The translational goal of Project 4 is to identify markers of the DNA damage response (DDR) pathway that will improve our ability to predict outcome in breast cancer and prevent the over, or under, treatinent of disease. Our foundation for evaluating candidate markers of outcome is a population-based cohort of 2337 women (approximately 1900 with available tumors) ages 45-79 diagnosed with invasive breast cancer who are being followed for recurrence and death (QUILT Study). This well-characterized cohort, which was specifically designed to assess determinants of recurrence and mortality, offers unique benefits in elucidating insights into outcomes, including: comprehensive pre- and post-diagnostic exposure data, complete treatment and medical history data, flexibility and efficiency in examining different hypotheses, information on and ability to control for many different potential confounders, and inclusion of a broad spectrum of cases. Breast cancer morbidity and mortality is substantial and there is an acute need for additional tumor markers (beyond histopathology, ER and Her2) that can predict outcome, serve as therapeutic targets, and/or guide therapy in newly diagnosed patients. Compelling evidence, largely centered on p53, indicates that the DDR pathway is a promising (but understudied) source of clinical prognostic and predictive markers for breast cancer. The lack of a clinically tractable assay to assess DDR activity has inhibited investigations to date and also, because DDR involves both p53-dependent and p53-independent responses, p53 status alone is an insufficient measure of activity or functionality of the signal transduction cascade. We will conduct a comprehensive assessment of the DDR pathway activity in human breast cancers via a multi-analyte marker panel designed to capture DDR pathway function. We will assess the association of DDR activity with breast cancer prognosis and treatment response, using the population-based cohort described above.
Our specific aims are: (1) Using the QUILT Study population-based cohort and DDR markers identified from the literature and from discovery in Aim 2, test whether activation of the DNA damage response is predictive or prognostic in breast cancer;(2) Identify proteins and transcripts elevated upon activation of the DNA damage response in human mammary epithelial cells (ex vivo), and determine which of the responsive proteins are detectable in human breast cancer tissues.

Public Health Relevance

This project will investigate markers of DNA damage repair (DDR) pathway activity for their potential to predict future recurrence and death from breast cancer and to improve treatment decision-making. Candidate DDR markers will be tested for their relationship with recurrence and mortality in a wellcharacterized population-based cohort study of women with invasive breast cancer who are being followed for survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
O'Sullivan, Finbarr; O'Sullivan, Janet N; Huang, Jian et al. (2018) Assessment of a statistical AIF extraction method for dynamic PET studies with 15O water and 18F fluorodeoxyglucose in locally advanced breast cancer patients. J Med Imaging (Bellingham) 5:011010
Sorace, Anna G; Partridge, Savannah C; Li, Xia et al. (2018) Distinguishing benign and malignant breast tumors: preliminary comparison of kinetic modeling approaches using multi-institutional dynamic contrast-enhanced MRI data from the International Breast MR Consortium 6883 trial. J Med Imaging (Bellingham) 5:011019
Amornsiripanitch, Nita; Nguyen, Vicky T; Rahbar, Habib et al. (2018) Diffusion-weighted MRI characteristics associated with prognostic pathological factors and recurrence risk in invasive ER+/HER2- breast cancers. J Magn Reson Imaging 48:226-236
Balakrishnan, Ashwini; Goodpaster, Tracy; Randolph-Habecker, Julie et al. (2017) Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res 23:3061-3071
Wangerin, Kristen A; Muzi, Mark; Peterson, Lanell M et al. (2017) A virtual clinical trial comparing static versus dynamic PET imaging in measuring response to breast cancer therapy. Phys Med Biol 62:3639-3655
Rahbar, Habib; McDonald, Elizabeth S; Lee, Janie M et al. (2016) How Can Advanced Imaging Be Used to Mitigate Potential Breast Cancer Overdiagnosis? Acad Radiol 23:768-73
Sommermeyer, D; Hudecek, M; Kosasih, P L et al. (2016) Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30:492-500
Liu, Lingfeng; Sommermeyer, Daniel; Cabanov, Alexandra et al. (2016) Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy. Nat Biotechnol 34:430-4
Rahbar, Habib; Partridge, Savannah C (2016) Multiparametric MR Imaging of Breast Cancer. Magn Reson Imaging Clin N Am 24:223-238
Rahbar, Habib; Parsian, Sana; Lam, Diana L et al. (2016) Can MRI biomarkers at 3 T identify low-risk ductal carcinoma in situ? Clin Imaging 40:125-9

Showing the most recent 10 out of 54 publications