title: Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.
abstract: BACKGROUND
  Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999).
  
  
  METHODS
  Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis.
  
  
  RESULTS
  Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002).
  
  
  CONCLUSIONS
  BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.
authors.affiliation: Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. dsgroi@partners.org.|Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. dsgroi@partners.org.|Department of Pathology, Harvard Medical School, Boston, MA, USA. dsgroi@partners.org.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada. jachapma@aol.com.
authors.forename: Judy-Anne W
authors.initials: JA
authors.lastname: Chapman
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. tbadovin@gmail.com.
authors.forename: T
authors.initials: T
authors.lastname: Badovinac-Crnjevic
authors.affiliation: Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. e.richardson9@gmail.com.|Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. e.richardson9@gmail.com.|Department of Pathology, Harvard Medical School, Boston, MA, USA. e.richardson9@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zarella
authors.affiliation: Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA. shemeicabinns@gmail.com.|Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. shemeicabinns@gmail.com.|Department of Pathology, Harvard Medical School, Boston, MA, USA. shemeicabinns@gmail.com.
authors.forename: Shemeica
authors.initials: S
authors.lastname: Binns
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA. yi.zhang@biotheranostics.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: bioTheranostics, Inc., San Diego, CA, USA. cathy.schnabel@biotheranostics.com.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Schnabel
authors.affiliation: Trovagene Inc., San Diego, CA, USA. merlander@trovagene.com.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Sunnybrook Odette Cancer Centre and University of Toronto, Toronto, ON, Canada. kathy.pritchard@sunnybrook.ca.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada. lhan@ctg.queensu.ca.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, ON, Canada. lshepherd@ctg.queensu.ca.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. pgoss@partners.org.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.affiliation: Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada. pollak-lab.oncology@mcgill.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology; D008875:Middle Aged; D015282:Octreotide / Q000008:administration & dosage; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053722:Receptors, Interleukin-17; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C408922:IL17RB protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D013629:Tamoxifen; D015282:Octreotide