Martin Eklund

Our general aim is to use evidence-based modelling and simulation to reduce the burden due to cancer through effective and cost-effective prostate cancer screening. The Swedish government is currently investigating whether to introduce organised prostate cancer testing (OPT). However, policy makers lack key evidence on the long-term effectiveness and cost-effectiveness of organised testing compared with current opportunistic testing. We will combine the available trials evidence with simulation models to predict the long-term outcomes of a range of prostate cancer testing strategies. The specific aims are to:Measure health-related quality of life and health anxiety for men undergoing prostate cancer screening and diagnostics.Extend an existing prostate cancer screening model to represent opportunistic and organised testing.Evaluate novel prostate cancer screening tests and diagnostics, including a polygenic risk score, artificial intelligence as a dual rater for prostate pathology, and risk predictions based on screening history.Predict whether OPT will increase socio-economic inequalities in prostate cancer outcomes compared with current inequalities.Predict the long-term effectiveness and cost-effectiveness of OPT compared with current testing.These aims will support the decision on whether and how to introduce organised prostate cancer testing in Sweden and other European countries.

Rationale:Sarcomas are rare, aggressive cancers with highly diverse genomic landscapes, often leading to misclassification and suboptimal treatment selection. Whole-genome and transcriptome sequencing (WGTS) and methylation profiling have shown great promise in refining sarcoma diagnostics, but key genomic alterations—such as homologous recombination deficiency (HRD), chromothripsis, and complex structural variations—remain poorly understood.Aims and Purpose:(1) Identify novel diagnostic biomarkers, including fusion genes that improve classification.(2) Investigate HRD signatures and copy number alterations to guide targeted therapy.(3) Validate newly discovered biomarkers using tumor cohorts spanning over 30 years.Work Plan:WP1: Prospective WGTS and methylation profiling to identify novel genetic alterations in sarcomas.WP2: Copy number profiling and HRD analysis to characterize genome-wide instability patterns.WP3: Retrospective validation of biomarkers using targeted NGS, in-situ seqencing and methylome profiling and in vito assays. In-vitro validation of biomarkers using CRISPR and fuctional assays.Significance:Our preliminary findings have already redefined diagnoses in &gt

10% of sarcoma cases, directly influencing patient management. This project will establish genomic profiling as a clinical standard in sarcoma diagnostics and identify novel biomarkers for therapy selection, ultimately improving patient survival and enabling precision oncology in sarcoma care.

This study assesses the feasibility and clinical benefits of de‐escalating treatment in metastatic hormone‐sensitive prostate cancer (mHSPC) patients with undetectable circulating tumor DNA (ctDNA). In an open-label, 1:1 randomized, non-inferiority trial, we compare darolutamide monotherapy to the standard combination of androgen deprivation therapy (ADT) plus darolutamide.The primary endpoint is time to development of castration resistance, analyzed using Bayesian Weibull accelerated failure time models, while secondary endpoints include health-related quality of life (HR-QOL), testosterone recovery, bone health, and cost-effectiveness.Leveraging the established ProBio trial platform—with ongoing recruitment across Sweden, Belgium, Norway, and Switzerland and over 940 patients enrolled—the study aims to reduce ADT-associated adverse effects without compromising efficacy. Coordinated by experienced investigators at Karolinska Institutet and supported by a finalized drug supply contract with Bayer, approximately 400 patients will be enrolled over 2–3 years with interim analyses planned.If successful, this de-escalation strategy may establish a new treatment paradigm for mHSPC patients with favorable prognosis, improving quality of life while maintaining robust clinical outcomes.This abstract and tstudy proposal is a summary of the 20-page sub-protocol: ProBio-Darolutamide monotherapy. The full protocol is available after request to: henrik.gronberg@ki.se.

