Active Surveillance Cohort Research Articles

Adherence to the Mediterranean diet and grade group progression in localized prostate cancer: An active surveillance cohort.

The Mediterranean diet (MD) may be beneficial for men with localized prostate cancer (PCa) on active surveillance (AS) because of its anti-inflammatory, antilipidemic, and chemopreventive properties. This study prospectively investigated adherence to the MD with Gleason score progression and explored associations by diabetes status, statin use, and other factors. Men with newly diagnosed PCa on an AS protocol (n=410) completed a baseline food frequency questionnaire, and the MD score was calculated across 9 energy-adjusted food groups. Cox proportional hazards models were fit to evaluate multivariable-adjusted associations of the MD score with progression-free survival; progression was defined as an increase in the Gleason grade group (GG) score over a biennial monitoring regimen. In this cohort, 15% of the men were diabetic, 44% of the men used statins, and 76 men progressed (median follow-up, 36 months). After adjustments for clinical factors, higher adherence to the MD was associated with a lower risk of GG progression among all men (hazard ratio [HR] per 1-unit increase in MD score, 0.88; 95% confidence interval [CI], 0.77-1.01), non-White men (HR per 1-unit increase in MD score, 0.64; 95% CI, 0.45-0.92; P for interaction=.07), and men without diabetes (HR per 1-unit increase in MD score, 0.82; 95% CI, 0.71-0.96; P for interaction=.03). When joint effects of the MD score and statin use were examined, a similar risk reduction was observed among men with high MD scores who did not use statins in comparison with men with low/moderate MD scores with no statin use. The MD is associated with a lower risk of GG progression in men on AS, and this is consistent with prior reports about the MD and reduced cancer morbidity and mortality.

Utility of Serum miR-371a-3p in Predicting Relapse on Surveillance in Patients with Clinical Stage I Testicular Germ Cell Cancer

BackgroundOptimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown. ObjectiveTo explore the association between serum miR-371a-3p and CSI surveillance relapse. Design, setting, and participantsSerial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested. Outcome measurements and statistical analysisUsing the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse. Results and limitationsThirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p = 0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p = 0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87–2.02, p = 0.18; NSGCT: OR 0.45, 95% CI 0.21–1.00, p = 0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p = 0.05). Limitations include small numbers of relapses and variable time points of serum collection. ConclusionsIn our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy. Patient summaryThe promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.

Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability

Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost. To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments. The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data. Active surveillance for prostate cancer. Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy. A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P < .001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P < .001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P < .001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P < .001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P = .003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P < .001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile. In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.

878 - Assessing focality of dominant tumor on serial biopsy in an active surveillance cohort - implications for focal therapy

878 - Assessing focality of dominant tumor on serial biopsy in an active surveillance cohort - implications for focal therapy

1042 - Role of age in a MRI-based active surveillance cohort: Association with clinical and radiological progression

1042 - Role of age in a MRI-based active surveillance cohort: Association with clinical and radiological progression

Clinically significant prostate cancer detection and segmentation in low-risk patients using a convolutional neural network on multi-parametric MRI

ObjectivesTo develop an automatic method for identification and segmentation of clinically significant prostate cancer in low-risk patients and to evaluate the performance in a routine clinical setting.MethodsA consecutive cohort (n = 292) from a prospective database of low-risk patients eligible for the active surveillance was selected. A 3-T multi-parametric MRI at 3 months after inclusion was performed. Histopathology from biopsies was used as reference standard. MRI positivity was defined as PI-RADS score ≥ 3, histopathology positivity was defined as ISUP grade ≥ 2. The selected cohort contained four patient groups: (1) MRI-positive targeted biopsy-positive (n = 116), (2) MRI-negative systematic biopsy-negative (n = 55), (3) MRI-positive targeted biopsy-negative (n = 113), (4) MRI-negative systematic biopsy-positive (n = 8). Group 1 was further divided into three sets and a 3D convolutional neural network was trained using different combinations of these sets. Two MRI sequences (T2w, b = 800 DWI) and the ADC map were used as separate input channels for the model. After training, the model was evaluated on the remaining group 1 patients together with the patients of groups 2 and 3 to identify and segment clinically significant prostate cancer.ResultsThe average sensitivity achieved was 82–92% at an average specificity of 43–76% with an area under the curve (AUC) of 0.65 to 0.89 for different lesion volumes ranging from > 0.03 to > 0.5 cc.ConclusionsThe proposed deep learning computer-aided method yields promising results in identification and segmentation of clinically significant prostate cancer and in confirming low-risk cancer (ISUP grade ≤ 1) in patients on active surveillance.Key Points• Clinically significant prostate cancer identification and segmentation on multi-parametric MRI is feasible in low-risk patients using a deep neural network.• The deep neural network for significant prostate cancer localization performs better for lesions with larger volumes sizes (> 0.5 cc) as compared to small lesions (> 0.03 cc).• For the evaluation of automatic prostate cancer segmentation methods in the active surveillance cohort, the large discordance group (MRI positive, targeted biopsy negative) should be included.

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Controversies and uncertainty persist in prostate cancer grading. To update grading recommendations. Critical review of the literature along with pathology and clinician surveys. Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Development of an Ordinal Scale Treatment Endpoint for Adults Hospitalized With Influenza.

An obstacle in influenza therapeutics development is the lack of clinical endpoints, especially in hospitalized patients. A single time-point binary outcome measure is limited by patients' diverse clinical trajectories and low event rates. A 6-point ordinal scale with ascending clinical status severity (scoring: discharged; subacute care; acute care without/with respiratory failure; intensive care unit [ICU]; death) was proposed to study outcomes of adults hospitalized with influenza. Individual patient data from 2 active surveillance cohorts' datasets (2015/2016-2017/2018; Edmonton, Hong Kong) was used for evaluation. The impact of neuraminidase inhibitor (NAI) treatment on longitudinal ordinal outcome changes over 30 days was analyzed using mixed-effects ordinal logistic regression and group-based trajectory models. Patient (n = 1226) baseline characteristics included age (mean 68.0 years), virus-type (A 78.1%, B 21.9%), respiratory failure (57.2%), ICU admittance (14.4%), and NAI treatment within 5 days of illness (69.2%). Outcomes at 30 days included discharged (75.2%), subacute care (13.7%), acute care (4.5%), and death (6.6%). Two main clinical trajectories were identified, predictive by baseline scoring (mean ± SD, 4.3 ± 0.6 vs 3.5 ± 0.6, P < .001). Improved outcomes with NAI treatment within 5 days were indicated by significantly lower clinical status scores over time (unadjusted odds ratio [OR], 0.53; 95% confidence interval [CI], .41-.69; P < .001; adjusted OR, 0.62; 95% CI, .50-.77; P < .001, for baseline score, age, and within-patient correlations). In subanalysis, influenza vaccination was also associated with lower scores (adjusted OR, 0.67; 95% CI, .50-.90; P = .007). Analyses of binary endpoints showed insignificant results. The ordinal outcome scale is a potentially useful clinical endpoint for influenza therapeutic trials, which could account for the diverse clinical trajectories of hospitalized patients, warranting further development.

Re: Prostate Cancer Mortality and Metastasis under Different Biopsy Frequencies in North American Active Surveillance Cohorts

Re: Prostate Cancer Mortality and Metastasis under Different Biopsy Frequencies in North American Active Surveillance Cohorts

Costs and Complications After a Diagnosis of Prostate Cancer Treated With Time-Efficient Modalities: An Analysis of National Medicare Data

PurposeRecent trends in payer and patient preferences increasingly incentivize time-efficient (≤2-week treatment time) prostate cancer treatments. Methods and MaterialsNational Medicare claims from January 1, 2011, through December 31, 2014, were analyzed to identify newly diagnosed prostate cancers. Three “radical treatment” cohorts were identified (prostatectomy, brachytherapy, and stereotactic body radiation therapy [SBRT]) and matched to an active surveillance (AS) cohort by using inverse probability treatment weighting via propensity score. Total costs at 1 year after biopsy were calculated for each cohort, and treatment-specific costs were estimated by subtracting total 1-year costs in each radical treatment group from those in the AS group. ResultsMean 1-year adjusted costs were highest among patients receiving SBRT ($26,895), lower for prostatectomy ($23,632), and lowest for brachytherapy ($19,980), whereas those for AS were $9687. Costs of radical modalities varied significantly by region, with the Mid-Atlantic and New England regions having the highest cost ranges (>$10,000) and the West South Central and Mountain regions the lowest range in costs (<$2000). Quantification of toxic effects showed that prostatectomy was associated with higher genitourinary incontinence (hazard ratio [HR] = 10.8 compared with AS) and sexual dysfunction (HR = 3.5), whereas the radiation modalities were associated with higher genitourinary irritation/bleeding (brachytherapy HR = 1.7; SBRT HR = 1.5) and gastrointestinal ulcer/stricture/fistula (brachytherapy HR = 2.7; SBRT HR = 3.0). Overall mean toxicity costs were highest among patients treated with prostatectomy ($3500) followed by brachytherapy ($1847), SBRT ($1327), and AS ($1303). ConclusionsTime-efficient treatment techniques exhibit substantial variability in toxicity and costs. Furthermore, geographic location substantially influenced treatment costs.

PD53-01 DEVELOPMENT OF A WHOLE-URINE, MULTIPLEXED, NEXT GENERATION RNA-SEQUENCING ASSAY FOR AGGRESSIVE PROSTATE CANCER EARLY DETECTION

INTRODUCTION AND OBJECTIVE: Despite advances in biomarker development, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed the Michigan Prostate Score (MiPS) for individualized risk prediction of aggressive prostate cancer. MiPS uses transcription-mediated amplification to quantify expression of TMPRSS2:ERG (T2:ERG) and PCA3 from whole urine obtained after a digital rectal exam (DRE), combined with serum PSA. To improve upon MiPS, herein we describe the pre-clinical development and validation of a targeted next generation RNA sequencing assay (NGS-MiPS). METHODS: We selected patients with available MiPS scores as well as representing a spectrum of disease grade on biopsy (Benign to Grade Group 5). We used 2.5 mL of post-DRE whole urine to asses ∼90 PCa transcriptomic biomarkers: including T2:ERG, PCA3, and additional isoforms of common PCa gene fusions, mRNAs, lncRNAs, and expressed mutations. RESULTS: NGS-MiPS showed a 98% informative sample rate, high technical reproducibility, robustness and concordance with orthogonal methods (TMA and RT-qPCR), and was able to detect an expressed HOXB13 p.G84E variant and SPOP mutations. NGS-MiPS accurately recapitulated clinical MiPS-measured risk scores for presence of PCa or high-grade PCa (Gleason Score >6) on biopsy as determined by clinical MiPS vs. the same model but with NGS-MiPS data. In an extreme design cohort (Benign or Gleason 6 vs. Gleason ≥ 4+3=7 cancer) NGS-MiPS showed expected differences in the levels of T2:ERG T1E4 (p<0.00001) and PCA3 (p=0.02), with additional T2:ERG splice isoforms and other biomarkers also showing significantly different expression between low vs. high grade cancer. We used a machine learning approach trained on a subset of the extreme design cohort (n=73) to generate a 29-transcript model that outperformed MiPS and serum PSA in two validation cohorts: 1. A held-out set from the extreme design cohort n=36, (AUC 0.82 vs. 0.73 and 0.69, respectively); and 2. A separate PCa active surveillance cohort n=45, (AUC 0.66 vs. 0.58 and 0.53, respectively). CONCLUSIONS: These results support the potential utility and continued development of our urine based targeted NGS assay to supplement serum PSA for improved early detection of aggressive prostate cancer. Source of Funding: University of Michigan Prostate Cancer S.P.O.R.E. Grant P50 CA186786-05. AKC was supported by the NIH Training Program in Translational Research T32-GM113900 and by the University of Michigan Precision Health, 2018 Scholars Awards.TMM and SAT have been supported by the A. Alfred Taubman Biomedical Research Institute.

Genetic variants in epithelial-mesenchymal transition genes as predictors of clinical outcomes in localized prostate cancer.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of prostate cancer (PCa). However, little is known about genetic variants in the EMT pathway as predictors of aggressiveness, biochemical recurrence (BCR) and disease reclassification in localized PCa. In this multistage study, we evaluated 5186 single nucleotide polymorphisms (SNPs) from 264 genes related to EMT pathway to identify SNPs associated with PCa aggressiveness and BCR in the MD Anderson PCa (MDA-PCa) patient cohort (N = 1762), followed by assessment of the identified SNPs with disease reclassification in the active surveillance (AS) cohort (N = 392). In the MDA-PCa cohort, 312 SNPs were associated with high D'Amico risk (P < 0.05), among which, 14 SNPs in 10 genes were linked to BCR risk. In the AS cohort, 2 of 14 identified SNPs (rs76779889 and rs7083961) in C-terminal Binding Proteins 2 gene were associated with reclassification risk. The associations of rs76779889 with different endpoints were: D'Amico high versus low, odds ratio [95% confidence interval (CI)] = 2.89 (1.32-6.34), P = 0.008; BCR, hazard ratio (HR) (95% CI) = 2.88 (1.42-5.85), P = 0.003; and reclassification, HR (95% CI) = 2.83 (1.40-5.74), P = 0.004. For rs7083961, the corresponding risk estimates were: D'Amico high versus low, odds ratio (95% CI) = 1.69 (1.12-2.57), P = 0.013; BCR, HR (95% CI) = 1.87 (1.15-3.02), P = 0.011 and reclassification, HR (95% CI) = 1.72 (1.09-2.72), P = 0.020. There were cumulative effects of these two SNPs on modulating these endpoints. Genetic variants in EMT pathway may influence the risks of localized PCa's aggressiveness, BCR and disease reclassification, suggesting their potential role in the assessment and management of localized PCa.

