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Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes

  • Epidemiology
  • Published:
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Abstract

Purpose

Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM).

Methods

This nested case–control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008–2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0–30,000, (3)30,001–136,000, (4)136,001–293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1–500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use.

Results

There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55–0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42–0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46–0.82,p < 0.01) compared to the 0 mg/day group.

Conclusions

Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin’s chemoprotective effect.

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Data availability

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The data that support the findings of this study are available from IMS, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.

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Acknowledgements

This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.

Funding

This research received no funding from any agency in the public, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmaceutical Health Outcomes and Policy, University of Houston, Houston, TX, USA

    Soumya G. Chikermane, Susan M. Abughosh, Rajender R. Aparasu & Michael L. Johnson

  2. Department of Pharmacy Administration, School of Pharmacy, The University of Mississippi, 235 Faser Hall, Oxford, MS, 38677, USA

    Manvi Sharma

  3. Department of Pharmaceutical Practice and Translational Research, University of Houston, Houston, TX, USA

    Meghana V. Trivedi

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  1. Soumya G. Chikermane
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Contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by SGC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Individual contributions are: SGC: Conceptualization, data curation, formal analysis, methodology, writing, reviewing, editing. MS: Conceptualization, methodology, reviewing and editing. SMA: Conceptualization, methodology, reviewing and editing. Rajender R. Aparasu: Conceptualization, methodology and reviewing. MVT: Conceptualization, methodology and reviewing. MLJ: Resources, funding acquisition, conceptualization, methodology, reviewing and editing.

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Correspondence to Manvi Sharma.

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Previous meeting presentation: Meeting date: ISPOR 2021, May 17-20, 2021. Meeting date: ASCO 2021, June 4-8, 2021.

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Supplementary eFigure 1 Schematic representation of the study design (PDF 20 kb)

10549_2022_6706_MOESM2_ESM.pdf

Supplementary eFigure 2 (Forest plot of multivariable analysis (odds ratios with 95% confidence intervals) (Model 2). [Legend: Average daily intensity of metformin: Category 0: 0 mg/day, Category 1: 0 mg/day < intensity ≤ 500 mg/day, Category 2: intensity > 500 mg/day (category 2)]Abbreviations: aDCSI- adapted Diabetes Complications Severity Index. Description: The horizontal axis shows the odds ratios in the multivariable model. The blue dot represent the odds ratio estimate for the variable and the bounds around the dot represent the 95% confidence interval. (PDF 295 kb)

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Chikermane, S.G., Sharma, M., Abughosh, S.M. et al. Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes. Breast Cancer Res Treat 195, 421–430 (2022). https://doi.org/10.1007/s10549-022-06706-0

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