Tamoxifen & Second Breast Cancer: Epidemiology/Pathology

描述（由申请人提供）：鉴于乳腺癌的发病率和生存率正在增加，第二原发性或对侧乳腺癌（CBC）是一个日益重要的问题。他莫昔芬治疗可使CBC风险降低47%。然而，它只推荐用于雌激素受体阳性（ER+）乳腺癌的女性，因为它对雌激素受体阴性（ER-）肿瘤没有影响。不幸的是，所有ER+首次乳腺癌中有一半对他莫昔芬没有反应，并且大多数反应最终发展为他莫昔芬耐药性。初步数据显示，他莫昔芬使用者可能比预期产生更多的ER-CBC.因此，我们的目标之一是检验使用他莫昔芬会增加ER-CBC风险的假设。此外，虽然他莫昔芬降低了女性的ER+ CBC的风险，但许多接受他莫昔芬治疗的女性仍然会发生它。他莫昔芬抑制某些ER+ CBC的发展的机制，但不是全部，可能与ER或ER下游因子的表达改变有关，导致某些肿瘤中与他莫昔芬的相互作用改变。因此，本研究的第二个目的是评估他莫昔芬如何影响选定的他莫昔芬耐药相关因子的表达。与这些因素相关的发现可能指向其他机制，通过这些机制，耐药性可能会出现，并提高我们定制治疗的能力。我们建议对400名年龄在40-79岁之间被诊断为CBC的妇女和800名首次但从未被诊断为CBC的匹配对照进行一项基于人群的巢式病例对照研究。需要评估的具体问题是：（1）他莫昔芬治疗首次乳腺癌是否会影响ER-和ER+ CBC的风险？(2)他莫昔芬治疗首次乳腺癌如何改变CBC中导致他莫昔芬耐药的肿瘤标志物的表达？(3)这些肿瘤标志物的表达是否可以通过首次乳腺癌或其他患者特征预测哪些女性使用他莫昔芬会增加或减少发生CBC的风险？(4)在CBC病例中，与对侧癌症相比，他莫昔芬如何首先改变这些肿瘤标志物的表达？

DESCRIPTION (provided by applicant): Second primary or contralateral breast cancer (CBC) is an issue of growing importance given that breast cancer incidence and survival rates are increasing. Treatment with tamoxifen decreases risk of CBC by 47 percent. However, it is only recommended for women with estrogen receptor-positive (ER+) breast cancer, as it has no effect on estrogen receptor-negative (ER-) tumors. Unfortunately, half of all ER+ first breast cancers fail to respond to tamoxifen, and most that do respond eventually develop tamoxifen resistance. Preliminary data suggest that tamoxifen users may develop more ER- CBC's than expected. Thus, one of our objectives is to test the hypothesis that tamoxifen use increases risk of ER- CBC. Additionally, while tamoxifen reduces a woman's risk of ER+ CBC, many women treated with tamoxifen nonetheless do develop it. Mechanisms by which tamoxifen inhibits the development of some ER+ CBC's, but not all, may be related to altered expression of ER or factors downstream of the ER resulting in altered interaction with tamoxifen in some tumors. Thus, a second objective of this study is to evaluate how tamoxifen affects the expression of selected tamoxifen resistance-associated factors. Findings related to these factors may point toward additional mechanisms by which resistance may unfold and improve our ability to tailor treatments. We propose to conduct a population-based nested case-control study of 400 women aged 40-79 who have been diagnosed with CBC and 800 matched controls diagnosed with a first but never a CBC. The specific questions to be evaluated are: (1) Does tamoxifen therapy for a first breast cancer influence risk of ER- and ER+ CBC? (2) How does tamoxifen therapy for a first breast cancer alter the expression of tumor markers involved in pathways leading to tamoxifen resistance in CBC? (3) Do the expression of these tumor markers by first breast cancers or other patient characteristics predict which women have increased or decreased risks of developing CBC if they use tamoxifen? (4) Among the CBC cases, how does tamoxifen alter the expression of these tumor markers in first compared to contralateral cancers?