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.

PUBLIC HEALTH RELEVANCE: To address a major gap in knowledge regarding long-term trends in breast cancer tumor profiles, overall and in relation to race/ethnicity and socioeconomic position, our proposed secondary analysis will add new assays-for DNA copy number alteration-to our pilot study that is assessing the feasibility, using data from the United States and New Zealand, of: (1) locating breast cancer patients' tumor specimens and medical charts, dating back to the 1940s up through 2010, and (2) using current biomarker assays on the older as well as more recent tumor specimens, so as to determine (3) if it is feasible to conduct a well-designed and sufficiently large cross-country investigation of long-term trends in breast cancer tumor profiles and racial/ethnic and socioeconomic disparities in these biomarkers. The value of these long-term data is that they can uniquely reveal what aspects of tumor biology are amenable to change. Knowledge produced by the proposed study has the potential to change significantly concepts, methods, and preventive interventions regarding US socioeconomic and racial/ethnic disparities in breast cancer, thereby addressing priorities of the "Health Disparities Research" agenda of the National Cancer Institute's Center to Reduce Cancer Health Disparities.