Epidemiological Study on Menopausal Hormone Therapy and Breast Cancer Risk

Introduction

This study aims to explore the relationship between Menopausal Hormone Therapy (HT) and the risk of Breast Cancer (BC). While HT can relieve menopausal symptoms in women (such as hot flashes, fatigue, and urinary pain), it may also pose other health risks like an increased risk of breast cancer. Therefore, scientists attempt to gain deeper insights into the effect of different types, administration routes, and specific HT drugs on breast cancer risk on a larger scale, to provide more scientific treatment recommendations for women.

Background and Objective of the Study

Menopausal Hormone Therapy has been proven to increase the risk of breast cancer, a risk that can persist even ten years after stopping treatment. Therefore, the European Medicines Agency emphasized in its 2020 update of the Summary of Product Characteristics that using such therapy comes with an increased risk of breast cancer. Despite this, many women still need HT to alleviate severe menopausal symptoms. Hence, there is a need for large-scale studies to help women and physicians choose the safest treatment method. This study detailed the effects of various HT types, administration routes, and specific drugs on breast cancer risk through a large cohort study involving 1,275,783 women across Norway. The results were categorized and analyzed according to molecular subtypes, detection modes, diagnostic stages, and Body Mass Index (BMI).

Study Source and Authors

This study was jointly conducted by the Norwegian Cancer Registry Research Department, Oslo University Hospital’s Obstetrics and Gynecology Division, and several other institutions. The main authors include Nathalie C. Støer, Siri Vangen, Deependra Singh, among others. The article was published in the 2024 issue of the British Journal of Cancer, accepted on January 17, 2024, and published online on May 13, 2024.

Research Methods

Data Source and Study Population

The study population consists of women living in Norway from January 1, 2004, to December 31, 2018. Personal information for these women was obtained from national databases such as the Norwegian Population Registry, Cancer Registry, and Prescriptions Database. Additionally, BMI data was gathered from summary questionnaires and regional health surveys.

Cox Proportional Hazard Model

Each woman in the study was followed up starting from January 1, 2004, or the month they turned 45. The Cox Proportional Hazard Model was used to estimate the association between HT type, administration route, and specific drugs with breast cancer risk, adjusting for variables such as ethnicity, number of children, education level, income, and region.

Molecular Subtypes and Detection Modes

Breast cancer was classified according to detection modes (screening detection, symptomatic detection) and molecular subtypes (such as ER+, PR+, HER2-). Molecular subtypes were defined through immunohistochemical markers, and groups were formed based on HT usage during the follow-up period.

Statistical Analysis

The Cox Proportional Hazard Model was used to estimate the Hazard Ratio (HR) with a 95% Confidence Interval (CI). R language was used for data analysis, adjusting for various potential confounding factors, and performed multiple sensitivity analyses.

Study Results

Overall Risk Assessment

During the follow-up period, 454,262 women used HT, and 33,654 women were diagnosed with breast cancer. Compared to women who did not use HT, those currently using HT had an increased risk of breast cancer (HR 1.45; 95% CI 1.41–1.49), with the greatest risk observed in women using oestradiol-neta combination therapy (HR 2.23; 95% CI 2.14–2.33).

Administration Route

Oral estrogen and transdermal estrogen increased breast cancer risk, while vaginal estrogen did not show a significant association. Regarding specific drugs, women using Cliovelle® had a 63% increased risk (HR 1.63; 95% CI 1.35–1.96), and those using Kliogest® had a 167% increased risk (HR 2.67; 95% CI 2.37–3.00).

Molecular Subtypes and Detection Modes

HT usage was most closely associated with Luminal A type breast cancer (HR 1.97; 95% CI 1.86–2.09). Compared to stromal breast cancer, the risk of breast cancer detected through screening was lower. Additionally, in women with lower BMI, the association between HT usage and breast cancer risk was stronger.

Conclusions and Significance

Main Conclusions

This study confirmed that oral and transdermal HT significantly increased the risk of breast cancer, while vaginal use posed no significant risk. HT usage was most strongly associated with Luminal A type breast cancer, with higher risks in women with lower BMI. The study also showed a stronger correlation between HT usage and stromal breast cancer risk, possibly due to HT increasing breast density, thereby reducing screening sensitivity.

Applicative Value

The study provides important data for guiding menopausal women and healthcare professionals in selecting HT, emphasizing the significant association between specific HT types and breast cancer risk, and providing the necessary scientific basis for the development of safer HT preparations.

Study Highlights

• The study offers a comprehensive analysis of breast cancer risk at the levels of HT types, administration routes, and specific drugs.
• It is a large-scale study based on Norway’s national databases, ensuring high data completeness and accuracy, avoiding recall bias and population selection bias.
• The study accounts for updated HT usage time, effectively avoiding underestimation of the related risk.

Other Important Findings

• Drugs such as MHT (oestradiol-neta and transdermal oestradiol combinations) showed a significant increase in cancer risk.
• Menopausal Hormone Therapy (MHT) users exhibited more frequent aberrant molecular characteristics and dysregulated proliferation of breast cancer cells.

Conclusion

This large-scale nationwide cohort study clarified the significant association between various types and administration routes of Menopausal Hormone Therapy and breast cancer risk. It provided more valuable guidelines on the risk of different HT drugs for preventing breast cancer and scientifically and rationally addressing menopausal treatment challenges, thereby safeguarding women’s health.