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      The precision prevention and therapy of HPV‐related cervical cancer: new concepts and clinical implications

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          Abstract

          Cervical cancer is the third most common cancer in women worldwide, with concepts and knowledge about its prevention and treatment evolving rapidly. Human papillomavirus ( HPV) has been identified as a major factor that leads to cervical cancer, although HPV infection alone cannot cause the disease. In fact, HPV‐driven cancer is a small probability event because most infections are transient and could be cleared spontaneously by host immune system. With persistent HPV infection, decades are required for progression to cervical cancer. Therefore, this long time window provides golden opportunity for clinical intervention, and the fundament here is to elucidate the carcinogenic pattern and applicable targets during HPV‐host interaction. In this review, we discuss the key factors that contribute to the persistence of HPV and cervical carcinogenesis, emerging new concepts and technologies for cancer interventions, and more urgently, how these concepts and technologies might lead to clinical precision medicine which could provide prediction, prevention, and early treatment for patients.

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          Most cited references156

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Improved survival with bevacizumab in advanced cervical cancer.

            Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).
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              Human papillomavirus and cervical cancer.

              Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If these prevention strategies can be implemented in developing countries, many thousands of lives could be saved. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                dma@tjh.tjmu.edu.cn
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                14 September 2018
                October 2018
                : 7
                : 10 ( doiID: 10.1002/cam4.2018.7.issue-10 )
                : 5217-5236
                Affiliations
                [ 1 ] Department of Gynecological oncology The First Affiliated Hospital of Sun Yat‐sen University Zhongshan 2nd Road Yuexiu, Guangzhou Guangdong China
                [ 2 ] Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan, Hubei 430030 China
                Author notes
                [*] [* ] Correspondence

                Ding Ma, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Tel: +86 13632120686; Fax: 027‐83662681; E‐mail: dma@ 123456tjh.tjmu.edu.cn

                Article
                CAM41501
                10.1002/cam4.1501
                6198240
                30589505
                23b0607b-a38f-4488-98b6-57bdbb32464f
                © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 October 2017
                : 14 February 2018
                : 21 March 2018
                Page count
                Figures: 4, Tables: 0, Pages: 20, Words: 14503
                Funding
                Funded by: National Basic Research Program of China
                Award ID: 2015CB553903
                Award ID: 2013CB911304
                Funded by: National Science‐technology Supporting Plan Projects
                Award ID: 2015BAI13B05
                Funded by: Chinese National Key Plan of Precision Medicine Research
                Award ID: 2016YFC0902901
                Funded by: Nature and Science Foundation of China
                Award ID: 81402158
                Award ID: 81472783
                Award ID: 81230038
                Award ID: 81372805
                Categories
                Review
                Cancer Prevention
                Review
                Custom metadata
                2.0
                cam41501
                October 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0.1 mode:remove_FC converted:23.10.2018

                Oncology & Radiotherapy
                cervical carcinogenesis,cervical screening,genome editing tools,hpv integration,ngs‐based hpv testing

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