EarlyR: A Robust Gene Expression Signature for Predicting Outcomes of Estrogen Receptor–Positive Breast Cancer

Steven A. Buechler, Yesim Polar, Sunil Badve

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2 Citations (Scopus)

Abstract

Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. We describe a novel 5-gene signature that is a robust prognostic assay that performed similarly to currently available signatures in concordance analyses. However, it identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Introduction: Early stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. Methods: The EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. Results: The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13% of patients were intermediate risk and at least 66% patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. Conclusion: The 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing.

Original languageEnglish (US)
JournalClinical Breast Cancer
DOIs
StateAccepted/In press - Jan 1 2018

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Transcriptome
Estrogens
Breast Neoplasms
Estrogen Receptors
Recurrence
Lymph
Drug Therapy
Kaplan-Meier Estimate
Microarray Analysis
Survival Analysis
Proportional Hazards Models
Paraffin
Formaldehyde
Genes
Real-Time Polymerase Chain Reaction
Breast
Hormones

Keywords

  • Estrogen receptor-positive
  • Gene signature
  • Molecular diagnostic
  • Prognosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{419e326ca86c45b795f6531a9f9b052b,
title = "EarlyR: A Robust Gene Expression Signature for Predicting Outcomes of Estrogen Receptor–Positive Breast Cancer",
abstract = "Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. We describe a novel 5-gene signature that is a robust prognostic assay that performed similarly to currently available signatures in concordance analyses. However, it identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Introduction: Early stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. Methods: The EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. Results: The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13{\%} of patients were intermediate risk and at least 66{\%} patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. Conclusion: The 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing.",
keywords = "Estrogen receptor-positive, Gene signature, Molecular diagnostic, Prognosis",
author = "Buechler, {Steven A.} and Yesim Polar and Sunil Badve",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.clbc.2018.07.011",
language = "English (US)",
journal = "Clinical Breast Cancer",
issn = "1526-8209",
publisher = "Elsevier",

}

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T2 - A Robust Gene Expression Signature for Predicting Outcomes of Estrogen Receptor–Positive Breast Cancer

AU - Buechler, Steven A.

AU - Polar, Yesim

AU - Badve, Sunil

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. We describe a novel 5-gene signature that is a robust prognostic assay that performed similarly to currently available signatures in concordance analyses. However, it identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Introduction: Early stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. Methods: The EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. Results: The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13% of patients were intermediate risk and at least 66% patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. Conclusion: The 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing.

AB - Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. We describe a novel 5-gene signature that is a robust prognostic assay that performed similarly to currently available signatures in concordance analyses. However, it identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Introduction: Early stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. Methods: The EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. Results: The EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13% of patients were intermediate risk and at least 66% patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. Conclusion: The 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing.

KW - Estrogen receptor-positive

KW - Gene signature

KW - Molecular diagnostic

KW - Prognosis

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