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Glucocorticoids and breast cancer risk
BMC Medicine ( IF 7.0 ) Pub Date : 2021-08-02 , DOI: 10.1186/s12916-021-02036-y
Kelly A Hirko ₁ , A Heather Eliassen _{2,

3}

Affiliation

Glucocorticoids are essential endogenous steroid hormones secreted in response to stress, and treatment with synthetic forms is widespread for numerous inflammatory conditions including asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, and arthritis [1]. Emerging evidence suggests that glucocorticoids can exert both anti- and pro-inflammatory effects, modulated through suppressing or augmenting immune response [1]. Given these divergent biologic properties, glucocorticoids could theoretically reduce breast cancer risk via anti-inflammatory effects or could increase breast cancer risk and progression by inducing insulin resistance and promoting immunosuppression [2]. Yet, despite biological plausibility, epidemiologic studies of glucocorticoid use and breast cancer are limited.

As such, the recent prospective cohort study by Cairat et al. [3] is an important contribution to the literature as an investigation into the potential role of glucocorticoids in breast cancer etiology. In this study, authors evaluated associations between glucocorticoid use and breast cancer risk among over 65,000 postmenopausal French women in the E3N cohort. Using linkage to outpatient health expenditures, authors observed that receipt of at least two reimbursements of systemic glucocorticoids was associated with a reduced risk of invasive breast cancer, which appeared to follow a dose-response trend with increasing number of reimbursements. The observed associations did not differ substantially by type of glucocorticoid, or by timing or duration of use. However, inverse associations were significant only among women older than 60 years at first use. In stratified analyses, the inverse associations were restricted to estrogen receptor (ER)-positive tumors, and stage I and II disease. Interestingly, authors also observed positive associations between glucocorticoids and risk of in situ breast cancer and stage III/IV breast cancer, although confidence intervals for these measures of association were wide given smaller numbers of cases. In sensitivity analysis, only recurrent users (not occasional users) were at higher risk of in situ or stage III or IV disease and only recurrent users were at lower risk of stage I or II breast cancer. The authors conclude that the association between systemic glucocorticoid use and breast cancer risk may differ by tumor subtypes and stage of disease.

Unlike prior studies, Cairat et al. were able assess whether the associations of glucocorticoids and breast cancer differed according to hormone receptor status, histological subtype, tumor grade, and stage at diagnosis. This is particularly important given the various pharmacological properties of glucocorticoids and evidence for cross-talk between estrogen receptors and glucocorticoid receptors in mammary epithelial cells [4], which suggests that glucocorticoids could differentially impact breast cancer subtypes. An additional strength of this study was the inclusion of comprehensive information on potential confounders including body mass index, alcohol consumption, family history of breast cancer, and use of nonsteroidal anti-inflammatory medication; factors which were not considered in prior population registry-based studies in Denmark [5, 6] where no associations between receipt of glucocorticoid prescription and breast cancer risk were observed.

This study is informative in teasing apart heterogeneity in glucocorticoid-breast cancer associations by hormone receptor status to isolate the potential impact of estrogen pathways. As authors of this study note, estrogen inhibition induced by glucocorticoids may explain the lower risk of ER-positive tumors observed in this study. Moreover, given that ER-positive tumors tend to be less aggressive than ER-negative tumors, the inverse associations observed for early stage disease may reflect the preponderance of ER-positive tumors in this group. Systemic glucocorticoid use also affects immune system function and insulin sensitivity, which could induce adipose aromatase activity and estrogen production and also directly stimulate breast cancer cell growth and invasion [7], thereby facilitating breast cancer progression and later stage of disease at diagnosis. However, biological plausibility for the observed positive association between glucocorticoids and in situ disease is less clear. Although a possible explanation for this finding may be increased surveillance for women prescribed glucocorticoids, the results were similar when restricted to women with a recent mammogram. Further, that the increased risk of in situ disease corresponds with findings for later, but not earlier, stage invasive disease, is not likely to be explained by surveillance bias, but also complicates the biological plausibility of these findings. The conflicting findings in this study underscore the need for continued research to elucidate the complex interactions between chronic inflammation, obesity, and insulin resistance in breast cancer.

The potential impact of these findings are substantial, given the widespread and increasing use of glucocorticoids over the past several decades [8, 9], and the extensive global breast cancer burden with an estimated 2.3 million new cases diagnosed in 2020 [10]. However, it should be emphasized that research on the impact of glucocorticoids and breast cancer risk is still in a nascent stage. Indeed, this is the first study to evaluate whether the relationship between glucocorticoids and breast cancer differs according to hormone receptor status, histology, and tumor stage. Thus, results need to be confirmed in large epidemiologic studies with detailed information on tumor characteristics to address the small number of in situ, ER-negative, and late stage breast cancers included in the current study. If findings are confirmed in future studies, clinical implications will also need to consider both the risks and benefits of glucocorticoid use in clinical care.

In conclusion, this study’s findings are intriguing and merit follow-up to further characterize the potential role of glucocorticoids and other anti-inflammatory therapies in breast cancer etiology. Specifically, future studies recognizing the complex interplay between inflammation and adaptive immune response in breast cancer are needed to inform our understanding of etiology and the development of personalized medicine approaches in breast cancer.

