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BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

BackgroundPathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low-risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance.MethodsMen prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively.ResultsOverall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2. The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36-2.06, p = 0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%).ConclusionThe frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.

Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p 0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

PurposeActive surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort.Materials and methodsParticipants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed.ResultsAt diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p

BackgroundMaintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.MethodsThis study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).ConclusionsA substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.Lay summaryThis analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

PurposeWe investigated the ability of prostate magnetic resonance imaging to detect Gleason Grade Group 2 or greater cancer in a standardized, multi-institutional active surveillance cohort.Materials and methodsWe evaluated men enrolled in Canary Prostate Active Surveillance Study with Gleason Grade Group less than 2 and who underwent biopsy within 12 months of multiparametric magnetic resonance imaging. Our primary outcome was biopsy reclassification to Gleason Grade Group 2 or greater. We evaluated the performance of magnetic resonance imaging PI-RADS® score and clinical factors. Multivariable logistic regression models were fit with magnetic resonance imaging and clinical factors and used to perform receiver operating curve analyses.ResultsThere were 361 participants with 395 prostate magnetic resonance imaging studies with a median followup of 4.1 (IQR 2.0-7.6) years. Overall 108 (27%) biopsies showed reclassification. Defining positive magnetic resonance imaging as PI-RADS 3-5, the negative predictive value and positive predictive value for detecting Gleason Grade Group 2 or greater cancer was 83% (95% CI 76-90) and 31% (95% CI 26-37), respectively. PI-RADS was significantly associated with reclassification (PI-RADS 5 vs 1 and 2 OR 2.71, 95% CI 1.21-6.17, p=0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 vs 0.762). In 194 fusion biopsies higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer in the systematic cores.ConclusionsThis study adds the largest cohort data to the body of literature for magnetic resonance imaging in active surveillance, recommending systematic biopsy in patients with negative magnetic resonance imaging and the inclusion of systematic biopsy in patients with positive magnetic resonance imaging.

PurposeIn a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification.Materials and methodsThe Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men.ResultsOf the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99).ConclusionsOf men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.

BackgroundActive surveillance (AS) is an accepted means of managing low-risk prostate cancer. Because of the rarity of downstream events, data from existing AS cohorts cannot yet address how differences in surveillance intensity affect metastasis and mortality. This study projected the comparative benefits of different AS schedules in men diagnosed with prostate cancer who had Gleason score (GS) ≤6 disease and risk profiles similar to those in North American AS cohorts.MethodsTimes of GS upgrading were simulated based on AS data from the University of Toronto, Johns Hopkins University, the University of California at San Francisco, and the Canary Pass Active Surveillance Cohort. Times to metastasis and prostate cancer death, informed by models from the Scandinavian Prostate Cancer Group 4 trial, were projected under biopsy surveillance schedules ranging from watchful waiting to annual biopsies. Outcomes included the risk of metastasis, the risk of death, remaining life-years (LYs), and quality-adjusted LYs.ResultsCompared with watchful waiting, AS biopsies reduced the risk of prostate cancer metastasis and prostate cancer death at 20 years by 1.4% to 3.3% and 1.0% to 2.4%, respectively; and 5-year biopsies reduced the risk of metastasis and prostate cancer death by 1.0% to 2.4% and 0.6% to 1.6%, respectively. There was little difference between annual and 5-year biopsy schedules in terms of LYs (range of differences, 0.04-0.16 LYs) and quality-adjusted LYs (range of differences, -0.02 to 0.09 quality-adjusted LYs).ConclusionsAmong men diagnosed with GS ≤6 prostate cancer, obtaining a biopsy every 3 or 4 years appears to be an acceptable alternative to more frequent biopsies. Reducing surveillance intensity for those who have a low risk of progression reduces the number of biopsies while preserving the benefit of more frequent schedules.

