Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment

Abstract

IntroductionActivation 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.MethodsWe 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.ResultsInteractions 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.ConclusionsPatients 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.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50]. In the present study, we showed PTPN2 gene loss as a new potential marker of endocrine resistance.…”

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

“…The S6K1 antibody demonstrated high specificity and could serve as a clinical biomarker. Overactivated S6K has been suggested an upcoming prognostic and treatment predictive marker in ER-positive breast cancer (Noh et al 2008, Kim et al 2011, Beelen et al 2014. Here, we did not detect worse prognosis with high activity of the S6Ks, instead a somewhat improved prognosis was observed in the tamoxifen-untreated subset of patients when pS6K was highly expressed in the nucleus.…”

“…Here, we did not detect worse prognosis with high activity of the S6Ks, instead a somewhat improved prognosis was observed in the tamoxifen-untreated subset of patients when pS6K was highly expressed in the nucleus. Recently, Beelen et al (2014) have shown an improved prognosis with high levels of pS6K expression in the cytoplasm. It has been suggested that the p31 short isoform of S6K1 is the primary oncogenic protein in the S6K family (Rosner & Hengstschlager 2011).…”

Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy

“…Of note, the mTOR pathway, which is a known predictor of endocrine resistance (14), was found to be elevated in the liver metastases of patients 1 and 3 at the transcript level in comparison with the primary tumor ( Supplementary Fig. S2).…”