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Towards a prostate cancer risk calculator

By Dermot - 04th Jul 2017

The diagnosis and treatment of prostate cancer is controversial, with many critics arguing that it leads to over-treatment and unnecessary biopsies. A number of risk calculators have been developed but there is a need for a calculator to be validated in an Irish population to gain traction. Our project, funded by the Health Research Board (HRB), is designed to build such a prostate risk calculator arising from research involving 4,000 men at the rapid-access clinics in Dublin, Cork and Galway.

Prostate cancer is the most common solid-organ malignancy among men in Ireland, excluding non-melanoma skin cancer. The Prostate Cancer Research Consortium (PCRC) was established in 2004, funded by the Irish Cancer Society in collaboration with Molecular Medicine Ireland, to specifically bring together multidisciplinary scientific and clinical researchers from various academic institutions and hospitals in a co-ordinated approach to maximise research potential in prostate cancer. Bringing together researchers from different centres and disciplines with complementary ‘added value’ skills provides an excellent environment to tackle important questions in relation to prostate cancer diagnosis, prognosis and new therapies.

Our aspiration is to make a significant contribution to prostate cancer research with a clear focus on the cancer patient, while providing a teaching and mentoring environment that would encourage young scientists and clinicians to flourish, building a critical mass of prostate cancer clinicians and researchers in Ireland. The programme of research in the area of biomarker discovery and validation for indolent and aggressive disease has been subsequently refunded by the Irish Cancer Society in partnership with ‘Movember’ in 2006 and 2011.

During this time the consortium has grown its critical mass, resources, skills and collaborations to accelerate biomarker discovery, evaluation and validation in order to provide clinical utility and improve patient care. It has brought together expertise in the areas of tissue imaging, epigenetics, transcriptomics, proteomics, glycosylation and data integration, which allows the interrogation and analysis of biological matrices at multiple levels.

Essential to the activities of the PCRC are the bioresources across the hospital sites recruiting patients and collecting clinical information and biological samples from patients undergoing diagnosis in the rapid-access clinics and radical prostatectomy treatment for localised disease. Also, central to this federated collection is the Bioresource Information Management System (BIMS) architecture, which accommodates the collection and tracking of samples and integration of clinical and follow-up information.

The BIMS web-based database system accommodates all the de-identifiable data from the patients and their samples. This allows investigators to not only identify what samples are available and where they are located, but also their collection details. It also links to relevant clinical data in a completely confidential way, including family history and medications. The database is approved and licenced by the Data Protection Commissioner and fully complies with all national and European regulations.

<h3 class=”subheadMIstyles”>Diagnosis</h3>

One group of scientists, clinicians and statisticians within the PCRC have specifically identified the diagnosis of prostate cancer as a significant issue for investigation. As death from any cancer almost invariably results from disseminated disease, successful treatment of a tumour detected before it becomes disseminated should therefore prevent cancer-specific mortality. Hence, early detection of cancer remains the most promising strategy for cancer control.

In prostate cancer, the detection of cancer is key, but so too is the need to determine whether the disease is significant or not. The European Randomised Study of Screening for Prostate Cancer (ERSPC) has demonstrated a reduction in mortality in the screening arm, but the screening of men is associated with over-diagnosis and over-treatment.

The National Cancer Control Programme (NCCP) has responded to this by establishing rapid-access referral clinics at specific sites around Ireland to standardise the diagnosis of prostate cancer in Ireland. Specifically, eight diagnostic centres have been set up to assess patients on receipt of a referral letter.

The gold standard for the diagnosis of prostate cancer is a prostate biopsy. The clinical judgment and recommendation to proceed with a prostate biopsy hinges upon the assessment of factors such as prostate specific antigen (PSA), digital rectal exam (DRE), a positive family history of prostate cancer, age, previous prostate biopsy as well as patient’s life expectancy, physiological status and shared decision-making with the patient.