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

Outcomes after cancer diagnosis and treatment are often observed at discrete times via doctor-patient encounters or specialized diagnostic examinations. Despite their ubiquity as endpoints in cancer studies, such outcomes pose challenges for analysis. In particular, comparisons between studies or patient populations with different surveillance schema may be confounded by differences in visit frequencies. We present a statistical framework based on multistate and hidden Markov models that represents events on a continuous time scale given data with discrete observation times. To demonstrate this framework, we consider the problem of comparing risks of prostate cancer progression across multiple active surveillance cohorts with different surveillance frequencies. We show that the different surveillance schedules partially explain observed differences in the progression risks between cohorts. Our application permits the conclusion that differences in underlying cancer progression risks across cohorts persist after accounting for different surveillance frequencies.

BackgroundFor men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial.ObjectiveTo develop prediction methods for utilizing serial PSA and evaluate frequency of collection.Design, setting, and participantsData were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels.Outcome measurements and statistical analysisThe association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models.Results and limitationsA total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk=1.6 [95% confidence interval 1.2-2.1, p

BackgroundMany patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident.ObjectiveTo define the association between negative surveillance PNBs and risk of reclassification on AS.Design, setting, and participantsAll men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3+4 prostate cancer and

BackgroundActive surveillance (AS) is increasingly accepted for managing low-risk prostate cancer, yet there is no consensus about implementation. This lack of consensus is due in part to uncertainty about risks for disease progression, which have not been systematically compared or integrated across AS studies with variable surveillance protocols and dropout to active treatment.ObjectiveTo compare risks for upgrading from a Gleason score (GS) of 6 or less to 7 or more across AS studies after accounting for differences in surveillance intervals and competing treatments and to evaluate tradeoffs of more versus less frequent biopsies.DesignJoint statistical model of longitudinal prostate-specific antigen (PSA) levels and risks for biopsy upgrading.SettingJohns Hopkins University (JHU); Canary Prostate Active Surveillance Study (PASS); University of California, San Francisco (UCSF); and University of Toronto (UT) AS studies.Patients2576 men aged 40 to 80 years with a GS between 2 and 6 and clinical stage T1 or T2 prostate cancer enrolled between 1995 and 2014.MeasurementsPSA levels and biopsy GSs.ResultsAfter variable surveillance intervals and competing treatments were accounted for, estimated risks for biopsy upgrading were similar in the PASS and UT studies but higher in UCSF and lower in JHU studies. All cohorts had a delay of 3 to 5 months in detecting upgrading with biennial biopsies starting after a first confirmatory biopsy versus annual biopsies.LimitationThe model does not account for possible misclassification of biopsy GS.ConclusionMen in different AS studies have different risks for biopsy upgrading after variable surveillance protocols and competing treatments are accounted for. Despite these differences, the consequences of more versus less frequent biopsies seem to be similar across cohorts. Biennial biopsies seem to be an acceptable alternative to annual biopsies.Primary funding sourceNational Cancer Institute.

BackgroundDiagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease.ObjectiveTo evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance.Design, setting, and participantsPlasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA).Outcome measurements and statistical analysisThe endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit.Results and limitationsSignificant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.ConclusionsThe 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies.Patient summaryActive surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.

