Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease

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1 OPINION Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease Chad A. Reichard and Eric A. Klein Abstract Treatment choices for men with indolent prostate cancer include active surveillance or definitive local therapy. Overtreatment of these patients is an important current problem. Treatment decisions are often made jointly by the clinician and the patient, partly based on the tumour s Gleason score. To reduce the burden of overtreatment, the clinical significance of Gleason score = 6 prostate cancer has been questioned and some have advocated that Gleason pattern 3 should be stripped of its cancer status. However, removing the cancer descriptor would have far-reaching clinical consequences that might result in poor patient outcomes, as the evidence of a lack of malignancy is inconclusive in several areas. For example, molecular data suggest that the genomic instability underlying tumour progression precedes histologically visible changes and the absolute risk of metastasis or mortality from Gleason score 6 prostate cancer is not zero. Extreme caution is required when weighing a decision to reclassify Gleason pattern 3 disease as a non-cancer. Adoption of active surveillance for indolent prostate cancer in appropriate candidates is on the rise, but overtreatment in this group of patients remains a relevant and persistent public health issue. Multiple approaches for how to best address this problem exist, which include, but are not limited to, the debate regarding the clinical significance of Gleason score = 6 (grade group 1) cancer. Some have advocated that Gleason pattern 3 should be stripped of its cancer status entirely. Central to this debate are reports of evolving molecular data that suggest that the genomic instability underlying tumour progression precedes histologically visible changes inherent to a specific Gleason grade and is even present in histologically normal tissue 1. Certainly, many Gleason score 6 prostate cancers are clinically indolent, posing minimal increased mortality risk to the majority of patients. However, the absolute risk of metastasis or mortality from Gleason score 6 cancer is not zero. Despite the application of increasingly stringent histological criteria, the levels of molecular instability found in Gleason score 6 cancers remain heterogeneous. The removal of the cancer descriptor for Gleason score 6 disease would have far-reaching clinical consequences that might result in poor patient outcomes. If all patients with a life expectancy >20 years who have been diagnosed with Gleason score 6 prostate cancer on biopsy were cleared of their cancer diagnosis, then the impetus for their continued monitoring would disappear and these men would be effectively excused from active surveillance as currently defined. Even if they were evaluated using MRI, underwent saturation biopsy or had a favourable molecular risk score, none of these tests provide perfect diagnostic or prognostic results alone or in combination. For example, one study investigated the combination of multiparametric MRI and the Prostate Health Index (phi) in 279 men undergoing repeat transperineal biopsy, of whom 94 men PERSPECTIVES had negative MRIs. Analysis found that the addition of phi resulted in an area under the curve of 0.76 (95% CI ) for predicting presence of clinically significant cancer in the setting of a negative MRI 2. These numbers are encouraging and clinically useful. However, we would posit that, in the absence of a prognosticator that is truly 100% sensitive and specific and can rule out any possibility of long-term adverse outcome, adequate evidence is lacking to tell an individual patient with Gleason score 6 disease that he does not have cancer and has no need to participate in follow up monitoring. When an increased number of young men are undergoing active surveillance, the biological changes that initially gave rise to their low-risk cancer will have a prolonged time to advance. A subset of these patients might harbour genomic aberrations that indicate future aggressive disease, despite their initial low-risk diagnosis 3. For example, a report from the active surveillance cohort at the Johns Hopkins Brady Urological Institute demonstrated a 0.4% risk of metastatic disease or prostate-cancer-specific death even in patients with very-low-risk disease who underwent yearly biopsy 4. Retrospectively determining the possible histology or genetics of a prostate many years before an initial clinical presentation of high-volume, high-grade cancer or de novo metastatic disease is impossible. However, autopsy studies estimate the mean prevalence of incidental prostate cancer in men aged years at 15 20% 5. Together with the apparent spatial genomic heterogeneity within localized but multifocal prostate cancer, these findings indicate that it is not improbable that a high percentage of men with adverse pathology at initial clinical presentation would have had pure Gleason score 6 cancer based on a hypothetical biopsy performed many years before. Although not directly provable, both clinical and molecular data support the plausibility of this scenario. Miah et al. 6 have argued that Gleason pattern 3 prostate cancer might not merit its cancer descriptor based on several population-based studies and comparison with similar paradigm shifts in other cancers. We feel that attention NATURE REVIEWS UROLOGY ADVANCE ONLINE PUBLICATION MacmilanPublishersLimited,partofSpringerNature.Alrightsreserved.

