Hierarchical clustering of activated proteins in the PI3K and MAPK pathways in ER-positive, HER2-negative breast cancer with potential therapeutic consequences

Dinja T. Kruger, Karin J. Beelen, Mark Opdam, Joyce Sanders, Vincent van der Noort, Epie Boven, Sabine C. Linn

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2− breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. Methods: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2− breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. Results: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). Conclusions: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2− postmenopausal breast cancer patients.
Original languageEnglish
Pages (from-to)832-839
Number of pages8
JournalBritish Journal of Cancer
Volume119
Issue number7
DOIs
Publication statusPublished - 2018

Cite this

@article{b5a53e677f0845138df16a13702afb73,
title = "Hierarchical clustering of activated proteins in the PI3K and MAPK pathways in ER-positive, HER2-negative breast cancer with potential therapeutic consequences",
abstract = "Background: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2− breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. Methods: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2− breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. Results: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). Conclusions: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2− postmenopausal breast cancer patients.",
author = "Kruger, {Dinja T.} and Beelen, {Karin J.} and Mark Opdam and Joyce Sanders and {van der Noort}, Vincent and Epie Boven and Linn, {Sabine C.}",
year = "2018",
doi = "10.1038/s41416-018-0221-8",
language = "English",
volume = "119",
pages = "832--839",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "7",

}

Hierarchical clustering of activated proteins in the PI3K and MAPK pathways in ER-positive, HER2-negative breast cancer with potential therapeutic consequences. / Kruger, Dinja T.; Beelen, Karin J.; Opdam, Mark; Sanders, Joyce; van der Noort, Vincent; Boven, Epie; Linn, Sabine C.

In: British Journal of Cancer, Vol. 119, No. 7, 2018, p. 832-839.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Hierarchical clustering of activated proteins in the PI3K and MAPK pathways in ER-positive, HER2-negative breast cancer with potential therapeutic consequences

AU - Kruger, Dinja T.

AU - Beelen, Karin J.

AU - Opdam, Mark

AU - Sanders, Joyce

AU - van der Noort, Vincent

AU - Boven, Epie

AU - Linn, Sabine C.

PY - 2018

Y1 - 2018

N2 - Background: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2− breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. Methods: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2− breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. Results: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). Conclusions: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2− postmenopausal breast cancer patients.

AB - Background: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2− breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. Methods: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2− breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. Results: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). Conclusions: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2− postmenopausal breast cancer patients.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30287915

U2 - 10.1038/s41416-018-0221-8

DO - 10.1038/s41416-018-0221-8

M3 - Article

VL - 119

SP - 832

EP - 839

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 7

ER -