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Purpose: To evaluate the psychosocial impact of semi-annual dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) screening in women at high-risk for breast cancer. Background: For women with BRCA1 and BRCA2 mutations and/or a personal or family history of breast cancer, annual breast MRI has shown improved sensitivity and cancer detection compared to mammography. However, MRI's heightened sensitivity may lead to increased: false positives requiring additional follow-up biopsy/imaging; iatrogenic risk; and psychosocial distress, which all may negatively impact women's overall health-related quality of life. Methods: Between 2004 and 2016, we assembled a prospective cohort of high-risk women undergoing semi-annual DCE-MRI and annual mammography. We reviewed a subset of this group. Participants completed psychosocial assessments at baseline and 6-month visits using the following measures: coping (MBSS); state/trait anxiety (STAI-S/T); depression (BDI-II); risk perception; and mental health (SF-36). Participants were classified according to Monitor or Blunter coping style. Mixed-effects logistic regressions models examined effects of demographics on psychosocial changes over time. Results: 295 women were recruited to the study; 44% of the study participants had pathogenic mutations in BRCA1 or BRCA2 genes. 232 of 295 enrolled participants (78.6%) completed psychosocial assessments. For the total population: median age 44y (range: 21-73), 71% ≥college/post-graduate education; 84% Caucasian; 8% African American; 2% Latino; 99% with health insurance; 72% annual income of >$60,000. One third of women had a personal cancer history. Participants were evenly split between baseline Monitoring and Blunting coping style (49% and 51%, respectively). No significant differences were found between demographics (age, race, income, mutation, cancer type, cancer history) or psychosocial factors (baseline trait anxiety (p =0.64), depression (p =0.65), SF36 global health (p=0.66). After adjusting for education, race, cancer history and coping, women with ≥$60,000 income had lower trait anxiety (p Conclusion: Semi-annual DCE-MRI did not cause a significantly elevated state anxiety or depression, nor was there a significant decline in mental health over time for groups regardless of cancer history and genetic mutation status. Coping style may have an impact on psychosocial outcomes for those undergoing heightened surveillance over time. Citation Format: Amico AL, Fang R, Raoul A, Wroblewski K, Nielsen S, Weipert C, Abe H, Sheth D, Romero I, Kulkarni K, Schacht D, Patrick-Miller L, Verp M, Bradbury AR, Hlubocky F, Olopade OI. Psychosocial impact of a multi-modality surveillance program for women at high-risk for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-04.

Rationale: Treatment of patients with triple-negative breast cancer (TNBC) remains challenging due to unpredictable disease progression and acquired resistance to chemotherapy. Finding novel targets in TNBC is important for the development of anticancer therapy. Cancer cells frequently adapt to cytotoxicity of existing pharmacological agents by exploiting metabolic pathways. Elevated copper metabolism and adaptations to oxidative stress have been linked to cancer progression. Copper chelation with tetrathiomolybdate (TM) was reported to control disease progression, especially in patients with TNBC. However, long-term consequences of global copper depletion are still under investigation. An alternative strategy is provided by a recently developed small molecule DCAC50 that blocks the copper transfer interface of two major copper chaperons, ATOX-1 and CCS. Protein levels of ATOX-1 and CCS are elevated in TNBC cells compared to normal cells. Thus, we hypothesized that disrupting copper transport by targeting ATOX-1 and CCS with DCAC50 may suppress TNBC progression. Results: We investigated efficacy and potency of novel small molecule DCAC50 to induce cytotoxicity in a panel of TNBC cells lines. DCAC50 reduced cell proliferation in dose-dependent manner, measured by MTS assay. IC50 doses ranged from 3-10uM. Most importantly, DCAC50 induced apoptosis in TNBC cells, detected by Caspase 3/7 activity and Annexin V/PI staining. As expected, DCAC50 elevated intracellular copper levels. Moreover, TNBC cells treated with DCAC50 had significantly higher levels of oxidized glutathione (GSSG) and caused increased oxidation of DCF-DA reagent, demonstrating elevated oxidative stress. Surprisingly, activity of CCS downstream target, SOD1, was not affected by selective inhibition of copper transport with DCAC50; suggesting that intracellular copper accumulation and oxidative stress is mediated by ATOX-1 inhibition. Interestingly, copper depletion with TM inhibited SOD1 activity but failed to significantly impact oxidative stress in TNBC cells. Recognizing DCAC50 generates oxidative stress triggering apoptosis in TNBC cells we evaluated benefits of combining DCAC50 treatment with paclitaxel. Multi-drug combination dose-response analysis revealed that co-treatment induced synergistic cytotoxicity and resulted in favorable dose reduction of both drugs. Conclusions: Selective inhibition of copper metabolism with novel small molecule DCAC50 elevates oxidative stress triggering apoptosis in TNBC cells. This approach may be valuable in combination with chemotherapy especially when tumor cells acquire resistance to first line therapy in TNBC. Ongoing studies comparing selective inhibition of copper transport to global copper chelation, and investigating efficacy and biological activity of DCAC50 in vivo will help further estimate benefits and clinical relevance of this approach for treatment of TNBC patients. Citation Format: Olga Karginova, Claire Weekley, Akila Raoul, Alhareth Alsayed, Tong Wu, Chuan He, Olufunmilayo I. Olopade. Selective inhibition of copper metabolism as a novel approach to treat triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3552. doi:10.1158/1538-7445.AM2017-3552