These mutations have been shown to result in in vitro activa tion of the PI3K AKT mTOR pathway, leading to endocrine resistance. Nevertheless, the prognostic and predictive value regarding endocrine selleck Enzastaurin resistance of these mutations in ER positive breast cancer remains unclear. An important limitation of many conflicting clinical studies is the analysis of these mutations in consecutive series of endocrine treated patients, which is unsuitable to discern prognosis from prediction. Only one previous study analyzed these muta tions in the context of a clinical trial that randomized between adjuvant tamoxifen and control. In this study, PIK3CA mutations did not predict endocrine resistance, but were associated with a decreased risk for local recur rence.

Inhibitors,Modulators,Libraries In neoadjuvant endocrine therapy trials, PIK3CA mutation status was not associated with treatment induced Ki67 changes, a surrogate marker for recurrence free sur vival, nor with pathologic response, whereas the Inhibitors,Modulators,Libraries kinase domain mutations were associated with improved overall survival. Several other studies have suggested a rela tively favorable survival in patients with kinase domain mutated breast cancers, in comparison with patients without such mutated tumors. Several other known molecular alterations in the PI3K and or the MAPK pathway have been studied for their validity to predict endocrine resistance. Loss of PTEN, a negative regulator of the PI3K AKT mTOR pathway, frequently occurs in breast cancer, but did not have clinical validity as a single marker in a previous study.

The same holds true for HER2, although the clinical validity of IGF 1R has not been analyzed in the context of a randomized clinical trial. The aim of our study was to investigate the prognostic and treatment predictive value of different molecular alterations in the PI3K and or MAPK pathways in postmenopausal breast cancer patients randomized be Inhibitors,Modulators,Libraries tween adjuvant tamoxifen and no systemic treatment. In addition, we studied the association between these molecular alterations and downstream activated pro teins in the PI3K and or MAPK pathways. Methods Patients and material We recollected primary tumor tissue Inhibitors,Modulators,Libraries blocks from stage I through III postmenopausal breast Inhibitors,Modulators,Libraries cancer patients who were randomized between 1 year tamoxifen and no adjuvant therapy. Study data were part of the Oxford meta analysis.

After 1989, based on two interim analyses showing a significant improvement in recurrence free survival in lymph node positive patients, node positive patients in this trial skipped the first randomization, and all received 1 year of tamoxifen. After 1 year, a second randomization was performed to receive another 2 years of tamoxifen Nutlin-3a purchase or to stop further treatment. In total, 1,662 patients were included. None of these patients received adjuvant chemotherapy. The patient characteristics and clinical outcome of the original study group were presented elsewhere.