Abstract Background: Little is known regarding the effect of somatic tumor genomic testing on patient perceptions and psychological well-being. We previously demonstrated that patient perceptions of care can be negatively affected if their next cancer treatment is not supported by the genomic test. To further understand this, we investigated psychological effects of genomic testing, as well as sociodemographic and genomic comprehension factors that may attenuate these effects. Methods: In a prospective, single institution, single-arm trial, patients with metastatic breast cancer underwent next-generation sequencing (NGS) using Foundation Medicine at study entry, with sequencing results released to providers at time of next disease progression. We evaluated patient survey data before and after NGS, including questions about psychosocial characteristics, genetic comprehension, and perceived risks and expectations of the genomic testing. We evaluated psychosocial characteristics using 4 validated psychology measures: the Center for Epidemiologic Studies Depression Scale (CES-D), the Beck Anxiety Inventory (BAI), the Trust in Physician Scale (TPS), and the Communication and Attitudinal Self-Efficacy scale for Cancer (CASE-cancer). CASE-cancer measures self-efficacy, how confident patients are in their ability to navigate their cancer care. Genetic comprehension was assessed with a 7-question objective measure and a 6-question subjective measure. No formal genetic education was provided, but the informed consent process included an introduction to NGS. We included exploratory questions on perceived risks and expectations of NGS. Results: Among the 58 patients who completed the pre-NGS survey, we found high rates of depression (38%) and anxiety (47%) using validated metrics. Depression and anxiety were positively correlated (Pearson’s r=0.61; p<0.0001) but both were negatively correlated with self-efficacy (Pearson’s r=-0.43 and -0.42 for depression and anxiety, respectively; p=0.001 for both). Baseline genetic knowledge was significantly lower for non-white and lower income status patients (p=0.04 and 0.001, respectively). Genetic knowledge was not associated with any of the 4 validated psychological measures. The validated psychological measures were not associated with demographic characteristics, treatment decisions, or number of treatment options offered by the NGS test. The average time between pre-test and post-test surveys was 7.6 months. Additionally, the validated psychology measures did not significantly change from pre- to post-study (n=40 patients). However, there was a strong trend of self-efficacy decreasing from pre- to post-NGS testing (p=0.05). Subjectively, patients gained confidence in their ability to teach others about genetics from the start (33% “confident”) to the end of study (46%). Yet, objective comprehension of genetics remained modest throughout the study, with an average score of 72% in both the pre- and post-NGS surveys. The exploratory patient perception questions revealed that 33% of patients felt learning their cancer had a high chance of progressing would be too much to cope with emotionally. Conclusions: This is the first study, to our knowledge, to longitudinally evaluate multiple validated psychological metrics in MBC. NGS did not have a significant effect on depression, anxiety, or trust, but there was a trend towards decreased self-efficacy. This may be influenced by the already high rates of depression, anxiety, and trust in this population. In this study, patient genetic knowledge was limited and associated with race and income. These findings raise important questions about how to support MBC patient emotional well-being and how to improve comprehension of somatic genomic testing in future studies. Citation Format: Elizabeth J Adams, Sarah Asad, Mahmoud Abdel-Rasoul, Raquel E Reinbolt, Robert Wesolowski, Kaitlyn Tolliver, Susan Gillespie, Katherine A Collier, Anne Noonan, Sargar Sardesai, Jeffrey VanDeusen, Nicole Williams, Charles L Shapiro, Erin R Macre, Bhuvaneswari Ramaswamy, Clara N Lee, Maryam B Lustberg, Daniel G Stover. Perceptions of somatic genomic testing in patients with metastatic breast cancer: Psychosocial factors, emotional well-being, and genetic comprehension [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-10-03.