2 to the outcome of the individual patient encourages extreme caution when weighing a decision to reclassify Gleason pattern 3 disease as a non-cancer. This concern is especially pertinent to young patients, as the rate of diagnosis of high-grade disease increases with age 7. In this Perspectives, we seek to provide a balanced synthesis of the available clinical and molecular data that we believe argues against the redefinition of Gleason score = 6 prostate cancer as a non-cancer entity (FIG. 1). Gleason grading Undoubtedly, over the past few years, a considerable grade migration of prostate cancer has occurred, with fewer men being diagnosed with Gleason score 6 disease, which resulted in artefactual improvement in clinical outcomes for both Gleason score 6 and score 7 cancers However, even with the improved risk stratification following the International Society of Urological Pathology (ISUP) 2005 update of Gleason grading 11, a diagnosis of Gleason score 6 cancer has not turned out to be entirely benign. A study that included data from >7,000 patients with Gleason score 6 cancer at radical prostatectomy in reported 4% failure of cure at 5 years (5 year biochemical-recurrence-free progression probability 96%) 12. The potential upheaval that a proposed redefinition of Gleason pattern 3 as non-cancer would cause in the granularity and prognostic accuracy of the existing pathological grading systems should also be considered. A patient with Gleason score = 8, with limited pattern 5, would be considered to only have pattern 5 cancer; however, his risk prognosis is clearly different from a patient with Gleason score = 10 disease. In addition, having to distinguish between Gleason score and disease (groups with clear differences in clinical outcomes) using the relative amounts of non-cancer pattern 3 tissue to pattern 4 tissue is similarly confounding for pathologists. The 2014 ISUP update of Gleason grading should further help clarify the important pathological features directly associated with prognosis (for example, cribriform glands should be assigned Gleason pattern 4, regardless of morphology). In addition, the newly developed grade groups 1 5 should help clinicians in communicating the risk level associated with a patient s cancer diagnosis more clearly Gleason score 6 cancer previously seemed to connote high intermediate risk disease on the backdrop of a score scale of Now, newly renamed as grade group 1 on a scale of 1 5, the excellent prognosis of patients with Gleason score 6 disease is more readily apparent to the layperson. Thus, the hope is that patients who are being counselled regarding a diagnosis of grade group 1 prostate cancer are more willing to choose active surveillance, if appropriate considering other important clinical variables. The goal is to reduce overtreatment while still respecting the morphological and molecular characteristics of cancer that Gleason pattern 3 disease possesses 15,16. Biopsy, upgrading and undersampling As MRI ultrasonography (MRI US) fusion biopsy becomes precise enough to enable sampling of the exact same tumour foci in a reliable manner for sequential assessment, collection of actual prospective data on the propensity of Gleason score 6 cancer to evolve to a higher grade will become possible. We suspect that this type of study will be likely to demonstrate that histologically lower-grade cancer that harbours worrisome genomic instability evolves to histologically higher-grade cancer over time. A study published in 2014 applied this approach in a limited fashion by evaluating 74 sites in 53 patients who underwent a follow up MRI US fusion biopsy at a median of 11 months. On second biopsy, 14% of sampled sites that had Gleason score 6 on first biopsy were upgraded 17. These data have been used to characterize the true upgrading event as a rare occurrence. However, the fact that upgrading occurred at all, and potentially in such a short time period, should give pause when considering the possible ramifications of redefining Gleason pattern 3 disease as non-cancer. In addition, the absolute number of lesions that were upgraded was small, but extrapolating a 14% rate of true lesion upgrading to a large active surveillance cohort that is followed over a period of time results in a worrisomely high number of affected patients. A new report demonstrated concordant ERG status in initial and 1 year follow up MRI US biopsies of target lesions in 25 of 26 patients, suggesting accurate resampling of the same anatomic and clonal tumour