63586
document
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 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 .
63587
Intervention_Pharmacological
Phosphorylated p-70S6K
63588
Intervention_Pharmacological
tamoxifen
63589
Intervention_Pharmacological
tamoxifen
63590
Intervention_Control
no systemic treatment .
63591
Intervention_Pharmacological
phosphatidylinositol-3-kinase ( PI3K )
63592
Intervention_Pharmacological
mitogen-activated protein kinase ( MAPK )
63593
Intervention_Pharmacological
rapamycine ( mTOR )
63594
Intervention_Control
adjuvant endocrine treatment
63595
Intervention_Pharmacological
tamoxifen
63596
Intervention_Pharmacological
adjuvant tamoxifen ( 1-3 years
63597
Intervention_Control
observation
63598
Intervention_Physical
tissue micro-array
63599
Outcome_Physical
tamoxifen resistance
63600
Outcome_Physical
anti-estrogen resistance
63601
Outcome_Physical
intrinsic tamoxifen resistance
63602
Outcome_Other
assess hazard ratios
63603
Outcome_Physical
with tamoxifen resistance
63604
Outcome_Other
decreased risk for recurrence
63605
Participant_Condition
postmenopausal breast cancer patients
63606
Participant_Condition
metastatic breast cancer patients with previous exposure to endocrine therapy
63607
Participant_Condition
primary tumor tissue
63608
Participant_Condition
tumor