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Br J Cancer. 2018 Oct;119(7):832-839. doi: 10.1038/s41416-018-0221-8. Epub 2018 Oct 5.

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

Author information

1
Department of Medical Oncology, VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
2
Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
3
Department of Medical Oncology, Reinier de Graaf Groep, Reinier de Graafweg 5, 2625 AD, Delft, The Netherlands.
4
Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
5
Division of Biometrics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
6
Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.linn@nki.nl.
7
Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.linn@nki.nl.
8
Department of Pathology, University Medical Centre Utrecht, and Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. s.linn@nki.nl.

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.

PMID:
30287915
DOI:
10.1038/s41416-018-0221-8

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