17-Gene Genomic Prostate Score Test Results in the Canary Prostate Active Surveillance Study (PASS) Cohort.

The 17-gene Oncotype DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade (P = .48). In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

Assessing focality of dominant tumor on serial biopsy in an active surveillance cohort: Implications for focal therapy.

352 Background: Focal therapy (FT) has been proposed as an alternative to active surveillance (AS) for men with low/intermediate risk prostate cancer (PCa). We aim to understand progression within and outside the dominant tumor (DT) in terms of changes in focality, tumor volume and histologic grading on serial biopsy of the prostate (Bx) to identify reasonable candidates for FT. Methods: Men enrolled on AS at UCSF between 1996 and 2017 with low\intermediate risk PCa at diagnosis (PSA &lt; 20ng\ml, stage cT1\2, Gleason score (GS) ≤3+4) and at least 1 Bx after diagnosis were included. All Bx were systematic. Changes in Bx laterality and/or grade were assessed over time. DT was defined as the tumor with highest GS and size on Bx confined to 1 or 2 contiguous sextants. Those with unifocal disease (Un), multifocal in contiguous sextants (Mc), or a small volume of GS 3+3 on the contralateral side were considered candidates for FT. Results: Among 1272 men, mean age was 62 years, median PSA was 5.42 ng\ml and median follow up was 78 months (IQR 46-108). Median number of Bx was 3 (min 2, max 12) and 18% had &gt;5 Bx. At diagnosis 90% and 10% of patients had GS 3+3 and 3+4 disease respectively. At first surveillance Bx (fsBX) findings were negative in 20%, unchanged in 56% and upgraded in 24%. Findings were similar at the following 3 Bx. Across all biopsies 27% were negative and 7-year upgrade-free survival was 39%. At diagnosis, 88% of tumors were in locations viable for FT (50% Un and 38% Mc versus 12% multifocal in non-contiguous sextants (Mn-c)). At fsBX, 21% of Bx were negative and 85% of the remainder were viable for FT (29% Un and 56% Mc versus 15% Mn-c). Across all Bx DT remained stable in 592 (47%), changed prostate side or expanded to bilateral in 128 (10%), upgraded on the original dominant side in 407 (32%), and upgraded on the opposite side in 145 (11%). Of those upgraded on the non-dominant side, 74% were GS 3+4, 21% were GS 4+3 and 5% were GS ≥4+4. Conclusions: On serial biopsy, tumor location remains relatively stable and significant changes in grade and/or volume occur in the DT. A low percentage of patients show significant progression outside the DT. Such information is relevant when considering FT in this patient population.