foci 18. At 1 year, ten of these patients progressed to higher-grade cancer and all of these had ERG concordance between initial and follow-up biopsy samples. In two Clinical factors Biochemical-recurrence probability is not zero Molecular factors Mutations in tissues without morphology of aggressive disease Risk of death in conservatively managed patients Definitive local therapy is not always curative Gleason pattern 3 cancer Mutation profile similar to higher-risk grade groups High-risk gene expression profiles in clinically low-risk disease Long-term risk of metastasis or death even after aggressive treatment Mutations in initial MRI US biopsy samples shared with those upgraded at second biopsy Figure 1 The malignant potential of Gleason pattern 3 prostate cancer. Gleason pattern 3 prostate cancer can have clinical and molecular characteristics that demonstrate the malignant potential of this tumour type. In the absence of a prognostic tool that can rule out the presence of clinically significant cancer with 100% certainty, the potential risks of not treating select men with this disease stand against reclassifying Gleason score = 6 prostate cancer as a non-cancer entity. 2 ADVANCE ONLINE PUBLICATION

3 patients, driver mutations were detected in both the initial Gleason score 6 cancer and the subsequently detected higher-grade tumour, implying that the harbinger of progression was present before its histological detection. Additional extensive and longitudinal studies of this type are needed to more accurately characterize rates and risks of true lesion grade progression. These findings are of course independent of the upgrading at repeat biopsy or at prostatectomy that can occur owing to straightforward initial undersampling or the fact that MRI does not detect all clinically significant lesions 17. Clinical outcomes Definitive local therapy. Data from large radical prostatectomy cohorts do demonstrate an extremely high prostatecancer-specific survival in patients with Gleason score 6 prostate cancer. Eggener et al. 19 reported a % 15 year prostatecancer-specific mortality after radical prostatectomy in patients stratified by age at diagnosis with Gleason score 6. Schiffmann et al. 20 found a 10 year prostatecancer-specific-mortality of 0.5% after radical prostatectomy in 451 patients with Gleason score 6 and tumour volume of cm 3. How these findings support an argument for reclassification of Gleason score 6 as non-cancer is unclear, as the patients included in these studies underwent definitive local therapy for low-risk disease. The fact that the vast majority of these patients are curable is reassuring; however, the expected outcome of patients with a non-cancer is absolute 100% cure not almost 100% cure as seen in these studies as, by definition, they should not require treatment in the first place. Watchful waiting and active surveillance. Much information can be gathered from closely scrutinizing series in which the natural history of conservatively managed patients with Gleason score 6 cancers are reported. Zero adverse outcomes would be expected in patients with non-cancer; however, patients with Gleason score 6 disease at risk of adverse events do exist. One study reports a low risk of prostate-cancerspecific mortality with a 20 year follow up period in patients with clinically localized disease managed conservatively, of whom the vast majority had been diagnosed using needle biopsy or transurethral resection 21. This low risk is referenced by Miah et al. 6 as evidence for reclassification of Gleason pattern 3 as non-cancer. However, the risk is substantially higher than zero. Of 294 men diagnosed with Gleason score 6 prostate cancer, 81 men (27%) died of this disease, which includes 18 men aged years. Critics might point out that these adverse outcomes might be attributable to understaging or undergrading, a hypothesis that could be applied to most of the mature clinical data discussed in this Perspectives. Nevertheless, it is difficult to retrospectively prove this theory in a robust enough manner to draw the conclusion that every single one of these deaths is unrelated to what might still be classified as Gleason score 6 cancer according to updated ISUP criteria. Interestingly, 26 patients with Gleason scores of 2 5 also died from prostate cancer 21. Reclassification of all these patients to modern Gleason score = 7 or higher upon pathological review is unlikely. Thus, at least a some of these deaths must have resulted from pure Gleason pattern 3 or