New Research Demonstrates Insights into Prostate Cancer Identification, Management

San Francisco, CA (UroToday.com) -- Prostate cancer diagnosis and treatment is an ever-changing field, with new research showcasing different ways to identify and manage patients with this disease. Three new abstracts – highlighting how beta blockers may impact prostate cancer risk, the advantages and disadvantages of using magnetic resonance imaging (MRI) to monitor men on active surveillance protocols and the combined role of the Prostate Health Index (PHI) with MRI in prostate cancer detection – will be presented to the media at the 2019 AUA Annual Meeting in Chicago. This special session for press will be moderated by Dr. Sam Chang on Friday, May 3, 2019 at 10 a.m. Dr. Chang is the Patricia and Rodes Hart Endowed Chair of Urologic Surgery at Vanderbilt University Medical Center in Nashville. 

Abstracts presented include: 
Publication # MP33-06 Atenolol Reduces Incident Low And Intermediate Risk Prostate Cancer 
Oral beta blocker medications are commonly prescribed for the treatment of a variety of conditions, including high blood pressure and migraines. In this study, researchers conducted a retrospective review of more than 4,182 men who had undergone a biopsy for prostate cancer, including a cohort of 669 men who had taken a beta blocker medication – either atenolol (Tenormin), metoprolol (Lopressor/Toprol XL) or carvedilol (Coreg) – within one year of their biopsy to determine whether an association exists between these medications and incident prostate cancer on biopsy. 

Key findings include: 
  • Atenolol was associated with a reduction in incident intermediate risk prostate cancer of approximately 50 percent compared to men not taking a beta blocker. 
  • Researchers also identified a significant reduction in incident low-risk disease on biopsy in men taking atenolol. 
Publication # MP15-08 Assessment of MRI Performance in the Canary Prostate Active Surveillance Study (PASS) 

In recent years, multiparametric MRI (mpMRI) has emerged as a tool to aid in the detection of prostate cancer. Additionally, it is also being used during follow-up for men on active surveillance protocols. This multi-institutional study examined the effectiveness of mpMRI, compared to systematic biopsy, to detect Gleason Grade (GG) 2 or higher in a cohort of 325 men on active surveillance who underwent a biopsy within one year of having a mpMRI . 

Key findings include:
  • The negative predictive value of MRI for GG2 or greater cancers was 76 percent, with a false positive rate of 49 percent.
  •  In a sensitivity analysis of 287 MRI in 270 men with GG1 cancer prior to imaging, biopsy reclassification to GG2 was observed in 21 percent of men with negative MRI and 35 percent of men with positive MRI. 
  • Systemic biopsy performed higher than targeted biopsies in identifying higher GG, suggesting that systematic biopsies should not be omitted in the setting of positive or negative MRI. 
Publication # PD21-02 Use Of The PHI Assay As A First Line Triaging Test In An Image-Guided Prostate Cancer Diagnostic Pathway. The PHI In Refining MRI Study (PRIM) 

Multiparametric MRI (mpMRI) and the Prostate Health Index assay (PHI), a blood test used to identify prostate cancer and predict likelihood of disease progression, are growing in their use as tools to detect prostate cancer and improve accuracy of prostate biopsies. In this study of 289 men, using findings from the prospective UK PHI in Refining MRI (PRIM) study, researchers explored whether the PHI test could be used to refine the use of mpMRI in prostate cancer diagnosis.
Key findings include: 
  • PHI was an independent predictor of a positive mpMRI, and outperformed both mpMRI and PSA density in predicting significant cancer detection.
  • The combination of mpMRI and PHI had the highest predictive value for a significant cancer. Using an initial threshold PHI of 30 as a cut-point for referrals and biopsying only men with a positive mpMRI would have saved 23 percent of mpMRI and biopsies, while only missing a small percentage of significant cancers (6 percent). 
“The field of prostate cancer diagnosis and management is ever-changing, and these studies mark potentially important steps forward in our research,” Dr. Chang said. “Although none of the current testing optionsare perfect, a combination of MRI and markers, like the Prostate Health Index, may represent the best approach to maximize the identification of clinically significant cancer and reduce the number of biopsies.”
Abstracts: 

MP48-16 

Atenolol Reduces Incident Low And Intermediate Risk Prostate Cancer 
Ali Zahalka, Ethan Fram, Wilson Lin, Larkin Mohn, Paul Frenette, Ilir Agalliu, Kara Watts 

Introduction: Recent evidence from pre-clinical models of prostate cancer (PCa) suggests that disruption of adrenergic signaling by beta-adrenergic receptor blockade inhibits PCa progression to more aggressive pathology. We examined the in vivo association between use of oral beta-blockers and incident PCa on initial prostate biopsy in a diverse, urban academic center. 

