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'lizbeth · 05-25-2014, 10:54 AM

Phosphorylated p-70S6K Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients Randomized Between Adjuvant Tamoxifen Versus No Systemic Treatment

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

Breast Cancer Res. 2014;16(1)

Abstract and Introduction

Abstract

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.
Introduction

Activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways confers anti-estrogen resistance in vitro.^[1–3] Apart from activation by the canonical pathway drivers (PIK3CA mutations,^[4] loss of PTEN^[5] or overexpression of growth factor receptors such as human epidermal growth factor receptor 2 (HER2)^[6] and insulin like growth factor 1 receptor^[7]), in vitro data have shown that the PI3K pathway can also be activated in response to estrogen depletion. This results in acquired hormone-resistant breast cancer cells that are sensitive to PI3K/mammalian target of rapamycine (mTOR) inhibition.^[8] These preclinical data support the clinical observation that estrogen receptor alpha (ERα)-positive metastatic breast cancer patients with prior exposure to aromatase inhibitors derive substantial benefit from the addition of an mTOR inhibitor.^[9] Whether or not patients who are primarily resistant to adjuvant endocrine therapy might benefit from PI3K and/or MAPK pathway inhibition remains to be defined. A biomarker of an activated PI3K and/or MAPK pathway with clinical validity to predict resistance in the adjuvant setting has not been identified,^[10] but could potentially be used as a companion diagnostic for non-ERα-targeted drugs, such as an mTOR inhibitor.
Several canonical pathway drivers, such as PIK3CA mutations,^[11,12] loss of PTEN,^[12] and HER2,^[13] have been studied for their validity to predict resistance. However, none of these drivers significantly predicts lack of benefit from endocrine therapy. An important issue to be considered is that the presence of these drivers in clinical samples may not necessarily result in high activation of downstream proteins.^[12,14] In vitro, PI3K pathway activation leads to phosphorylation of AKT and subsequently of mTOR and p70S6K.^[10] Phosphorylation of extracellular signal-regulated kinase (ERK)1/2 is a result of MAPK pathway activation^[15] and mediates activation of p70S6K.^[16] However, relatively moderate activation of the PI3K pathway was seen in tumors with a PIK3CA exon 20 mutation-associated gene signature.^[14] In addition, in a large series of primary breast cancer tumors, reverse-phase protein analysis did not show activation of the typical downstream proteins in the PI3K pathway in PIK3CA mutated luminal A tumors.^[17] The activation status of downstream proteins rather than the presence or absence of a canonical driver therefore probably ultimately defines anti-estrogen sensitivity in breast cancer patients.
We hypothesized that activated proteins downstream in the PI3K and/or MAPK kinase pathways could potentially be used as a marker that separates patients who are likely to benefit from adjuvant tamoxifen treatment from those who are primarily resistant to this drug. The aim of our study was therefore to investigate the predictive value of different downstream activated proteins in the PI3K and/or MAPK pathways in a large series of ERα-positive postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment.

05-25-2014, 10:54 AM	#1
'lizbeth Senior Member Join Date: Apr 2008 Location: Sunny San Diego Posts: 2,214	Phosphorylated p-70S6K Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Phosphorylated p-70S6K Predicts Tamoxifen Resistance in Postmenopausal Breast Cancer Patients Randomized Between Adjuvant Tamoxifen Versus No Systemic Treatment Karin Beelen, Mark Opdam, Tesa M Severson, Rutger HT Koornstra, Andrew D Vincent, Jelle Wesseling, Jettie J Muris, Els MJJ Berns, Jan B Vermorken, Paul J van Diest, Sabine C Linn Breast Cancer Res. 2014;16(1) Abstract and Introduction Abstract 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. Introduction Activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways confers anti-estrogen resistance in vitro.^[1–3] Apart from activation by the canonical pathway drivers (PIK3CA mutations,^[4] loss of PTEN^[5] or overexpression of growth factor receptors such as human epidermal growth factor receptor 2 (HER2)^[6] and insulin like growth factor 1 receptor^[7]), in vitro data have shown that the PI3K pathway can also be activated in response to estrogen depletion. This results in acquired hormone-resistant breast cancer cells that are sensitive to PI3K/mammalian target of rapamycine (mTOR) inhibition.^[8] These preclinical data support the clinical observation that estrogen receptor alpha (ERα)-positive metastatic breast cancer patients with prior exposure to aromatase inhibitors derive substantial benefit from the addition of an mTOR inhibitor.^[9] Whether or not patients who are primarily resistant to adjuvant endocrine therapy might benefit from PI3K and/or MAPK pathway inhibition remains to be defined. A biomarker of an activated PI3K and/or MAPK pathway with clinical validity to predict resistance in the adjuvant setting has not been identified,^[10] but could potentially be used as a companion diagnostic for non-ERα-targeted drugs, such as an mTOR inhibitor. Several canonical pathway drivers, such as PIK3CA mutations,^[11,12] loss of PTEN,^[12] and HER2,^[13] have been studied for their validity to predict resistance. However, none of these drivers significantly predicts lack of benefit from endocrine therapy. An important issue to be considered is that the presence of these drivers in clinical samples may not necessarily result in high activation of downstream proteins.^[12,14] In vitro, PI3K pathway activation leads to phosphorylation of AKT and subsequently of mTOR and p70S6K.^[10] Phosphorylation of extracellular signal-regulated kinase (ERK)1/2 is a result of MAPK pathway activation^[15] and mediates activation of p70S6K.^[16] However, relatively moderate activation of the PI3K pathway was seen in tumors with a PIK3CA exon 20 mutation-associated gene signature.^[14] In addition, in a large series of primary breast cancer tumors, reverse-phase protein analysis did not show activation of the typical downstream proteins in the PI3K pathway in PIK3CA mutated luminal A tumors.^[17] The activation status of downstream proteins rather than the presence or absence of a canonical driver therefore probably ultimately defines anti-estrogen sensitivity in breast cancer patients. We hypothesized that activated proteins downstream in the PI3K and/or MAPK kinase pathways could potentially be used as a marker that separates patients who are likely to benefit from adjuvant tamoxifen treatment from those who are primarily resistant to this drug. The aim of our study was therefore to investigate the predictive value of different downstream activated proteins in the PI3K and/or MAPK pathways in a large series of ERα-positive postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment.