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

BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients. METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1-3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers 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 interaction between these markers and treatment. RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12-0.47, p < 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48-2.21, p = 0.95), p for interaction 0.003. CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients. [ABSTRACT FROM AUTHOR]