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Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2
(HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival
by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first
primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010
to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site
of de novo metastasis, were examined using Chi-squared tests. Kaplan–Meier and Cox proportional hazards analyses were
used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular
subtypes. Compared to HR+/HER2−, patients with HR−/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain,
lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk
relative to HR+/HER2− was twice as high for triple-negative (hazard ratio = 2.02, 95% CI 1.89–2.16) and modestly lower
for HR+/HER2+ (hazard ratio = 0.83, 95% CI 0.78–0.88). The median survival difference between metastatic patients with
and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR−/HER2+, but only 10.9 months in
triple-negative and 5.2 months in HR+/HER2−. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+
breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype
and site of de novo metastasis may predict prognosis and guide treatment.