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Research article
Association between menopausal hormone therapy, mammographic density and breast cancer risk: results from the E3N cohort study
Gianluca Severi
INSERM
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7157-419X
License:
This work is licensed under a CC BY 4.0 License. Read Full License
BACKGROUND Menopausal hormone therapy (MHT) is a risk factor for breast cancer (BC). Evidence suggests that its effect on BC risk could be partly mediated by mammographic density. The aim of this study was to investigate the relationship between MHT, mammographic density and BC risk using data from a prospective study.
METHODS We used data from a case-control study nested within the French cohort E3N including 453 cases and 453 matched controls. Measures of mammographic density, history of MHT use during follow-up and information on potential confounders were available for all women. The association of mammographic density with MHT was evaluated by linear regression models. Mediation modelling techniques were applied to estimate under the hypothesis of a causal model the proportion of the effect of MHT on BC risk mediated by percent mammographic density for BC overall and by hormonal receptor status.
RESULTS Among MHT users, only 4.2% used exclusively estrogens compared with 68.3% who used exclusively estrogens plus progestogens. Mammographic density was higher in current users (mean percent mammographic density for a 60 year old woman 33%; 95% CI: 31% to 35%) than in past (29%; 27% to 31%) and never users (24%; 22% to 26%). Mammographic density increased with the duration of MHT within one year of therapy and reached a steady state thereafter. After MHT discontinuation, mammographic density decreased with time since last use and reached values similar to those of never users after 8 years. The OR of BC for current versus never MHT users, adjusted for age, year of birth, menopausal status at baseline and BMI, was 1.67 (95% CI, 1.04 to 2.68). The proportion of effect mediated by percent mammographic density was 34% for any BC and became 48% when the correlation between BMI and percent mammographic density was accounted for. These effects were limited to hormone receptor positive BC.
CONCLUSIONS Our results suggest that under a causal model nearly half of the effect of MHT on hormone receptor positive BC risk is mediated by mammographic density, which appears to be modified by MHT for up to 8 years after MHT termination.
Keywords
mammographic density, menopausal hormone therapy, menopause, breast cancer risk, mediation analysis
Figure 1
This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1.SupplementarytablesS1andS2.docx
- SupplementaryTableS1.docx
Supplementary Table S1. Characteristics of the study sample in comparison with the whole E3N cohort.
- SupplementaryTableS2.docx
Supplementary Table S2. Values of the Akaike Information Criterion (AIC) for regression models with the square root of percent mammographic density (PMD), dense area (DA) and non-dense area (NDA) as polynomial functions of duration of MHT use and time since last use.
- SupplementaryTableS3.docx
Supplementary Table S3. Mediation analysis of the effect of ever versus never use (reference category) of menopausal hormone therapy on breast cancer risk, overall and by ER and PR status. The table reports the OR and 95% confidence intervals from the unconditional logistic models adjusted for age at mammogram and the matching variables (reference age, year of birth and menopausal status at baseline).
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CURRENT STATUS: Under Review
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Posted 04 Jan, 2021
No community comments so far
Reviewer #2 agreed
On 13 Jan, 2021
Review #1 received
Received 05 Jan, 2021
Reviewers invited
Invitations sent on 21 Dec, 2020
Reviewer #1 agreed
On 21 Dec, 2020
Editor assigned
On 15 Dec, 2020
Submission checks complete
On 15 Dec, 2020
Editor invited
On 15 Dec, 2020
No comments provided
Review #2 received
Received 25 Oct, 2020
Editorial decision: Major Revision
On 25 Oct, 2020
Reviewer #3 agreed
On 24 Sep, 2020
Review #1 received
Received 15 Aug, 2020
Reviewers invited
Invitations sent on 11 Aug, 2020
Reviewer #1 agreed
On 11 Aug, 2020
Reviewer #2 agreed
On 11 Aug, 2020
Editor invited
On 11 Aug, 2020
Editor assigned
On 04 Aug, 2020
First submitted
On 03 Aug, 2020
Submission checks complete
On 03 Aug, 2020
Metrics
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PDF Downloads: ...
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Subject Areas
Oncology
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This preprint is under consideration at Breast Cancer Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Association between menopausal hormone therapy, mammographic density and breast cancer risk: results from the E3N cohort study
Gianluca Severi
INSERM
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7157-419X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 2
Posted 04 Jan, 2021
No community comments so far
Reviewer #2 agreed
On 13 Jan, 2021
Review #1 received
Received 05 Jan, 2021
Reviewers invited
Invitations sent on 21 Dec, 2020
Reviewer #1 agreed
On 21 Dec, 2020
Editor assigned
On 15 Dec, 2020
Submission checks complete
On 15 Dec, 2020
Editor invited
On 15 Dec, 2020
No comments provided
Review #2 received
Received 25 Oct, 2020
Editorial decision: Major Revision
On 25 Oct, 2020
Reviewer #3 agreed
On 24 Sep, 2020
Review #1 received
Received 15 Aug, 2020
Reviewers invited
Invitations sent on 11 Aug, 2020
Reviewer #1 agreed
On 11 Aug, 2020
Reviewer #2 agreed
On 11 Aug, 2020
Editor invited
On 11 Aug, 2020
Editor assigned
On 04 Aug, 2020
First submitted
On 03 Aug, 2020
Submission checks complete
On 03 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Oncology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
BACKGROUND Menopausal hormone therapy (MHT) is a risk factor for breast cancer (BC). Evidence suggests that its effect on BC risk could be partly mediated by mammographic density. The aim of this study was to investigate the relationship between MHT, mammographic density and BC risk using data from a prospective study.
METHODS We used data from a case-control study nested within the French cohort E3N including 453 cases and 453 matched controls. Measures of mammographic density, history of MHT use during follow-up and information on potential confounders were available for all women. The association of mammographic density with MHT was evaluated by linear regression models. Mediation modelling techniques were applied to estimate under the hypothesis of a causal model the proportion of the effect of MHT on BC risk mediated by percent mammographic density for BC overall and by hormonal receptor status.
RESULTS Among MHT users, only 4.2% used exclusively estrogens compared with 68.3% who used exclusively estrogens plus progestogens. Mammographic density was higher in current users (mean percent mammographic density for a 60 year old woman 33%; 95% CI: 31% to 35%) than in past (29%; 27% to 31%) and never users (24%; 22% to 26%). Mammographic density increased with the duration of MHT within one year of therapy and reached a steady state thereafter. After MHT discontinuation, mammographic density decreased with time since last use and reached values similar to those of never users after 8 years. The OR of BC for current versus never MHT users, adjusted for age, year of birth, menopausal status at baseline and BMI, was 1.67 (95% CI, 1.04 to 2.68). The proportion of effect mediated by percent mammographic density was 34% for any BC and became 48% when the correlation between BMI and percent mammographic density was accounted for. These effects were limited to hormone receptor positive BC.
CONCLUSIONS Our results suggest that under a causal model nearly half of the effect of MHT on hormone receptor positive BC risk is mediated by mammographic density, which appears to be modified by MHT for up to 8 years after MHT termination.
Figure 1