Multiplexed assessment of the Southwest Oncology Group-directed Intergroup Breast Cancer Trial S9313 by AQUA shows that both high and low levels of HER2 are associated with poor outcome

Am J Pathol. 2010 Apr;176(4):1639-47. doi: 10.2353/ajpath.2010.090711. Epub 2010 Feb 11.

Abstract

Assessment of key breast cancer tissue biomarkers is often done using nonquantitative methods. We hypothesized that use of continuous analysis of expression with the AQUA method of automated quantitative analysis will provide prognostic information beyond that attainable with conventional methods. A tissue microarray was made from 2123 of 3122 patients accrued to SWOG 9313, in which sequential doxorubicin (A) and cyclophosphamide (C) was compared with combination AC and in which all patients except premenopausal estrogen receptor (ER)-negative patients received tamoxifen. Multiplexed assays of 1) HER2 and estrogen receptor and 2) progesterone receptor (PgR) and p53 were performed on the two slides using the immunofluorescence-based AQUA method of automated quantitative analysis. Both ER and PgR showed unimodal distributions and significantly predicted disease-free survival when tested as continuous variables and adjusted for node status, tumor size, treatment, and menopausal status (P = 0.005 and P < 0.001, respectively). HER2, measured as a continuous variable, showed a biphasic effect on disease-free survival. Both high and low expressers of HER2 have worse outcomes (when low levels are equivalent to that seen in normal breast ducts). In patients who were uniformly treated with AC chemotherapy and tamoxifen (when indicated), both ER and PgR, assessed as continuous variables, were highly prognostic, whereas p53 expression was not. This assay method may provide a new companion diagnostic approach for targeted therapies.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Automation
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / therapy*
  • Chemotherapy, Adjuvant / methods
  • Disease-Free Survival
  • Female
  • Humans
  • Medical Oncology / methods
  • Microscopy, Fluorescence / methods
  • Oligonucleotide Array Sequence Analysis
  • Proportional Hazards Models
  • Prospective Studies
  • Receptor, ErbB-2 / biosynthesis*
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Receptor, ErbB-2

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