PurposeDuring active surveillance for localized prostate cancer, the timing of the first surveillance biopsy varies. We analyzed the Canary PASS (Prostate Cancer Active Surveillance Study) to determine biopsy timing influence on rates of prostate cancer adverse reclassification at the first active surveillance biopsy.Materials and methodsOf 1,085 participants in PASS, 421 had fewer than 34% of cores involved with cancer and Gleason sum 6 or less, and thereafter underwent on-study active surveillance biopsy. Reclassification was defined as an increase in Gleason sum and/or 34% or more of cores with prostate cancer. First active surveillance biopsy reclassification rates were categorized as less than 8, 8 to 13 and greater than 13 months after diagnosis. Multivariable logistic regression determined association between reclassification and first biopsy timing.ResultsOf 421 men, 89 (21.1%) experienced reclassification at the first active surveillance biopsy. Median time from prostate cancer diagnosis to first active surveillance biopsy was 11 months (IQR 7.8-13.8). Reclassification rates at less than 8, 8 to 13 and greater than 13 months were 24%, 19% and 22% (p = 0.65). On multivariable analysis, compared to men biopsied at less than 8 months the OR of reclassification at 8 to 13 and greater than 13 months were 0.88 (95% CI 0.5,1.6) and 0.95 (95% CI 0.5,1.9), respectively. Prostate specific antigen density 0.15 or greater (referent less than 0.15, OR 1.9, 95% CI 1.1, 4.1) and body mass index 35 kg/m2 or greater (referent less than 25 kg/m2, OR 2.4, 95% CI 1.1,5.7) were associated with increased odds of reclassification.ConclusionsTiming of the first active surveillance biopsy was not associated with increased adverse reclassification but prostate specific antigen density and body mass index were. In low risk patients on active surveillance, it may be reasonable to perform the first active surveillance biopsy at a later time, reducing the overall cost and morbidity of active surveillance.

BackgroundGiven the uncertainties inherent in clinical measures of prostate cancer aggressiveness, clinically validated tissue biomarkers are needed. We tested whether Alpha-2-Glycoprotein 1, Zinc-Binding (AZGP1) protein levels, measured by immunohistochemistry, and RNA expression, by RNA in situ hybridization (RISH), predict recurrence after radical prostatectomy independent of clinical and pathological parameters.MethodsAZGP1 IHC and RISH were performed on a large multi-institutional tissue microarray resource including 1,275 men with 5 year median follow-up. The relationship between IHC and RISH expression levels was assessed using the Kappa analysis. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazards models and the Log-rank test.ResultsAbsent or weak expression of AZGP1 protein was associated with worse recurrence free survival (RFS), disease specific survival, and overall survival after radical prostatectomy in univariable analysis. AZGP1 protein expression, along with pre-operative serum PSA levels, surgical margin status, seminal vesicle invasion, extracapsular extension, and Gleason score predicted RFS on multivariable analysis. Similarly, absent or low AZGP1 RNA expression by RISH predicted worse RFS after prostatectomy in univariable and multivariable analysis.ConclusionsIn our large, rigorously designed validation cohort, loss of AZGP1 expression predicts RFS after radical prostatectomy independent of clinical and pathological variables. Prostate 76:1409-1419, 2016. © 2016 Wiley Periodicals, Inc.

Key Points: Question: What are the long-term outcomes for patients with prostate cancer whose cases are managed with protocol-directed active surveillance? Findings: In this multicenter cohort study that included 2155 individuals with a median follow-up time of 7.2 years, the 10-year incidence of upgrading at biopsy and definitive treatment were 43% and 49%, respectively. The 10-year incidence of metastasis or prostate cancer mortality were 1.4% and 0.1%, respectively. There was no significant difference in adverse outcomes in men treated within the first 2 years of surveillance vs later on. Meaning: Protocol-directed active surveillance is a safe management strategy for avoiding overtreatment and preventing undertreatment. Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer–related deaths. The estimated rates of metastasis or prostate cancer–specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer. This prospective, multicenter cohort study evaluates the long-term outcomes of men diagnosed with favorable-risk prostate cancer managed with protocol-directed active surveillance, including regular biopsies and prostate-specific antigen screening, from 2008 to 2022. [ABSTRACT FROM AUTHOR]

PurposeActive surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance.Materials and methodsWe studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance.ResultsAt a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of 103 participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76).ConclusionsMost men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.

