Abstract Background: Genomic analyses of patient tumors have unearthed an overwhelming number of recurrent somatic alterations in genes that have dramatic effects on tumor biology, patient drug responses, and clinical outcomes. In one study, high-grade triple negative breast cancer (TNBC) accounts for 34% of breast cancers in African American women versus 21% in white women. African American women have biologically more aggressive disease, independent of social determinants, and suffer the highest mortality rates. In advanced TNBC, a poor prognosis subtype, there is an urgent need to translate this emerging patient genomic data into new therapeutic paradigms. Objectives: Our study focuses on emerging compounds that are already approved (i.e., Dasatinib) or in testing for human use and we expect that this work will serve as a prelude to one or more clinical trials in TNBC. We seek to determine if the treatment of metastatic TNBC recurrence with more targeted genotype-specific agents could improve the outcomes/survival of all women in this particularly aggressive poor prognosis subset, including African American women. Methods: To guide the development of genotype-specific therapies in TNBC, we have established an isogenic cell-line drug screen that measures the impact of gene activation on a panel of emerging, clinically relevant compounds targeting a variety of cancer pathways. Using engineered isogenic cells, we generated an unbiased and quantitative chemical-genetic interaction map that measures the influence of 51 aberrant cancer genes on 90 drug responses. We believe that this approach can identify core synthetic lethal interactions, which underlie drug sensitivity and can be used as a foundation to identify patient populations that will selectively respond to drug treatments. Results: Using our systems approach, our interaction map highlights both known and novel connections between oncogene activation and drug responses and provides a modular roadmap for the exploration of synthetic lethal relationships. Applied to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene including resistance to AKT/PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic-lethal manner. Ensuring that the voice of the patient is represented in our scientific inquiry, advocacy has played a significant role in the development and realization of this project. Aligning experiential and professionalized expertise, trained advocates explore relentless challenges and opportunities for moving the science forward. Conclusion: A novel systems biology approach that uses module maps of oncogenes and emerging therapeutics can define synthetic-lethal interactions and actionable therapeutics to help decrease TNBC outcomes/survival disparities in African American women. Citation Format: Alicia Y. Zhou, Maria M. Martins, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan Shamji, Stuart Schreiber, Nevan J. Krogan, Kevan M. Shokat, Frank McCormick, Susan Samson, Andrei Goga, Sourav Bandyopadhyay. A systems approach combining genomics, advocacy, and emerging novel therapeutics to address triple-negative breast cancer (TNBC) outcomes disparities. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B44.