糖尿病、二甲双胍与乳腺癌关系复杂

　　回顾研究发现，二型糖尿病与乳腺癌风险增加相关，但是二甲双胍等糖尿病常用处方药物可减少乳腺癌风险。不过，调查二型糖尿病及其药物与乳腺癌相关性的前瞻研究极少。

　　2021年1月28日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国国家环境卫生科学研究所、维思达特、国家少数民族健康与健康差异研究所的前瞻研究分析报告，调查了二型糖尿病、二甲双胍与乳腺癌风险的相关性。

　　该分析报告数据来自2003～2009年参加姐妹研究时自己无乳腺癌、其同父同母或同父异母或同母异父的姐妹有乳腺癌史、年龄35～74岁并随访至2017年9月15日的4万4541例女性。从参加研究时和随访时的调查问卷，获取随着时间的推移、自己报告或医师诊断、原有或新发二型糖尿病和糖尿病用药及其相关因素。根据医疗记录确认新发乳腺癌。对不同乳腺癌的风险比和95%置信区间进行比较。

　　结果，中位随访8.6年期间，参加研究至少1年后新发乳腺癌2678例。

　　二型糖尿病原有3227例（7.2%）、新发2389例（5.3%），其中3386例（61%）用过二甲双胍治疗。

　　有二型糖尿病与无二型糖尿病相比：

  • 全部乳腺癌风险相似（风险比：0.99，95%置信区间：0.87～1.13）

  • 雌激素受体阳性乳腺癌风险相似（风险比：0.92，95%置信区间：0.78～1.07）

  • 雌激素受体阴性乳腺癌风险相似（风险比：1.07，95%置信区间：0.75～1.53）

  • 三阴性乳腺癌风险高40%（风险比：1.40，95%置信区间：0.90～2.16）

　　用过二甲双胍治疗二型糖尿病与无二型糖尿病相比：

  • 全部乳腺癌风险相似（风险比：0.98，95%置信区间：0.83～1.15）

  • 雌激素受体阳性乳腺癌风险低14%（风险比：0.86，95%置信区间：0.70～1.05）

  • 雌激素受体阴性乳腺癌风险高25%（风险比：1.25，95%置信区间：0.84～1.88）

  • 三阴性乳腺癌风险高74%（风险比：1.74，95%置信区间：1.06～2.83）

　　用过二甲双胍治疗二型糖尿病≥10年与无二型糖尿病相比：

  • 全部乳腺癌风险低19%（风险比：0.81，95%置信区间：0.57～1.16，趋势P=0.81）

  • 雌激素受体阳性乳腺癌风险低38%（风险比：0.62，95%置信区间：0.38～1.01，趋势P=0.09）

　　敏感性分析支持上述结果。

　　因此，该研究结果表明，二型糖尿病与乳腺癌风险的相关性可能由于激素受体状态而不同，尤其对于三阴性乳腺癌，长期服用二甲双胍可能削弱二型糖尿病与雌激素受体阳性乳腺癌的相关性。

　　对此，加拿大西安大略大学伦敦健康科学中心、多伦多大学西奈山医院发表同期评论：糖尿病、二甲双胍与乳腺癌的关系错综复杂。

Ann Oncol. 2021 Jan 28. Online ahead of print.

A prospective study of type 2 diabetes, metformin use, and risk of breast cancer.

Park YMM, Bookwalter DB, O'Brien KM, Jackson CL, Weinberg CR, Sandler DP.

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, USA; Westat, Durham, USA; National Institute on Minority Health and Health Disparities, National Institutes of Health, Department of Health and Human Services, Bethesda, USA.

HIGHLIGHTS

  • Breast cancer risk associated with type 2 diabetes (T2D) and antidiabetic medication use was studied prospectively in the Sister Study.

  • Time varying information on self-reported diagnoses of T2D and medication use was available for 44 541 women.

  • Compared with no T2D, T2D with metformin use was associated with lower risk of estrogen receptor (ER)-positive breast cancer.

  • By contrast, T2D with metformin use was associated with higher risk of ER-negative and triple-negative breast cancer.

  • Associations between T2D and breast cancer may be altered by metformin use and differ by hormone receptor status.

BACKGROUND: Type 2 diabetes (T2D) has been associated with increased breast cancer risk, but commonly prescribed antidiabetic medications such as metformin may reduce risk. Few studies have investigated T2D and medications together in relation to breast cancer.

PATIENTS AND METHODS: Data came from 44 541 Sister Study participants aged 35 to 74 years at enrollment (2003-2009) who satisfied eligibility criteria, followed through 15 September 2017. Information on time-varying, self-reported, physician-diagnosed, prevalent and incident T2D, use of antidiabetic medications, and covariates was obtained from baseline and follow-up questionnaires. Incident breast cancers were confirmed with medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated.

RESULTS: During follow-up (median, 8.6 years), 2678 breast cancers were diagnosed at least 1 year after enrollment. There were 3227 women (7.2%) with prevalent and 2389 (5.3%) with incident T2D, among whom 61% (n = 3386) were ever treated with metformin. There was no overall association between T2D and breast cancer risk (HR 0.99; 95% CI, 0.87-1.13). However, T2D was associated with increased risk of triple-negative breast cancer (HR 1.40; 95% CI, 0.90-2.16). Compared with not having T2D, T2D with metformin use was not associated with overall breast cancer risk (HR 0.98; 95% CI, 0.83-1.15), but it was associated with decreased risk of estrogen receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple-negative breast cancer (HR 1.74; 95% CI, 1.06-2.83). The inverse association with ER-positive cancer was stronger for longer duration (≥10 year) metformin use (HR 0.62; 95% CI, 0.38-1.01; P for trend = 0.09). Results were supported by sensitivity analyses.

CONCLUSION: Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use.

KEYWORDS: type 2 diabetes; metformin; antidiabetic medication; breast cancer; estrogen receptor; triple-negative

DOI: 10.1016/j.annonc.2020.12.008

Ann Oncol. 2021 Jan 28. Online ahead of print.

Diabetes, metformin and breast cancer: a tangled web.

Lohmann AE, Goodwin PJ.

London Health Sciences Centre, University of Western Ontario, London, Canada; Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Canada.

DOI: 10.1016/j.annonc.2020.12.014

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