Purpose: About 50% of breast cancers are defined as HER2-low HER2-0 MBC. There were no differences in ERBB2 alterations and may benefit from HER2-directed antibody–drug conjugates. or oncogenic pathways between HER2-low and HER2-0 MBC. While tissue sequencing has evaluated potential differences in genomic Patients with HER2-positive MBC had more ERBB2 alterations profiles for patients with HER2-low breast cancer, genetic alterations in (RRR, 12.43; P ¼ 0.002 for amplification; RRR, 3.22; P ¼ 0.047 for circulating tumor DNA (ctDNA) have not been well described. mutations, in the hormone receptor–positive cohort), fewer ERS1 Experimental Design: We retrospectively analyzed 749 patients mutations (RRR, 0.458; P ¼ 0.029), and fewer ER pathway alterawith metastatic breast cancer (MBC) and ctDNA evaluation by tions (RRR, 0.321; P < 0.001). There was no difference in OS for Guardant360 from three academic medical centers. Tumors were HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-(CI), 0.79–1.29], while OS was improved in HER2-positive MBC nucleotide variants, copy-number variants, and oncogenic path-(HR, 0.32; 95% CI, 0.21–0.49; P < 0.001). ways were compared across the spectrum of HER2 expression. Conclusions: We observed a higher rate of PIK3CA mutations, Overall survival (OS) was evaluated by HER2 status and according but no significant difference in ERBB2 alterations, oncogenic path-to oncogenic pathways. ways, or prognosis, between patients with HER2-low and HER2-0 Results: Patients with HER2-low had higher rates of PIK3CA MBC. If validated, our findings support the conclusion that mutations [relative risk ratio (RRR), 1.57; P ¼ 0.024] compared with HER2-low MBC does not represent a unique biological subtype.