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Randomized Controlled Trial
. 2014 Jan 27;16(1):R13.
doi: 10.1186/bcr3606.

"VSports注册入口" PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Karin Beelen, Mark Opdam, Tesa M Severson, Rutger H T Koornstra, Andrew D Vincent, Jelle Wesseling, Jettie J Muris, Els M J J Berns, Jan B Vermorken, Paul J van Diest, Sabine C Linn
Randomized Controlled Trial

"V体育安卓版" PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Karin Beelen et al. Breast Cancer Res. .

Abstract

Introduction: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins VSports手机版. .

Methods: Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry V体育安卓版. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. .

Results: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins V体育ios版. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found. .

Conclusion: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive, postmenopausal, early breast cancer patients VSports最新版本. .

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Figures

Figure 1
Figure 1
Hierarchic clustering of the downstream-activated PI3K and/or MAPK proteins. Heat map representing unsupervised hierarchic clustering of tumor samples and corresponding downstream activated proteins in the PI3K and/or MAPK pathways from patients for whom the status of all five proteins was known (N = 350). Patients are represented horizontally. Phosphorylated proteins are indicated vertically. Red represents high/any expression of phosphorylated protein, and green represents no/low expression of phosphorylated protein (dichotomization was performed according to the Akaike information criteria [29]). In addition, the presence (red) or absence (green) of different molecular alterations in the PI3K and or MAPK pathways is shown. (1)Defined as the presence of either a PIK3CA mutation, positive HER2 status, or IGF-1R overexpression (IHC score 3).
Figure 2
Figure 2
Numbers of patients per randomization group before and after interim analysis. Numbers of patients per randomization group before interim analysis (A) and after interim analysis (B), for the total subset of 563 ERα-positive patients. From 1989, based on two interim analyses showing a significant improvement in recurrence-free survival among lymph node-positive patients, these node-positive patients were all allocated to the tamoxifen treatment arm (that is, skipped the first randomization). Numbers of lymph node-negative patients are depicted in green. In red are depicted the numbers of lymph node-positive patients. LN neg, lymph node negative; LN pos, lymph node positive; R1, randomization 1; R2, randomization 2.
See this image and copyright information in PMC

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