New risk definitions in prostate cancer. Traffic light system
Yellow disease represents a tumour focus greater than 0.2 cc but less than 0.5 cc as predicted by the maximum cancer core length that is greater than or equal to 4 mm. Alternatively, any secondary pattern 4 in a lower burden of cancer would trigger a status of yellow disease. Yellow disease is typically indeterminate. I don’t think anyone today, hand on heart, can predict which way it will go. In the older man, an agreement to watch it might be reasonable. In the younger man, treatment might be more sensible, until that is we know the true biological potential of such lesions.
Red disease , characterized as it is by longer cancer core lengths (>/=6 mm) and/or by dominant Gleason pattern 4 in a smaller lesion, is the type of disease that most of us would want to treat. Red disease meets or exceeds the threshold for lesions of 0.5 cc volume.
It has to be said that all these definitions are very conservative. They need to be at this stage if they are going to be adopted. Recent reports from the European Prostate Cancer Screening study suggest that provided tumour volumes remain on the lesser side of 1.3 cc and are populated exclusively by Gleason pattern 3 that men have little to worry about .
The Current Role of Biomarkers and Genomics in the Diagnostic Pathway
Screening, overdiagnosis and overtreatment are current topics of debate and intense investigation in prostate cancer, and there are some cases where mpMRI is not conclusive or not helpful (young patients, indeterminate lesions). Biomarkers are an alternative in the diagnostic pathway of prostate cancer. The ideal prostate cancer biomarker would be capable of distinguishing prostate cancer from benign prostate conditions and differentiating between aggressive and indolent tumours.
Sampling errors inherent with the random tissue collection of the biopsy procedure result in a false-negative rate of approximately 25%. This imprecision poses a diagnostic dilemma, often resulting in multiple repeat biopsies from the fear of missed cancer in men with persistent risk factors, resulting in added morbidity and cost. Although diminishing rates of cancers are detected during these invasive repeat procedures, a high rate of clinically significant (i.e., a Gleason score ≥7) cancer is still on the second, third and fourth or more biopsies (65%, 53% and 52%, respectively). Molecular testing is another option to help identify occult cancer in this situation .
Prostate Health Index (PHI) is a blood test that combines the relative concentrations of three different PSA forms, total PSA, free PSA and [−2]proPSA, using a mathematical formula: ([−2]proPSA/free PSA) × √PSA. The 2016 National Comprehensive Cancer Network guidelines offer PHI as option to increase specificity before initial or repeat biopsy, and it has regulatory approval in more than 50 countries [21, 22].
PHI has been consistently shown to outperform PSA to distinguish malignant and benign prostate conditions in men with a PSA level >2 and/or suspicious DRE. Several studies have demonstrated that PHI significantly improves prostate cancer detection in high-risk cases and also predicts the aggressiveness of disease . In the clinic, PHI is less expensive than other test like the 4K score or PCA3 and does not require a physician to conduct a digital rectal examination, making it logistically attractive for both clinicians and patients .
In a recent study combining PHI and mpMRI in men requiring a repeat biopsy, the potential value of the PHI in the context of image-guided repeat biopsies was explored. In this study adding PHI to mpMRI improved overall and significant cancer prediction (AUC 0.71 and 0.75) compared to mpMRI + PSA alone (AUC 0.64 and 0.69, respectively). At a threshold of ≥35, PHI + mpMRI demonstrated a negative predictive value (NPV) of 0.97 for excluding significant tumours. In mpMRI negative men, the PHI again improved prediction of significant cancers, AUC 0.76 vs 0.63 (mpMRI + PSA). Using a PHI ≥35, only 1/21 significant cancers was missed, and 31/73 (42%) men are potentially spared a re-biopsy (NPV of 0.97, sensitivity 0.95). In this way, the authors proposed PHI adds predictive performance to image-guided detection of clinically significant cancers and has value in determining the need for re-biopsy in men with a negative mpMRI .
Prostate cancer antigen 3 (PCA3) score measures the ratio of PSA3 and PSA mRNA in the urine after vigorous DRE using transcription-mediated amplification. Although PCA3 can be offered to patients with a previous negative biopsy, the best threshold value for repeat biopsy is controversial. In addition, its relationship to cancer aggressiveness is subject to debate and generally inferior to other markers .
The 4K score is a risk calculator for the detection of PCa on the biopsy based on a 4-kallikrein panel combined with the patient age, DRE and biopsy history. The 4-kallikrein panel includes total PSA, fPSA, iPSA and hK2, a kallikrein with high homology with PSA. The 4K score is associated with an improvement of 8–10% in predicting biopsy-confirmed PCa, indicating that the use of the 4K score could potentially reduce the number of prostate biopsies currently conducted by an estimated 48–56% .
