title: Primary breast cancer phenotypes associated with propensity for central nervous system metastases.
abstract: 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.
authors.affiliation: Breast Care Center, Baylor College of Medicine and Methodist Hospital, Houston, Texas 77030, USA.
authors.forename: Yee-Lu
authors.initials: YL
authors.lastname: Tham
authors.forename: Krystal
authors.initials: K
authors.lastname: Sexton
authors.forename: Rita
authors.initials: R
authors.lastname: Kramer
authors.forename: Susan
authors.initials: S
authors.lastname: Hilsenbeck
authors.forename: Richard
authors.initials: R
authors.lastname: Elledge
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone