Publications by authors named "Peter Carroll"

549 Publications

SelectMDx and Multiparametric Magnetic Resonance Imaging of the Prostate for Men Undergoing Primary Prostate Biopsy: A Prospective Assessment in a Multi-Institutional Study.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Department of Urology and Renal Transplantation, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy.

Prostate-specific antigen (PSA) testing as the sole indication for prostate biopsy lacks specificity, resulting in overdiagnosis of indolent prostate cancer (PCa) and missing clinically significant PCa (csPCa). SelectMDx is a biomarker-based risk score to assess urinary HOXC6 and DLX1 mRNA expression combined with traditional clinical risk factors. The aim of this prospective multi-institutional study was to evaluate the diagnostic accuracy of SelectMDx and its association with multiparametric magnetic resonance (mpMRI) when predicting PCa in prostate biopsies. Overall, 310 consecutive subjects were included. All patients underwent mpMRI and SelectMDx prior to prostate biopsy. SelectMDx and mpMRI showed sensitivity and specificity of 86.5% vs. 51.9%, and 73.8% vs. 88.3%, respectively, in predicting PCa at biopsy, and 87.1% vs. 61.3%, and 63.7% vs. 83.9%, respectively, in predicting csPCa at biopsy. SelectMDx was revealed to be a good predictor of PCa, while with regards to csPCa detection, it was demonstrated to be less effective, showing results similar to mpMRI. With analysis of strategies assessed to define the best diagnostic strategy to avoid unnecessary biopsy, SelectMDx appeared to be a reliable pathway after an initial negative mpMRI. Thus, biopsy could be proposed for all cases of mpMRI PI-RADS 4-5 score, and to those with Prostate Imaging-Reporting and Data System (PI-RADS) 1-3 score followed by a positive SelectMDx.
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http://dx.doi.org/10.3390/cancers13092047DOI Listing
April 2021

Biomarkers in Prostate Cancer Diagnosis: From Current Knowledge to the Role of Metabolomics and Exosomes.

Int J Mol Sci 2021 Apr 22;22(9). Epub 2021 Apr 22.

Department of Urology, Sapienza Rome University, Policlinico Umberto I, 00161 Rome, Italy.

Early detection of prostate cancer (PC) is largely carried out using assessment of prostate-specific antigen (PSA) level; yet it cannot reliably discriminate between benign pathologies and clinically significant forms of PC. To overcome the current limitations of PSA, new urinary and serum biomarkers have been developed in recent years. Although several biomarkers have been explored in various scenarios and patient settings, to date, specific guidelines with a high level of evidence on the use of these markers are lacking. Recent advances in metabolomic, genomics, and proteomics have made new potential biomarkers available. A number of studies focused on the characterization of the specific PC metabolic phenotype using different experimental approaches has been recently reported; yet, to date, research on metabolomic application for PC has focused on a small group of metabolites that have been known to be related to the prostate gland. Exosomes are extracellular vesicles that are secreted from all mammalian cells and virtually detected in all bio-fluids, thus allowing their use as tumor biomarkers. Thanks to a general improvement of the technical equipment to analyze exosomes, we are able to obtain reliable quantitative and qualitative information useful for clinical application. Although some pilot clinical investigations have proposed potential PC biomarkers, data are still preliminary and non-conclusive.
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http://dx.doi.org/10.3390/ijms22094367DOI Listing
April 2021

Residual Benign Prostate Glandular Tissue after Radical Prostatectomy is Not Associated with the Development of Detectable Postoperative Serum PSA.

J Urol 2021 Apr 27:101097JU0000000000001793. Epub 2021 Apr 27.

Department of Urology, UCSF-Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.

Purpose: To determine if benign glandular tissue at the surgical margin (BGM) is associated with detectable PSA and/or biochemical recurrence (BCR) after radical prostatectomy (RP).

Materials And Methods: Participants underwent RP for localized prostate cancer between 2004 and 2018. Regression analysis was used to identify demographic, clinical, and surgical factors associated with the likelihood of BGM presence on surgical pathology. Oncologic outcomes included detectable PSA (>0.03 ng/mL), BCR (≥0.2 ng/mL), and progression to BCR or salvage treatment after detectable PSA. Life tables and Cox proportional hazards regression models were used to determine the association of BGM and risk of oncologic outcomes.

Results: A total of 1,082 men underwent RP for localized prostate cancer with BGM reported on surgical pathology and an undetectable postoperative PSA. BGM was present on 249 (23%) specimens. Younger age, bilateral nerve sparing surgery, and robotic approach were associated with presence of BGM while malignancy at the surgical margin (MSM) was not. At 7 years after RP, 29% experienced detectable PSA and 11% had BCR. In the subgroup of men who reached detectable PSA, 79% had progression within 7 years. On multivariate Cox proportional hazards regression, BGM status was not independently associated with detectable PSA, BCR, and/or progression from detectable PSA to BCR or salvage treatment.

Conclusions: The presence of BGM at RP was not associated with increased risk of MSM, detectable PSA, BCR, or progression after detectable PSA.
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http://dx.doi.org/10.1097/JU.0000000000001793DOI Listing
April 2021

Prostate-specific Membrane Antigen and Fluciclovine Transporter Genes are Associated with Variable Clinical Features and Molecular Subtypes of Primary Prostate Cancer.

Eur Urol 2021 Apr 8. Epub 2021 Apr 8.

Department of Urology, University of California-San Francisco, San Francisco, CA, USA; Department of Radiation Oncology, University of California-San Francisco, San Francisco, CA, USA; UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address:

F-Fluciclovine-based positron emission tomography (PET) imaging is recommended in the USA for biochemical recurrence (BCR) after prostate cancer treatment. However, prostate-specific membrane antigen (PSMA)-based PET imaging is more common worldwide, supported by international guidelines, and is now approved by the Food and Drug Administration in the USA for initial staging of primary prostate cancer. Little is known about the molecular profiles of lesions detected by PSMA-targeted PET/computed tomography (CT) versus F-fluciclovine PET/CT. We examined the expression of PSMA (FOLH1) and the fluciclovine transporter genes LAT1-4 and ASCT1/2 in a combined cohort of more than 18 000 radical prostatectomy specimens and their associations with clinical outcomes. Expression of PSMA and all but one fluciclovine transporter gene was higher in prostate cancer than in benign tissue. PSMA expression was associated with Gleason score (GS) ≥8 and lymph node involvement (LNI), and had a positive linear correlation with Decipher risk score. By contrast, expression of the fluciclovine transporters LAT2, LAT3, and ASCT2 was negatively associated with GS ≥ 8, LNI, and high Decipher score. The top decile of PSMA expression was associated with poorest metastasis-free survival (MFS), while the bottom deciles of LAT3 and ASCT2 expression were associated with poorest MFS. PATIENT SUMMARY: We measured the expression of genes that encode the targets for two different radiotracers in PET (positron emission tomography) scans of the prostate. We found that PSMA gene expression (PSMA-based tracer) is associated with worse clinical outcomes, while expression of ASCT2, LAT2, and LAT3 genes (fluciclovine tracer) is associated with better outcomes.
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http://dx.doi.org/10.1016/j.eururo.2021.03.017DOI Listing
April 2021

Post-diagnostic coffee and tea consumption and risk of prostate cancer progression by smoking history.

Cancer Causes Control 2021 Jun 9;32(6):635-644. Epub 2021 Apr 9.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Purpose: Post-diagnostic coffee and tea consumption and prostate cancer progression is understudied.

Methods: We examined 1,557 men from the Cancer of the Prostate Strategic Urologic Research Endeavor who completed a food frequency questionnaire a median of 28 months post-diagnosis. We estimated associations between post-diagnostic coffee (total, caffeinated, decaffeinated) and tea (total, non-herbal, herbal) and risk of prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer death) using Cox proportional hazards regression. We also examined whether smoking (current, former, never) modified these associations.

Results: We observed 167 progression events (median follow-up 9 years). Higher coffee intake was associated with higher risk of progression among current smokers (n = 95). The hazard ratio (HR) [95% confidence interval (CI)] for 5 vs 0 cups/day of coffee was 0.5 (CI 0.2, 1.7) among never smokers, but 4.5 (CI 1.1, 19.4) among current smokers (p-interaction: 0.001). There was no association between total coffee intake and prostate cancer progression among never and former smokers. However, we observed an inverse association between decaffeinated coffee (cups/days) and risk of prostate cancer progression in these men (HR  : 1.1 (CI 0.7, 1.8); HR: 0.7 (CI 0.3, 1.4); HR: 0.6 (CI 0.3, 1.1); p-trend = 0.03). There was no association between tea and prostate cancer progression, overall or by smoking status.

Conclusion: Among non-smoking men diagnosed with localized prostate cancer, moderate coffee and tea consumption was not associated with risk of cancer progression. However, post-diagnostic coffee intake was associated with increased risk of progression among current smokers.
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http://dx.doi.org/10.1007/s10552-021-01417-1DOI Listing
June 2021

The Long-Term Risks of Metastases in Men on Active Surveillance for Early Stage Prostate Cancer. Reply.

J Urol 2021 Mar 8:101097JU0000000000001711. Epub 2021 Mar 8.

Department of Urology, UCSF-Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California.

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http://dx.doi.org/10.1097/JU.0000000000001711DOI Listing
March 2021

Utilization of focal therapy for patients discontinuing active surveillance of prostate cancer: Recommendations of an international Delphi consensus.

Urol Oncol 2021 Mar 3. Epub 2021 Mar 3.

Division of Urology, Duke University Medical Center, Durham, NC. Electronic address:

Background: With the advancement of imaging technology, focal therapy (FT) has been gaining acceptance for the treatment of select patients with localized prostate cancer (CaP). We aim to provide details of a formal physician consensus on the utilization of FT for patients with CaP who are discontinuing active surveillance (AS).

Methods: A 3-stage Delphi consensus on CaP and FT was conducted. Consensus was defined as agreement by ≥80% of physicians. An in-person meeting was attended by 17 panelists to formulate the consensus statement.

Results: Fifty-six respondents participated in this interdisciplinary consensus study (82% urologist, 16% radiologist, 2% radiation oncology). The participants confirmed that there is a role for FT in men discontinuing AS (48% strongly agree, 39% agree). The benefit of FT over radical therapy for men coming off AS is: less invasive (91%), has a greater likelihood to preserve erectile function (91%), has a greater likelihood to preserve urinary continence (91%), has fewer side effects (86%), and has early recovery post-treatment (80%). Patients will need to undergo mpMRI of the prostate and/or a saturation biopsy to determine if they are potential candidates for FT. Our limitations include respondent's biases and that the participants of this consensus may not represent the larger medical community.

Conclusions: FT can be offered to men coming off AS between the age of 60 to 80 with grade group 2 localized cancer. This consensus from a multidisciplinary, multi-institutional, international expert panel provides a contemporary insight utilizing FT for CaP in select patients who are discontinuing AS.
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http://dx.doi.org/10.1016/j.urolonc.2021.01.027DOI Listing
March 2021

Cell-free DNA concentration and fragment size as a biomarker for prostate cancer.

Sci Rep 2021 Mar 3;11(1):5040. Epub 2021 Mar 3.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR = 1.34, P = 0.027) or to being a control (OR = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.
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http://dx.doi.org/10.1038/s41598-021-84507-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930042PMC
March 2021

A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with F-DCFPyL in Prostate Cancer Patients (OSPREY).

J Urol 2021 Feb 26:101097JU0000000000001698. Epub 2021 Feb 26.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Prostate specific membrane antigen-targeted positron emission tomography/computerized tomography has the potential to improve the detection and localization of prostate cancer. OSPREY was a prospective trial designed to determine the diagnostic performance of F-DCFPyL-positron emission tomography/computerized tomography for detecting sites of metastatic prostate cancer.

Materials And Methods: Two patient populations underwent F-DCFPyL-positron emission tomography/computerized tomography. Cohort A enrolled men with high-risk prostate cancer undergoing radical prostatectomy with pelvic lymphadenectomy. Cohort B enrolled patients with suspected recurrent/metastatic prostate cancer on conventional imaging. Three blinded central readers evaluated the F-DCFPyL-positron emission tomography/computerized tomography. Diagnostic performance of F-DCFPyL-positron emission tomography/computerized tomography was based on imaging results compared to histopathology. In cohort A, detection of pelvic nodal disease (with specificity and sensitivity as co-primary end points) and of extrapelvic metastases were evaluated. In cohort B, sensitivity and positive predictive value for prostate cancer within biopsied lesions were evaluated.

Results: A total of 385 patients were enrolled. In cohort A (252 evaluable patients), F-DCFPyL-positron emission tomography/computerized tomography had median specificity of 97.9% (95% CI: 94.5%-99.4%) and median sensitivity of 40.3% (28.1%-52.5%, not meeting prespecified end point) among 3 readers for pelvic nodal involvement; median positive predictive value and negative predictive value were 86.7% (69.7%-95.3%) and 83.2% (78.2%-88.1%), respectively. In cohort B (93 evaluable patients, median prostate specific antigen 11.3 ng/ml), median sensitivity and positive predictive value for extraprostatic lesions were 95.8% (87.8%-99.0%) and 81.9% (73.7%-90.2%), respectively.

Conclusions: The primary end point for specificity was met while the primary end point for sensitivity was not. The high positive predictive value observed in both cohorts indicates that F-DCFPyL-positive lesions are likely to represent disease, supporting the potential utility of F-DCFPyL-positron emission tomography/computerized tomography to stage men with high-risk prostate cancer for nodal or distant metastases, and reliably detect sites of disease in men with suspected metastatic prostate cancer.
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http://dx.doi.org/10.1097/JU.0000000000001698DOI Listing
February 2021

Diagnostic Performance of F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter Study.

Clin Cancer Res 2021 Feb 23. Epub 2021 Feb 23.

University of California San Francisco, San Francisco, California.

Purpose: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen-targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.

Experimental Design: Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.

Results: A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2-98.4 ng/mL) underwent F-DCFPyL-PET/CT. The CLR was 84.8%-87.0% (lower bound of 95% CI: 77.8-80.4). A total of 63.9% of evaluable patients had a change in intended management after F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by F-DCFPyL-PET/CT by central readers).

Conclusions: Performance of F-DCFPyL-PET/CT achieved the study's primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4573DOI Listing
February 2021

A modified Delphi study to develop a practical guide for selecting patients with prostate cancer for active surveillance.

BMC Urol 2021 Feb 4;21(1):18. Epub 2021 Feb 4.

Department of Surgery, University of Melbourne, Melbourne, Australia.

Background: Active surveillance (AS) is a management option for men diagnosed with lower risk prostate cancer. There is wide variation in all aspects of AS internationally, from patient selection to investigations and follow-up intervals, and a lack of clear evidence on the optimal approach to AS. This study aimed to provide guidance for clinicians from an international panel of prostate cancer experts.

Methods: A modified Delphi approach was undertaken, utilising two rounds of online questionnaires followed by a face-to-face workshop. Participants indicated their level of agreement with statements relating to patient selection for AS via online questionnaires on a 7-point Likert scale. Factors not achieving agreement were iteratively developed between the two rounds of questionnaires. Draft statements were presented at the face-to-face workshop for discussion and consensus building.

Results: 12 prostate cancer experts (9 urologists, 2 academics, 1 radiation oncologist) participated in this study from a range of geographical regions (4 USA, 4 Europe, 4 Australia). Complete agreement on statements presented to the participants was 29.4% after Round One and 69.0% after Round Two. Following robust discussions at the face-to-face workshop, agreement was reached on the remaining statements. PSA, PSA density, Multiparametric MRI, and systematic biopsy (with or without targeted biopsy) were identified as minimum diagnostic tests required upon which to select patients to recommend AS as a treatment option for prostate cancer. Patient factors and clinical parameters that identified patients appropriate to potentially receive AS were agreed. Genetic and genomic testing was not recommended for use in clinical decision-making regarding AS.

Conclusions: The lack of consistency in the practice of AS for men with lower risk prostate cancer between and within countries was reflected in this modified Delphi study. There are, however, areas of common practice and agreement from which clinicians practicing in the current environment can use to inform their clinical practice to achieve the best outcomes for patients.
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http://dx.doi.org/10.1186/s12894-021-00789-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863517PMC
February 2021

Multicenter Comparison of 17-Gene Genomic Prostate Score as a Predictor of Outcomes in African American and Caucasian American Men with Clinically Localized Prostate Cancer.

J Urol 2021 Apr 1;205(4):1047-1054. Epub 2020 Dec 1.

Genomic Health Inc., an Exact Sciences corporation, Redwood City, California.

Purpose: Adoption of prognostic molecular assays for prostate cancer requires evidence of robust performance in different racial groups. Retrospective analysis was conducted to assess the performance of the Oncotype DX Genomic Prostate Score test in African American and Caucasian American men with surgically treated prostate cancer.

