Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES

V Speirs, G Viale, K Mousa, C Palmieri, S N Reed, H Nicholas, M Cheang, J Jassem, P E Lønning, E Kalaitzaki, C J H van de Velde, B B Rasmussen, D M Verhoeven, A M Shaaban, J M S Bartlett, J M Bliss, R C Coombes, PathIES Sub-Committee

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Abstract

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms.

PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs.

RESULTS: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS.

CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

Original languageEnglish
Pages (from-to)1890-1897
Number of pages8
JournalAnnals of Oncology
Volume26
Issue number9
Early online date22 May 2015
DOIs
Publication statusPublished - Sep 2015

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exemestane
Tamoxifen
Disease-Free Survival
Survival
Confidence Intervals
Aromatase Inhibitors
Therapeutics
Proportional Hazards Models
Population
Neoplasms
Biomarkers

Keywords

  • Aged
  • Androstadienes
  • Antineoplastic Agents
  • Aromatase Inhibitors
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Disease-Free Survival
  • Double-Blind Method
  • Estrogen Receptor beta
  • Female
  • Humans
  • Middle Aged
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies
  • Tamoxifen
  • Treatment Outcome
  • Clinical Trial, Phase III
  • Journal Article
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Cite this

Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES. / Speirs, V; Viale, G; Mousa, K; Palmieri, C; Reed, S N; Nicholas, H; Cheang, M; Jassem, J; Lønning, P E; Kalaitzaki, E; van de Velde, C J H; Rasmussen, B B; Verhoeven, D M; Shaaban, A M; Bartlett, J M S; Bliss, J M; Coombes, R C; PathIES Sub-Committee.

In: Annals of Oncology, Vol. 26, No. 9, 09.2015, p. 1890-1897.

Research output: Contribution to journalArticle

Speirs, V, Viale, G, Mousa, K, Palmieri, C, Reed, SN, Nicholas, H, Cheang, M, Jassem, J, Lønning, PE, Kalaitzaki, E, van de Velde, CJH, Rasmussen, BB, Verhoeven, DM, Shaaban, AM, Bartlett, JMS, Bliss, JM, Coombes, RC & PathIES Sub-Committee 2015, 'Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES', Annals of Oncology, vol. 26, no. 9, pp. 1890-1897. https://doi.org/10.1093/annonc/mdv242
Speirs, V ; Viale, G ; Mousa, K ; Palmieri, C ; Reed, S N ; Nicholas, H ; Cheang, M ; Jassem, J ; Lønning, P E ; Kalaitzaki, E ; van de Velde, C J H ; Rasmussen, B B ; Verhoeven, D M ; Shaaban, A M ; Bartlett, J M S ; Bliss, J M ; Coombes, R C ; PathIES Sub-Committee. / Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES. In: Annals of Oncology. 2015 ; Vol. 26, No. 9. pp. 1890-1897.
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title = "Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES",
abstract = "BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms.PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27{\%} IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs.RESULTS: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95{\%} confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95{\%} CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS.CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.",
keywords = "Aged, Androstadienes, Antineoplastic Agents, Aromatase Inhibitors, Biomarkers, Tumor, Breast Neoplasms, Disease-Free Survival, Double-Blind Method, Estrogen Receptor beta, Female, Humans, Middle Aged, Prognosis, Proportional Hazards Models, Retrospective Studies, Tamoxifen, Treatment Outcome, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't",
author = "V Speirs and G Viale and K Mousa and C Palmieri and Reed, {S N} and H Nicholas and M Cheang and J Jassem and L{\o}nning, {P E} and E Kalaitzaki and {van de Velde}, {C J H} and Rasmussen, {B B} and Verhoeven, {D M} and Shaaban, {A M} and Bartlett, {J M S} and Bliss, {J M} and Coombes, {R C} and {PathIES Sub-Committee}",
note = "Research supported by Cancer Research UK (C37/A8434) and Pfizer (GA9001DP). Cancer Research UK also provided programme grants to the Institute of Cancer Research Clinical Trials and Statistics Unit and the Division of Cancer at Imperial College London. This study was supported by Imperial Experimental Cancer Medicine Centre, Imperial Biomedical Research Centre and Imperial Cancer Research UK Centre. MCUC is supported by the CRUK Core grant (grant number C1491/A15955). Research at the Ontario Institute for Cancer Research is supported by the Ontario Government.",
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TY - JOUR

T1 - Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)-first results from PathIES

AU - Speirs, V

AU - Viale, G

AU - Mousa, K

AU - Palmieri, C

AU - Reed, S N

AU - Nicholas, H

AU - Cheang, M

AU - Jassem, J

AU - Lønning, P E

AU - Kalaitzaki, E

AU - van de Velde, C J H

AU - Rasmussen, B B

AU - Verhoeven, D M

AU - Shaaban, A M

AU - Bartlett, J M S

AU - Bliss, J M

AU - Coombes, R C

AU - PathIES Sub-Committee

N1 - Research supported by Cancer Research UK (C37/A8434) and Pfizer (GA9001DP). Cancer Research UK also provided programme grants to the Institute of Cancer Research Clinical Trials and Statistics Unit and the Division of Cancer at Imperial College London. This study was supported by Imperial Experimental Cancer Medicine Centre, Imperial Biomedical Research Centre and Imperial Cancer Research UK Centre. MCUC is supported by the CRUK Core grant (grant number C1491/A15955). Research at the Ontario Institute for Cancer Research is supported by the Ontario Government.

PY - 2015/9

Y1 - 2015/9

N2 - BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms.PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs.RESULTS: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS.CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

AB - BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms.PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs.RESULTS: Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS.CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

KW - Aged

KW - Androstadienes

KW - Antineoplastic Agents

KW - Aromatase Inhibitors

KW - Biomarkers, Tumor

KW - Breast Neoplasms

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Estrogen Receptor beta

KW - Female

KW - Humans

KW - Middle Aged

KW - Prognosis

KW - Proportional Hazards Models

KW - Retrospective Studies

KW - Tamoxifen

KW - Treatment Outcome

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/annonc/mdv242

DO - 10.1093/annonc/mdv242

M3 - Article

VL - 26

SP - 1890

EP - 1897

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 9

ER -