Metastatic phenotype and post-metastatic survival across HER2-0, HER2-low, and HER2-positive breast cancer.

PURPOSE: HER2-low breast cancer is treatment-relevant, but whether it is clinically distinct from HER2-0 disease remains unclear. We evaluate metastasis-free interval (MFI), first metastatic site, and survival after metastasis among HER2 classes in metastatic breast cancer. METHODS: We retrospectively examined patients with metastatic breast cancer classified as HER2-0, HER2-low, or HER2-positive. Analyses included the chi-square test of independence, Welch one-way ANOVA, Kaplan-Meier estimation, and binary and ordinal logistic and Cox regression models. RESULTS: Among 1,599 patients, 647 (40.5%) had HER2-0 tumors, 672 (42%) had HER2-low tumors, and 280 (17.5%) had HER2-positive tumors. HER2-positive tumors had the shortest MFI compared with HER2-low and HER2-0 tumors (median 2.7 vs. 3.3 vs. 3.7 years, respectively; p = 0.002) and lower odds of late recurrence (≥ 5 years) compared with HER2-0 tumors (OR 0.39, 95% CI 0.22-0.68). HER2-low and HER2-0 tumors had similar metastatic timing. First metastatic site differed across HER2 groups in unadjusted analyses, although HER2 status was not independently associated with bone-only or CNS-only presentation in adjusted binary models. In adjusted Cox regression, HER2-low disease (HR 0.85, 95% CI 0.74-0.97) and HER2-positive disease (HR 0.73, 95% CI 0.60-0.88) were associated with lower hazard of death compared with HER2-0 disease. CONCLUSION: HER2-positive disease was associated with earlier metastatic recurrence but more favorable post-metastatic survival. HER2-low disease had modestly improved post-metastatic survival but otherwise resembled HER2-0 disease in metastatic timing and adjusted metastatic presentation. These findings support HER2-low status for outcome stratification but suggest it may not independently define a distinct metastatic pattern. CLINICAL TRIAL NUMBER: Not applicable.