Materials And Methods: We compared the assay results (scale 0-100) and the 4 gene group scores in biopsy specimens from 201 African American and 1,144 Caucasian American men with clinically localized prostate cancer in 6 cohorts. Adverse pathology was defined as high grade (primary Gleason pattern 4 or any pattern 5) and/or nonorgan-confined disease (≥pT3). Binary logistic regression models were used for adverse pathology. Biochemical recurrence was defined as 2 successive prostate specific antigen levels >0.2 ng/ml or initiation of salvage therapy after radical prostatectomy. Cox proportional hazards models evaluated the association of the assay result or racial group with time to biochemical recurrence.

Results: Each cohort had different clinical risk distributions and percentages of African Americans, although median and interquartile ranges of the assay results and gene group scores were similar between both racial groups. In a multivariable model with the assay and pathological/clinical features including race, the assay was significantly associated with adverse pathology (p ≤0.004) and biochemical recurrence (p <0.001). Race was not a significant predictor of either end point.

Conclusions: The assay is similarly predictive of outcomes in African American and Caucasian American patients, and improves risk stratification in men with newly diagnosed prostate cancer from both racial groups.
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http://dx.doi.org/10.1097/JU.0000000000001484DOI Listing
April 2021

Diagnostic Accuracy and Prognostic Value of Serial Prostate Multiparametric Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer.

Eur Urol Oncol 2021 Jan 19. Epub 2021 Jan 19.

Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Background: Multiparametric magnetic resonance imaging (MRI) is increasingly utilized to improve the detection of clinically significant prostate cancer. Evidence for serial MRI in men on active surveillance (AS) is lacking.

Objective: To evaluate the role of MRI in detecting Gleason grade group (GG) ≥2 disease in confirmatory and subsequent surveillance biopsies for men on AS.

Design, Setting, And Participants: This was a single-center study of men with low-risk prostate cancer enrolled in an AS cohort between 2006 and 2018. All men were diagnosed by systematic biopsy and underwent MRI prior to confirmatory ("MRI1") and subsequent surveillance ("MRI2") biopsies. MRI lesions were scored with Prostate Imaging Reporting and Data System (PI-RADS) version 2.

Outcome Measurements And Statistical Analysis: The primary outcome was biopsy upgrade to GG ≥ 2 prostate cancer, and the secondary outcome was definitive treatment. Test characteristics for PI-RADS score were calculated. Multivariable logistic and Cox proportional hazard regression models were used to determine the associations between PI-RADS score change and outcomes, on a per-examination basis.

Results And Limitations: Of 125 men with a median follow-up of 78 mo, 38% experienced an increase in PI-RADS scores. The sensitivity and positive predictive value of PI-RADS ≥3 for GG ≥ 2 disease improved from MRI1 to MRI2 (from 85% to 91% and from 26% to 49%, respectively). An increase in PI-RADS scores from MRI1 to MRI2 was associated with GG ≥ 2 (odds ratio [OR] 4.8, 95% confidence interval [CI] 1.7-13.2) compared with PI-RADS 1-3 on both MRI scans. Men with PI-RADS 4-5 lesions on both MRI scans had a higher likelihood of GG ≥ 2 than patients with PI-RADS 1-3 lesions on both (OR 3.3, 95% CI 1.3-8.6). Importantly, any increase in PI-RADS scores was independently associated with definitive treatment (hazard ratio 3.9, 95% CI 1.3-11.9). This study was limited by its retrospective, single-center design.

Conclusions: The prognostic value of MRI improves with serial examination and provides additional risk stratification. Validation in other cohorts is needed.

Patient Summary: We looked at the role of serial prostate magnetic resonance imaging in men with low-risk prostate cancer on active surveillance at the University of California, San Francisco. We found that both consistently visible and increasingly suspicious lesions were associated with biopsy upgrade and definitive treatment.
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http://dx.doi.org/10.1016/j.euo.2020.11.007DOI Listing
January 2021

Feasibility and Acceptability of a Remotely Delivered, Web-Based Behavioral Intervention for Men With Prostate Cancer: Four-Arm Randomized Controlled Pilot Trial.

J Med Internet Res 2020 12 31;22(12):e19238. Epub 2020 Dec 31.

Oregon Health and Science University, Portland, OR, United States.

Background: Diet and exercise may be associated with quality of life and survival in men with prostate cancer.

Objective: This study aimed to determine the feasibility and acceptability of a remotely delivered web-based behavioral intervention among men with prostate cancer.

Methods: We conducted a multi-site 4-arm pilot randomized controlled trial of a 3-month intervention (TrueNTH Community of Wellness). Eligibility included self-reported prostate cancer diagnosis, having a personal device that connected to the internet, age ≥18 years, and ability to read English and receive text messages and emails. Men receiving chemotherapy or radiation, or those who reported contraindications to exercise, could participate with physician clearance. Participants were randomized (1:1:1:1) to additive intervention levels: website; website and personalized diet and exercise prescription; website, personalized prescription, Fitbit, and text messages; and website, personalized prescription, Fitbit, text messages, and 2 30-minute phone calls-one with an exercise trainer and one with a registered dietician. Primary outcomes were feasibility (accrual and attrition) and acceptability (survey data and website use). We described self-reported diet and exercise behavior at the time of enrollment, 3 months, and 6 months as secondary outcomes.

