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Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

Publication ,  Journal Article
Barry, WT; Kernagis, DN; Dressman, HK; Griffis, RJ; Hunter, JD; Olson, JA; Marks, JR; Ginsburg, GS; Marcom, PK; Nevins, JR; Geradts, J; Datto, MB
Published in: J Clin Oncol
May 1, 2010

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.

Duke Scholars

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

May 1, 2010

Volume

28

Issue

13

Start / End Page

2198 / 2206

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Reproducibility of Results
  • Recurrence
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Predictive Value of Tests
  • Oncology & Carcinogenesis
 

Citation

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Barry, W. T., Kernagis, D. N., Dressman, H. K., Griffis, R. J., Hunter, J. D., Olson, J. A., … Datto, M. B. (2010). Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J Clin Oncol, 28(13), 2198–2206. https://doi.org/10.1200/JCO.2009.26.7245
Barry, William T., Dawn N. Kernagis, Holly K. Dressman, Ryan J. Griffis, J’vonne D. Hunter, John A. Olson, Jeff R. Marks, et al. “Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.J Clin Oncol 28, no. 13 (May 1, 2010): 2198–2206. https://doi.org/10.1200/JCO.2009.26.7245.
Barry WT, Kernagis DN, Dressman HK, Griffis RJ, Hunter JD, Olson JA, et al. Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J Clin Oncol. 2010 May 1;28(13):2198–206.
Barry, William T., et al. “Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.J Clin Oncol, vol. 28, no. 13, May 2010, pp. 2198–206. Pubmed, doi:10.1200/JCO.2009.26.7245.
Barry WT, Kernagis DN, Dressman HK, Griffis RJ, Hunter JD, Olson JA, Marks JR, Ginsburg GS, Marcom PK, Nevins JR, Geradts J, Datto MB. Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J Clin Oncol. 2010 May 1;28(13):2198–2206.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

May 1, 2010

Volume

28

Issue

13

Start / End Page

2198 / 2206

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Reproducibility of Results
  • Recurrence
  • Receptors, Progesterone
  • Receptors, Estrogen
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Predictive Value of Tests
  • Oncology & Carcinogenesis