Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers

J Clin Oncol. 2010 Oct 1;28(28):4316-23. doi: 10.1200/JCO.2009.27.2419. Epub 2010 Aug 30.

Abstract

Purpose: The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers.

Methods: We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients.

Results: We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value.

Conclusion: Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Antineoplastic Agents, Hormonal / therapeutic use
  • B-Lymphocytes / pathology
  • Biopsy, Fine-Needle
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Chi-Square Distribution
  • Collagen Type IV / genetics
  • Extracellular Matrix Proteins
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Metagenome / genetics
  • Neoplasm Recurrence, Local
  • Phospholipid Transfer Proteins / genetics
  • Prognosis
  • Proportional Hazards Models
  • Prospective Studies
  • Protease Nexins
  • Protein Serine-Threonine Kinases / genetics
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Cell Surface / genetics
  • Receptors, Estrogen / genetics*
  • Receptors, Transforming Growth Factor beta / genetics
  • Survival Analysis
  • Tamoxifen / therapeutic use

Substances

  • Amyloid beta-Protein Precursor
  • Antineoplastic Agents, Hormonal
  • COL4A2 protein, human
  • Collagen Type IV
  • ECM1 protein, human
  • Extracellular Matrix Proteins
  • PLTP protein, human
  • Phospholipid Transfer Proteins
  • Protease Nexins
  • Receptors, Cell Surface
  • Receptors, Estrogen
  • Receptors, Transforming Growth Factor beta
  • Tamoxifen
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II