Primary breast cancer phenotypes associated with propensity for central nervous system metastases

BACKGROUND. There is anecdotal evidence that the incidence of central nervous system (CNS) metastases in breast cancer patients is increasing. It is unclear whether specific tumor biological properties or the use of systemic therapies influence this risk. METHODS. Using a database of 10,782 patients, 2685 patients were identified who experienced recurrence distantly. Clinical and biological features were analyzed in 2 ways: 1) patients who ever had versus those who never had CNS metastases, and 2) CNS metastases as the first site of recurrence versus those who had other sites. Correlations of survival after CNS metastasis with clinical and biologic features were also analyzed. RESULTS. In the ever versus never analysis, CNS metastases were significantly associated with younger age, premenopausal status, infiltrating ductal carcinoma histology (IDC), estrogen receptor (ER) and progesterone receptor (PR) negativity, low Bcl-2, high S-phase, aneuploidy, and altered p53. Tumor size, lymph node status, and use of adjuvant systemic therapy played little role. HER-2 overexpression was not associated with an increased risk in these patients (none of whom were treated with trastuzumab) (P =.91). However, epidermal growth factor receptor (EGFR) overexpression was associated with increased risk (P =.02). A multivariate analysis revealed ER negativity (odds ratio [OR] 2.8, P <.001), IDC histology (OR 2.5, P =.02), and young age (P <.001) as independent factors for CNS metastases. The clinical and biologic profiles of primary tumors with CNS metastases at first recurrence did not differ from those with CNS metastases after recurrence to other sites, except for HER-2 status. HER-2-positive tumors were not more likely to undergo recurrence initially in the CNS (P =.04). The median survival after CNS metastases was 5.5 months and HER-2-positive patients had a shorter survival. CONCLUSIONS. Younger patients with hormone receptor-negative, highly proliferative, genomically unstable, and p53-altered tumors were at increased relative risk for CNS metastases. HER-2 expression and adjuvant systemic therapies did not increase this risk.