The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome

Carmela Ricciardelli, Tina Bianco-Miotto, Shalini Jindal, Lisa Butler, Samuel Leung, Catriona M. McNeil, Sandra A. O'Toole, Esmaeil Ebrahimie, Ewan K.A. Millar, Andrew J. Sakko, Alexandra I. Ruiz, Sarah L. Vowler, David G. Huntsman, Stephen N. Birrell, Robert L. Sutherland, Carlo Palmieri, Theresa E. Hickey, Wayne D. Tilley

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77% and 79% estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity 78% had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

LanguageEnglish
Pages2328-2341
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number10
DOIs
Publication statusPublished - 15 May 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ricciardelli, Carmela ; Bianco-Miotto, Tina ; Jindal, Shalini ; Butler, Lisa ; Leung, Samuel ; McNeil, Catriona M. ; O'Toole, Sandra A. ; Ebrahimie, Esmaeil ; Millar, Ewan K.A. ; Sakko, Andrew J. ; Ruiz, Alexandra I. ; Vowler, Sarah L. ; Huntsman, David G. ; Birrell, Stephen N. ; Sutherland, Robert L. ; Palmieri, Carlo ; Hickey, Theresa E. ; Tilley, Wayne D. / The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 10. pp. 2328-2341.
@article{be45a9208b174e3289cb43d14f0590b6,
title = "The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome",
abstract = "Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77{\%} and 79{\%} estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48{\%}) previous studies that performed multivariate analyses. Most studies used cut-points of 1{\%} or 10{\%} nuclear positivity. Herein, neither 1{\%} nor 10{\%} cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78{\%} positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity 78{\%} had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.",
author = "Carmela Ricciardelli and Tina Bianco-Miotto and Shalini Jindal and Lisa Butler and Samuel Leung and McNeil, {Catriona M.} and O'Toole, {Sandra A.} and Esmaeil Ebrahimie and Millar, {Ewan K.A.} and Sakko, {Andrew J.} and Ruiz, {Alexandra I.} and Vowler, {Sarah L.} and Huntsman, {David G.} and Birrell, {Stephen N.} and Sutherland, {Robert L.} and Carlo Palmieri and Hickey, {Theresa E.} and Tilley, {Wayne D.}",
year = "2018",
month = "5",
day = "15",
doi = "10.1158/1078-0432.CCR-17-1199",
language = "English",
volume = "24",
pages = "2328--2341",
journal = "Clinical Cancer Research",
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Ricciardelli, C, Bianco-Miotto, T, Jindal, S, Butler, L, Leung, S, McNeil, CM, O'Toole, SA, Ebrahimie, E, Millar, EKA, Sakko, AJ, Ruiz, AI, Vowler, SL, Huntsman, DG, Birrell, SN, Sutherland, RL, Palmieri, C, Hickey, TE & Tilley, WD 2018, 'The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome', Clinical Cancer Research, vol. 24, no. 10, pp. 2328-2341. https://doi.org/10.1158/1078-0432.CCR-17-1199

The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome. / Ricciardelli, Carmela; Bianco-Miotto, Tina; Jindal, Shalini; Butler, Lisa; Leung, Samuel; McNeil, Catriona M.; O'Toole, Sandra A.; Ebrahimie, Esmaeil; Millar, Ewan K.A.; Sakko, Andrew J.; Ruiz, Alexandra I.; Vowler, Sarah L.; Huntsman, David G.; Birrell, Stephen N.; Sutherland, Robert L.; Palmieri, Carlo; Hickey, Theresa E.; Tilley, Wayne D.

In: Clinical Cancer Research, Vol. 24, No. 10, 15.05.2018, p. 2328-2341.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome

AU - Ricciardelli, Carmela

AU - Bianco-Miotto, Tina

AU - Jindal, Shalini

AU - Butler, Lisa

AU - Leung, Samuel

AU - McNeil, Catriona M.

AU - O'Toole, Sandra A.

AU - Ebrahimie, Esmaeil

AU - Millar, Ewan K.A.

AU - Sakko, Andrew J.

AU - Ruiz, Alexandra I.

AU - Vowler, Sarah L.

AU - Huntsman, David G.

AU - Birrell, Stephen N.

AU - Sutherland, Robert L.

AU - Palmieri, Carlo

AU - Hickey, Theresa E.

AU - Tilley, Wayne D.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77% and 79% estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity 78% had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

AB - Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77% and 79% estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity 78% had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

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U2 - 10.1158/1078-0432.CCR-17-1199

DO - 10.1158/1078-0432.CCR-17-1199

M3 - Article

VL - 24

SP - 2328

EP - 2341

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10

ER -