Primary Gleason Pattern Research Articles

A novel prognostic model of de novo metastatic hormone-sensitive prostate cancer to optimize treatment intensity.

The treatment and prognosis of de novo metastatic hormone-sensitive prostate cancer (mHSPC) vary. We established and validated a novel prognostic model for predicting cancer-specific survival (CSS) in patients with mHSPC using retrospective data from a contemporary cohort. 1092 Japanese patients diagnosed with de novo mHSPC between 2014 and 2020 were registered. The patients treated with androgen deprivation therapy and first-generation anti-androgens (ADT/CAB) were assigned to the Discovery (N = 467) or Validation (N = 328) cohorts. Those treated with ADT and androgen-receptor signaling inhibitors (ARSIs) were assigned to the ARSI cohort (N = 81). Using the Discovery cohort, independent prognostic factors of CSS, the extent of disease score ≥ 2 or the presence of liver metastasis; lactate dehydrogenase levels > 250U/L; a primary Gleason pattern of 5, and serum albumin levels ≤ 3.7g/dl, were identified. The prognostic model incorporating these factors showed high predictability and reproducibility in the Validation cohort. The 5-year CSS of the low-risk group was 86% and that of the high-risk group was 22%. Approximately 26.4%, 62.7%, and 10.9% of the patients in the Validation cohort defined as high-risk by the LATITUDE criteria were further grouped into high-, intermediate-, and low-risk groups by the new model with significant differences in CSS. In the ARSIs cohort, high-risk group had a significantly shorter time to castration resistance than the intermediate-risk group. The novel model based on prognostic factors can predict patient outcomes with high accuracy and reproducibility. The model may be used to optimize the treatment intensity of de novo mHSPC.

Predicting PAM50 subtypes from whole slide images of prostate cancer biopsies.

e17001 Background: Computational analysis of digitized pathological images has been shown to have diagnostic and prognostic applications. Recent research suggests that molecular features, previously defined at the genomic level, might be additionally recognized. In prostate cancer, transcriptomic PAM50 molecular subtypes may correlate with patient response to systemic therapy. Here we investigate whether computational analysis of digital prostate biopsy slides can predict PAM50 category. Methods: Our study utilized digitized images of 704 prostate biopsy slides from 336 patients with prostate cancer at Northwestern Memorial Hospital with Decipher testing (Veracyte, Inc San Diego, CA). All slides analyzed contain carcinoma with the majority being primary Gleason pattern 3 (545 out of 704). Hematoxylin and eosin stained slides were scanned on a Leica GT450 scanner at 40x magnification. PAM50 subtypes were derived from the Decipher Genomic Resource Information Database (GRID). Data were split at the subject level using 80% for training, 10% for validation, and 10% for evaluation, facilitating model development and assessment. We devised a model comprising two decoupled parts: a multi-instance learning model that utilizes a multi-class attention mechanism to explore relevant class-specific information from slides, and a pre-trained network to extract high-dimensional semantic features from the tiles of WSIs. The model trained based on the WSIs of the training set to predict PAM50 subtypes (luminal A, luminal B, and basal). This attention-based training approach allowed the model to capture relevant patterns and information present in the WSIs. Following the training phase, the model was subsequently evaluated on the testing set. Results: Model AUC on the evaluation set was 0.78. Among evaluation set misclassifications, no luminal samples were misclassified as basal subtype. Conclusions: Our investigation provides preliminary results on the ability to predict RNA expression-based subtypes from prostate cancer biopsy histology. This approach may help to preserve tissue, minimize costs, and decrease turnaround time associated with molecular testing in prostate cancer while offering patients with prostate cancer opportunities for precision medicine.

