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Randomized Controlled Trial
. 2018 Apr 1;4(4):545-553.
doi: 10.1001/jamaoncol.2017.5524.

Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Ivana Sestak  1 , Richard Buus  2   3 , Jack Cuzick  1 , Peter Dubsky  4   5 , Ralf Kronenwett  6 , Carsten Denkert  7 , Sean Ferree  8 , Dennis Sgroi  9 , Catherine Schnabel  10 , Frederick L Baehner  11 , Elizabeth Mallon  12 , Mitch Dowsett  2   3
Affiliations
Randomized Controlled Trial

Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Ivana Sestak et al. JAMA Oncol. .

Abstract

Importance: Multiple molecular signatures are available for managing estrogen receptor (ER)-positive breast cancer but with little direct comparative information to guide the patient's choice.

Objective: To conduct a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years.

Design, setting, and participants: This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer. This analysis was performed as a preplanned secondary study of data from the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs tamoxifen with 10-year follow-up data. The signatures included the Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score. Data were collected from January 2009, through April 2015.

Main outcomes and measures: The primary objective was to compare the prognostic value of these signatures in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0 to 10 years and 5 to 10 years after diagnosis. Likelihood ratio (LR) statistics were used with the χ2 test and C indexes to assess the prognostic value of each signature.

Results: In this study of 774 postmenopausal women with ER-positive, ERBB2-negative disease (mean [SD] age, 64.1 [8.1] years), 591 (mean [SD] age, 63.4 [7.9] years) had node-negative disease. The signatures providing the most prognostic information were the ROR (hazard ratio [HR], 2.56; 95% CI, 1.96-3.35), followed by the BCI (HR, 2.46; 95% CI, 1.88-3.23) and EPclin (HR, 2.14; 95% CI, 1.71-2.68). Each provided significantly more information than the Clinical Treatment Score (HR, 1.99; 95% CI, 1.58-2.50), the recurrence score (HR, 1.69; 95% CI, 1.40-2.03), and the 4-marker immunohistochemical score (HR, 1.95; 95% CI, 1.55-2.45). Substantially less information was provided by all 6 molecular tests for the 183 patients with 1 to 3 positive nodes, but the BCI (ΔLR χ2 = 9.2) and EPclin (ΔLR χ2 = 7.4) provided more additional prognostic information than the other signatures.

Conclusions and relevance: For women with node-negative disease, the ROR, BCI, and EPclin were significantly more prognostic for overall and late distant recurrence. For women with 1 to 3 positive nodes, limited independent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy.

Trial registration: isrctn.com Identifier: ISRCTN18233230.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sestak reports receiving a speaker’s fee from Myriad Genetics. Dr Dubsky reports grant support from Agendia, Sividon, Myriad Genetics, and Nanostring; performing an advisory role for Amgen; and receiving speaker’s fees from Myriad Genetics, Sividon, and Amgen. Dr Kronenwett reports being an inventor on the EndoPredict patent and an employee and previous shareholder of Sividon. Dr Ferree reports being an employee and shareholder of Nanostring Technologies. Dr Schnabel reports being an employee and shareholder of Biotheranostics. Dr Baehner reports being an employee and shareholder of Genomic Health. Dr Dowsett reports receiving fees for an advisory board role from Genoptix and for lectures from Myriad Genetics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curves for Recurrence During Years 0 to 10
Includes 591 patients with node-negative and 183 patients with node-positive disease. Data are stratified by signature and nodal status. Gene signatures include the Oncotype Dx recurrence score (Genomic Health), PAM50-based Prosigna risk of recurrence score (NanoString), Breast Cancer Index (bioTheranostics), and EPclin (EndoPredict clinical score [Myriad Genetics]). Cutoffs for risk of recurrence score were trained separately in patients with node-negative and node-positive disease in the Translational Study of Anastrozole or Tamoxifen Alone or Combined cohort.
Figure 2.
Figure 2.. Kaplan-Meier Curves for Recurrence During Years 5 to 10
Includes 535 patients with node-negative and 154 with node-positive disease. Data are stratified by signature and nodal status. Gene signatures include the Oncotype Dx recurrence score (Genomic Health), PAM50-based Prosigna risk of recurrence score (NanoString), Breast Cancer Index (bioTheranostics), and EPclin (EndoPredict clinical score [Myriad Genetics]). Cutoffs for risk of recurrence score were trained separately in patients with node-negative and node-positive disease in the Translational Study of Anastrozole or Tamoxifen Alone or Combined cohort.
See this image and copyright information in PMC

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