AbstractIntroductionWe explored characteristics and clinical outcomes of HER2‐negative and HER2‐low metastatic breast cancers using real‐world data.MethodsWe queried the National Cancer Database to identify MBC patients that were HER2‐low or HER2‐negative per immunohistochemical staining. A binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA) and propensity‐match analysis were performed to identify correlates of survival.ResultsExcluding missing data, 24,636 MBC patients diagnosed between 2008 and 2015 were identified; 27.9% were HER2‐negative and 72.1% were HER2‐low. There were no relevant demographic differences between the groups. HER2‐low tumors were half as likely to have concomitant hormone receptor‐positive status (p < 0.01). The 3‐year survival rate among hormone receptor‐negative patients was 33.8% for HER2‐low and 32.2% for HER2‐negative (p < 0.05), and 60.9% and 55.6% in HER2‐low and HER2‐negative cases among hormone receptor‐positive patients (p < 0.05), respectively. HER2‐low cases were associated with better survival on MVA (HR =0.95, 95% CI 0.91–0.99) and remained superior with propensity‐matching (HR = 0.92, 95% CI 0.89–0.96). In a subset analysis isolated to hormone receptor‐positive cases, HER2‐low remained correlated with improved survival (HR = 0.93, 95% CI 0.89–0.98) with propensity‐matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02, 95% CI 1.02–1.02) and Black race (HR = 1.26, 95% CI 1.20–1.32) [all p < 0.01].ConclusionsIn the largest such analysis performed to date, our study demonstrates a small but statistically significant association with improved survival for HER2‐low tumors compared to HER2‐negative tumors in MBC.