BackgroundThe uncertainties inherent in clinical measures of prostate cancer (CaP) aggressiveness endorse the investigation of clinically validated tissue biomarkers. MUC1 expression has been previously reported to independently predict aggressive localized prostate cancer. We used a large cohort to validate whether MUC1 protein levels measured by immunohistochemistry (IHC) predict aggressive cancer, recurrence and survival outcomes after radical prostatectomy independent of clinical and pathological parameters.Material and methodsMUC1 IHC was performed on a multi-institutional tissue microarray (TMA) resource including 1,326 men with a median follow-up of 5 years. Associations with clinical and pathological parameters were tested by the Chi-square test and the Wilcoxon rank sum test. Relationships with outcome were assessed with univariable and multivariable Cox proportional hazard models and the Log-rank test.ResultsThe presence of MUC1 expression was significantly associated with extracapsular extension and higher Gleason score, but not with seminal vesicle invasion, age, positive surgical margins or pre-operative serum PSA levels. In univariable analyses, positive MUC1 staining was significantly associated with a worse recurrence free survival (RFS) (HR: 1.24, CI 1.03-1.49, P = 0.02), although not with disease specific survival (DSS, P>0.5). On multivariable analyses, the presence of positive surgical margins, extracapsular extension, seminal vesicle invasion, as well as higher pre-operative PSA and increasing Gleason score were independently associated with RFS, while MUC1 expression was not. Positive MUC1 expression was not independently associated with disease specific survival (DSS), but was weakly associated with overall survival (OS).ConclusionIn our large, rigorously designed validation cohort, MUC1 protein expression was associated with adverse pathological features, although it was not an independent predictor of outcome after radical prostatectomy.

BackgroundMen on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly.ObjectiveTo use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes.Design, setting, and participantsBiopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed.Outcome measurements and statistical analysisLogistic regression was used to predict progression, defined as an increase in Gleason score from ≤6 to ≥7 or increase in percentage of cores positive for cancer from

PurposeActive surveillance is used to manage low-risk prostate cancer. Both PCA3 and TMPRSS2:ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort.Experimental designUrine was collected after digital rectal examination prospectively as part of the multi-institutional Canary Prostate Active Surveillance Study (PASS). PCA3 and TMPRSS2:ERG levels were analyzed in urine collected at study entry. Biomarker scores were correlated to clinical and pathologic variables.ResultsIn 387 men, both PCA3 and TMPRSS2:ERG scores were significantly associated with higher volume disease. For a negative repeat biopsy, and 1% to 10%, 11% to 33%, 34% or more positive cores, median PCA3, and TMPRSS2:ERG scores increased incrementally (P < 0.005). Both PCA3 and TMPRSS2:ERG scores were also significantly associated with the presence of high-grade disease. For a negative repeat biopsy, Gleason 6 and Gleason ≥7 cancers, the median PCA3, and TMPRSS2:ERG scores also increased incrementally (P = 0.02 and P = 0.001, respectively). Using the marker scores as continuous variables, the ORs for a biopsy in which cancer was detected versus a negative repeat biopsy (ref) on modeling was 1.41 (95% CI: 1.07-1.85), P = 0.01 for PCA3 and 1.28 (95% CI: 1.10-1.49), P = 0.001 for TMPRSS2:ERG.ConclusionsFor men on active surveillance, both PCA3 and TMPRSS2:ERG seem to stratify the risk of having aggressive cancer as defined by tumor volume or Gleason score.

Tissue microarrays (TMAs) provide unique resources for rapid evaluation and validation of tissue biomarkers. The Canary Foundation Retrospective Prostate Tissue Microarray Resource used a rigorous statistical design, quota sampling, a variation of the case-cohort study, to select patients for inclusion in a multicenter, retrospective prostate cancer TMA cohort. The study is designed to definitively validate tissue biomarkers of prostate cancer recurrence after radical prostatectomy. Tissue samples from over 1000 participants treated for prostate cancer with radical prostatectomy between 1995 and 2004 were selected at 6 participating institutions in the United States and Canada. This design captured the heterogeneity of screening and clinical practices in the contemporary North American population. Standardized clinical data were collected in a centralized database. The project has been informative in several respects. The scale and complexity of assembling TMAs with over 200 cases at each of 6 sites involved unanticipated levels of effort and time. Our statistical design promises to provide a model for outcome-based studies where tissue localization methods are applied to high-density TMAs.