Long-term trends in breast cancer DNA copy number alterations & disparities

 描述(由申请人提供)：在本R03中，我们建议增加DNA拷贝数改变的新检测方法，以使我们能够测试对可追溯到20世纪50年代的较老的乳腺肿瘤标本使用这些检测方法的可行性和可靠性。这些新的分析和分析将创新性地和显著地建立在我们资助的R21(5 R21 CA166115-02)的基础上，R21(5 R21 CA166115-02)专注于确定获取可追溯到20世纪50年代的乳腺癌肿瘤标本的可行性，以便研究肿瘤特征的趋势和这些特征的社会差异。我们的R21解决的重大问题是：缺乏关于乳腺癌肿瘤概况的长期趋势的数据，总体上以及按种族/民族和社会经济地位划分。正如最初的申请中所阐明的那样，这种长期数据可以唯一地揭示肿瘤生物学的哪些方面能够发生变化。相关的例子包括我们最近的一项研究，该研究记录了在1992至2005年间，美国乳腺癌病例中ER肿瘤的白人/黑人的赔率同样有升有降，这可能与2002年妇女健康倡议结果公布后激素治疗使用的变化有关。主要的影响是：(A)乳腺癌的生物学表现和社会模式远未固定，是可以改变的，(B)分析长期趋势的数据对于了解乳腺癌发病率、存活率和死亡率方面的种族/民族和社会经济差异的原因并减少这些差异具有重要意义。我们新提出的目标2d包括两个部分：目标2d1：从目标1获得的30个肿瘤块中提取DNA(1947-1959年至2000年-2009年，每十年随机抽取5个样本，从50岁的女性浸润性乳腺癌病例中随机选择-，从北加州凯撒永久(KP)研究部获得)；目标2d2：确定当前的DNA拷贝数改变检测方法是否可以有效地用于研究样本。新的检测方法是对AIMS 2a-c的补充，初步结果表明，所有标本都显示出良好的组织形态和关键免疫组织化学标志物：雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER2)、细胞角蛋白(CK)5/6、表皮生长因子受体(EGFR)和Ki67的适当取值和极好的重测可靠性，从而允许对分子表型进行分类。研究结果将为R21‘S目标3：确定AIMS 2的结果是否支持开发R01的可行性提供依据，以研究乳腺癌肿瘤分布的患病率以及种族/民族和社会经济差异的长期趋势(使用KP&NZ数据)，以及目标4：利用结果准备R01，以对乳腺癌肿瘤分布以及这些生物标记物中的种族/民族和社会经济差异的趋势进行首次长期和跨国(美国和新西兰)分析，这对预防和治疗具有重大意义。

 DESCRIPTION (provided by applicant): In this R03, we propose to add new assays for DNA copy number alteration, to allow us to test for feasibility and reliability of using these assays o older breast tumor specimens, dating back to the 1950s. These new assays and new analysis will innovatively and significantly build on our funded R21 (5 R21 CA166115-02), which is focusing on ascertaining the feasibility of obtaining breast cancer tumor specimens dating back to the 1950s, to allow for research on trends in both tumor characteristics and social disparities in these characteristics. The significant problem our R21 addresses is: the absence of data on long-term trends in breast cancer tumor profiles, overall and by race/ethnicity and socioeconomic position. As articulated in the original application, such long-term data can uniquely reveal what aspects of tumor biology are amenable to change. Relevant examples include our recent study documenting that between 1992 and 2005, the US white/black odds ratio for ER+ tumors among breast cancer cases likewise rose and fell, likely linked to changes in hormone therapy use after publication of the Women's Health Initiative results in 2002. Key implications are that: (a) the biological expression and social patterning of breast cancer, far from being fixed, can change, and (b) analyzing data on long-term trends has important implications for both understanding the causes of and reducing racial/ethnic and socioeconomic disparities in breast cancer incidence, survival, and mortality. Our newly proposed Aim 2d has two parts: Aim 2d1: extract DNA from the 30 tumor blocks obtained for Aim 1 (5 specimens per decade, from 1947-1959 to 2000-2009, randomly selected from invasive cases of breast cancer diagnosed among women age 50-64, obtained from the Kaiser Permanent (KP) Division of Research in Northern California); Aim 2d2: determine whether current assays for DNA copy number alteration can validly be employed with the study specimens. The new assays complement those for Aims 2a-c, for which preliminary results indicate all specimens displayed excellent histo-morphology and both appropriate values and excellent test-retest reliability for key immune-histo-chemical markers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), and Ki67, allowing for classification of molecular phenotypes. Results will inform the R21's Aim 3: Determine if results for Aims 2 support the feasibility of developing an R01 to study long-term trends in prevalence of - and racial/ethnic and socioeconomic disparities in - breast cancer tumor profiles (using the KP & NZ data), and Aim 4: use results to prepare an R01 to conduct the first long- term and cross-country (US and NZ) analysis of trends in breast cancer tumor profiles and racial/ethnic and socioeconomic disparities in these biomarkers, with major implications for prevention and treatment.