A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer

Clin Cancer Res. 2008 May 1;14(9):2601-8. doi: 10.1158/1078-0432.CCR-07-5026.

Abstract

Purpose: Histologic tumor grade is a well-established prognostic factor for breast cancer, and tumor grade-associated genes are the common denominator of many prognostic gene signatures. The objectives of this study are as follows: (a) to develop a simple gene expression index for tumor grade (molecular grade index or MGI), and (b) to determine whether MGI and our previously described HOXB13:IL17BR index together provide improved prognostic information.

Experimental design: From our previously published list of genes whose expression correlates with both tumor grade and tumor stage progression, we selected five cell cycle-related genes to build MGI and evaluated MGI in two publicly available microarray data sets totaling 410 patients. Using two additional cohorts (n = 323), we developed a real-time reverse transcription PCR assay for MGI, validated its prognostic utility, and examined its interaction with HOXB13:IL17BR.

Results: MGI performed consistently as a strong prognostic factor and was comparable with a more complex 97-gene genomic grade index in multiple data sets. In patients treated with endocrine therapy, MGI and HOXB13:IL17BR modified each other's prognostic performance. High MGI was associated with significantly worse outcome only in combination with high HOXB13:IL17BR, and likewise, high HOXB13:IL17BR was significantly associated with poor outcome only in combination with high MGI.

Conclusions: We developed and validated a five-gene reverse transcription PCR assay for MGI suitable for analyzing routine formalin-fixed paraffin-embedded clinical samples. The combination of MGI and HOXB13:IL17BR outperforms either alone and identifies a subgroup ( approximately 30%) of early stage estrogen receptor-positive breast cancer patients with very poor outcome despite endocrine therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Validation Study

MeSH terms

  • Autoantigens / genetics
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone / genetics
  • Cohort Studies
  • Gene Expression Profiling
  • Genes, Neoplasm
  • Homeodomain Proteins / genetics
  • Humans
  • Kaplan-Meier Estimate
  • NIMA-Related Kinases
  • Prognosis
  • Proportional Hazards Models
  • Protein-Serine-Threonine Kinases / genetics
  • Receptors, Interleukin / genetics
  • Ribonucleoside Diphosphate Reductase / genetics

Substances

  • Autoantigens
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone
  • HOXB13 protein, human
  • Homeodomain Proteins
  • IL17RB protein, human
  • Receptors, Interleukin
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • Bub1 spindle checkpoint protein
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases