Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

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.

Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial.

BACKGROUND: Direct high-quality evidence is lacking evaluating perioperative pharmacologic prophylaxis (PP) after radical prostatectomy (RP) to prevent venous thromboembolism (VTE) leading to significant practice variation. OBJECTIVE: To study the impact of in-hospital PP on symptomatic VTE incidence and adverse events after RP at 30 d, with the secondary objective of evaluating overall VTE in a screening subcohort. DESIGN, SETTING, AND PARTICIPANTS: A prospective, phase 4, single-center, randomized trial of men with prostate cancer undergoing open or robotic-assisted laparoscopic RP was conducted (July 2017-November 2018). INTERVENTION: PP (subcutaneous heparin) plus routine care versus routine care alone. The screening subcohort was offered lower extremity duplex ultrasound at 30 d. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy outcome was symptomatic VTE incidence (pulmonary embolism [PE] or deep venous thrombosis [DVT]). Primary safety outcomes included the incidence of symptomatic lymphocele, hematoma, or bleeding after surgery. Secondary outcomes were overall VTE, estimated blood loss, total surgical drain output, complications, and surveillance imaging bias. Fisher's exact test and modified Poisson regression were performed. RESULTS AND LIMITATIONS: A total of 501 patients (75% robotic) were randomized and >99% (500/501) completed follow-up. At second interim analysis (N = 445), the symptomatic VTE rate was 2.3% (four PE + DVT and one DVT) for routine care versus 0.9% (one PE + DVT and one DVT) for PP (relative risk 0.40 [95% confidence interval 0.08-2.03], p = 0.3) meeting a futility threshold for early stopping. In the screening subcohort, the overall VTE rate was 3.3% versus 2.4% (p = 0.7). Results were similar at the final analysis (symptomatic VTE: 2.0% vs 0.8%, p = 0.3; overall VTE: 2.9% vs 2.8%, p = 1). No differences were observed in safety or secondary outcomes. All VTE events (seven symptomatic and three asymptomatic) occurred in patients undergoing pelvic lymph node dissection. CONCLUSIONS: This study was not able to demonstrate a statistically significant reduction in symptomatic VTE associated with PP. There was no increase in the development of symptomatic lymphoceles, bleeding, or other adverse events. Given that the event rate was lower than powered for, further research is needed among high-risk patients (Caprini score ≥8) or patients receiving pelvic lymph node dissection. PATIENT SUMMARY: In this report, we randomized patients undergoing radical prostatectomy to perioperative pharmacologic prophylaxis or routine care alone. We found that pharmacologic prophylaxis did not reduce postoperative symptomatic venous thromboembolism significantly for men at routine risk. Importantly, pharmacologic prophylaxis did not increase adverse events, such as formation of lymphoceles or bleeding, and can safely be implemented when indicated for patients with risk factors undergoing radical prostatectomy.

Active Surveillance of Grade Group 1 Prostate Cancer: Long-term Outcomes from a Large Prospective Cohort.

BACKGROUND: Active surveillance (AS) is the preferred management option for most men with grade group (GG) 1 prostate cancer (PCa). Questions persist regarding long-term outcomes and the optimal approach to AS. OBJECTIVE: To determine survival and metastatic outcomes in AS patients. Secondary objectives were to measure the cumulative incidence and association of patient-level factors on biopsy grade reclassification. DESIGN, SETTING, AND PARTICIPANTS: A prospective, active, open-enrollment cohort study was conducted from 1995 through July 2018 at a tertiary-care academic institution. Patients with very-low-risk or low-risk PCa were enrolled. INTERVENTION: AS with semiannual prostate-specific antigen (PSA) and digital rectal examination, serial prostate biopsy, and multiparametric magnetic resonance imaging (mpMRI). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The 10- and 15-yr cumulative incidences of primary and secondary outcomes were determined. RESULTS AND LIMITATIONS: Overall, 1818 men were monitored on AS for a median of 5.0yr (interquartile range 2.0-9.0). There were 88 non-PCa deaths, four PCa deaths, and one additional case of metastasis. The cumulative incidence of PCa-specific mortality or metastasis was 0.1% (95% confidence interval, 0.04-0.6%) at both 10 and 15yr. The 5-, 10-, and 15-yr cumulative incidences of biopsy grade reclassification were 21%, 30%, and 32%, respectively. On multivariable analysis, biopsy grade reclassification was associated with older age, African-American race, PSA density, and increased cancer volume on biopsy, and men who underwent mpMRI prior to enrollment were less likely to undergo grade reclassification. Our selection and monitoring are more stringent than many other contemporary AS programs. CONCLUSIONS: In a large, single-institution, prospective AS cohort, the risk of cancer death or metastasis was <1% over long-term follow-up. Consistent with clinical guidelines, these data support the use of AS for the management of most men diagnosed with GG1 PCa. PATIENT SUMMARY: This study investigated long-term outcomes in patients with grade group 1 prostate cancer managed with active surveillance (AS). Ten years after enrolling in AS, the risk of metastasis or death from prostate cancer was <1%, while 48% of men switched to treatment. Patients who underwent multiparametric magnetic resonance imaging (mpMRI)/ultrasound-fusion targeted biopsy prior to enrollment were less likely to experience biopsy grade reclassification during follow-up, suggesting a role for mpMRI as part of a comprehensive risk assessment to confirm AS eligibility. These findings support the safety of AS in most men with grade group 1 prostate cancer, but specific outcomes may differ in programs with less intensive monitoring.

Evaluation of Apparent Diffusion Coefficient as a Predictor of Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

OBJECTIVE: To evaluate the association between apparent diffusion coefficient (ADC) on initial multiparametric MRI (mpMRI) and biopsy grade reclassification (GR) to grade group (GG) ≥2 prostate cancer (CaP) in men on active surveillance (AS) with GG 1 CaP. METHODS: We retrospectively identified 242 AS patients with reported ADC values on their initial mpMRI. ADC value from the index lesion was assessed as an independent predictor of GR using a Cox model. To ease clinical interpretation, we used a log-rank test to establish an ADC cutoff of 1128 × 10-6 mm2/s for Kaplan-Meier analysis. RESULTS: Of the 242 men, 70 underwent GR following initial mpMRI, of which 26 (37%) had GR at the index lesion. There was no significant difference in the median interval between biopsies for men with and without GR (P >.9). Men with GR had significantly lower median ADC than those without GR (P = .01). In multivariable analysis adjusting for age, prostate-specific antigen density, and National Comprehensive Cancer Network risk group, a 100-unit decrease in ADC was associated with a 12% increase in the risk of GR (HR = 1.12, 95% CI: 1.01-1.22, P = .03). Two- and 4-year rates of freedom from GR were significantly lower for men with ADC <1128 × 10-6 mm2/s vs ADC ≥1128 × 10-6 mm2/s (62% and 42% vs 78% and 68%, respectively; P <.001). CONCLUSION: For AS patients, lower ADC on initial mpMRI index lesion is associated with increased risk of GR to GG ≥2 CaP and would be a useful component of multivariable risk prediction tools.

Prostate cancer mortality and metastasis under different biopsy frequencies in North American active surveillance cohorts.

BACKGROUND: Active 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. METHODS: Times 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. RESULTS: Compared 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). CONCLUSIONS: Among 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.

The association between clinically determined periodontal disease and prostate-specific antigen concentration in men without prostate cancer: the 2009-2010 National Health and Nutrition Examination Survey.

PURPOSE: We evaluated the association between clinically assessed periodontal disease and serum prostate-specific antigen (PSA) concentration in men without a prostate cancer diagnosis in a US nationally representative sample of non-institutionalized men. METHODS: Included were 1263 men aged ≥ 40 years who participated in the National Health and Nutrition Examination Survey in 2009-2010. Measurements of periodontal health and tooth count were used to define periodontal disease severity (no, mild, moderate, severe) and edentulism. Linear and logistic regressions were used to estimate the association of periodontal disease severity and edentulism with PSA concentration and elevated PSA, respectively. RESULTS: Adjusting for age and other factors including race, body mass index, and education, the natural logarithm of PSA concentration did not change with increasing severity (mild - 0.20, 95% confidence interval [CI] - 0.34 to - 0.05; moderate - 0.12, 95% CI - 0.26 to 0.01; severe - 0.16, 95% CI - 0.43 to 0.12; edentulism - 0.16, 95% CI - 0.35 to 0.04; P-trend 0.13) compared with dentate men without periodontal disease. Although the multivariable-adjusted ORs of elevated PSA were not statistically significant, participants with more severe periodontal disease were less likely to have PSA > 2.0 and > 2.5 ng/mL, but more likely to have PSA > 4.0 ng/mL, compared to dentate men without periodontal disease. Similar non-significant associations with PSA were observed when comparing edentulous men to dentate men without periodontal disease. CONCLUSIONS: In this US nationally representative sample, men with periodontal disease did not have higher serum PSA and were not more likely to have clinically elevated PSA after taking into account age and other factors, contrary to the hypothesis. This study suggests that periodontal disease does not notably affect the specificity of PSA for prostate cancer screening.

