The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

  • Zwiener I
  • Frisch B
  • Binder H
 et al. 
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Abstract

PURPOSE To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression-based "intrinsic" subtypes luminal A, luminal B, HER2-enriched, and basal-like. METHODS A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. RESULTS: The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%. CONCLUSION Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy.

Author-supplied keywords

  • Breast cancer
  • Cell lines
  • Copy number alteration
  • DNA mutation
  • Heterogeneous
  • MRNA expression
  • Molecular portraits
  • PDX
  • Reverse-phase protein array
  • adp-ribose
  • advisory role
  • assay
  • biobank
  • calgb breast committee
  • cell line
  • charles m
  • claudin proteins
  • consultant
  • disclosures
  • drug development
  • drug screen
  • gene expression profiling
  • intellectual property rights
  • inventor or patent holder
  • microarray analysis
  • ownership interest
  • patent filed on pam50
  • patient-derived tumor organoids
  • patient-derived xenograft
  • perou
  • poly
  • polymerase
  • three-dimensional culture
  • triple-negative breast cancer
  • tumor organoids
  • university genomics

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Authors

  • Isabella Zwiener

  • Barbara Frisch

  • Harald Binder

  • A. Goodspeed

  • L. M. Heiser

  • J. W. Gray

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