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      Outcome of Everolimus-Based Therapy in Hormone-Receptor-Positive Metastatic Breast Cancer Patients After Progression on Palbociclib

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          Abstract

          Background:

          Despite the approval of mTOR inhibitor everolimus and CDK4/6 inhibitors in the management of hormone-receptor-positive HER2 non-amplified metastatic breast cancer (HR+ HER2-MBC), the optimal sequence of therapy is unclear. There are no clinical data on efficacy of everolimus in HR+ HER2-MBC after cancer progresses on CDK4/6 inhibitors.

          Objective:

          The objective of this study is to find the efficacy of everolimus in HR+ HER2-MBC after they progress on a CDK4/6 inhibitor palbociclib.

          Methods:

          This is a retrospective, 2-institute review of HR+ HER2-MBC from Jan 2015 to March 2018 treated with everolimus after progression on palbociclib. Primary end point was median progression-free survival (PFS), secondary end points objective response rate (ORR), clinical benefit ratio (CBR), and overall survival (OS).

          Results:

          Out of 41 women with median age 61 years (33, 87) enrolled, 66% had received adjuvant systemic therapy, 61% had visceral disease, and 95% had prior nonsteroidal aromatase inhibitors. About 83% women had 3 or more chemotherapy or hormonal therapies prior to everolimus. Kaplan-Meier estimates showed a median PFS of 4.2 months (95% confidence interval [CI]: 3.2-6.2). The median OS was 18.7 months (95% CI 9.5 to not reached). Objective response rate and CBR were both 17.1%.

          Conclusion:

          Everolimus was associated with modest PFS and ORR in HR+ HER2-MBCs postprogression on palbociclib.

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          Most cited references9

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          Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.

          The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here.
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            G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells.

            Ovarian cancer is one of the most common cancers among women. Recent studies demonstrated that the gene encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K) is frequently amplified in ovarian cancer cells. PI3K is involved in multiple cellular functions, including proliferation, differentiation, antiapoptosis, tumorigenesis, and angiogenesis. In this study, we demonstrate that the inhibition of PI3K activity by LY-294002 inhibited ovarian cancer cell proliferation and induced G(1) cell cycle arrest. This effect was accompanied by the decreased expression of G(1)-associated proteins, including cyclin D1, cyclin-dependent kinase (CDK) 4, CDC25A, and retinoblastoma phosphorylation at Ser(780), Ser(795), and Ser(807/811). Expression of CDK6 and beta-actin was not affected by LY-294002. Expression of the cyclin kinase inhibitor p16(INK4a) was induced by the PI3K inhibitor, whereas steady-state levels of p21(CIP1/WAF1) were decreased in the same experiment. The inhibition of PI3K activity also inhibited the phosphorylation of AKT and p70S6K1, but not extracellular regulated kinase 1/2. The G(1) cell cycle arrest induced by LY-294002 was restored by the expression of active forms of AKT and p70S6K1 in the cells. Our study shows that PI3K transmits a mitogenic signal through AKT and mammalian target of rapamycin (mTOR) to p70S6K1. The mTOR inhibitor rapamycin had similar inhibitory effects on G(1) cell cycle progression and on the expression of cyclin D1, CDK4, CDC25A, and retinoblastoma phosphorylation. These results indicate that PI3K mediates G(1) progression and cyclin expression through activation of an AKT/mTOR/p70S6K1 signaling pathway in the ovarian cancer cells.
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              Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt.

              The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.
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                Author and article information

                Journal
                Breast Cancer (Auckl)
                Breast Cancer (Auckl)
                BCB
                spbcb
                Breast Cancer : Basic and Clinical Research
                SAGE Publications (Sage UK: London, England )
                1178-2234
                23 July 2020
                2020
                : 14
                : 1178223420944864
                Affiliations
                [1 ]Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
                [2 ]Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
                [3 ]Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
                [4 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
                [5 ]Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
                Author notes
                [*]Ajay Dhakal, Wilmot Cancer Institute, University of Rochester Medical Center, 125 Red Creek Drive, Suite 211, Rochester, NY 14623, USA. Email: ajaydhakal@ 123456gmail.com
                Author information
                https://orcid.org/0000-0002-5140-158X
                https://orcid.org/0000-0002-7536-1746
                https://orcid.org/0000-0001-9739-8462
                https://orcid.org/0000-0003-2454-7441
                Article
                10.1177_1178223420944864
                10.1177/1178223420944864
                7378710
                32753876
                58363563-29c5-4a91-b11b-b9c064ff8fff
                © The Author(s) 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 8 April 2020
                : 2 July 2020
                Funding
                Funded by: national cancer institute, FundRef https://doi.org/10.13039/100000054;
                Funded by: Clinical Data Network Shared Resources, ;
                Categories
                Original Research
                Custom metadata
                January-December 2020
                ts1

                Oncology & Radiotherapy
                metastatic breast cancer,everolimus,palbociclib,estrogen receptor-positive breast cancer

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