Results: In total, 202 men consented and were randomized between August 2017 and September 2018 (level 1: 49, level 2: 51, level 3: 50, level 4: 52). A total of 160 men completed the onboarding process and were exposed to their randomly assigned intervention (38, 38, 42, and 42 in levels 1, 2, 3, and 4, respectively). The follow-up rate was 82.7% (167/202) at 3 months and 77.2% (156/202) at 6 months. Participants had a median age of 70 years and were primarily White and college educated. Website visit frequency over the 3-month intervention period increased across levels (median: 2, 9, 11, and 16 visits for levels 1, 2, 3, and 4, respectively). Most were satisfied or very satisfied with the intervention (20/39, 51%; 27/42, 64%; 23/44, 52%; and 27/42, 64% for levels 1, 2, 3, and 4, respectively). The percentage of men who reported being very satisfied was highest among level 4 participants (10/42, 24% vs 4/39, 10%; 5/42, 12%; and 5/44, 11% for levels 1, 2, and 3, respectively). Dissatisfaction was highest in level 1 (5/39, 13% vs 1/42, 2%; 3/44, 7%; and 2/42, 5% for levels 2, 3, and 4, respectively). We observed small improvements in diet and physical activity at 3 months among men in level 4 versus those in level 1.

Conclusions: A web-based, remotely delivered, tailored behavioral intervention for men with prostate cancer is feasible. Future studies are warranted to increase the effect of the intervention on patient behavior while maintaining sustainability and scalability as well as to design and implement interventions for more diverse populations.

Trial Registration: ClinicalTrials.gov NCT03406013; http://clinicaltrials.gov/ct2/show/NCT03406013.
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http://dx.doi.org/10.2196/19238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808895PMC
December 2020

Natural language processing systems for pathology parsing in limited data environments with uncertainty estimation.

JAMIA Open 2020 Oct 14;3(3):431-438. Epub 2020 Oct 14.

Department of Statistics, University of California, Berkeley, California, USA.

Objective: Cancer is a leading cause of death, but much of the diagnostic information is stored as unstructured data in pathology reports. We aim to improve uncertainty estimates of machine learning-based pathology parsers and evaluate performance in low data settings.

Materials And Methods: Our data comes from the Urologic Outcomes Database at UCSF which includes 3232 annotated prostate cancer pathology reports from 2001 to 2018. We approach 17 separate information extraction tasks, involving a wide range of pathologic features. To handle the diverse range of fields, we required 2 statistical models, a document classification method for pathologic features with a small set of possible values and a token extraction method for pathologic features with a large set of values. For each model, we used isotonic calibration to improve the model's estimates of its likelihood of being correct.

Results: Our best document classifier method, a convolutional neural network, achieves a weighted F1 score of 0.97 averaged over 12 fields and our best extraction method achieves an accuracy of 0.93 averaged over 5 fields. The performance saturates as a function of dataset size with as few as 128 data points. Furthermore, while our document classifier methods have reliable uncertainty estimates, our extraction-based methods do not, but after isotonic calibration, expected calibration error drops to below 0.03 for all extraction fields.

Conclusions: We find that when applying machine learning to pathology parsing, large datasets may not always be needed, and that calibration methods can improve the reliability of uncertainty estimates.
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http://dx.doi.org/10.1093/jamiaopen/ooaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751177PMC
October 2020

Regional Variation in Active Surveillance for Low-Risk Prostate Cancer in the US.

JAMA Netw Open 2020 12 1;3(12):e2031349. Epub 2020 Dec 1.

Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Importance: Active surveillance (AS) is now recognized as the preferred management option for most low-risk prostate cancers to minimize risks of overtreatment. Despite increasing use of AS in the US, wide regional variability has been observed, and these regional variations in contemporary practice have not been well described.

Objective: To explore variations between county and Surveillance, Epidemiology, and End Results (SEER) regions in AS in the US.

Design, Setting, And Participants: A cohort study using the SEER Prostate with Watchful Waiting (WW) database linked to the County Area Health Resource File for detailed county-level demographics and physician distribution data was conducted from January 2010 to December 2015. Analysis was performed in October 2020. A total of 79 825 men with clinically localized, low-risk prostate cancer eligible for AS or WW were included.

Exposures: Multiple patient-, county-, and SEER region-level factors, including age, year of diagnosis, county-level densities of urologists, radiation oncologists, primary care physicians, and SEER registry region.

Main Outcomes And Measures: Use of AS or WW as the initial reported treatment strategy were noted. Hierarchical mixed-effect logistic regression models were used to evaluate clustered random regional variation on use of AS or WW. Temporal trends by year in proportions of initial treatment type, as well as county-level local variation, were also estimated.

Results: Of 79 825 men (mean [SD] age, 62.8 [7.6] years, 11 292 [14.1%] non-Hispanic Black, 7506 [9.4%] Hispanic) with low-risk prostate cancer, the mean annualized percent increase in AS rates from 2010 to 2015 ranged from 6.3% in New Mexico to 81.0% in New Jersey. Differences across SEER regions accounted for 17% of the total variation in AS. Increasing age (51-60 years: odds ratio [OR], 1.33; 95% CI, 1.21-1.46; 61-70 years: OR, 1.86; 95% CI, 1.70-2.04; 71-80 years: OR, 2.26; 95% CI, 2.05-2.50) was associated with greater odds of AS. Hispanic ethnicity (OR, 0.79; 95% CI, 0.74-0.85), T category (OR, 0.79; 95% CI, 0.73-0.84), and Medicaid enrollment (OR, 0.73; 95% CI, 0.66-0.81) were associated with lower odds of AS. Black race, county-level socioeconomic factors (household income, educational level, and city type), and specialist densities were not associated with AS use.

Conclusions And Relevance: In this US cohort study based on the SEER-WW database, although the use of AS increased, considerable practice variation appeared to be associated with geographic location, but use of AS was not associated with Black race, specialty professional density, or socioeconomic factors. This small area variation underlies the broader national trends in AS practice and may inform policies aimed at continuing to affect risk-appropriate care for men throughout the US.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.31349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770559PMC
December 2020

Editorial Comment.