Gleason score 6 disease. Results from an active surveillance cohort suggest that some patients with Gleason score 6 prostate cancer have a risk of metastasis and death, despite additional stringent clinical selection criteria 22. The initial Gleason score of the 15 patients who died from prostate cancer is not specified, but the authors do report that 16 of 28 patients (66%) who developed metastatic disease had Gleason score 6 cancer. The average patient age in this cohort was almost 68 years; thus, one might estimate that the risk of metastasis and death might increase further, as this cohort is enriched in men who are, on average, younger than those reported on in the past. In addition, the newly published 10 year follow up data of a prospective, randomized trial comparing active monitoring, surgery or radiotherapy for localized prostate cancer in 1,643 men, show 17 total prostate-cancer-specific deaths, of which eight deaths occurred in men with Gleason score 6 disease at diagnosis 23. Metastatic capability Even if patients ultimately die of competing causes rather than prostate cancer, development of metastatic disease is also an important end point to evaluate, owing to the high morbidity and costs associated with advanced disease. Results from the Scandinavian Prostate Cancer Group Study Number 4 demonstrated that treatment of low-grade cancer reduces metastatic events 24, which would be an unexpected finding for a benign, non-cancer entity. In addition, in a cohort used in the development of the Oncotype Dx genomic prostate score, a 6% rate of metastasis or death at 15 years despite aggressive therapy in patients who only had Gleason score 6 tumours was observed 25. We would argue that this finding demonstrates the biological potential for aggressive behaviour of Gleason score 6 disease, warranting its continued status as cancer. At first glance, some studies seem to show that Gleason score 6 cancers do not have any potential to metastasize. One study examined the risk of positive pelvic lymph nodes in 14,123 patients who underwent radical prostatectomy, concluding that in 19 of 22 men who had originally been classified as having Gleason score 6 disease with lymph node metastases tissue with primary, secondary or tertiary Gleason pattern 4 or pattern 5 was present (three patients were unavailable for review) 26. Thus, the authors argued that no lymphnode-metastatic event could be attributed to Gleason pattern 3. However, the study result is not surprising and should not be used as an argument for the absence of metastatic potential of Gleason pattern 3 tissue. The use of timely definitive local therapy in patients with accurately characterized Gleason score 6 cancer (in accordance with ISUP 2005 and in absence of tertiary pattern 4 or pattern 5 tissue) is well reported to have cure rates and long-term cancer-specific survival that approach 100%. Hence, we should not expect lymph node metastases to be present at the time of immediate treatment of very-low-risk prostate cancer. These data are also susceptible to a self-fulfilling prophecy bias. If a pathologist believes that no reviewed case of Gleason score 6 ever metastasizes, the impetus to exhaustively search for a higher-grade cancer in a patient with metastatic disease might be very strong. Distinguishing between zero probability (or potential) versus low probability of metastasis is important, as well as defining the time period during which that probability is measured. What we really need to know is what happens to patients in the long term, after stringent initial evaluation that finds only Gleason pattern 3 cancer using multimodal diagnostic techniques (that is, MRI US fusion biopsy, saturation biopsy, molecular risk profiling and ISUP 2014 Gleason scoring). The mature data on which the population-based arguments regarding the metastatic potential and lethality of Gleason score 6 prostate cancer are based are largely reflective of the overtreatment era from which we are slowly emerging. NATURE REVIEWS UROLOGY ADVANCE ONLINE PUBLICATION 3

