title: Surrogacy of tumor response and progression-free survival for overall survival in metastatic breast cancer resistant to both anthracyclines and taxanes.
abstract: BACKGROUND
  In breast cancer, the validity of surrogate endpoints for overall survival (OS) is a matter of controversy.
  
  
  METHODS
  In order to generate a hypothesis, we evaluated whether tumor response or progression-free survival (PFS) could be valid surrogates for OS in patients with metastatic breast cancer. Data from 30 patients were available from a phase II study of trastuzumab and capecitabine in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer resistant to both anthracyclines and taxanes. The proportional hazards (PH) model was applied to evaluate the relationship between OS and tumor response or PFS. In addition, to explore prognostic factors influencing OS or post-progression survival, the PH model with a stepwise regression procedure was applied.
  
  
  RESULTS
  The relationship between tumor response and PFS was highly significant (P = 0.0036); however, there was no significant relationship between tumor response and OS or between PFS and OS. In the multivariate analysis, the sum of the longest diameter of target lesions (P = 0.0011), neutrophil count (P = 0.0033), and creatinine (P = 0.0085) were statistically significantly associated with OS.
  
  
  CONCLUSIONS
  We generated a hypothesis that neither PFS nor tumor response were valid as surrogate endpoints for OS, at least in the phase II trial for metastatic breast cancer resistant to both anthracyclines and taxanes. We also found that the sum of the longest diameter of target lesions, neutrophil count, and creatinine were prognostic factors for OS.
authors.affiliation: Translational Research Informatics Center, 1-5-4 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. yoshihiro.matsubara@tri-kobe.org
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Satomi
authors.initials: S
authors.lastname: Sakabayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishimura
authors.forename: Takanori
authors.initials: T
authors.lastname: Ishida
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ohuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Teramukai
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D003404:Creatinine / Q000097:blood; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015996:Survival Rate; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D015415:Biomarkers; D003404:Creatinine; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C508053:ERBB2 protein, human