Methods:
A retrospective review of men who underwent initial prostate biopsy for any clinical indication between 2006-2016 at a large urban academic center was performed. The oral use of a Beta-blocker - Atenolol, Metoprolol, or Carvedilol - was assessed by reviewing patients’ active prescriptions (determined by prescription refill history) within one year preceding their corresponding biopsy. Patient demographics, pre-biopsy prostate specific antigen (PSA), biopsy pathology, and clinical stage were collected. Multinomial logistic regression analysis was used to evaluate the association of Beta-blocker use with subsequent incident PCa risk group (controls were used as reference category). 

Results:
4,182 men underwent initial prostate biopsy during the study period and were included in the study. 64% self-identified as Black or Hispanic. 669 (16%) men were included in the B-blocker cohort based on preceding prescription refill history, of which 350 (17.7%) had benign pathology and 319 (14.5%) with PCa. Of all men with PCa on biopsy, risk groups (NCCN criteria) were as follows: 337 (8.1%) high risk, 1,029 (25.0%) intermediate risk, 169 (4%) low risk, and 671 (16.0%) very low risk PCa. On multivariate analysis, the beta-blocker, Atenolol, displayed a significant protective effect on both incident low risk and intermediate risk PCa (OR 0.55, P=0.02; OR 0.11, P=0.03, respectively) after adjusting for age, PSA, BMI, socioeconomic status (SES), cardiovascular disease, and race (presented in the Table). 

Conclusions: The oral beta-blocker, Atenolol, showed an approximately 50% reduction in incident intermediate risk PCa compared to men not taking a beta-blocker, as well as a dramatic reduction in incident low risk disease on prostate biopsy. Our results, combined with recent results from pre-clinical models of PCa, provide preliminary support for further research into the use of Atenolol as a potential protective pharmacologic agent against de novo PCa or PCa disease progression. 

Funding: NIH National Cancer Institute F30CA203446 and T32 NS007098 

PD50-01 
Assessment of MRI Performance in the Canary Prostate Active Surveillance Study (PASS) 
Michael Liss, Michael Garcia, Yingye Zheng, Lisa Newcomb, Christopher Filson, Hilary Boyer, James Brooks, Peter Carroll, Martin Gleave, Francis Martin, Todd Morgan, Peter Nelson, Andrew Wagner, Ian Thompson, Daniel Lin 

Introduction: MRI has been shown to increase detection of clinically significant cancer in the initial diagnosis of prostate cancer. We aim to investigate the ability of multiparametric MRI to detect Gleason Grade Group (GG) &[ge]2 cancer in a multi-institutional active surveillance cohort with standardized follow up and biopsy protocols. 

Methods:
Men enrolled in PASS across ten institutions were examined to identify men who underwent a biopsy within 12 months of a multiparametric MRI. Local interpretation of MRI PIRADS scores and biopsy GG were used in the analysis. MRI with no lesions or PIRADS 1-3 were considered negative and MRI with PIRADS 4-5 was considered positive. We investigate the performance MRI to detect GG2 or greater disease, controlling for the clinical factors of age, BMI, the proportion of positive cores, prostate size and PSA. We also compared GG found in systematic vs targeted cores in fusion biopsies. 

Results:
We evaluated 351 MRIs from 325 individuals. The negative predictive value (NPV) of MRI for any GG2 or greater was 76% with a false positive rate of 49%. A negative MRI was significant in a multivariable logistic regression (OR 0.55, CI 0.32-0.93; P=0.03). In a sensitivity analysis of 287 MRI in 270 men with only GG1 cancer prior to MRI, biopsy reclassification to GG2 was observed in 27/127 (21%) of negative MRI and 49/139 (35%) of positive MRI. In this subset, negative MRI was not associated with reclassification to GG &[ge]2 in the multivariable model. In 192 fusion biopsies, GG concordance between the target and systematic biopsies was 81% (156/192). Targeted biopsies identified higher GG than systematic biopsy in 8% (15/192) of men; whereas, systematic biopsy identified higher GG than targeted in 11% (21/192). 