Prostate cancer is the most common form of cancer and the leading cause of cancer death among men in Sweden. In 2018, over 10,000 men were diagnosed with prostate cancer and 2,350 died from the disease. A bottleneck in the effort to reduce prostate cancer mortality is the difficulty in making objective and reproducible pathological assessments of tissue samples (biopsies) from the prostate. Histopathological evaluation of prostate biopsies is used to diagnose the disease and grade its severity, and is of crucial importance for the clinical management and treatment of men diagnosed with prostate cancer. Despite the importance of histopathological assessment of prostate biopsies, there are major challenges. The so-called Gleason grade is crucial for treatment decisions for men diagnosed with prostate cancer. As the Gleason grade often differs between different pathologists' assessments, treatment decisions can be made on incorrect information about the severity of the disease. This can lead to the man not receiving sufficiently aggressive treatment or receiving unnecessarily aggressive treatment. My research group has developed a system based on artificial intelligence (AI) to assist the pathologists, with the overall goal of solving these challenges. In the proposed research, we will continue the development of the AI system, link it to genomic information from the tissue samples, and conduct rigorous clinical validation of the system through a network of international collaborators and through a randomized clinical trial. The overall aim of the research is to make prostate cancer diagnosis more accurate, in order to provide better information to make correct treatment decisions for men diagnosed with prostate cancer and thus achieve better treatment results and fewer side effects of the treatment.

Histopathological evaluation of prostate biopsies is critical to the clinical management of men suspected of having prostate cancer. Despite this importance, the histopathological diagnosis of prostate cancer is associated with a number of challenges: The large number of prostate biopsies being performed worldwide together with the shortage of well-trained uro-pathologists and the high inter- pathologist variability leads to suboptimal prostate cancer diagnostics and prognostication, with risks for under- and overtreatment.My research group has over the last years developed an artificial intelligence (AI) system to assist the pathologists in the evaluation of prostate biopsies, with the overarching aim of solving these problems. In a recent article in the Lancet Oncology, we demonstrate that the system performs on par with internationally leading uro-pathologist for grading prostate needle biopsies.In this research proposal, we aim to:Perform retrospective international multisite validation of the AI system to assess the AI’s performance across different labs, technical platforms (scanners), and disease subtypesDevelop methods to go beyond today’s grading to improve prognosticationLink the AI system with genomic profiling of tumor tissue to improve treatment selectionPerform prospective validation of the AI system in a randomized diagnostic histopathology trial

More than 2,500 men die each year from prostate cancer in Sweden. Although PSA sampling every two years between ages 50 and 70 has been shown to nearly halve mortality, PSA has significant diagnostic limitations leading to many unnecessary biopsies, over-diagnosis, and over-treatment, which is why prostate cancer screening is not recommended by healthcare. The need for improved methods for early detection of prostate cancer is thus great. In recent years, we have conducted the SHLM3 studies, where we show that we can significantly improve prostate cancer diagnosis using the STHLM3 test and the use of magnetic camera studies. Active monitoring of men with diagnosed low-risk prostate cancer is a method for reducing over-treatment, which involves following up the patient with repeated PSA tests and biopsies to be able to subsequently distinguish those who need to be treated. One disadvantage of active monitoring is the many biopsies that men are exposed to, which can lead to serious infections and impaired opportunities for effective surgery if active treatment is needed. We want to develop methods for monitoring low-risk patients who are safe and less invasive using the STHLM3 test and magnetic camera surveys. The research aims to improve the methods for active monitoring in order to reduce the negative consequences of early diagnostics for prostate cancer. Considering that over-diagnosis and over-treatment were the main reason why prostate cancer screening was not recommended, improved methods of managing mites that are diagnosed with low-risk prostate cancers are required so that we can move towards effective organized screening for prostate cancer to reduce morbidity and mortality in Sweden's most deadly cancer.

