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Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor-positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

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      Abstract

      Introduction:Biomarkers predictive of response to mechanistic target of rapamycin (mTOR) inhibitor, everolimus, in endocrine receptor (ER)-positive metastatic breast cancer (MBC) are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN) expression and correlating their expression with response and survival.Materials and Methods:MBC patients who received everolimus with endocrine therapy (ET) after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test.Results:Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6%) patients and retained in 2/13 patients (15.4%). mTOR activity was absent in four patients (30.7%), weak in six patients (46.1%), and moderate in 3 patients (23.2%). Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months) than those with weak and moderate activity, respectively (P = 0.043). There was no correlation between loss of PTEN expression and PFS.Conclusions:Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

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      The phosphoinositide 3-kinase pathway.

       Lewis Cantley (2002)
      Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.
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        The functions and regulation of the PTEN tumour suppressor.

        The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein-protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies.
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          Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

          Introduction Effective treatments for hormone-receptor-positive (HR+) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. Methods BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR+ advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Results Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials. Conclusion The addition of everolimus to exemestane markedly prolonged PFS in patients with HR+ advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655. Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0060-1) contains supplementary material, which is available to authorized users.
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            Author and article information

            Affiliations
            Deparment of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
            Author notes
            Correspondence to: Dr. Jyoti Bajpai, E-mail: dr_jyotibajpai@ 123456yahoo.co.in
            Journal
            South Asian J Cancer
            South Asian J Cancer
            SAJC
            South Asian Journal of Cancer
            Medknow Publications & Media Pvt Ltd (India )
            2278-330X
            2278-4306
            Jul-Sep 2017
            : 6
            : 3
            : 102-105
            5615875
            SAJC-6-102
            10.4103/sajc.sajc_113_17
            Copyright: © 2017 The South Asian Journal of Cancer

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

            Categories
            ORIGINAL ARTICLE: Breast Cancer

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