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Affiliations

Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, 909 Fee Road, East Lansing, MI, 48824, USA
Kelly A. Hirko
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
A. Heather Eliassen
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
A. Heather Eliassen

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Hirko, K.A., Eliassen, A.H. Glucocorticoids and breast cancer risk. BMC Med 19, 187 (2021). https://doi.org/10.1186/s12916-021-02036-y

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Received: 14 June 2021
Accepted: 14 June 2021
Published: 02 August 2021
DOI: https://doi.org/10.1186/s12916-021-02036-y

Keywords

Glucocorticoids
Breast cancer
Estrogen receptor

中文翻译：

糖皮质激素和乳腺癌风险

糖皮质激素是应对压力而分泌的重要内源性类固醇激素，合成形式的治疗广泛用于治疗多种炎症性疾病，包括哮喘、慢性阻塞性肺病、炎症性肠病和关节炎[1]。新的证据表明，糖皮质激素可以发挥抗炎和促炎作用，并通过抑制或增强免疫反应进行调节[1]。鉴于这些不同的生物学特性，糖皮质激素理论上可以通过抗炎作用降低乳腺癌风险，或者可以通过诱导胰岛素抵抗和促进免疫抑制来增加乳腺癌风险和进展[2]。然而，尽管具有生物学合理性，但糖皮质激素使用和乳腺癌的流行病学研究仍然有限。

因此，Cairat 等人最近的前瞻性队列研究。 [3] 作为对糖皮质激素在乳腺癌病因学中潜在作用的研究，这是对文献的重要贡献。在这项研究中，作者评估了 E3N 队列中超过 65,000 名绝经后法国女性的糖皮质激素使用与乳腺癌风险之间的关联。通过与门诊医疗支出的联系，作者观察到，接受至少两次全身性糖皮质激素报销与浸润性乳腺癌风险降低相关，随着报销次数的增加，这似乎遵循剂量反应趋势。观察到的关联性在糖皮质激素类型、使用时间或持续时间方面没有显着差异。然而，仅在首次使用时年龄超过 60 岁的女性中，负相关性才显着。在分层分析中，负相关仅限于雌激素受体（ER）阳性肿瘤以及 I 期和 II 期疾病。有趣的是，作者还观察到糖皮质激素与原位乳腺癌和 III/IV 期乳腺癌的风险之间存在正相关，尽管考虑到病例数量较少，这些关联指标的置信区间很宽。在敏感性分析中，只有经常使用者（不是偶尔使用者）患原位或 III 期或 IV 期乳腺癌的风险较高，只有经常使用者患 I 期或 II 期乳腺癌的风险较低。作者得出的结论是，全身性糖皮质激素的使用与乳腺癌风险之间的关联可能因肿瘤亚型和疾病阶段而异。

与之前的研究不同，Cairat 等人。我们能够根据激素受体状态、组织学亚型、肿瘤分级和诊断分期来评估糖皮质激素与乳腺癌的关联是否有所不同。考虑到糖皮质激素的各种药理学特性以及乳腺上皮细胞中雌激素受体和糖皮质激素受体之间的串扰证据，这一点尤其重要[4]，这表明糖皮质激素可能对乳腺癌亚型产生不同的影响。这项研究的另一个优点是包含了潜在混杂因素的综合信息，包括体重指数、饮酒量、乳腺癌家族史以及非甾体类抗炎药物的使用；丹麦之前基于人口登记的研究没有考虑这些因素[5, 6]，这些研究没有观察到接受糖皮质激素处方与乳腺癌风险之间存在关联。

这项研究通过激素受体状态来梳理糖皮质激素与乳腺癌关联的异质性，以分离雌激素途径的潜在影响，提供了丰富的信息。正如本研究的作者指出的那样，糖皮质激素诱导的雌激素抑制可能解释了本研究中观察到的 ER 阳性肿瘤风险较低的原因。此外，鉴于 ER 阳性肿瘤往往比 ER 阴性肿瘤更具侵袭性，观察到的早期疾病的负相关可能反映了该组中 ER 阳性肿瘤的优势。全身使用糖皮质激素还会影响免疫系统功能和胰岛素敏感性，从而诱导脂肪芳香酶活性和雌激素产生，并直接刺激乳腺癌细胞生长和侵袭[7]，从而促进乳腺癌进展和诊断时的晚期疾病。然而，所观察到的糖皮质激素与原位疾病之间的正相关性的生物学合理性尚不清楚。尽管这一发现的可能解释可能是增加了对服用糖皮质激素的女性的监测，但当仅限于最近接受乳房X光检查的女性时，结果相似。此外，原位疾病风险的增加与后期而非早期侵袭性疾病的发现相对应，这不可能用监测偏差来解释，而且也使这些发现的生物学合理性变得复杂化。这项研究中相互矛盾的发现强调需要继续研究以阐明乳腺癌中慢性炎症、肥胖和胰岛素抵抗之间复杂的相互作用。

鉴于过去几十年来糖皮质激素的广泛使用和不断增加[8, 9]，以及全球乳腺癌负担广泛（预计 2020 年诊断出 230 万新病例），这些发现的潜在影响是巨大的 [10]。然而，应该强调的是，关于糖皮质激素和乳腺癌风险影响的研究仍处于起步阶段。事实上，这是第一项评估糖皮质激素与乳腺癌之间的关系是否因激素受体状态、组织学和肿瘤分期而异的研究。因此，结果需要在大型流行病学研究中得到证实，并提供有关肿瘤特征的详细信息，以解决当前研究中包括的少数原位、ER 阴性和晚期乳腺癌问题。如果这些发现在未来的研究中得到证实，临床意义还需要考虑在临床护理中使用糖皮质激素的风险和益处。

总之，这项研究的结果很有趣，值得后续研究，以进一步描述糖皮质激素和其他抗炎疗法在乳腺癌病因学中的潜在作用。具体来说，未来的研究需要认识到乳腺癌中炎症和适应性免疫反应之间复杂的相互作用，以帮助我们了解乳腺癌的病因学和个性化医疗方法的发展。

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文章 PubMed 谷歌学术

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