A precision medicine basis for estrogen therapy for advanced breast cancer

表达雌激素受体α(ER)而不表达HER2(ER+/HER2-)的乳腺肿瘤占大多数 乳腺癌的复发和死亡。在早期疾病患者中，抗雌激素治疗 抑制ER活性可防止癌症复发，但约33%的患者(每年约30万名女性确诊) 最终发展为复发性疾病。晚期/转移性乳腺癌采用进一步的抗肿瘤药物治疗 雌激素治疗、靶向治疗和DNA损伤化疗。几乎所有的转移性乳腺 癌症最终会对这些疗法变得完全难以治愈。在他莫昔芬获得批准之前， 雌激素经常用于乳腺癌的治疗。这似乎有违常理，因为我们 现在依靠抗雌激素进行疾病管理，但对雌激素的应答率与 晚期疾病背景下的抗雌激素治疗。大约三分之一的抗雌激素耐药乳腺癌 对雌激素治疗的反应，转化为每年可受益的约100,000名新患者。同样， 一些癌症对停用抗雌激素治疗有反应，这可能是由ER重新激活引起的。乳房 肿瘤对雌激素治疗的反应和抗雌激素撤除已经观察了70年，但是 缺乏A)对治疗机制的了解(S)，以及B)确定可能受益的患者的标准 已经阻碍了临床应用。使这种廉价、可广泛使用、经过时间考验、相对安全和 可耐受的治疗选择，并提供精准医学基础，将其限制在癌症患者使用 可能的回应是，需要解决以下关键问题：1)理解机制(S) 抗雌激素耐药乳腺癌对雌激素治疗和抗雌激素药物的潜在敏感性 停药；2)确定预测ER重新激活治疗受益的肿瘤标志物；3)确定 增强反应的策略；4)了解治疗反应/耐药的动态。我们 假设在适应抗雌激素和雌激素剥夺的过程中，ER+乳腺癌细胞获得 使雌激素依赖的内质网重新激活的分子变化具有蛋白毒性和危害性。我们将测试 这一假设通过以下具体目的：1)确定内质网转录的有限窗口是否 激活促进乳腺癌细胞的生长，以及这一窗口如何随着抗雌激素的获得而改变 抗性；2)确定内质网重新激活如何引起蛋白毒性应激依赖的细胞死亡；3)确定 抗雌激素抵抗乳房逃避17b-雌二醇治疗的最佳剂量、持续时间和机制 肿瘤；4)确定预测17b-雌二醇治疗反应的基线和药效学生物标志物 抗雌激素耐药乳腺癌患者。

Breast tumors expressing estrogen receptor alpha (ER) but not HER2 (ER+/HER2-) account for the majority of recurrences and deaths from breast cancer. In patients with early-stage disease, anti-estrogen therapies that suppress ER activity prevent cancer recurrence, but ~33% of patients (~300,000 women diagnosed each year) eventually develop recurrent disease. Advanced/metastatic breast cancer is managed with further anti- estrogen therapies, targeted therapies, and DNA-damaging chemotherapies. Nearly all metastatic breast cancers eventually become completely refractory to these therapies. Prior to the approval of tamoxifen, estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly, some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER reactivation. Breast tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but the lack of A) understanding of therapeutic mechanism(s), and B) criteria to identify patients likely to benefit have hindered clinical use. To legitimize this inexpensive, widely accessible, time-tested, relatively safe and tolerable treatment option, and to provide a precision medicine basis to limit its use to patients with cancers likely to respond, the following critical issues need to be addressed: 1) understanding the mechanism(s) underlying sensitivity of anti-estrogen-resistant breast cancers to estrogen therapy and anti-estrogen withdrawal; 2) identifying tumor markers that predict benefit from ER reactivation therapy; 3) identifying strategies to enhance response; 4) understanding the dynamics of therapeutic response/resistance. We hypothesize that during adaptation to anti-estrogens and estrogen deprivation, ER+ breast cancer cells acquire molecular changes that render estrogen-dependent ER reactivation proteotoxic and deleterious. We will test this hypothesis through the following Specific Aims: 1) Determine whether a finite window of ER transcriptional activation promotes growth of breast cancer cells, and how this window shifts with acquisition of anti-estrogen resistance; 2) Determine how ER reactivation elicits proteotoxic stress-dependent cell death; 3) Determine the optimal dose, duration, and mechanisms of escape from 17b-estradiol therapy in anti-estrogen-resistant breast tumors; 4) Identify baseline and pharmacodynamic biomarkers that predict response to 17b-estradiol therapy in patients with anti-estrogen-resistant breast cancer.