especially if they had been taking it for more than several years. This was consistent across all treatments.

Implications and Impact

Our findings derive from a single piece of original research and use data representative of treatment practice and outcomes within the UK population. As such, they provide clearer, more detailed, and more robust and generalisable information for doctors and patients about the relative increases in risk of breast cancer for all HRT treatments used in the UK. They will both facilitate and increase confidence in treatment choices, and should be useful in the development of best-practice guidelines.

Funding Source

NIHR School for Primary Care Research

Public Benefit Statement

Research Team

Dr Yana Vinogradova, Prof Carol Coupland (University of Nottingham), Prof Julia Hippisley-Cox (University of Oxford)

Podcasts

Woman's Hour - BBC Radio 4 - 2nd November 2020

The Liz Earle Wellbeing Show - 2nd November 2020

SuperHuman Radio with Carl Lanore - 9th November 2020

OxCODE news

Publications

  • Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases
    Authors: Yana Vinogradova, Carol Coupland, Julia Hippisley-Cox
    Ref:
    https://www.bmj.com/content/371/bmj.m3873
  • Author's Reply to Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases
    Authors: Hippisley-Cox, J
    Ref: BMJ 2020;371:m3873
    https://www.bmj.com/content/371/bmj.m3873/rr-9

Press Releases

Access Type

Trusted Research Environment (TRE)

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