4 When examined on an individual, in depth basis, Gleason pattern 3 tumour has in fact been shown to be the cause of lethality. A case report highlighting this concern identified a 47 year-old man who eventually died from metastasis of a molecular clone that arose from a Gleason score 6 lesion, identified by whole-mount sectioning and microdissection of his radical prostatectomy specimen by an expert pathologist 27. Indeed, this lesion was part of an overall higher-grade tumour. Nevertheless, whether the metastatic potential of Gleason pattern 3 tissue is increased only in the presence of adjacent pattern 4 remains to be proven. A clinical series of men with castrationresistant prostate cancer (with or without clinical metastases) demonstrated that some Gleason score 6 cancers can be lethal 28. Of a total of 622 men, 81 patients were classified as having Gleason score 6 cancer on biopsy, of whom 42 men underwent prostatectomy. Of these 42 patients, 32 patients were upgraded to Gleason scores 7 on radical prostatectomy. However, the authors of this report point out that the actual effect of upgrading alone on patient outcome is difficult to evaluate, owing to the lack of centralized pathological review. In addition, they emphasize that their study reflects community grading practices over the past 30 years 28, which are heterogeneous and have evolved with modifications to the grading system. Despite these limitations, the authors report seven deaths from prostate cancer in ten patients whose biopsy Gleason score of 6 was not upgraded at the time of radical prostatectomy, all of whom had developed castration-resistant disease. Hence, unless all these cases reflect inaccurate grading of whole prostatectomy specimens, one must acknowledge the aggressiveness and lethal potential of some Gleason score 6 cancers. Molecular analyses Ample evidence shows that Gleason pattern 3 tumours are molecularly more benign than their Gleason pattern 4 and pattern 5 counterparts. This finding is expected given the strong prognostic value of Gleason score alone. However, several studies suggest that Gleason pattern 3 cancer can behave like a wolf in sheep s clothing. Biological risk prediction: high-risk features in low-risk groups. A molecular analysis of 337 Gleason score 6 prostate cancers using the Decipher genomic classifier, which predicts the 5 year metastasis risk after radical prostatectomy, revealed high-risk and intermediaterisk scores in 7% and 13% of patients, respectively 29. Thus, according to the categorical risk groups previously reported 30,31, 25 patients had a sevenfold and 43 patients had a twofold higher risk of metastasis than the remaining 269 patients in this cohort. This cohort comprised both prospectively submitted tumour samples from 407 urology practices for clinical Decipher testing as well as prostatectomy tissue previously collected in research studies of the Decipher test. All of these patients tumours were re reviewed by expert genitourinary pathologists using the ISUP 2005 Gleason grading criteria. On re review of the 102 prospectively collected tumour sample blocks, a substantial proportion of pattern 4 disease was identified, but no statistically significant difference existed between Decipher scores of those that were upgraded compared with those that were not upgraded. This finding suggests that the argument that some Gleason pattern 3 cancers are more aggressive only because of the presence of underdiagnosed tertiary patterns 4 or 5 does not tell the entire story. One study in a cohort of 126 men with low-to-intermediate-risk disease analysed biopsy-based genomic and microenvironmental parameters to develop four prognostic indices to predict 5 year risk of biochemical recurrence after local therapy. They validated their findings in two independent cohorts of 154 and 117 radical prostatectomy specimens from patients with low-to-high-risk cancer 32. The data revealed that several individual Gleason score 6 tumours had a higher percentage of genome alteration as measured by copy number variation than some Gleason score 8 tumours and substantial overlap in the genomic instability of Gleason score = 6 tumours and higher-grade tumours. Percentage of genome alteration has a strong prognostic value independently of clinical covariates: every 1% increase imparts a 5 8% decrease in 5 year biochemicalrecurrence-free survival 32. Interestingly, in the low-risk and intermediate-risk prostatectomy cohorts, the risk signature was more strongly predictive of biochemical recurrence than clinical variables. Of the patients with good prognosis ( 7.49% genome alteration), 89% (95% CI 85 96%) were free of biochemical recurrence at 5 years compared with 58% (95% CI 35 96%) of patients with poor prognosis (>7.49% genome alteration). TMPRSS2 ERG gene fusion is a critical and probably early occurrence in prostate cancer pathogenesis. One study reported that this gene fusion is present and expressed at the transcriptional and translational