Long term evaluation of optimized Gleason grading in a large cohort of men with prostate cancer in Canada

ObjectivesTo evaluate the International Society of Urological Pathology (ISUP) 5-tier grade grouping (GG) system of prostate cancers as well as previously proposed optimizations. Patients and methodsThe PROCURE biobank is a prospective cohort study of patients with localized prostate cancer who underwent radical prostatectomy in Quebec province between 2005 and 2013. Surgical specimens were graded by experienced genitourinary pathologists using 2019 ISUP criteria. Follow-up was conducted until November 2021. The current 5-tier and a proposed 6-tier GG system were evaluated, the latter having two changes: 1) Gleason 3 + 4 and 4 + 3 tumors with minor/tertiary Gleason 5 patterns were upgraded to GG 3 and 4, respectively; and 2) patients in GG5 were separated based on primary Gleason pattern (4 or 5). Cox proportional hazards models and Harrell's concordance (C) indices were used for statistical analyses. Results2003 patients were included (median follow-up: 8.7 years). The current 5-tier GG system predicted time to recurrence (hazard ratio [HR] 2.12, 95% confidence interval [95%CI] 1.99–2.25, C 0.717), androgen-deprivation therapy (HR 2.58, 95%CI 2.38–2.80, C 0.790), metastasis (HR 2.48, 95%CI 2.17–2.83, C 0.806), castration-resistant prostate cancer (HR 2.67, 95%CI 2.28–3.13, C 0.829), and cancer-specific mortality (HR 2.80, 95%CI 2.27–3.44, C 0.835). Goodness-of-fit further improved with the proposed 6-tier GG system, with Harrell's C of 0.733, 0.807, 0.827, 0.853, and 0.853, respectively. ConclusionsThe 5-tier GG system predicted short- and long-term outcomes for patients with localized prostate cancer, and the proposed 6-tier GG system further improved its accuracy.

Risk Factors Predicting Relapse 10 Years Following Extreme Dose-Escalated SBRT for Intermediate-Risk Prostate Cancer: Is De-Intensification Feasible in Unfavorable Subgroups?

Adding short-term androgen-deprivation therapy (ADT) to radiotherapy is recommended in unfavorable intermediate-risk (UIR) prostate cancer (PCa). Data supporting the addition of ADT to stereotactic body radiotherapy (SBRT) in intermediate-risk (IR) patients are limited. Given ADT has well-documented toxicities, we sought to identify the UIR prognostic factors that predict for relapse following SBRT without ADT. We combined results from two mature multicenter trials to determine if extreme dose-escalated SBRT yielded UIR subgroups in which the omission of ADT may be considered. Between 2008 and 2011, two prospective national trials enlisted 39 centers to enroll 285 patients with IR PCa: 182 had Memorial Sloan Kettering (MSK) favorable intermediate-risk (FIR) and 103 had MSK UIF PCa. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. Two dose regimens were used: 40Gy in 5 fractions of 8Gy, and 38Gy in 4 fractions of 9.5Gy. ADT was not allowed. Univariate and multivariate analyses using a Cox proportional hazards model was performed for relapse free survival (RFS): relapse included pathologic or radiographic failure, initiation of salvage or systemic therapy, or biochemical relapse by the nadir + 2 definition. Insufficient events prevented similar analyses for local control, metastasis-free and PCa-specific survival. Examined risk factors included dose regimen, clinical T-stage, Gleason score, pre-treatment PSA, % positive biopsy cores, and number of unfavorable risk factors (URFs). All reported rates are actuarial, using Kaplan-Meier method. Median follow-up was 8.1 years. 71 patients were followed 10 years. There were no statistically significant differences in rates of toxicity, local failure, RFS, overall nor metastasis-free survival between the two dose regimens. For the entire group, 10-year overall survival was 82.9%, RFS was 83.2%, and the local failure rate was 3.6%. On univariate analysis, primary Gleason pattern 4 (PGP4) and >2 URFs predicted for RFS. On multivariate analysis, only PGP4 (hazard ratio: 3.71, p = 0.0053) was statistically significant. Examining the UIR subgroup, the only predictor for RFS was PGP4 (HR: 3.64, p = 0.0253). 10-year RFS was 88.4% for FIR and 89.1% for UIR without PGP4; this fell to 58.5% in patients with a PGP4. Following dose-escalated SBRT monotherapy, 10-year RFS rates were favorable in UIR patients without PGP4. Extreme dose escalation appeared to effectively address UIR factors correlating with tumor bulk (i.e., CS T2b, >50% cores+, PSA 10-20), but was less effective with biologically aggressive pathology (PGP4). A randomized trial, ideally including genomic classification, would be necessary to determine if dose-escalated SBRT allows de-intensification (omission of ADT) in such biologically less aggressive UIR subgroups. The high relapse rate observed in UIR patients with PGP4 affirms the need for adjuvant ADT in this subgroup.