<h3 class=”subheadMIstyles”>Referrals</h3>

Ireland operates a referral system for assessment for prostate biopsy based upon PSA and DRE findings. However, both have errors associated with these features: Issues with a PSA at a cut-off level of 4ng/mL yields a specificity of 63.1 per cent and sensitivity of 34.9 per cent. However, some studies have indicated that substantial numbers of clinically-significant cancers could also be found in patients with PSA levels below 4.0ng/mL.

PSA is also not specific to prostate cancer and can be raised in other common conditions such as benign prostatic hypertrophy, inflammatory responses and catheterisation, thus leading to the over-diagnosis of prostate cancer. DRE also has specificity issues and the tip of the index finger only appreciates a small area of the prostate gland, and tumours in the anterior and medial lobes of the prostate may be undetectable.

The other issue is that a biopsy is an invasive procedure which is associated with morbidity including urosepsis, urinary retention and hospitalisation, and patients may endure great anxiety throughout the process, as results can take weeks to return. In addition, an increasing number of men have low-grade, insignificant cancer detected that does not require treatment, resulting in the over-diagnosis of disease.

What clinicians seek is a method that will inform the need for a biopsy only in those at high risk of significant cancer, thereby greatly reducing the numbers requiring a biopsy. A risk calculator can be used to identify those at most risk and these individuals can be targeted, saving many men from unnecessary biopsies, their side-effects and impact on their quality of life, as well as alleviating the pressures on our already over-burdened healthcare sector by reducing the need to carry out the biopsies. Risk calculators are becoming increasingly important in clinical practice for the management of prostate cancer.

Through the systematic use of patient risk factors in the form of prostate cancer clinical prediction models, risk stratification can be standardised and used to guide clinical decision-making. Furthermore, the recent European Association of Urology guidelines on prostate cancer diagnosis recommend the use of a multivariate approach to the decision to proceed to prostate biopsy.

However, widespread traction for their use has not been garnered, possibly due to the great variation which exists in the relatively limited validation of these tools. It is important to validate a clinically available risk calculator in an Irish population and the establishment of national rapid-access clinics allows us a unique opportunity to gather national data and develop an ‘Irish risk calculator for Irish men’.

<h3 class=”subheadMIstyles”>Solution</h3>

A number of prediction tools are already available for this purpose. One of these tools is the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) and the other is the European Randomised Study for Prevention of Prostate Cancer Risk Calculator (ERSPC-RC).

Previous work by our group has demonstrated that these tools can be applied to an Irish population and it was shown that the ERSPC-RC had a greater net benefit on decision-curve analysis for both prostate cancer and high-grade prostate cancer with AUC values of 0.710 (95 per cent CI 0.688-0.733) and 0.741 (95 per cent CI 0.717-0.763) respectively, compared to PSA alone with AUC values of  0.581 (95 per cent CI 0.556-0.606) for prostate cancer and 0.641 (95 per cent CI 0.611- 0.666). But these levels of predictions are still not good enough to warrant roll-out across the rapid-access clinics, indicating the need for improvements and an appropriate model to be built.

There is another option: To build an Irish prostate cancer risk calculator.

Our current research, funded by the HRB, is designed to build just such a calculator involving 4,000 men attending rapid-access clinics. It will investigate ways to improve on prediction of prostate cancer and high-grade disease with the addition of serum and urine biomarkers.

Previous research from the researchers involved in the project have identified serum protein biomarkers and urine epigenetic biomarkers for significant disease. These biomarkers will be assessed for their value at the initial decision to biopsy men.

In an initial cohort of 250 Irish patients recruited from three of the tertiary referral rapid-access clinics, we have demonstrated that we can build an Irish risk calculator and that the inclusion of the current commercially-available Prostate Health Index panel of biomarkers improves on the prediction of prostate cancer and high-grade disease with AUC values of 0.77 and 0.79.

We will recruit patients from the rapid-access clinics in Dublin, Galway and Cork and collect their clinical details, including family history, as well as blood and urine sample from a cohort of these patients.

This data will be used by the multidisciplinary team to build an Irish risk calculator relevant to Irish men attending the clinics and used for subsequent men presenting to the clinics to inform the need for a biopsy.

<p class=”referencesonrequestMIstyles”><strong>References on request</strong>

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