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

 描述（由申请方提供）：在本R 03中，我们建议增加新的DNA拷贝数改变检测试剂盒，以使我们能够检测这些检测试剂盒用于20世纪50年代早期乳腺肿瘤标本的可行性和可靠性。这些新的检测方法和新的分析方法将以我们资助的R21（5 R21 CA 166115 -02）为基础，具有创新性和显著性，该研究重点是确定获得可追溯到20世纪50年代的乳腺癌肿瘤标本的可行性，以研究肿瘤特征和这些特征中的社会差异的趋势。我们的R21解决的重要问题是：缺乏关于乳腺癌肿瘤概况的长期趋势的数据，总体上以及种族/民族和社会经济地位。正如在原始申请中所阐述的那样，这种长期数据可以独特地揭示肿瘤生物学的哪些方面可以改变。相关的例子包括我们最近的一项研究，该研究记录了1992年至2005年期间，美国乳腺癌病例中ER+肿瘤的白色/黑色比值比也同样上升和下降，这可能与2002年妇女健康倡议结果发表后激素治疗使用的变化有关。主要影响是：（a）乳腺癌的生物学表现和社会模式远非固定不变，而是可以改变的，（B）分析长期趋势数据对理解乳腺癌发病率、生存率和死亡率的原因和减少种族/民族和社会经济差异具有重要意义。我们新提出的目标2d有两个部分：目标2d 1：从目标1获得的30个肿瘤块中提取DNA（从1947-1959年至2000-2009年，每十年5个样本，从50-64岁女性中诊断的浸润性乳腺癌病例中随机选择，从北方加州的Kaiser Permanent（KP）研究部获得）;目标2d 2：确定当前的DNA拷贝数改变检测方法是否可有效用于研究标本。新的检测方法补充了目标2a-c的检测方法，其初步结果表明，所有标本均显示出良好的组织形态学，关键免疫组织化学标志物的数值适当且具有良好的重测可靠性：雌激素受体（ER）、孕酮受体（PR）、人表皮生长因子受体2（HER 2）、细胞角蛋白（CK）5/6、表皮生长因子受体（EGFR）和Ki 67，允许分子表型的分类。结果将告知R21的目标3：确定目标2的结果是否支持开发R 01的可行性，以研究乳腺癌肿瘤特征的患病率以及种族/民族和社会经济差异的长期趋势（使用金伯利进程和新西兰的数据）和目标4：使用结果准备R 01进行第一次长期和越野（美国和新西兰）分析乳腺癌肿瘤特征的趋势以及这些生物标志物的种族/民族和社会经济差异，对预防和治疗有重要意义。

 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.