In-office Transperineal Prostate Biopsy Using Biplanar Ultrasound Guidance: A Step-by-Step Guide.

OBJECTIVE: To provide a step-by-step guide for performing in-office transperineal prostate biopsy using biplanar ultrasound guidance. PATIENTS AND METHODS: Biopsies are performed using a freehand technique with the PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD). This disposable needle guide includes 3 components: a rail/clamp subassembly, a needle carriage with 5 aperture holes, and a 15 gauge access needle. The device is clamped to a side-fire biplanar ultrasound probe, ensuring alignment of the biopsy needle with the probe's ultrasound arrays. Once the patient is sufficiently anesthetized using 1% lidocaine, the access needle is engaged into the perineal skin. This allows for multiple passes of the biopsy needle through a common puncture site. A separate puncture is made for each side of the prostate and the aperture hole is chosen based on the overall height of the prostate. Biopsies are taken using a disposable 18 gauge biopsy gun. RESULTS: The presented video details our approach for performing transperineal prostate biopsy under local anesthesia. Biopsies are performed in the office setting without the need for periprocedural antibiotics. The PrecisionPoint Transperineal Access System ensures proper alignment of the biopsy needle with the ultrasound probe, while minimizing the number of individual needle sticks to the perineal skin. The use of biplanar ultrasound makes it possible to guide the biopsy needle with excellent precision to virtually any area of the prostate. The descried technique can be used for systematic biopsies as well as for targeted biopsies using cognitive fusion with magnetic resonance imaging. CONCLUSION: We provide a step-by-step guide for performing in-office transperineal prostate biopsy. The presented technique minimizes the risk of infectious complications by eliminating the need for biopsy needles to pass through the rectal mucosa. Biopsies are performed without the need for periprocedural antibiotics, thus furthering the goals of antibiotic stewardship.

Association between Liver Fibrosis and Serum PSA among U.S. Men: National Health and Nutrition Examination Survey (NHANES), 2001-2010.

BACKGROUND: To evaluate the association of liver fibrosis scores with PSA level among U.S. adult men overall and by race/ethnicity. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES), 2001-2010, were used. Males ages ≥40 years without a prostate cancer diagnosis and who had serum PSA, liver enzymes, albumin, and platelet counts measured as part of NHANES protocol were included. Liver fibrosis was measured using three scores: aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 index (FIB-4), and NAFLD fibrosis score (NFS). We assessed overall and race/ethnicity-stratified geometric mean PSA by fibrosis score using predictive margins by linear regression, and the association of abnormal fibrosis scores (APRI > 1, FIB-4 > 2.67, NFS > 0.676) and elevated PSA (>4 ng/mL) by logistic regression. RESULTS: A total of 6,705 men were included. Abnormal liver fibrosis scores were present in 2.1% (APRI), 3.6% (FIB-4), and 5.6% (NFS). Men with higher fibrosis scores had lower geometric mean PSA (all P trend < 0.02). Men with abnormal APRI had a lower odds of PSA > 4 ng/mL [adjusted OR (aOR) = 0.33; 95% confidence interval (CI), 0.11-0.96]. Compared with men with 0 abnormal scores, those with 2 or 3 abnormal fibrosis scores had a lower odds of PSA > 4 ng/mL (aOR = 0.55; 95% CI, 0.33-0.91). The patterns were similar by race/ethnicity. CONCLUSIONS: Men of all race/ethnicities with higher liver fibrosis scores had lower serum PSA, and men with advanced fibrosis scores had a lower odds of an elevated PSA. IMPACT: These findings support further research to inform the likelihood of delay in prostate cancer detection in men with abnormal liver function.

PTEN status assessment in the Johns Hopkins active surveillance cohort.

BACKGROUND: Up to half of men with Gleason score 6 (GS6) prostate cancers initially managed with active surveillance (AS) will eventually require definitive therapy, usually due to tumor grade reclassification during follow-up. We examined the association between PTEN status on biopsy and subsequent clinicopathologic outcomes in men with GS6 cancers who enrolled in AS. METHODS: We performed a case-control study of men enrolled in the Johns Hopkins AS cohort with diagnostic biopsy tissue available for immunohistochemical (IHC) staining. IHC was performed for PTEN using genetically validated protocols for all patients. Cases included men who underwent grade reclassification to GS ≥ 3 + 4 = 7 on biopsy within 2 years of follow-up (i.e., early reclassification) or reclassification to GS ≥ 4 + 3 = 7 on biopsy or radical prostatectomy during follow-up (i.e., extreme reclassification). Control patients were diagnosed with GS6 cancer and monitored on AS for at least 8 years without undergoing biopsy reclassification. RESULTS: Among 67 cases with adequate tissue, 31 men underwent early reclassification and 36 men underwent extreme reclassification. Cases were compared to 65 control patients with adequate tissue for assessment. On initial prostate biopsy, cases were older (median age 67 vs. 65, p = 0.024) and were less likely to meet very-low-risk criteria (64 vs 79%, p = 0.042) as compared to controls. Although not statistically significant, PTEN loss was observed in only 1 (1.5%) of 65 controls as compared to 6 (9%) of 67 cases (p = 0.062). CONCLUSIONS: PTEN loss was rare among men with GS6 prostate cancer enrolled in AS at Johns Hopkins. Despite this, PTEN loss was more frequent among men who underwent early or extreme reclassification to higher-grade cancer as compared to controls. Additional studies in larger low-risk cohorts may better elucidate a potential role for PTEN in selecting patients for AS.

Older Age Predicts Biopsy and Radical Prostatectomy Grade Reclassification to Aggressive Prostate Cancer in Men on Active Surveillance.

PURPOSE: Age at prostate cancer diagnosis has been positively associated with prostate cancer specific mortality and in men on active surveillance with a higher risk of biopsy grade reclassification to Gleason score 3 + 4 or greater (Grade Group 2 or greater). However, to our knowledge the association between age and biopsy grade reclassification to an aggressive phenotype (Gleason score 4 + 3 or greater [Grade Group 3 or greater]) has not been explored. MATERIALS AND METHODS: From 1995 to 2016 we followed 1,625 men 41 to 81 years old with NCCN® (National Comprehensive Cancer Network®) very low (68%) or low (32%) risk prostate cancer on active surveillance. We determined the rate of biopsy grade reclassification to Grade Group 3 or greater. Competing risk analysis was applied to evaluate the association between age at enrollment and the risk of biopsy grade reclassification. Additionally, in men who underwent radical prostatectomy after biopsy grade reclassification we assessed the rate of radical prostatectomy grade reclassification (ie radical prostatectomy Grade Group greater than biopsy Grade Group). RESULTS: The 5-year incidence of biopsy grade reclassification to Grade Group 3 or greater was 4%, 7% and 14% in men younger than 60, 60 to 69 and 70 years old or older, respectively (p <0.001). On univariate analysis older age was associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.43, p <0.001). On multivariable analysis adjusting for year of diagnosis, race, prostate specific antigen density and cancer volume at diagnosis older age remained associated with biopsy grade reclassification to Grade Group 3 or greater (per 10-year increase HR 2.19, p <0.001). In men who underwent radical prostatectomy after biopsy grade reclassification those who were older had a higher rate of radical prostatectomy grade reclassification (p <0.05). CONCLUSIONS: In men on active surveillance older age at diagnosis was positively associated with biopsy grade reclassification to Grade Group 3 or greater and radical prostatectomy grade reclassification. These observations imply that for many older men, active surveillance as opposed to watchful waiting remains a more appropriate management strategy.

