To phenotype the psychoneurologic (PN) symptom cluster in individuals with metastatic breast cancer and associate those phenotypes with individual characteristics and cancer genomic variables from circulating tumor DNA. This study included 201 individuals with metastatic breast cancer recruited in western Pennsylvania. A descriptive, cross-sectional design was used. Symptom data were collected via the MD Anderson Symptom Inventory, and cancer genomic data were collected via ultra-low-pass whole-genome sequencing of circulating tumor DNA from participant blood. Three distinct PN symptom phenotypes were described in a population with metastatic breast cancer: mild symptoms, moderate symptoms, and severe mood-related symptoms. Breast cancer TP53 deletion was significantly associated with membership in a moderate to severe symptoms phenotype (p = 0.013). Specific cancer genomic changes associated with increased genomic instability may be predictive of PN symptoms. This finding may enable proactive treatment or reveal new therapeutic targets for symptom management.