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Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.

Publication ,  Journal Article
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Potti, A ...
Published in: JAMA
April 2, 2008

CONTEXT: Gene expression profiling may be useful for prognostic and therapeutic strategies in breast carcinoma. OBJECTIVES: To demonstrate the value in integrating genomic information with clinical and pathological risk factors, to refine prognosis, and to improve therapeutic strategies for early stage breast cancer. DESIGN, SETTING, AND PATIENTS: Retrospective study of patients with early stage breast carcinoma who were candidates for adjuvant chemotherapy; 964 clinically annotated breast tumor samples (573 in the initial discovery set and 391 in the validation cohort) with corresponding microarray data were used. All patients were assigned relapse risk scores based on their respective clinicopathological features. Signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of deregulation that correspond with relapse risk scores to refine prognosis with the clinicopathological prognostic model alone. Predictors of chemotherapeutic response were also applied to further characterize clinically relevant heterogeneity in early stage breast cancer. MAIN OUTCOME MEASURES: Gene expression signatures and clinicopathological variables in early stage breast cancer to determine a refined estimation of relapse-free survival and sensitivity to chemotherapy. RESULTS: In the initial data set of 573 patients, prognostically significant clusters representing patterns of oncogenic pathway activation and tumor biology/microenvironment states were identified within the low-risk (log-rank P = .004), intermediate-risk (log-rank P = .01), and high-risk (log-rank P = .003) model cohorts, representing clinically important genomic subphenotypes of breast cancer. As an example, in the low-risk cohort, of 6 prognostically significant clusters, patients in cluster 4 had an inferior relapse-free survival vs patients in cluster 1 (log-rank P = .004) and cluster 5 (log-rank P = .03). Median relapse-free survival for patients in cluster 4 was 16 months less than for patients in cluster 1 (95% CI, 7.5-24.5 months) and 19 months less than for patients in cluster 5 (95% CI, 10.5-27.5 months). Multivariate analyses confirmed the independent prognostic value of the genomic clusters (low risk, P = .05; high risk, P = .02). The reproducibility and validity of these patterns of pathway deregulation in predicting relapse risk was established using related but not identical clusters in the independent validation cohort. The prognostic clinicogenomic clusters also have unique sensitivity patterns to commonly used cytotoxic therapies. CONCLUSIONS: These results provide preliminary evidence that incorporation of gene expression signatures into clinical risk stratification can refine prognosis. Prospective studies are needed to determine the value of this approach for individualizing therapeutic strategies.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

April 2, 2008

Volume

299

Issue

13

Start / End Page

1574 / 1587

Location

United States

Related Subject Headings

  • Risk Assessment
  • Retrospective Studies
  • Prognosis
  • Pharmacogenetics
  • Oligonucleotide Array Sequence Analysis
  • Middle Aged
  • Humans
  • General & Internal Medicine
  • Gene Expression Profiling
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
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Acharya, C. R., Hsu, D. S., Anders, C. K., Anguiano, A., Salter, K. H., Walters, K. S., … Potti, A. (2008). Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA, 299(13), 1574–1587. https://doi.org/10.1001/jama.299.13.1574
Acharya, Chaitanya R., David S. Hsu, Carey K. Anders, Ariel Anguiano, Kelly H. Salter, Kelli S. Walters, Richard C. Redman, et al. “Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.JAMA 299, no. 13 (April 2, 2008): 1574–87. https://doi.org/10.1001/jama.299.13.1574.
Acharya CR, Hsu DS, Anders CK, Anguiano A, Salter KH, Walters KS, et al. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008 Apr 2;299(13):1574–87.
Acharya, Chaitanya R., et al. “Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.JAMA, vol. 299, no. 13, Apr. 2008, pp. 1574–87. Pubmed, doi:10.1001/jama.299.13.1574.
Acharya CR, Hsu DS, Anders CK, Anguiano A, Salter KH, Walters KS, Redman RC, Tuchman SA, Moylan CA, Mukherjee S, Barry WT, Dressman HK, Ginsburg GS, Marcom KP, Garman KS, Lyman GH, Nevins JR, Potti A. Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer. JAMA. 2008 Apr 2;299(13):1574–1587.

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

April 2, 2008

Volume

299

Issue

13

Start / End Page

1574 / 1587

Location

United States

Related Subject Headings

  • Risk Assessment
  • Retrospective Studies
  • Prognosis
  • Pharmacogenetics
  • Oligonucleotide Array Sequence Analysis
  • Middle Aged
  • Humans
  • General & Internal Medicine
  • Gene Expression Profiling
  • Female