levels in the stem cell compartment of primary human prostate cancers, including three of five analysed Gleason score = 6 tumours 33. This finding is important, as the cancer stem cell population potentially drives metastasis as well as therapy resistance, leading to recurrence and relapse. In addition, 10 20% of Gleason score 6 cancers demonstrate loss of important tumour suppressor genes, such as PTEN 34,35. The importance of PTEN loss is clearly demonstrated in an animal model of prostate cancer in which the combination of PTEN loss and MYC activation is sufficient to lead to genomic instability and lethal metastatic disease 36. Biological field effect. Data suggest that the multiple tumour foci found in patients with prostate cancer have independent origins. However, whole-genome sequencing of multiple metastatic sites from several patients primary tumours demonstrated a common clonal origin that contains 40 90% of all mutations and the majority of driver mutations 37. These findings imply that widespread metastases commonly originate from only one of many tumour foci. This lesion might be small enough to be easily missed under normal pathological examination, regardless of its grade. An in depth analysis of the genetic phylogeny of multifocal prostate cancer from three patients identified multiple independent clonal expansions of cells in both neoplastic and morphologically normal prostate tissue 38. This discovery is important, as the mutations that define the clonal expansion of morphological normal tissue were the same as those in malignant tissue. Large numbers of mutations were shared among foci of Gleason score 6 and score 7 tumours, and a smaller but substantial number of mutations was shared with the adjacent normal tissue. Interestingly, in one patient, discontinuous foci of Gleason score 7 lesions shared a single verified substitution, demonstrating the possibility of a mutational field effect in prostate cancer pathogenesis. In a second patient, ten mutations were common among morphologically normal prostate tissue, one Gleason score 6 lesion and one Gleason score = 7 lesion 38. Three other unique-identifier mutations were shared between a Gleason score = 7 lesion and 4 ADVANCE ONLINE PUBLICATION

5 a spatially separate Gleason score = 6 lesion. This observation shows that at least two cell clones existed before the evolution of the distinct cancer lineages (that is, the cell populations that eventually gave rise to histologically and spatially distinct lesions). Thus, in a patient in whom only Gleason score 6 cancer is histologically visible, a cell population could exist concomitantly that is the origin of a lesion that is histologically normal or low-grade, but is also capable of giving rise to histologically higher-grade cancer. Another study supports the argument for an important biological field effect in prostate cancer. The authors demonstrate the predictive value of presence of PTEN loss, gain of MYC in 8q and loss of LPL in 8p in Gleason pattern 3 biopsy samples for the presence of unsampled Gleason pattern 4 cancer 39. The presence of these markers in a Gleason pattern 3 core makes it much more probable that the biopsied prostate also harbours Gleason pattern 4 tissue, suggesting that molecular changes of tumour aggressiveness are present before histological changes occur. These findings demonstrate again that biologically important markers for adverse pathology are found in Gleason pattern 3 tissues. Finally, one report describes the genomic correlates to the new prognostic grade groups 1 5, demonstrating that Gleason score 6 cancers harbour mutations that are similar to higher-grade cancers, albeit at a lower frequency 40. The molecular profile of some low-grade tumours looked remarkably similar to that more frequently found in higher-grade cancer. Looking beyond histology. Taken together, these studies demonstrate the very real possibility that genetic changes characteristic of aggressive and even lethal prostate cancer exist which might only be present in a subpopulation of cells that does not exhibit the morphological changes necessary to garner a histological classification that corresponds to the seriousness of the underlying molecular perturbations (TABLE 1). The implications of this what you see is not what you get phenomenon are twofold. First, we should not redefine a histological entity as non-cancer when a clear risk exists that it might harbour molecular drivers of disease aggressiveness. Second, continued development and integration