Authors:
Peter R Carroll

J Urol 2021 03 23;205(3):777-778. Epub 2020 Dec 23.

Department of Urology, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1097/JU.0000000000001362.01DOI Listing
March 2021

Enzalutamide response in a panel of prostate cancer cell lines reveals a role for glucocorticoid receptor in enzalutamide resistant disease.

Sci Rep 2020 12 10;10(1):21750. Epub 2020 Dec 10.

Department of Biomedical Engineering, Oregon Health & Science University, 2730 SW Moody Ave CLSB Rm 3N018, Portland, OR, 97201, USA.

Representative in vitro model systems that accurately model response to therapy and allow the identification of new targets are important for improving our treatment of prostate cancer. Here we describe molecular characterization and drug testing in a panel of 20 prostate cancer cell lines. The cell lines cluster into distinct subsets based on RNA expression, which is largely driven by functional Androgen Receptor (AR) expression. KLK3, the AR-responsive gene that encodes prostate specific antigen, shows the greatest variability in expression across the cell line panel. Other common prostate cancer associated genes such as TMPRSS2 and ERG show similar expression patterns. Copy number analysis demonstrates that many of the most commonly gained (including regions containing TERC and MYC) and lost regions (including regions containing TP53 and PTEN) that were identified in patient samples by the TCGA are mirrored in the prostate cancer cell lines. Assessment of response to the anti-androgen enzalutamide shows a distinct separation of responders and non-responders, predominantly related to status of wild-type AR. Surprisingly, several AR-null lines responded to enzalutamide. These AR-null, enzalutamide-responsive cells were characterized by high levels of expression of glucocorticoid receptor (GR) encoded by NR3C1. Treatment of these cells with the anti-GR agent mifepristone showed that they were more sensitive to this drug than enzalutamide, as were several of the enzalutamide non-responsive lines. This is consistent with several recent reports that suggest that GR expression is an alternative signaling mechanism that can bypass AR blockade. This study reinforces the utility of large cell line panels for the study of cancer and identifies several cell lines that represent ideal models to study AR-null cells that have upregulated GR to sustain growth.
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http://dx.doi.org/10.1038/s41598-020-78798-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729982PMC
December 2020

A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer.

Eur Urol 2021 Mar 5;79(3):374-383. Epub 2020 Dec 5.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Context: Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use.

Objective: To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC).

Evidence Acquisition: The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-52) and American Urology Association (AUA) criteria.

Evidence Synthesis: In total, 42 studies and 30407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n=12141), prospective registries (n=17053), and prospective and post hoc randomized trial analyses (n=1213). In 32 studies (n=12600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n=8543). GC use changed the management in active surveillance (number needed to test [NNT]=9) and postprostatectomy (NNT=1.5-4) settings in five studies (n=4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state.

Conclusions: Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making.

Patient Summary: In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.
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http://dx.doi.org/10.1016/j.eururo.2020.11.021DOI Listing
March 2021

Liposomal Bupivacaine Decreases Postoperative Length of Stay and Opioid Use in Patients Undergoing Radical Cystectomy.

Urology 2021 Mar 3;149:168-173. Epub 2020 Dec 3.

Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA.

Objective: To analyze differences in length of stay, opioid use, and other perioperative outcomes in patients undergoing radical cystectomy with urinary diversion who received either liposomal bupivacaine (LB) or epidural analgesia.

Methods: This was a single center, retrospective cohort study of patients undergoing open radical cystectomy with urinary diversion from 2015-2019 in the early recovery after surgery (ERAS) pathway. Patients received either LB or epidural catheter analgesia for post-operative pain control. LB was injected at the time of fascial closure to provide up to 72 hours of local analgesia. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative opioid use, time to solid food, time to ambulation, and direct hospitalization costs. Multivariable Cox proportional hazards regression was used to determine associations between analgesia type and discharge.

Results: LB use was independently associated with shorter post-operative length of stay compared to epidural use (median (IQR) 4.9 days (3.9-5.8) vs 5.9 days (4.9-7.9), P<.001), less total opioid use (mean 188.3 vs 612.2 OME, P <.001), earlier diet advancement (mean 1.6 vs 2.4 days, P <.001), and decreased overall direct costs ($23,188 vs $29,628, P <.001). 45% of patients who received LB were opioid-free after surgery, none in the epidural group. On multivariable Cox proportional hazards regression modeling, LB use was independently associated with earlier discharge (HR 2.1, IQR 1.0-4.5).

Conclusion: Use of LB in open radical cystectomy is associated with reduced LOS, less opioid exposure, and earlier diet advancement.
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http://dx.doi.org/10.1016/j.urology.2020.11.036DOI Listing
March 2021

The Clinical Significance of Multiple Negative Surveillance Prostate Biopsies for Men on Active Surveillance-Does Cancer Vanish or Simply Hide?

J Urol 2021 Jan 17;205(1):109-114. Epub 2020 Nov 17.

Department of Urology, UCSF-Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California (CEC, JEC, SLW, CdlC, JS, PRC), and Department of Urology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy (VF).

Purpose: Men with low risk prostate cancer on active surveillance undergo multiple biopsies over time. The long-term clinical significance of consecutively negative biopsies is not known.

Materials And Methods: Men with low risk prostate cancer prospectively enrolled in an active surveillance database with at least 4 biopsies were included in the study. Exposure variables were 0, 1 or 2 consecutively negative biopsies after diagnosis. Other variables included age, prostate specific antigen, prostate specific antigen density, Gleason grade group, percent positive cores and magnetic resonance imaging findings. Outcome variables were the detection of any cancer at fourth biopsy and active treatment.

