Again, we observed similar magni tudes of inhibition of HER2, but cell lines wi

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 Again, we observed similar magni tudes of inhibition of HER2, but cell lines wi Empty Again, we observed similar magni tudes of inhibition of HER2, but cell lines wi

Post  jy9202 on Wed Jun 25, 2014 6:27 am

Apart from activation by the canonical pathway drivers and insulin like growth factor 1 receptor in vitro data have shown that the PI3K pathway can also ARQ 197 supplier 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 inhibition. These preclinical data support the clinical observation that estrogen receptor alpha positive metastatic breast cancer patients with prior exposure to aromatase inhibitors derive substantial benefit from the addition of an mTOR inhibitor. Whether or not patients who are primarily resistant to adjuvant endocrine therapy might benefit from PI3K and or MAPK pathway inhib ition remains to be defined.

A biomarker of an activated PI3K and or MAPK pathway with clinical validity to pre dict resistance in the adjuvant setting has not been iden tified, but could potentially be used as a companion diagnostic for non ER targeted drugs, such as an mTOR inhibitor. Several canonical pathway drivers, オーダー AZD0530 such as PIK3CA mutations, loss of PTEN, and HER2, 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 acti vation of downstream proteins. In vitro, PI3K pathway activation leads to phosphorylation of AKT and subsequently of mTOR and p70S6K. Phosphoryl ation of extracellular signal regulated kinase 1 2 is a result of MAPK pathway activation and mediates activation of p70S6K.

However, relatively moderate activation of the PI3K pathway was seen in tumors with a PIK3CA exon 20 mutation associated gene signature. In addition, in a large series of primary breast Alvocidib 構造 can cer tumors, reverse phase protein analysis did not show activation of the typical downstream proteins in the PI3K pathway in PIK3CA mutated luminal A tumors. The activation status of downstream proteins rather than the presence or absence of a canonical driver there fore 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 poten tially 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 predict ive value of different downstream activated proteins in the PI3K and or MAPK pathways in a large series of ER positive postmenopausal breast cancer patients ran domized between adjuvant tamoxifen versus no systemic treatment. Methods Patients and materials We have recollected primary tumor tissue blocks from stage I to III postmenopausal breast cancer patients who were randomized between 1 year of tamoxi fen versus 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.

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