Abstract P6-16-06: Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy

Abstract Purpose Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision and radiation treatment, and often adjuvant endocrine therapy (ET). However, this may constitute overtreatment for some women. The purpose of this neoadjuvant ET study in patients with biopsy-proven DCIS was to evaluate the relationship between the primary outcome of upstaging at surgery (invasive disease) and changes in the pre- and post-ET MRI appearances of both (1) lesion and (2) background parenchymal enhancement (BPE), with the goal to better inform de-escalated therapy. Methods Outcomes of patients with DCIS who were prospectively enrolled in a neoadjuvant ET trial between 2002 and 2009 were retrospectively analyzed with IRB approval. All patients had dynamic contrast-enhanced breast MRI prior to and following an average of 3.1 months of ET (range 1.9 – 5 months), followed by surgical excision within one year of the second MRI. Pathology reports were used to confirm initial biopsy results and to determine the nature and extent of disease postoperatively. Surgeon and radiologist’s reports were used to assess improvement of lesion after ET based on 1) less prominently enhancing pattern or 2) reduction in size of DCIS lesion after treatment. BPE response to ET on imaging was assessed by two radiologists specialized in breast imaging who compared pre- and post-ET MRI’s, blinded to all imaging reports. The change in BPE of the ipsilateral breast with treatment was scored subjectively as increased, decreased, or unchanged. Readers reached a consensus on discordant classifications of the change in BPE. The correlation between imaging change (of lesion and BPE) and incidence of invasive ductal carcinoma (IDC) at surgery was determined using Fisher’s exact test. Results: Of 34 patients evaluated, six (18%) had IDC at surgery. The prevalence of IDC in each group is shown in Table 2. Those with improvement of lesion on MRI had a lower likelihood of IDC at surgery compared to patients with no imaging improvement (Table 2, p= 0.048). Addition of change in BPE to the evaluation of lesion improvement significantly increased the chance of identifying specific patients who were much more likely to have an underlying invasive cancer at surgery (Table 2, p= 0.032). The risk of having IDC at surgery was considerably higher in the group whose lesion was assessed as not improved and who had decreased BPE scores on MRI (Table 2, p= 0.018). Conclusion: In our unique population of patients with mostly ER+ DCIS receiving pre-operative endocrine therapy, the combination of lack of lesion improvement and reduction in BPE score in blinded reads was significantly associated with the finding of invasive disease at surgical excision. This result may reflect the unmasking of a more aggressive lesion in those with underlying IDC and help identify patients with a higher likelihood of the presence of IDC at surgery. Although this study is small, it suggests that risk-stratifying patients with DCIS based on lesion and parenchymal imaging features associated with treatment response may aid in tailoring therapy for DCIS. We are testing this prospectively in an active surveillance cohort. Table 1. Incidence of IDC at surgery depending on image features (n= 34)Improvement of lesion in MRINo Improvement of lesion in MRIP-value (Fisher’s Exact Test)&amp; No Reduction in BPE&amp; Reduction in BPE&amp; No Reduction in BPE&amp; Reduction in BPEIncidence of IDC at surgery (n)0204Incidence of Not IDC at surgery (n)121024%IDC at surgery when assessing lesion only (%)9.1%40%0.048*%IDC at surgery when assessing lesion AND BPE (%)0%16.7%0%50%0.032*%IDC at surgery when assessing lesion AND BPE (%)8.3%50%0.018* Citation Format: Paul Kim, Heather I. Greenwood, Rita I. Freimanis, Gillian L Hirst, Megan Fischer-Colbrie, Jessica Gibbs, Nola M Hylton, Christina Yau, Eun-Sil Shelley Hwang, Laura J. Esserman, Rita A Mukhtar. Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-06.

MRI-Based Prostate-Specific Antigen Density Predicts Gleason Score Upgrade in an Active Surveillance Cohort.

OBJECTIVE. Elevated prostate-specific antigen density (PSAD) based on transrectal ultrasound (TRUS) measurements has been shown to be strongly associated with clinically significant disease and to predict progression on active surveillance (AS) for men with disease that is at a low stage or grade. We hypothesized that elevated MRI PSAD is similarly associated with increased risk of progression on subsequent biopsy. MATERIALS AND METHODS. In this retrospective study, men with Gleason score of 3+3 on diagnostic TRUS-guided biopsy who were managed with AS, had undergone MRI, and had at least one additional biopsy were included. MRI PSAD was calculated using prostate volume on MRI and prostate-specific antigen level temporally closest to the MRI. Multivariable logistics regression models were used to evaluate the association between MRI PSAD and predictors of upgrade on serial biopsy. RESULTS. A total of 166 patients were identified, of whom 74 (44.6%) were upgraded to a Gleason score of 7 or higher on subsequent biopsy. Lesions with Prostate Imaging Reporting and Data System (PI-RADS) scores of 4 and 5 more commonly had MRI PSAD of 0.15 ng/mL2 or higher (51.93% vs 22.22%, p = 0.01) than lesions with PI-RADS scores of 1-3. Median MRI PSAD was significantly higher in the upgraded group compared with the group that was not upgraded (0.15 ng/mL2 vs 0.11 ng/mL2, p = 0.01). MRI PSAD was significantly associated with increased odds of upgrading on subsequent biopsy (log transformation; odds ratio, 1.9 [95% CI, 1.2-2.8]; p = 0.01) after adjusting for age and length of follow-up. CONCLUSION. MRI PSAD was significantly associated with Gleason score upgrading on subsequent biopsy for men initially diagnosed with Gleason 3+3 disease. Although this result is intuitive, to our knowledge it has not been previously shown. As MRI utilization increases, MRI PSAD can aid in risk stratification for men managed with AS.