ConfirmMDx® is a methylation assay that measures changes in methylation in benign tissue in order to identify peritumour regions adjacent a missed cancer (termed the ‘halo effect ’). This test evaluates methylation patterns of three genes: glutathione Stransferase pi 1 (GSTP1) , adenomatous polyposis coli (APC) and Ras association (RalGDS/AF6) domain family member 1 (RASSF1) .
Investigators in the MATLOC study specifically examined the ConfirmMDX® test by running this assay on core prostate biopsy samples from men with prior negative biopsy. After adjusting for patient characteristics, the assay was a significant predictor of repeat biopsy outcome on multivariate analysis (OR 3.17; 95% CI 1.81–5.53) with a negative predictive value of 90%. A subsequent study of 350 American men demonstrated a negative predictive value of 88%, and ConfirmMDx was the most significant independent predictor of finding prostate cancer in repeat biopsy samples (OR 2.69; CI 95% 1.60–4.51) .
The Prostate Core Mitomic Test™ is another field effect laboratory test that is based upon detection of a single 3.4 kb mitochondrial DNA deletion. An early study involves a cohort of 183 men including those with benign, malignant or premalignant biopsy samples, with a reported AUC of 0.87 in the validation phase of this study.
In a follow-up study of 101 patients undergoing repeat biopsy procedures, 20 were found to have prostate cancer within 1 year of the initial biopsy; analysis of biopsy samples for prostate cancer using the PCMT was associated with a sensitivity and specificity of 84% and 54%, respectively, a negative predictive value of 91% and an AUC of 0.75 (34). Larger validation studies are required before the widespread use of this assay can be recommended [28, 29].
A Convergence of Pathways
Much of what we have written above is evidence based. Advances in imaging and targeted biopsy have improved the ability to differentiate intermediate and high-grade cancers from indolent ones. It is here that things get difficult. Remember, fewer men are biopsied overall. Those that are biopsied are more likely to have significant disease by current and possibly by modern criteria – that is what the radiological phenotype confers. Fewer men exit this process with a label of clinically insignificant prostate cancer. Surely a good thing as the label brings with it little clinical utility if it is a correct attribution. The reduction in insignificant prostate cancer diagnoses is the product of two processes. The first is that fewer men are biopsied overall. And second, that biopsies moves from random towards a more targeted sampling in those men with lesions on MRI. If, however, urologists insist on random sampling , possibly in addition to targeted sampling, the rates of clinically insignificant disease will rise, but will still be less than they are currently.
It follows therefore that with fewer men diagnosed overall and fewer men labelled with clinically insignificant prostate cancer (green disease), there should be a reduction in the requirement for AS in the future. The only thing that will challenge this is a reappraisal of our notion of risk. In all AS protocols, there are many men that exceed our upper threshold; we just don’t know about them. It just may be that yellow disease might be perfectly acceptable to watch in some men because we can be 95% sure that no red disease is present concurrently. This new precision should give us confidence. We just need the data, but this will take time to mature. Even red disease might be acceptable in some men especially if it augmented with information on biology. The deep sequencing of these lesions – possible only through representative pathology – it is hoped will assist in the more refined classification of the more ‘aggressive’ lesions.
So what of focal therapy? Focal therapy, by definition , has always required a target. Well-characterized and precise targets will be the product of the new imaging-based pathway. It is possible that the question of focal therapy may come up much sooner than it currently does; at present it usually requires the patient to raise the issue himself. The reason for it coming to the forefront rather earlier in the pathway is that the patient and the treating physician will be faced with information on location very early – in fact before the biopsy. This, as it does today (when available), triggers discussion – often initiated by the patient – of whether it is absolutely necessary to treat all of that normal tissue.
The ability to better determine cancer grade and extent has led to a renewed interest in partial gland ablation treatments such as FT, whereby only the area of the prostate harbouring clinically significant disease is treated, sparing collateral structures and resulting in less morbidity than a whole-gland approach. FT would be an ideal approach for localized small-volume cancers of intermediate or high grade if they could be accurately targeted and treated completely, leaving areas of indolent cancer that do not pose a biological threat to be actively monitored with AS . Conceptually, if detected early enough and treated effectively, this approach would alter the long-term risk of disease progression. The key to this approach is patient selection ; this strategy has a greater likelihood of success when applied to an individual with a suitable disease burden. The rate of technological and biological advances has outpaced the ability to accrue meaningful data regarding the best patient selection criteria.