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

Clinical Evaluation of an Individualized Risk Prediction Tool for Men on Active Surveillance for Prostate Cancer.

OBJECTIVE: To determine whether providing individualized predictions of health outcomes to men on active surveillance (AS) alleviates cancer-related anxiety and improves risk understanding. MATERIALS AND METHODS: We consecutively recruited men from our large, institutional AS program before (n = 36) and after (n = 31) implementation of a risk prediction tool. Men in both groups were surveyed before and after their regular visits to assess their perceived cancer control, biopsy-specific anxiety, and burden from cancer-related information. We compared pre-/post-visit differences between men who were and were not shown the tool using two-sample t-tests. Satisfaction with and understanding of the predictions were elicited from men in the intervention period. RESULTS: Men reported a relatively high level of cancer control at baseline. Men who were not shown the tool saw a 6.3 point increase (scaled from 0 to 100) in their perceived cancer control from before to after their visit whereas men who were shown the tool saw a 12.8 point increase, indicating a statistically significant difference between groups (p = .04). Biopsy-specific anxiety and burden from cancer information were not significantly different between groups. Men were satisfied with the tool and demonstrated moderate understanding. CONCLUSION: Providing individualized predictions to men on AS helps them better understand their cancer risk and should be considered at other clinical sites.

Subtyping the Risk of Intermediate Risk Prostate Cancer for Active Surveillance Based on Adverse Pathology at Radical Prostatectomy.

PURPOSE: Intermediate risk prostate cancer is a heterogenous classification with favorable proposed criteria based on men treated with radiation therapy. However, there is uncertain application to active surveillance. We quantified the rate of adverse surgical pathology and implications for survival in patients at favorable intermediate risk compared to those with low risk prostate cancer. MATERIALS AND METHODS: We performed a comparative cohort study of men with prostate cancer from 2009 to 2013 in the National Cancer Database who underwent radical prostatectomy. The study primary end point was adverse pathology, defined as Grade Group 3 or greater/pT3b/pN1. Various favorable intermediate risk definitions were evaluated, including the Memorial Sloan Kettering Cancer Center definition of Grade Group 2 or less with only 1 intermediate risk factor (Grade Group 2/cT2b/prostate specific antigen 10 to 20 ng/ml), which we defined as type 1 intermediate risk. The remaining patients at intermediate risk were classified as type 2 intermediate risk. Log binomial, logistic and Cox proportional hazards regression models were applied. RESULTS: Adverse pathological findings were noted in 3,519 of the 51,688 patients (6.8%) at low risk and 8,888 of the 42,720 Grade Group 2 patients (20.8%) at intermediate risk (RR 3.06, 95% CI 2.95-3.17, p <0.001). Stratification by prostate specific antigen and volume minimally impacted the absolute rate. Results were similar for the Memorial Sloan Kettering Cancer Center definition (type 1 intermediate risk). Type 2 intermediate risk led to a greater risk of adverse pathology (RR 8.52, 8.23-8.82, p <0.001) and Grade Group 1 intermediate risk led to lower risk (RR 2.00, 1.86-2.16, p <0.001). Patients at favorable intermediate risk had worse overall survival than patients at low risk in adjusted models due to adverse pathology. CONCLUSIONS: Adverse pathology at radical prostatectomy was observed at a threefold higher rate in patients classified at favorable intermediate risk compared to low risk, leading to worse overall survival. Men at intermediate risk may be better classified as types 1 and 2 since none showed pathological outcomes similar to those of men at low risk.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Managing high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands on prostate biopsy.

Prostate biopsy is the gold standard for diagnosing prostate cancer and reliable pathological assessment is essential for guiding management. Research efforts over the past few years have aimed to establish a more universal approach to management according to pathological grading; however, high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands suspicious for carcinoma are two diagnoses without standardized follow-up and treatment pathways. Much of this uncertainty is due to limited evidence describing the subsequent rates of cancer and high-grade cancer when HGPIN or atypical glands are detected on initial biopsy. Fortunately, data from the past decade have shed light on these phenomena, and an improved understanding of the implications of the presence of HGPIN and atypical glands on prostate biopsy means that clinical recommendations can be made for the management of patients with these diagnoses.