Determining Clinically Based Factors Associated With Reclassification in the Pre-MRI Era using a Large Prospective Active Surveillance Cohort

ObjectiveTo report biopsy-related and oncologic outcomes in a large prospective active surveillance cohort that was initiated in the premagnetic resonance imaging era and to additionally identify clinical factors associated with disease reclassification in order to inform future studies designed to improve enrollment and follow-up on active surveillance. MethodsPatients were prospectively enrolled at a single institution from 2006 to 2014 and followed until 2016. Men with Gleason 6 or 7 disease were eligible, and those with >6 months follow-up were included in the analysis. Patients were risk stratified based on clinical/pathologic criteria, including based on a combination of baseline and confirmatory biopsy tumor characteristics. Reclassification-free survival, based on tumor volume increase or Gleason score increase, was analyzed using multivariable Cox proportional hazards models. ResultsOf 825 enrolled patients, 682 met inclusion criteria. Median follow-up was 40 months (range 6.6-126.8). Disease was reclassified in 249 (36.5%), and 157 (23.0%) underwent treatment. A single positive core with a negative confirmatory biopsy was significantly associated with time to reclassification (median not met vs 43 months, log rank test P <.001). Composite tumor length, defined as the combined tumor length between baseline and confirmatory biopsies, was associated with shorter Gleason upgrade-free survival (hazard ratio 1.24, 95% confidence interval 1.11-1.40, P <.001) in multivariable analysis. ConclusionBaseline stratification using clinical factors including tumor length may refine risk stratification and offer the foundation on which new systems that incorporate modalities such as magnetic resonance imaging may be based.

Active surveillance for intermediate-risk prostate cancer: yes, but for whom?

Active surveillance is becoming more widely accepted as an initial management option for carefully selected men with favorable intermediate-risk prostate cancer (PCa). As prospective active surveillance cohorts mature sufficiently to begin evaluating longer-term outcomes, consensus on more precise evidence-based guidelines is needed to identify the patient cohorts who may be safely managed with active surveillance and what the ideal surveillance protocol entails. Long-term outcomes updates have suggested a trend toward worse 15-year survival outcomes for intermediate-risk patients on active surveillance compared with definitive treatment, but 'intermediate-risk' is a broad category and there is a subset of favorable intermediate-risk patients for whom survival outcomes remain equivalent. Promising updates to current risk stratification include consideration of genomic classifiers, advanced imaging and more nuanced interpretation of biopsy results. Despite widespread acknowledgement of the pitfalls of overtreatment in clinically localized PCa, utilization of active surveillance in the intermediate-risk population remains marginal, in part due to the absence of easily interpretable consensus recommendations. As more long-term outcomes data become available for this subgroup, the field is now poised to refine the definition of favorable intermediate-risk patients for whom active surveillance is a safe, evidence-based first-line management option.

AUTHOR REPLY

We agree with the important points raised in this commentary. There is indeed a lack of evidence as to what constitutes optimal follow-up following partial gland ablation (PGA). There can be no doubt that magnetic resonance imaging (MRI) has a significant part to play, and that it may indeed perform better than prostate specific antigen (PSA) profiles when it comes to predicting failure. 1 Dickinson L. Ahmed H.U. Hindley R.G. et al. Prostate-specific antigen vs. magnetic resonance imaging parameters for assessing oncological outcomes after high intensity-focused ultrasound focal therapy for localized prostate cancer. Urol Oncol. 2017; 35 (30 e9-30 e15) Crossref PubMed Scopus (55) Google Scholar A total of 32% of the patients undergoing PGA using high-intensity focused ultrasound (HIFU) in this study over a 9-year period were treated within a National Institute for Health Research (NIHR) portfolio study and as such prostate biopsies were mandated. Those treated outside of a trial followed a similar protocol, with the exception of routine biopsy. All patients were followed closely post-treatment with regular PSA testing and interval MRI scanning following a protocol which is very similar to that used for our current active surveillance cohort.

African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study.

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