More than 2,500 men die each year from prostate cancer in Sweden. Although PSA sampling every two years between ages 50 and 70 has been shown to nearly halve mortality, PSA has significant diagnostic limitations leading to many unnecessary biopsies, over-diagnosis, and over-treatment, which is why prostate cancer screening is not recommended by healthcare. The need for improved methods for early detection of prostate cancer is thus great. In recent years, we have conducted STHLM3, a study of 59,000 participants in Stockholm, where we show that we can significantly improve prostate cancer diagnosis using the risk-based STHLM test. STHLM3 is a step towards an organized, individualized and risk-based test program for prostate cancer. However, several questions remain to be answered in order to optimally use the results from STHLM3: (i) Between which ages and how often should men be tested? (ii) How should the results of STHLM3 be used after an initial negative biopsy? (iii) How should the results be used together with magnetic resonance camera surveys to further improve the test? The research in this application focuses on answering the first of these questions. Prostate cancer screening is emotionally charged and highly stained by over-diagnosis and over-treatment. The proposed research will reduce the negative consequences of prostate cancer screening without compromising the positive effects of reduced mortality. We now have the opportunity to move away from the current opportunistic screening situation in Sweden and instead construct a strategy that maximizes the benefit of the screening and utilizes the great research-related advances in risk assessment in the right way to reduce the mortality in prostate cancer.

More than 2,500 men die each year from prostate cancer in Sweden. Although PSA sampling every two years between ages 50 and 70 has been shown to nearly halve mortality, PSA has significant diagnostic limitations leading to many unnecessary biopsies, over-diagnosis, and over-treatment, which is why prostate cancer screening is not recommended by healthcare. The need for improved methods for early detection of prostate cancer is thus great. In recent years, we have conducted STHLM3, a study of 59,000 participants in Stockholm, where we show that we can significantly improve prostate cancer diagnosis using the risk-based STHLM test. STHLM3 is a step towards an organized, individualized and risk-based test program for prostate cancer. However, several questions remain to be answered in order to optimally use the results from STHLM3: (i) Between which ages and how often should men be tested? (ii) How should the results of STHLM3 be used after an initial negative biopsy? (iii) How should the results be used together with magnetic resonance camera surveys to further improve the test? The research in this application focuses on answering the first of these questions. Prostate cancer screening is emotionally charged and highly stained by over-diagnosis and over-treatment. The proposed research will reduce the negative consequences of prostate cancer screening without compromising the positive effects of reduced mortality. We now have the opportunity to move away from the current opportunistic screening situation in Sweden and instead construct a strategy that maximizes the benefit of the screening and utilizes the great research-related advances in risk assessment in the right way to reduce the mortality in prostate cancer.

More than 2,500 men die each year from prostate cancer in Sweden. Although PSA sampling every two years between ages 50 and 70 has been shown to nearly halve mortality, PSA has significant diagnostic limitations leading to many unnecessary biopsies, over-diagnosis, and over-treatment, which is why prostate cancer screening is not recommended by healthcare. The need for improved methods for early detection of prostate cancer is thus great. In recent years, we have conducted STHLM3, a study of 59,000 participants in Stockholm, where we show that we can significantly improve prostate cancer diagnosis using the risk-based STHLM test. STHLM3 is a step towards an organized, individualized and risk-based test program for prostate cancer. However, several questions remain to be answered in order to optimally use the results from STHLM3: (i) Between which ages and how often should men be tested? (ii) How should the results of STHLM3 be used after an initial negative biopsy? (iii) How should the results be used together with magnetic resonance camera surveys to further improve the test? The research in this application focuses on answering the first of these questions. Prostate cancer screening is emotionally charged and highly stained by over-diagnosis and over-treatment. The proposed research will reduce the negative consequences of prostate cancer screening without compromising the positive effects of reduced mortality. We now have the opportunity to move away from the current opportunistic screening situation in Sweden and instead construct a strategy that maximizes the benefit of the screening and utilizes the great research-related advances in risk assessment in the right way to reduce the mortality in prostate cancer.