title: Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature.
abstract: BACKGROUND
  Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.
  
  
  METHODS
  197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.
  
  
  RESULTS
  A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91-8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90-99%) and 72% (64-78%) respectively, for DMFS and 91% (84-95%) and 68% (61-75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86-15.14).
  
  
  CONCLUSIONS
  The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.
authors.affiliation: Breakthrough Breast Cancer Research Unit, King's College, London, UK. andrew.tutt@icr.ac.uk
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.forename: Alice
authors.initials: A
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Rowland
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gillett
authors.forename: Kit
authors.initials: K
authors.lastname: Lau
authors.forename: Karen
authors.initials: K
authors.lastname: Chew
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: Shirley
authors.initials: S
authors.lastname: Kwok
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ryder
authors.forename: Henry
authors.initials: H
authors.lastname: Shu
authors.forename: Robert
authors.initials: R
authors.lastname: Springall
authors.forename: Paul
authors.initials: P
authors.lastname: Cane
authors.forename: Blair
authors.initials: B
authors.lastname: McCallie
authors.forename: Lauren
authors.initials: L
authors.lastname: Kam-Morgan
authors.forename: Steve
authors.initials: S
authors.lastname: Anderson
authors.forename: Horst
authors.initials: H
authors.lastname: Buerger
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.forename: James
authors.initials: J
authors.lastname: Bennington
authors.forename: Laura
authors.initials: L
authors.lastname: Esserman
authors.forename: Trevor
authors.initials: T
authors.lastname: Hastie
authors.forename: Samuel
authors.initials: S
authors.lastname: Broder
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
authors.forename: Fred
authors.initials: F
authors.lastname: Waldman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000150:complications* / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D016016:Proportional Hazards Models; D012372:ROC Curve; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods*; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D011960:Receptors, Estrogen