MICA: The exploitation of a novel image-based risk stratification tool in early prostate cancer - the Re-IMAGINE Consortium

Background:
One in eight men will develop prostate cancer and the risk increases with age. Most will not die of it, but some do. Our ability to identify those men whose cancer will decrease either their quality or quantity of life remains poor. Nowhere else in modern medicine are the errors of over-diagnosis, over-treatment, missed-diagnoses and poor risk-stratification more extreme. These four errors - which impact directly on the 1million men who undergo prostate biopsy each year in Europe alone - result in the application of treatments that have little or no benefit, leave men suffering with significant life-long harms and waste valuable healthcare resources.

Aims:
Our Re-IMAGINE Consortium has been created to undertake discovery that will correct these four key errors. We will, for the first time, be able to combine the underlying molecular changes in the cancer with state-of-the-art imaging. This will allow us to predict prostate cancer status for the individual (low, medium or high risk) without recourse to biopsy. It will also allow us to predict which prostate cancers are likely to progress over time and which are not - something that has largely eluded us so far. By doing so, men will be subject to fewer but better biopsies, improved risk stratification, appropriate treatment allocation, more benefit, less harm and more cost-effective care.

Methods:
We will achieve this by building on established partnerships between patients, advocacy organisations, clinicians, imaging experts, molecular biologists, methodologists and a broad range of industrial partners. The vision of Re-IMAGINE is built on our recently published work showing that magnetic resonance imaging (MRI) of the prostate was 100% better at identifying men at risk compared to the standard prostate biopsy, and moreover missed no men with potentially fatal disease. MRI is now certain to become the future cornerstone of the risk-stratification process for men at risk of early prostate cancer. However, we know very little about the use of MRI in combination with other markers in the body.

Through working with patients and advocacy groups, we have developed several work strands (WS) that will allow us to realise our aims:

WS1 will create the first group (cohort) of men who receive a prostate cancer diagnosis by means of an MRI-based pathway. These men will, after appropriate consent, donate some tissue, blood and urine for marker analysis. They will be recruited from 3 major centres in London that have high quality MRI in place.


WS2 will test the performance of MRI in a population where cancer is less common - in men who have not had a PSA test. This will allow us to predict the exact proportion of men at risk within the community.

These work streams will generate a lot of data (clinical information, imaging data, as well as information from markers in blood, tissue, and urine). We will combine all this data for each patient using a secure data warehouse and analyse it using advanced mathematical techniques.

Such a complex project will require high levels of project management and coordination. This will be achieved by building on existing and fruitful collaborations.

Due to its ambition, likely impact and potential for positive disruption we are pleased that the early development work was both informed and driven by patients and their families and in some specific instances (WS2) by the public. This patient and public involvement will intensify during the period of data gathering, analysis and dissemination.

Impact:
Re-IMAGINE will transform the management of early prostate cancer from an era in which imprecision and uncertainty was the norm to one in which any patient can expect - and benefit from - a precise prediction of his own risk and better care as a result.

For the last 50 years we have been applying PSA-Biopsy risk-stratification to men at risk of prostate cancer and we now know it is unfit for purpose. It results in the greatest burden in all oncology of over-diagnosis, over-treatment, and of missed cancers that are of clinical importance.

This systematic error has biased our tissue archives, skewed our risk calculators, rendered our trials un-representative and undermined policy-making.

We have shown that MRI provides almost complete correction for each error associated with the traditional PSA-Biopsy approach by identifying a distinct stratum from the wider population at risk that is closely correlated to the two strongest progression predictors - grade and volume.

Encouraged by our patient/user groups within the Re-IMAGINE consortium, our aim has been to create a novel, image-based, measurable-disease endotype and to use it to risk stratify men with PCa and, as a result, improve our ability to derive prognostic information and allocate men to the most appropriate and effective therapies.

We will achieve this by creating unique cohorts, each defined by the presence of a specific MRI-derived endotype that will provide clinical, molecular and radiological inputs into a progression model that will be specified to predict disease status, radiological, clinical and metastatic progression. During this process, insight into the key mechanistic events that drive progression will be available to us for the first time. Machine learning algorithms from the radiology-pathology annotated training data sets will inform computer-assisted diagnosis.

Our 12 commercial partners (that have created biomarkers to risk-stratify, predict and prognosticate) are excited about the opportunity that Re-IMAGINE provides to refine their performance by means of enhanced precision and, in addition, create new risk models that integrate MRI-derived radiomics with their improved proprietary offerings.

Patients -
First and foremost it is patients who will benefit from direct participation in Re-IMAGINE by being the beneficiaries of a step change in the precision of the baseline risk-stratification - arguably the most important change to come about in the last 50 years of localised prostate cancer. Once data starts to emerge from Re-IMAGINE (within the period of funding) it is likely that the diagnostic pathway will be unrecognisable to the one we have been used to for the last 50 years. A new taxonomy of risk will emerge with many patients avoiding biopsy completely. Those who have biopsies will be subject to a individualised risk profiling that was previously elusive.

Payers -
The numbers needed to invite (n=6,000), to screen (n=1,700) and to treat (n=48) in order to prevent one prostate cancer related death have been amongst the highest of any cancer management pathway. The underlying cause has been the imprecision of our two standard tests: PSA and transrectal biopsy. Their combined imprecision (high levels of over-diagnosis, over-treatment and treatment related harm) have led to considerable resource waste and treatment-related harm for marginal benefit. Our MRI based approached to risk stratification mitigates most of these errors and avoids some of them completely. This translates to less cost per QALY as all health economic evaluations published to date favour an MRI-based approach to care compare with the current practice standard.

Scientists -
Much of our understanding of the underlying tumour dynamics in early prostate cancer has been hampered by the lack of precision in deriving tumour status by grade and/or volume. An MRI-based approach to care corrects this almost completely by virtue of enhanced sensitivity (compared to the practice standard) to the target condition (93% versus 48%) and by virtue of its reliability when re-applied. Re-IMAGINE corrects this by providing the scientist with representative tissue (historically the biopsy tissue was discordant to true cancer status in 30-50% of cases) on which status can be derived with precision. This will permit, for the first time, that fundamental questions of biology - such as the clonal versus transitional issue of prostate cancer progression can be addressed - and that the condition of progressor versus non-progressor can be elicited. These issues are important to get right as prostate cancer is one of the few cancers that can be monitored within a human in vivo model and therefore -with the necessary conditions - can provide insight into fundamental tumour dynamics that go beyond the prostate to a phase in cancer progression, where the pathways leading to metastatic progression are being formed.

Industry -
Most biomarkers (tissue, blood and urine) in early prostate cancer have been calibrated and undergone validation in order to correct the underlying imprecision in risk stratification. However, the diagnostic pathway is changing rapidly in favour of an MRI based approach for reasons argued earlier. Getting access to patients that have been exposed to high quality MRI is both difficult (in view of volume and quality) and in some jurisdictions prohibitively expensive (multi-parametric prostate MRI in the USA is associated with a tenfold greater charge compared to average EU research charges). All the major biotech / meditech companies working in early prostate cancer diagnostics are eager participants in the consortium. In addition, we have global healthcare companies such as Philips and Affidea, who are keen to participate because of the value they can add, but also because they can see that Re-IMAGINE will provide a glimpse of what future stratified health care will be like.