Cargando…
Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment
INTRODUCTION: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patie...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979131/ https://www.ncbi.nlm.nih.gov/pubmed/24447434 http://dx.doi.org/10.1186/bcr3598 |
_version_ | 1782310693674942464 |
---|---|
author | Beelen, Karin Opdam, Mark Severson, Tesa M Koornstra, Rutger HT Vincent, Andrew D Wesseling, Jelle Muris, Jettie J Berns, Els MJJ Vermorken, Jan B van Diest, Paul J Linn, Sabine C |
author_facet | Beelen, Karin Opdam, Mark Severson, Tesa M Koornstra, Rutger HT Vincent, Andrew D Wesseling, Jelle Muris, Jettie J Berns, Els MJJ Vermorken, Jan B van Diest, Paul J Linn, Sabine C |
author_sort | Beelen, Karin |
collection | PubMed |
description | INTRODUCTION: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. METHODS: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1–3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. RESULTS: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. CONCLUSIONS: Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored. |
format | Online Article Text |
id | pubmed-3979131 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-39791312014-04-08 Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment Beelen, Karin Opdam, Mark Severson, Tesa M Koornstra, Rutger HT Vincent, Andrew D Wesseling, Jelle Muris, Jettie J Berns, Els MJJ Vermorken, Jan B van Diest, Paul J Linn, Sabine C Breast Cancer Res Research Article INTRODUCTION: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. METHODS: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1–3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. RESULTS: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. CONCLUSIONS: Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored. BioMed Central 2014 2014-01-21 /pmc/articles/PMC3979131/ /pubmed/24447434 http://dx.doi.org/10.1186/bcr3598 Text en Copyright © 2014 Beelen et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Beelen, Karin Opdam, Mark Severson, Tesa M Koornstra, Rutger HT Vincent, Andrew D Wesseling, Jelle Muris, Jettie J Berns, Els MJJ Vermorken, Jan B van Diest, Paul J Linn, Sabine C Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title | Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title_full | Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title_fullStr | Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title_full_unstemmed | Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title_short | Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
title_sort | phosphorylated p-70s6k predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979131/ https://www.ncbi.nlm.nih.gov/pubmed/24447434 http://dx.doi.org/10.1186/bcr3598 |
work_keys_str_mv | AT beelenkarin phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT opdammark phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT seversontesam phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT koornstrarutgerht phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT vincentandrewd phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT wesselingjelle phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT murisjettiej phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT bernselsmjj phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT vermorkenjanb phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT vandiestpaulj phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment AT linnsabinec phosphorylatedp70s6kpredictstamoxifenresistanceinpostmenopausalbreastcancerpatientsrandomizedbetweenadjuvanttamoxifenversusnosystemictreatment |