Admin Suppl Gender-affirming estrogen therapy and breast cancer treatment outcome

项目摘要 我们的母公司R21赠款(R21 CA267088)是为了了解变性女性患者的风险和 乳腺癌(BC)期间继续性别肯定雌激素治疗(ET)的好处 治疗。变性女性在出生时被指定为男性，大多数人追求ET来确认他们的 女性身份。随着变性人人口的增加，将有相当数量的 跨性别者在未来20到50年内随着年龄的增长而面临患癌症的风险。为 被诊断为BC的变性患者，他们是否能继续下去没有临床指南 在BC治疗期间接受ET治疗，以及ET是否影响BC的预后。这个 对于变性人来说，停止使用性别肯定激素是不可取的，因为它 极大地影响他们的情绪健康和身体形象，并加剧他们的癌症诱因 精神上的痛苦。为了解决临床上的风险和益处问题， 变性患者在BC治疗期间继续ET，我们父母R21的总体策略 是使用三种BC小鼠模型-Pik3camut、Brca1mut或Tp53mut-来理解 ET对BC治疗结局的影响。我们将比较肿瘤生长速度，乳腺组织学， 以及在BC期间继续和停止ET的雄鼠之间的治疗结果 使用alpelisib(对于Pik3camut肿瘤)、olaparib(对于BRCA mut肿瘤)或eribuin(对于 Tp53抑制肿瘤)。在第一年，我们完成了Brca1mut肿瘤和奥拉帕利的实验 治疗。在第二年的上半年，我们将专注于完成Tp53mut的实验 肿瘤来补充我们的Brca1mut发现。这将使我们能够大致了解 ET如何影响雌激素受体阴性(ER-)BC治疗。本副刊提出三点建议 额外的分子分析来解释我们对Brca1mut和Tp53mut肿瘤模型的发现：1)到 用质谱仪测定肿瘤中奥拉帕利布/淫羊藿苷的水平；2)对ER-肿瘤进行轮廓分析 利用RNAseq鉴定性别和性激素相关的影响分子机制 BC治疗结果；以及3)评估性别和/或性激素对肿瘤的影响 免疫环境采用多重免疫荧光染色。总体而言，我们的工作将 有直接和即时的临床翻译，以告知ER-BC治疗选项和决定 对于变性女性群体来说。我们的发现也将告诉我们为什么在男性中发生BC 比女性更具攻击性，从而改进了对顺性男性和 患有不列颠哥伦比亚省的女性也是。

Project Summary Our parent R21 grant (R21 CA267088) was to understand transfeminine patients’ risks and benefits of continuing gender-affirming estrogen therapy (ET) during their breast cancer (BC) treatment. Transfeminine individuals are assigned male at birth and most pursue ET to affirm their feminine identity. As the transgender population increases, there will be a substantial number of transgender individuals at risk for cancer as they age within the next 20 to 50 years. For transfeminine patients diagnosed with BC, there is no clinical guideline whether they can continue receiving ET during BC treatment, and whether ET affects their BC prognosis. The discontinuation of gender-affirming hormones for a transgender individual is undesirable as it greatly affects their emotional well-being and body image, and compounds their cancer-induced emotional distress. In order to address the clinical question of the risks and benefits of transfeminine patients continuing ET during BC treatment, the overall strategy of our parent R21 was to use three mouse models of BC—Pik3camut, Brca1mut, or Tp53mut—to understand the effect of ET on BC treatment outcomes. We will compare tumor growth rates, breast histology, and treatment outcomes between male mice that continue and discontinue ET during BC treatment with alpelisib (for Pik3camut tumors), olaparib (for Brca mut tumors), or eribulin (for Tp53mut tumors). In Year 1, we completed the experiments for Brca1mut tumors and olaparib treatment. For the first half of Year 2, we will focus on completing experiments for Tp53mut tumors to complement our Brca1mut findings. This will allow us to obtain a general overview of how ET affects estrogen receptor negative (ER-) BC treatment. This supplement proposes three additional molecular assays to explain our findings for Brca1mut and Tp53mut tumor models: 1) to measure olaparib/eribulin levels in the tumors using mass spectrometry; 2) to profile ER- tumors using RNASeq to identify gender and sex-hormone related molecular mechanisms influencing BC treatment outcomes; and 3) assess the effect of gender and/or sex-hormone on tumor immune contexture using multiplex immunofluorescence staining. Collectively, our work will have direct and immediate clinical translation to inform ER- BC treatment options and decisions for the transfeminine community. Our findings will also inform us why BC occurring in males are more aggressive than in females, thus improving treatment strategies for cisgender men and women with BC as well.