Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)-PathIES

Title: Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)-PathIES
Authors: Szijgyarto, Z
Flach, KD
Opdam, M
Palmieri, C
Linn, SC
Wesseling, J
Ali, S
Bliss, JM
Cheang, MCU
Zwart, W
Coombes, RC
Item Type: Journal Article
Abstract: Purpose The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES). Methods Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini–Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (pBH). Results Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (pBH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (pBH > 0.05 for all). Conclusions This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.
Issue Date: 1-May-2019
Date of Acceptance: 18-Dec-2018
URI: http://hdl.handle.net/10044/1/72981
DOI: https://doi.org/10.1007/s10549-018-05110-x
ISSN: 0167-6806
Publisher: Springer (part of Springer Nature)
Start Page: 149
End Page: 163
Journal / Book Title: Breast Cancer Research and Treatment
Volume: 175
Issue: 1
Copyright Statement: © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Breast cancer
Aromatase
Tamoxifen
Prognosis
Biomarkers
ESTROGEN-RECEPTOR
ALPHA PHOSPHORYLATION
POSTMENOPAUSAL WOMEN
ENDOCRINE-THERAPY
SERINE 118
ER-ALPHA
ACTIVATION
RESISTANCE
SURVIVAL
PATHWAY
Aromatase
Biomarkers
Breast cancer
Prognosis
Tamoxifen
Adult
Aged
Androstadienes
Antineoplastic Agents
Breast Neoplasms
Female
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Middle Aged
Mitogen-Activated Protein Kinases
Neoplasm Grading
Neoplasm Staging
Phosphorylation
Prognosis
Proto-Oncogene Proteins c-akt
Receptors, Estrogen
Tamoxifen
Treatment Outcome
Humans
Breast Neoplasms
Tamoxifen
Androstadienes
Mitogen-Activated Protein Kinases
Receptors, Estrogen
Antineoplastic Agents
Neoplasm Staging
Prognosis
Treatment Outcome
Immunohistochemistry
Phosphorylation
Adult
Aged
Middle Aged
Female
Proto-Oncogene Proteins c-akt
Kaplan-Meier Estimate
Neoplasm Grading
Science & Technology
Life Sciences & Biomedicine
Oncology
Breast cancer
Aromatase
Tamoxifen
Prognosis
Biomarkers
ESTROGEN-RECEPTOR
ALPHA PHOSPHORYLATION
POSTMENOPAUSAL WOMEN
ENDOCRINE-THERAPY
SERINE 118
ER-ALPHA
ACTIVATION
RESISTANCE
SURVIVAL
PATHWAY
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-01-24
Appears in Collections:Division of Surgery
Division of Cancer



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