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Strong evidence supports conservative management for many men with early disease, making active surveillance an increasingly used option. However, a minority will progress and eventually require radical treatment, motivating investigation of interventions that could slow or abrogate progression. This narrative review analyzes literature on molecular and genetic mechanisms driving early evolution and highlights trial design elements for realistic therapeutic targeting.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/mechanisms-of-progression-and-challenges-for-intervention-in-the-natural-history-of-early-prostate-cancer-a-narrative-review/349358/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/mechanisms-of-progression-and-challenges-for-intervention-in-the-natural-history-of-early-prostate-cancer-a-narrative-review/349358.png","ImageObject",300,407,{"name":92,"@type":93},"4398046744996","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is active surveillance considered a mainstay for early prostate cancer?","Question",{"text":112,"@type":113},"Many men with early prostate cancer do not progress to cause morbidity or mortality and can be managed conservatively. Active surveillance monitors disease and intervenes only when treatment is needed.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What drives the need to consider interventions during active surveillance?",{"text":117,"@type":113},"Although progression rates are low for many men, a minority experience progression where radical treatment becomes necessary. Interventions are therefore considered to slow or abrogate the natural history in higher-risk subgroups.",{"name":119,"@type":110,"acceptedAnswer":120},"What does the review focus on regarding early prostate cancer mechanisms?",{"text":121,"@type":113},"The review summarizes known molecular and genetic events in early prostate cancer and emphasizes mechanisms that could be realistically targeted by therapeutics.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},349358,1790207232,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":66,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},4398046744996,"Review  \nMechanisms of Progression and Challenges for Intervention in the Natural History of Early Prostate Cancer: A Narrative Review  \nKieran Sandhu 1,2, Simon Pacey 3, Daniel S. Brewer 4,5 and Vincent J. Gnanapragasam 1,2, *  \nReceived: 5 April 2026  \nRevised: 3 June 2026  \nAccepted: 18 June 2026  \nPublished: 19 June 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Cambridge Prostate Cancer Research and Clinical Trials Office, S2, Cambridge Biomedical Campus, Addenbrooke’s Hospital Site, S Wards Building, Keith Day Rd, Cambridge CB2 0SL, UK; [kieran.sandhu7@nhs.net](kieran.sandhu7@nhs.net)  \n2 Department of Surgery, Division of Urology, Clinical School, University of Cambridge, R4 Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK  \n3 Department of Oncology, Clinical School, University of Cambridge, R4 Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK; [scp46@cam.ac.uk](scp46@cam.ac.uk)  \n4 Department of Metabolic Health, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK; [d.brewer@uea.ac.uk](d.brewer@uea.ac.uk)  \n5 Earlham Institute, Norwich NR4 7UZ, UK  \n* [Correspondence: vjg29@cam.ac.uk](Correspondence: vjg29@cam.ac.uk)  \nSimple Summary  \nIn this review, we discuss the known landscape of molecular and genetic events in early prostate cancer evolution which may or may not be realistic to target as a therapeutic strategy. We further discuss what is needed forbespoke and well-designed future interventional trials as a strategy to modify the natural history of early prostate cancer.  \nAbstract  \nProstate cancer is the most common cancer diagnosed in men and the incidence is rising globally. Disease-related mortality however remains comparatively low. There is now irrefutable evidence that many men do not need treatment if diagnosed with early cancer and can instead be safely managed conservatively. Active surveillance is therefore now an increasingly popular management option for these men. A minority of men on surveillance however will experience disease progression to a point where radical treatment is necessary. It is therefore logical to consider interventions that might slow down or abrogate this natural history. This is particularly important for subgroups of men with early cancer who are at a higher risk of progression and where the risk–benefit of therapeutic intervention is much more favourable. In this narrative review we explore the literature on known molecular and genetic events in prostate cancer which may drive progression. Our principal focus was to consider mechanisms that could be realistically targeted by therapeutics. We further consider key attributes that early cancer therapeutic trials should incorporate in their design. These include risk-stratified patient selection, bespoke dosing schedules and the importance of unambiguous, clinically meaningful endpoints in this new trial space.  \nKeywords: prostate cancer; early disease; biology; active surveillance; therapeutics; disease progression; natural history  \n1. Introduction  \nProstate cancer (PC) is a complex disease to manage because of its high incidence but relatively low mortality [1,2] . Up to one in three men will now present with disease that  \ncould be classified as “early” and are unlikely to result in disease morbidity or mortality [2] . This recognition has meant that active surveillance (AS) has now become a mainstay of management and its use is growing [3] . AS is a process of monitoring PC and only intervening when it reaches a stage where treatment is considered needed. Significant advances have been made in recent times to refine, risk stratify and personalise AS management. In prospectively implemented AS series using risk stratification and endpoint definitions of progression to ≥Cambridge Prognostic Group 3 (unfavourable intermediate ri","cbCaivpmRR4i1SSd","https://ap.wps.com/l/cbCaivpmRR4i1SSd","pdf",1369867,18,"English","# Introduction\n## Disease burden and active surveillance\n## Rationale for intervention targeting early evolution\n## Scope and aims\n# Literature Review Strategy","[{\"question\":\"Why is active surveillance considered a mainstay for early prostate cancer?\",\"answer\":\"Many men with early prostate cancer do not progress to cause morbidity or mortality and can be managed conservatively. Active surveillance monitors disease and intervenes only when treatment is needed.\"},{\"question\":\"What drives the need to consider interventions during active surveillance?\",\"answer\":\"Although progression rates are low for many men, a minority experience progression where radical treatment becomes necessary. Interventions are therefore considered to slow or abrogate the natural history in higher-risk subgroups.\"},{\"question\":\"What does the review focus on regarding early prostate cancer mechanisms?\",\"answer\":\"The review summarizes known molecular and genetic events in early prostate cancer and emphasizes mechanisms that could be realistically targeted by therapeutics.\"}]","Mechanisms of Progression and Challenges for Intervention in the Natural History of Early Prostate Cancer: A Narrative Review | PDF",1790083012,45]