Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Shady Grove, Bethesda, MD, 20850, USA.
Molecular and Digital Pathology Laboratory, Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA.
Breast Cancer Res. 2023 Aug 15;25(1):97. doi: 10.1186/s13058-023-01692-7.
Emerging data indicate that variations in quantitative epithelial and stromal tissue composition and their relative abundance in benign breast biopsies independently impact risk of future invasive breast cancer. To gain further insights into breast cancer etiopathogenesis, we investigated associations between epidemiological factors and quantitative tissue composition metrics of the normal breast.
The study participants were 4108 healthy women ages 18-75 years who voluntarily donated breast tissue to the US-based Susan G. Komen Tissue Bank (KTB; 2008-2019). Using high-accuracy machine learning algorithms, we quantified the percentage of epithelial, stromal, adipose, and fibroglandular tissue, as well as the proportion of fibroglandular tissue that is epithelium relative to stroma (i.e., epithelium-to-stroma proportion, ESP) on digitized hematoxylin and eosin (H&E)-stained normal breast biopsy specimens. Data on epidemiological factors were obtained from participants using a detailed questionnaire administered at the time of tissue donation. Associations between epidemiological factors and square root transformed tissue metrics were investigated using multivariable linear regression models.
With increasing age, the amount of stromal, epithelial, and fibroglandular tissue declined and adipose tissue increased, while that of ESP demonstrated a bimodal pattern. Several epidemiological factors were associated with individual tissue composition metrics, impacting ESP as a result. Compared with premenopausal women, postmenopausal women had lower ESP [β (95% Confidence Interval (CI)) = -0.28 (- 0.43, - 0.13); P < 0.001] with ESP peaks at 30-40 years and 60-70 years among pre- and postmenopausal women, respectively. Pregnancy [β (95%CI) = 0.19 (0.08, 0.30); P < 0.001] and increasing number of live births (P < 0.001) were positively associated with ESP, while breastfeeding was inversely associated with ESP [β (95%CI) = -0.15 (- 0.29, - 0.01); P = 0.036]. A positive family history of breast cancer (FHBC) [β (95%CI) = 0.14 (0.02-0.26); P = 0.02], being overweight or obese [β (95%CI) = 0.18 (0.06-0.30); P = 0.004 and 0.32 (0.21-0.44); P < 0.001, respectively], and Black race [β (95%CI) = 0.12 (- 0.005, 0.25); P = 0.06] were positively associated with ESP.
Our findings revealed that cumulative exposure to etiological factors over the lifespan impacts normal breast tissue composition metrics, individually or jointly, to alter their dynamic equilibrium, with potential implications for breast cancer susceptibility and tumor etiologic heterogeneity.
新出现的数据表明，良性乳腺活检中定量上皮和基质组织成分的变化及其相对丰度独立影响未来浸润性乳腺癌的风险。为了更深入地了解乳腺癌的病因发病机制，我们研究了流行病学因素与正常乳腺组织成分定量指标之间的关系。
该研究的参与者是 4108 名年龄在 18-75 岁之间的健康女性，她们自愿向美国苏珊·科曼组织库（KTB；2008-2019 年）捐献乳腺组织。我们使用高精度机器学习算法，对数字化苏木精和伊红（H&E）染色的正常乳腺活检标本中上皮、基质、脂肪和纤维腺体组织的百分比，以及纤维腺体组织中相对于基质的上皮比例（即上皮与基质比例，ESP）进行了量化。通过在组织捐献时使用详细的问卷从参与者那里获得了流行病学因素的数据。使用多变量线性回归模型研究了流行病学因素与平方根变换组织指标之间的关系。
随着年龄的增长，基质、上皮和纤维腺体组织的数量减少，脂肪组织的数量增加，而 ESP 则呈现双峰模式。一些流行病学因素与个别组织成分指标有关，从而影响 ESP。与绝经前女性相比，绝经后女性的 ESP 较低[β（95%置信区间（CI））= -0.28（-0.43，-0.13）；P < 0.001]，ESP 峰值分别出现在绝经前和绝经后女性的 30-40 岁和 60-70 岁。妊娠[β（95%CI）= 0.19（0.08，0.30）；P < 0.001]和活产数的增加（P < 0.001）与 ESP 呈正相关，而母乳喂养与 ESP 呈负相关[β（95%CI）= -0.15（-0.29，-0.01）；P = 0.036]。乳腺癌家族史阳性（FHBC）[β（95%CI）= 0.14（0.02-0.26）；P = 0.02]、超重或肥胖[β（95%CI）= 0.18（0.06-0.30）；P = 0.004 和 0.32（0.21-0.44）；P < 0.001]以及黑种人[β（95%CI）= 0.12（-0.005，0.25）；P = 0.06]与 ESP 呈正相关。
我们的研究结果表明，一生中累积暴露于病因因素会影响正常乳腺组织成分的定量指标，这些指标单独或共同作用，改变其动态平衡，从而影响乳腺癌的易感性和肿瘤病因异质性。
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