Conclusions: While MRI is often used in active surveillance, the NPV of MRI is only 76% and false positive rates may limit the widescale applicability. Systematic biopsy still detects higher GG lesions in 11% suggesting that systematic biopsy cannot be omitted in the setting of positive or negative MRI. 

Funding: Canary Foundation DoD grant #W81XWH1410595 DoD grant #W81XWH1510441 

PD35-09 
Use Of The PHI Assay As A First Line Triaging Test In An Image-Guided Prostate Cancer Diagnostic Pathway. The Phi In Refining MRI Study (PRIM) 
Vincent Gnanapragasam, Tristan Barrett, Keith Burling, Benjamin Lamb, Kasra Saeb-parsy, Christof Kastner, Syed Shah, Lorraine Starling, Anne George, Lois Kim 

Introduction: Multi-parametric MRI (mpMRI) has revolutionized prostate diagnostics in improving the detection and accuracy of biopsies. mpMRI however remains a resource intensive tool and has operator dependent variability in its performance. Here we tested the value of PHI test in reducing and refining the use of mpMRI in prostate diagnostics. 

Methods:
This study represents the initial findings of the ongoing prospective UK PRIM study. 289 men referred for the first time to a prostate diagnostic clinic in our centre had a PHI assay done prior to image-targeted fusion biopsy + systematic biopsies. mpMRI were scored using the Likert scale. Men with no mpMRI lesion had systematic biopsies. Measured parameters included PSA, PSA density (PSAd), PHI, PHI density and outcomes of interest were mpMRI positivity, and any and significant cancer detection (Grade Group 2 or more). Prostate volume was derived from the mpMRI measurements. 

Results:
The median age was 65y (IQR 59-69), PSA 8.5ng/ml (IQR5.6-12.4) and PHI 42 (IQR 31-64). 212/289 men (73%) were mpMRI positive. 183/289 (63%) and 126/289 (44%) had any and significant cancers detected respectively. The median PHI was 47 (IQR 34-72) and 33 (IQR 24-43) in mpMRI positive and negative men respectively and 61 ( IQR 44-81) and 34 (IQR 26-44) for significant cancers and non-significant cancers/benign lesions. In multivariate logistic regression, PHI was an independent predictor of a positive mpMRI (OR 1.7, 1.4-2.0) after adjustment for PSA, with an AUC of 0.72 (0.68-0.72) compared to 0.51 (0.44-0.58) for PSA (p<0.0005). PHI outperformed both mpMRI and PSAd in predicting significant cancer detection; AUC 0.81 (0.76-0.86) versus 0.68 (0.64-0.73) and 0.76 (0.71-0.82). It also outperformed mpMRI and PSAd in detection of any cancer though differences here were much smaller : AUC 0.77 (0.72-0.83) versus 0.71 (0.66-0.76) and 0.74 (0.68-0.80) respectively. The combination of mpMRI and PHI had the highest predictive value for a significant cancer (AUC of 0.84[0.79-0.88]) or any cancer (AUC 0.83[0.78-0.88]). Additional derivation of the PHI density did not add the performance characteristics in this study. Amongst mpMRI negative men, the AUC for predicting a significant cancer was 0.79 (0.63-0.95) and 0.68 (0.48-0.89) for PHI and PSAd respectively. For any cancer detection these values were 0.68 (0.54-0.81) and 0.62 (0.47-0.76) respectively. Using an initial threshold PHI of &[ge]30 as a cut-point for referrals and biopsying only men with a positive mpMRI would have saved 23% mpMRI and biopsies and missed only 7/126 significant cancers (6%). 

Conclusions:
Use of the PHI as an initial triage test can reduce the need for men to enter the diagnostic pathway, offering savings on imaging and biopsies yet still retaining a high level of significant cancer detection. Ongoing work will continue to evaluate its use in a larger multi-center cohort along with health economic modelling. 

Funding: Unrestricted educational grant from Beckman Coulter. The funders had no involvement in the study or its analysis

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