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

 描述（由申请人提供）：在本 R03 中，我们建议添加新的 DNA 拷贝数改变检测方法，以便我们能够测试在 20 世纪 50 年代的较旧乳腺肿瘤样本中使用这些检测方法的可行性和可靠性。这些新的测定和新的分析将创新地、显着地建立在我们资助的 R21 (5 R21 CA166115-02) 的基础上，该项目的重点是确定获取可追溯到 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 解决的重要问题是：缺乏关于乳腺癌肿瘤概况长期趋势的数据，总体上以及按种族/民族和社会经济地位划分的数据。正如原始申请中所述，此类长期数据可以独特地揭示肿瘤生物学的哪些方面值得改变。相关例子包括我们最近的研究，该研究记录了 1992 年至 2005 年间，美国乳腺癌病例中 ER 肿瘤的白人/黑人比值比同样上升和下降，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) 乳腺癌的生物表达和社会模式远未固定，可能会发生变化；(b) 分析长期趋势数据对于了解乳腺癌的成因具有重要意义。减少乳腺癌发病率、生存率和死亡率方面的种族/民族和社会经济差异。我们新提出的目标 2d 有两个部分：目标 2d1：从目标 1 获得的 30 个肿瘤块中提取 DNA（从 1947-1959 到 2000-2009 年，每十年 5 个样本，从 50-64 岁女性中诊断的侵袭性乳腺癌病例中随机选择，从北加州的 Kaiser Permanent (KP) 研究部门获得）； 目标 2d2：确定当前的 DNA 拷贝数改变测定是否可以有效地应用于研究样本。新的检测方法补充了 Aims 2a-c 的检测方法，初步结果表明，所有样本均显示出出色的组织形态学，并且关键免疫组织化学标记物的值适当，并且具有出色的重测可靠性：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，从而可以对分子进行分类表型。结果将告知 R21 的目标 3：确定目标 2 的结果是否支持开发 R01 的可行性，以研究乳腺癌肿瘤概况的患病率以及种族/民族和社会经济差异的长期趋势（使用 KP 和新西兰数据）；目标 4：使用结果准备 R01，以对乳腺癌肿瘤概况以及种族/民族和社会经济的趋势进行首次长期和跨国（美国和新西兰）分析这些生物标志物的差异，对预防和治疗具有重大影响。

 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.