Results: A total of 514 men were included, with 112 (22%) men having 1 negative biopsy and 78 (15%) with 2 consecutively negative biopsies. Median prostate specific antigen density was lower for men with 1 negative biopsy (0.11) and consecutively negative biopsies (0.10) compared to men who never had a negative biopsy (0.13, p <0.01). On univariable logistic regression higher prostate specific antigen density (OR 1.68, 95% CI 1.16-2.45) and suspicious magnetic resonance imaging lesions (OR 2.00, 95% CI 1.16-3.42) were associated with a higher likelihood of detecting cancer on fourth biopsy. On multivariable logistic regression 1 negative biopsy (OR 0.22, 95% CI 0.12-0.41) and consecutively negative biopsies (OR 0.12, 95% CI 0.06-0.24) were associated with a lower likelihood of detecting cancer at outcome biopsy. Unadjusted 10-year treatment-free survival was highest for patients with consecutively negative biopsies (84%) and 1 negative biopsy (74%) than those who had none (66%) (log rank p=0.02).

Conclusions: Consecutively negative surveillance biopsies are correlated with favorable clinical risk factors and independently associated with subsequent negative biopsy and lower risk of active treatment.
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http://dx.doi.org/10.1097/JU.0000000000001339DOI Listing
January 2021

Comparison of biopsy under-sampling and annual progression using hidden markov models to learn from prostate cancer active surveillance studies.

Cancer Med 2020 12 6;9(24):9611-9619. Epub 2020 Nov 6.

Department of Urology, University of Michigan, Ann Arbor, MI, USA.

This study aimed to estimate the rates of biopsy undersampling and progression for four prostate cancer (PCa) active surveillance (AS) cohorts within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium. We used a hidden Markov model (HMM) to estimate factors that define PCa dynamics for men on AS including biopsy under-sampling and progression that are implied by longitudinal data in four large cohorts included in the GAP3 database. The HMM was subsequently used as the basis for a simulation model to evaluate the biopsy strategies previously proposed for each of these cohorts. For the four AS cohorts, the estimated annual progression rate was between 6%-13%. The estimated probability of a biopsy successfully sampling undiagnosed non-favorable risk cancer (biopsy sensitivity) was between 71% and 80%. In the simulation study of patients diagnosed with favorable risk cancer at age 50, the mean number of biopsies performed before age 75 was between 4.11 and 12.60, depending on the biopsy strategy. The mean delay time to detection of non-favorable risk cancer was between 0.38 and 2.17 years. Biopsy undersampling and progression varied considerably across study cohorts. There was no single best biopsy protocol that is optimal for all cohorts, because of the variation in biopsy under-sampling error and annual progression rates across cohorts. All strategies demonstrated diminishing benefits from additional biopsies.
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http://dx.doi.org/10.1002/cam4.3549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774732PMC
December 2020

The Long-Term Risks of Metastases in Men on Active Surveillance for Early Stage Prostate Cancer.

J Urol 2020 12 6;204(6):1222-1228. Epub 2020 Nov 6.

Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.

Purpose: We assessd the long-term outcomes from a large prospective cohort of men diagnosed with prostate cancer managed with active surveillance and determined the clinical prognostic factors that may predict the risk of metastases.

Materials And Methods: We retrospectively reviewed data of men enrolled on active surveillance at our institution between 1990 and 2018 with low or intermediate risk disease (stage cT1-2, prostate specific antigen less than 20 ng/ml, and biopsy Grade Group [GG]1-2). Patients were classified into 3 groups by diagnostic GG and prostate specific antigen density. Primary outcome was metastatic prostate cancer detected on imaging or at prostatectomy. In addition, upgrade at surveillance biopsy, active treatment, and overall and prostate cancer specific survival outcomes were assessed. Cox proportional hazards regression models were used.

Results: A total of 1,450 men met the inclusion criteria. Median followup was 77 months (IQR 49-114). The 7-year metastasis-free survival rate was 99%. Metastases developed in 15 men at a median of 62 months (IQR 29-104), of which 69% were confined to lymph nodes. Men with GG2 had a lower metastasis-free survival rate compared to those with GG1 disease. GG2, prostate specific antigen velocity and PI-RADS® 4-5 lesions on multiparametric magnetic resonance imaging were associated with a higher risk of metastases. The 7-year prostate cancer specific survival was greater than 99%.

Conclusions: Active surveillance seems to preserve favorable long-term prognosis, as metastases and prostate cancer specific death are rare. However, the higher risk of metastases associated with higher Gleason grade, prostate specific antigen velocity, and characteristics on multiparametric magnetic resonance imaging should be considered when selecting and counseling patients for active surveillance.
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http://dx.doi.org/10.1097/JU.0000000000001313DOI Listing
December 2020

Multiple Tissue Biomarkers Independently and Additively Predict Prostate Cancer Pathology Outcomes.

Eur Urol 2021 01 2;79(1):141-149. Epub 2020 Nov 2.

Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Division of Hematology and Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Background: Distinguishing indolent from aggressive prostate cancer remains a key challenge for decision making regarding prostate cancer management. A growing number of biomarkers are now available to help address this need, but these have rarely been examined together in the same patients to determine their potentially additive value.

Objective: To determine whether two previously validated plasma markers (transforming growth factor β1 [TGFβ1] and interleukin-6 soluble receptor [IL6-SR]) and two validated tissue scores (the Genomic Evaluators of Metastatic Prostate Cancer [GEMCaP] and cell cycle progression [CCP] scores) can improve on clinical parameters in predicting adverse pathology after prostatectomy, and how much they vary within tumors with heterogeneous Gleason grade.

