Clinical breast cancer
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Clinical breast cancer · Nov 2010
ReviewTargeting endocrine resistance: is there a role for mTOR inhibition?
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a critical intracellular signaling cascade that mediates both growth factor-induced proliferation and cell survival with deregulated signaling through this pathway, a feature of most cancers. Here, we review the role of the PI3K/Akt/mTOR pathway in endocrine-resistant breast cancer and discuss preclinical and clinical studies combining endocrine therapy with mTOR inhibition. Key to the success of such an approach will be a clinical trial design incorporating appropriate tumor selection and validation of biomarkers predicting benefit. Ultimately, a greater understanding of the biology and compensatory mechanisms will allow the partnering of key signal transduction inhibitors together to provide maximal "vertical" or "horizontal" blockade with further preclinical and clinical studies planned to examine possible synergistic combinations with endocrine therapy.
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Clinical breast cancer · Nov 2010
ReviewEvolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/Akt/mTOR pathway.
Human epidermal growth factor receptor 2-positive (HER2+) breast cancers, which account for 25%-30% of breast cancers, are characterized by an aggressive course and a high propensity for recurrence in the 4 years following diagnosis. The use of trastuzumab-based chemotherapy in the adjuvant setting has markedly improved the outcome for patients with early stage HER2+ breast cancer. Likewise the use of trastuzumab in combination with chemotherapy in patients with metastatic HER2+ breast cancers has prolonged survival, with current expected median survival of about 3 years. ⋯ These results are being confirmed in ongoing phase III trials in the first-line and trastuzumab-resistant settings. The mechanism of how mTOR inhibitors reverse resistance to trastuzumab remains largely unexplained. Other agents targeting the PI3K pathway in trastuzumab-resistant breast cancers are in early phase clinical trials.
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Many cell kinases exert their proliferative and pro-survival effects through activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Basal-like breast cancer is a subtype that can be identified by molecular analysis and often includes tumors lacking expression of estrogen receptor/progesterone receptor or human epidermal growth factor receptor, also known as triple-negative breast cancers. ⋯ Most clinical trials which have attempted targeting the PI3K/Akt pathway in triple-negative breast cancer have involved the use of EGFR inhibitors with limited success. Novel agents targeting PI3K are under development in early-phase clinical trials and may demonstrate benefit in combination with chemotherapy or other targeted agents such as mitogen-activated protein kinase inhibitors for the treatment of triple-negative or basal-like breast cancer.