of molecular tumour analysis with pathological grading and staging is important to achieve the most accurate prognostic information possible. In the Table 1 Molecular features of aggressive disease found in Gleason score 6 tumours Characteristics of GS 6 tumour Clinical outcome Molecular markers or test Driver mutations present in subsequently upgraded lesions 6% rate of metastasis or death despite aggressive therapy 7% of GS 6 tumours have high risk scores Significant overlap between GS 6 and higher grades future, prognosis of individual tumour behaviour might be possible through characterization of molecular subtypes alone, predicting biological potential with improved accuracy, independent of grade or other clinical parameters 41. However, at present, grade still adds to the prognostic value of molecular markers and, in some instances, molecular analyses show no differences although differences are demonstrated by grade alone. Overtreatment Redefining Gleason score 6 prostate cancer as non-cancer is not only likely to be an unsafe strategy for limiting overtreatment, it is also not the only possible approach. The appropriate application of molecular testing can aid in choosing the right treatment, for the right patient, at the right time, which includes active surveillance and/or watchful waiting. The implementation of these two treatment options has already led to great achievements in decreasing overtreatment 42. In addition, tests such as phi and the 4Kscore, which have improved sensitivity and specificity in comparison with PSA alone, as well as expanding indications for multiparametric MRI, are important steps towards the goal of a screening test that can rule out the presence of clinically significant cancer with 100% certainty. A strategy that Upgrading at 1 year repeat MRI US fusion biopsy Refs ERG, IDH1, SPOP 18 Risk of metastasis or death Oncotype Dx 25 5 Year metastasis risk Decipher 29 5 Year metastasis risk Decipher 44,45 5 Year risk of biochemical recurrence Copy number variation, tumour hypoxia Present in many GS 6 tumours NA TMPRSS2 ERG fusion 33 Large number of shared mutations among normal tissue, GS 6 and GS 7 cancer in the same prostate Presence of mutations in GP 3 tissue that are common in GP 4 lesions Mutations in GS 6 tumours are similar to higher grade groups NA PTEN loss 34 Lethal metastatic disease NA Potential for validation to predict upgrading at prostatectomy or to select for active surveillance Correlation of genomic instability with grade groups PTEN loss, MYC activation GP, Gleason pattern; GS, Gleason score; NA, not applicable; US, ultrasonography. Genome-wide DNA sequencing PTEN loss, MYC gain in 8q, LPL loss in 8p Somatic copy number alterations will make biopsy unnecessary is likely to be a more prudent approach than continuing to perform biopsies in the same number of patients as we currently are, only to tell an even smaller proportion of them that they have cancer Conclusion Although Gleason score = 6 (grade group 1) prostate cancer is mostly not associated with an increased risk of death, even in the absence of immediate treatment, ample evidence suggests that marked molecular heterogeneity exists in this group of patients that has been prematurely declared by some as cleansed from poor clinical outcomes. These entities should not be redefined as non-cancer when they might, no matter how small the risk, contain molecular alterations that have been shown to be predictive of adverse clinicopathological outcomes, such as extraprostatic extension, biochemical recurrence, metastasis and even death 44,45. Chad A. Reichard and Eric A. Klein are at the Cleveland Clinic, Glickman Urological & Kidney Institute, 9500 Euclid Avenue, Q10 1, Cleveland, Ohio 44195, USA. Correspondence to E.A.K. kleine@ccf.org doi: /nrurol Published online 29 Nov 2016 NATURE REVIEWS UROLOGY ADVANCE ONLINE PUBLICATION 5

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Both authors discussed the article s content and reviewed and/or edited the manuscript before submission. Competing interests statement E.A.K. has served as consultant for GenomeDx, Genomic Health and Metamark, has previously received grant support from GenomeDx, Genomic Health and Metamark, and has received payment for lectures from Genomic Health. C.A.R. declares no competing interest. Point/Counterpoint This article forms part of a Point/Counterpoint discussion of Gleason scoring and the definition of cancer. The corresponding article can be found at nrurol ADVANCE ONLINE PUBLICATION