Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA 22908, United States.
J Steroid Biochem Mol Biol. 2013 Sep;137:150-6. doi: 10.1016/j.jsbmb.2013.05.008. Epub 2013 Jun 7.
An estimated 7% of 40-80 year old women dying of unrelated causes harbor occult breast tumors at autopsy. These lesions are too small to be detected by mammography, a method which requires tumors to be approximately 1cm in diameter to be diagnosed. Tumor growth rates, as assessed by "effective doubling times" on serial mammography range from 10 to >700 days with a median of approximately 200 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. One of our models is biologically based and includes parameters of a 200 day effective doubling time, 7% prevalence of occult tumors in the 40-80 aged female population and a detection threshold of 1.16 cm and the other involves computer based projections based on age related breast cancer incidence. Our models facilitate interpretation of the Women's Health Initiative (WHI) and anti-estrogen prevention studies. The biologically based model suggests that menopausal hormone therapy with conjugated equine estrogens plus medroxyprogesterone acetate (MPA) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. The paradoxical reduction of breast cancer incidence in women receiving estrogen alone is consistent with a model that this hormone causes apoptosis in women deprived of estrogen long term as a result of the cessation of estrogen production after the menopause. Understanding of the kinetics of occult tumors suggests that breast cancer "prevention" with anti-estrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our in vivo data suggest that the combination of a SERM, bazedoxifene (BZA), with conjugated equine estrogen (CEE) acts to block maturation of the mammary gland in oophorectomized, immature mice. This hormonal combination is defined by the generic term, tissue selective estrogen complex or TSEC. Xenograft studies with the BZA/CEE combination show that it blocks the growth of occult, hormone dependent tumors in nude mice. These pre-clinical data suggest that the BZA/CEE TSEC combination may prevent the growth of occult breast tumors in women. Based on the beneficial effects of this TSEC combination on symptoms and fracture prevention in menopausal women, the combination of BZA/CEE might be used as a means both to treat menopausal symptoms and to prevent breast cancer. This article is part of a Special Issue entitled 'CSR 2013'.
据估计，在因其他原因死亡的 40-80 岁女性中，有 7%在尸检时存在隐匿性乳腺癌。这些病变太小，无法通过乳房 X 光检查（一种需要肿瘤直径约 1 厘米才能诊断的方法）检测到。通过对连续乳房 X 光片进行“有效倍增时间”评估，肿瘤生长速度范围从 10 到 >700 天，中位数约为 200 天。我们之前根据这些参数的迭代分析报告了两种模型，以描述未确诊的隐匿性乳腺癌的生物学行为。我们的一个模型是基于生物学的，包括 200 天有效倍增时间、40-80 岁女性中 7%隐匿性肿瘤的患病率以及 1.16 厘米的检测阈值等参数，另一个模型则涉及基于年龄相关乳腺癌发病率的计算机预测。我们的模型有助于解释妇女健康倡议（WHI）和抗雌激素预防研究。基于生物学的模型表明，WHI 试验中用结合雌激素加醋酸美孕酮（MPA）进行的绝经后激素治疗主要促进了预先存在的隐匿性病变的生长，并最小程度地引发了新的肿瘤。接受单独雌激素治疗的女性乳腺癌发病率降低的现象与一种模型一致，即这种激素导致因绝经后雌激素产生停止而长期缺乏雌激素的女性发生细胞凋亡。对隐匿性肿瘤动力学的理解表明，用抗雌激素或芳香化酶抑制剂进行乳腺癌“预防”代表早期治疗，而不是减少新肿瘤的形成。我们的体内数据表明，选择性雌激素受体调节剂（SERM）巴多昔芬（BZA）与结合雌激素（CEE）的组合可阻止去卵巢、未成熟小鼠乳腺的成熟。这种激素组合被定义为组织选择性雌激素复合物或 TSEC。BZA/CEE 联合的异种移植研究表明，它可阻止裸鼠隐匿性、激素依赖性肿瘤的生长。这些临床前数据表明，BZA/CEE TSEC 联合可能预防女性隐匿性乳腺癌的生长。基于该 TSEC 联合对绝经后妇女症状和骨折预防的有益作用，BZA/CEE 联合可能既用于治疗绝经症状，也用于预防乳腺癌。本文是特刊“CSR 2013”的一部分。
