Exosomal microRNA in Predicting the Aggressiveness of Prostate Cancer in Chinese Patients

Study Overview
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Brief Summary
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The prostate gland is a clinically important male accessory sex gland and vital for its production of semen. Prostate cancer (PCa) is now ranked 3th in annual incidence of male cancer and ranked 5th for cancer-related death in men in Hong Kong which accounts for about 10.9 deaths per 100,000 persons. Its incidence is rising rapidly, almost tripled in the past 10 years. Fortunately, with the improvement in awareness of the disease and also increasing use of serum prostate specific antigen for early case identification, many patients are diagnosed at an earlier stage. However, unlike other malignancy, PCa is characterized by its slow progression nature. Therefore, some patients with low grade low volume disease might never suffered from PCa related complications or mortality. As a result, recent year, there is an increase use a more conservative approach, active surveillance (AS), for management of early prostate cancer. The principle of AS is selecting patients with low risk of disease and offered them regular monitoring, instead of radical local therapy, unless patient's cancer was noticed to progressing. By using this approach, patients might avoid possible complications related to treatment. Currently, people could use some clinical parameters, imaging and repeated prostate biopsy to assess and monitor the aggressiveness/ progression of PCa. However, these parameters suffered from defects, such as low correlation to the final PCa pathology or not readily repeatable for patients. Therefore, there is a need to identify more easy, safe and repeatable monitoring of the aggressiveness of prostate cancer. Exosome is genetic materials secreted by cells and could be measured in various body fluid. There are some studies suggested it is a potential marker for PCa diagnosis and monitoring. The aim of this study is to investigate the relationship of urinary exosome and the aggressiveness of prostate cancer.

Detailed Description
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Prostate cancer (PCa) is the third most common male cancer in Hong Kong. While the use of serum PSA has greatly improved the proportion of patients diagnosed at localized /early stage, there are also problems of overdiagnosis and overtreatment. Unfortunately, there was still no ideal markers that could help to predict the aggressiveness of PCa, especially in Chinese population. Exosome is an important media for cell-cell interaction. The content of exomsomes, including microRNAs, are believed to have important roles in PCa development and progression, and might also serve as potential markers in PCa management. Therefore, investigators would like to explore the role of exosomal microRNA in the prediction of tumour aggressiveness in local Chinese PCa patients. This is a prospective study divided into two parts. Subjects will be recruited consecutively from two hospitals. In Part I of the study (Candidate exosomal microRNA discovery and selection), a total of 60 patients from three groups (non-cancer, pathologically insignificant cancer and significant cancer patients) will be recruited. First portion of urine will be collected from them. For Group 2&3 patients, they are patients with clinically localized prostate cancer and planned for radical prostatectomy, urine will be collected before surgery for these two groups. Exosomal RNA will be extracted from urine and microRNAs expression profiles will be determined by next-generation sequencing. Candidate exosomal microRNAs that could differentiate pathological insignificant and significant PCa will be identified for Part II study. In Part II study (Candidate exosomal microRNAs validation), 180 patients with localized prostate cancer, planned for radical prostatectomy will be recruited. Urine will be again collected before surgery and the level of candidate exosomal microRNAs for each patient will be assessed. The diagnostic accuracy of these candidate exosomal microRNAs on predicting pathological insignificant cancer and also correlation with the final pathology will be assessed. The primary tasks for Part I study is the identification of potential exosomal microRNAs that could differentiate pathologically insignificant and significant PCa. The primary task for Part II study is the validation of the ability of those candidate exosomal microRNAs in differentiating pathological insignificant and significant PCa.

Official Title
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To Investigate the Diagnostic Accuracy of Exosomal microRNA in Predicting the Aggressiveness of Prostate Cancer in Chinese Patients

Conditions
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Prostate Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For non prostate cancer group Male subject with age 45 or above No clinical evidence of PCa, serum PSA <4 ng/dl and normal digital rectal examination. For prostate cancer group Male subject with age 45 or above Clinically diagnosed to have localized PCa and planned for radical prostatectomy No prior systemic therapy for PCa used, including hormonal or chemotherapy. Exclusion Criteria: History of medications usage that can affect serum PSA levels within 6 months of study enrolment. History of active urinary tract infection within 1 month of study enrolment. History of invasive prostate / bladder treatments within 6 months of study enrolment. History of concurrent renal/bladder cancer within 6 months of study enrolment.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Non-prostate cancer subjects<br>No clinical evidence of prostate cancer | |
| Subjects with pathologically insignificant prostate cancer<br>Insignificant prostate cancers were organ confined with tumor volumes less than 0.5 cc and Gleason score < 7. | |
| Subjects with pathologically significant prostate cancer<br>Significant cancers are those with either Gleason score > 7, evidences of extra-prostatic extension with positive margins, or seminal vesicles / lymph nodes involvement. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the differences in microRNA expression between non-prostate cancer subjects, pathologically insignificant and significant prostate cancer patients. | Urine will be collected prior to surgery. The urine sample will then be handled immediately for exosomal RNA extraction (refer to specific methodology). The extracted exosomal RNA would then be stored for next generation sequencing (NGS). Results of the 3 groups will then be compared, with reference to literatures findings. Candidate microRNAs that can differentiate between pathologically significant and insignificant cancer will be selected for Part II study. | Baseline, one-time point | 
| To assess the accuracy of selected microRNAs for the differentiation of patients with pathologically insignificant and significant prostate cancer after radical prostatectomy | Urine will be collected prior to surgery. The urine sample will then be handled immediately for exosomal RNA extraction (refer to specific methodology). The extracted exosomal RNA would then be stored for next generation sequencing (NGS). Results of the 3 groups will then be compared, with reference to literatures findings. Candidate microRNAs that can differentiate betten pathologically significant and insignificant cancer will be selected for Part II study.The preoperative patients and disease parameters, including age, clinical staging, serum PSA level, prostatic biopsy results, MRI findings, together with the prostatectomy pathology will be collected for subsequent data analysis. | Baseline, one-time point |