Design, Setting, And Participants: A case-control study was conducted among men with low-risk cancers defined by biopsy grade group (GG) 1, prostate-specific antigen (PSA) ≤10 ng/mL, and clinical stage ≤ T2 who underwent immediate prostatectomy. We collected paraffin-fixed prostatectomy tissue and presurgical plasma samples from 381 cases from the University of California, San Francisco, and 260 cases from the University of Washington.

Outcome Measurements And Statistical Analysis: Pathologic outcomes were minor upgrading/upstaging (GG 2 or pT3a) or major upgrading/upstaging (GG ≥ 3 or ≥ pT3b), and multinomial regression was performed to determine putative markers' ability to predict these outcomes, controlling for PSA, percent of positive biopsy cores, age, and clinical site. For upgraded tumors, a secondary analysis of the GEMCaP and CCP scores from the higher-grade tumor was also performed to evaluate for heterogeneity.

Results And Limitations: Overall, 357 men had no upgrading/upstaging event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFβ1 nor IL6-SR was statistically significantly associated with any upgrading/upstaging. On the contrary, both the CCP and the GEMCaP score obtained from Gleason pattern 3 tissue were directly associated with minor and major upgrading/upstaging on univariate analysis. The two scores correlated with each other, but weakly. On multinomial analysis including both scores in the model, the CCP score predicted minor upgrading/upstaging (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.05-2.49) and major upgrading/upstaging (OR 2.26, 95% CI 1.05-4.90), p =  0.04), and the GEMCaP score also predicted minor upgrading/upstaging (OR 1.05, 95% CI 1.03-1.08) and major upgrading/upstaging (OR 1.07, 95% CI 1.04-1.11), p <  0.01). The other clinical parameters were not significant in this model. Among upgraded tumors including both Gleason patterns 3 and 4, both the GEMCaP and the CCP score tended to be higher from the higher-grade tumor. The main limitation was the use of virtual biopsies from prostatectomy tissue as surrogates for prostate biopsies.

Conclusions: Biomarker signatures based on analyses of both DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy.

Patient Summary: Validated biomarker scores derived from both prostate cancer DNA and prostate cancer RNA can add independent information to help predict outcomes after prostatectomy.
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http://dx.doi.org/10.1016/j.eururo.2020.09.003DOI Listing
January 2021

Editorial Comment.

J Urol 2021 01 2;205(1):121. Epub 2020 Nov 2.

Department of Urology, UCSF-Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1097/JU.0000000000001241.01DOI Listing
January 2021

The Relative Impact of Urinary and Sexual Function vs Bother on Health Utility for Men With Prostate Cancer.

JNCI Cancer Spectr 2020 Oct 25;4(5):pkaa044. Epub 2020 May 25.

Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, CA, USA.

Function and bother are related but distinct aspects of health-related quality of life. The objective of this study was to compare quantitatively the relative impacts of function and bother in urinary, sexual, and bowel outcomes on health utility as a reflection of health-related quality of life in men with prostate cancer. Our analysis included participants in the Cancer of the Prostate Strategic Urologic Research Endeavor utility supplementary study, with a final cohort of 1617 men. Linear regression on the patients' function and bother summary scores (0-100) from the University of California, Los Angeles Prostate Cancer Index was performed to predict bias-corrected health utilities. Urinary and sexual bother were associated with each health utility, and their coefficients were 3.7 and 20.8 times greater, respectively, than those of the corresponding function. To our knowledge, our study provides the first quantitative and direct comparison of the impacts of function vs bother on health utility.
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http://dx.doi.org/10.1093/jncics/pkaa044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583149PMC
October 2020

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

JAMA Oncol 2020 12;6(12):1912-1920

Department of Radiation Oncology, Penn State Cancer Institute, Hershey, Pennsylvania.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus.

Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer.

Design, Setting, And Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019.

Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy.

Main Outcomes And Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts.

Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782).

Conclusions And Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.
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http://dx.doi.org/10.1001/jamaoncol.2020.4922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582232PMC
December 2020

Influence of pelvic lymph node dissection and node-positive disease on biochemical recurrence, secondary treatment, and survival after radical prostatectomy in men with prostate cancer.

Prostate 2021 Feb 19;81(2):102-108. Epub 2020 Oct 19.

Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.

Background: The benefit of pelvic lymph node dissection (PLND) at radical prostatectomy (RP) remains unclear given the low prevalence of known nodal disease (pN1) and concerns about its therapeutic utility.

Objective: To characterize the impact of PLND and secondary treatment on oncologic outcomes.

Design, Setting, And Participants: Cohort study of men who underwent primary RP with PLND for prostate cancer (PCa) at our institution since 2003. Men stratified by nodal status.

Outcome Measures And Statistical Analysis: Outcomes include biochemical recurrence-free survival (bRFS), overall survival, and PCa-specific mortality (PCSM). Multivariable Cox regression models used for each outcome.

Results And Limitations: Of 1,543 men who underwent primary RP, 174 (11%) had pN1 disease. Median follow-up was 34 months (interquartile range, 15-62). Seven-year outcomes were similar whether less than or ≥14 LNs dissected. Among node-positive patients, 29% had undetectable (UDT) prostate-specific antigen (PSA), 11% had UDT PSA + adjuvant therapy, and 60% had detectable PSA, and 7-year bRFS differed (75% for UDT PSA, 90% for UDT + adjuvant therapy, 38% for detectable PSA, p < .01). Survival outcomes did not differ. In multivariable analysis, detectable PSA (vs. UDT, HR 5.2, 95% CI 2.0-13.3) associated with worse bRFS. After salvage treatment, 7-year outcomes did not differ between groups. Study limited by retrospective review.
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http://dx.doi.org/10.1002/pros.24085DOI Listing
February 2021