Association of Radiation Facility Volume with Overall Survival in Patients with Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy.

Studies suggest an association of treatment at high volume facilities with improved survival in cancer patients receiving surgery or radiation therapy. This association has not been studied in patients with very high-risk prostate cancer, who are treated using a multimodality approach that often requires specialized care with advanced diagnostic imaging, complex radiotherapeutic planning, and multidrug antiandrogen regimens. We used the National Cancer Database (NCDB) to study the association of radiation treatment facility volume (FV) with overall survival (OS). We selected for patients with very high risk, localized prostate cancer by NCCN criteria (cT3b-T4, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high risk features). We included patients who received hormone therapy with either external beam radiation to a dose of ≥60 Gy or external beam radiation to a dose of ≥45 Gy combined with brachytherapy. Association of FV with OS was evaluated through a bias-adjusted log-rank test to identify the optimal cut point of FV for dichotomization. Kaplan-Meier curves were used to study the association of binary FV with overall survival (OS) with and without IPTW (inverse probability treatment weighting) balancing the following confounders: age, race, median income, education, insurance, academic treatment facility, Charlson comorbidity score, T stage, PSA, Gleason score, total radiation dose, year of diagnosis, and patient distance from treatment facility. Cox proportional hazards model was built using backward variable selection strategy (α of 0.05 for removal). We identified 25,219 very high-risk prostate cancer patients by NCCN criteria (median follow up 57.36 months; 95% CI 56.67 - 58.09) diagnosed between 2004 and 2015. High FV (n = 6,438) was associated with better OS on univariable analysis (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.77 - 0.86; p < 0.001) and multivariable analysis (HR = 0.89; 95% CI 0.84 - 0.95; p < 0.001). Other factors associated with improved OS on multivariable analysis included younger age, non-white/black race, higher income, private insurance, academic/research treatment facility, lower comorbidity, lower T-stage, lower PSA, and lower Gleason score. After IPTW adjustment, high FV remained associated with better OS (HR = 0.90; 95% CI 0.85 - 0.95; p < 0.001). Patients with NCCN very high-risk prostate cancer treated at a radiation facility with high case volume had better OS than patients treated at a facility with low volume, after adjustment for confounders. This may suggest that for very high-risk patients, outcomes may be improved by the expertise and optimal multidisciplinary care that typically accompany high facility treatment volume.

Radiation Facility Volume and Survival for Men With Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy

Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.

Development and validation of an AI-derived digital pathology-based biomarker to predict benefit of long-term androgen deprivation therapy with radiotherapy in men with localized high-risk prostate cancer across multiple phase III NRG/RTOG trials.

5001 Background: Androgen deprivation therapy (ADT) improves survival and reduces risk of metastasis in men with high-risk localized prostate cancer (PC) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration to maximize benefits and minimize risks. We sought to train and validate the first predictive biomarker for long-term (LT) vs short-term (ST) ADT using multiple phase III NRG Oncology randomized trials. Methods: Pre-treatment prostate biopsy slides were digitized from six phase III NRG/RTOG randomized trials of men receiving RT +/- ADT. The artificial intelligence (AI)-derived clinical and histopathological predictive biomarker was trained on RTOG 9408, 9413, 9902, 9910, and 0521 to predict differential benefit of LTADT on distant metastasis (DM). After the AI biomarker was locked, it was validated on RTOG 9202, which randomized men to RT + STADT (4 mo) vs LTADT (28 mo). The predictive utility of the AI biomarker was evaluated for the primary and secondary endpoints of DM and PC-specific mortality (PCSM), respectively, for ADT duration with Fine-Gray interaction models. Event rates were estimated by the cumulative incidence method. Deaths from other causes were treated as competing risks. Results: The AI-derived biomarker was trained on 2,641 men (median follow-up of 9.8 years, IQR [8.2, 11.5]) and validated on 1,192 men from RTOG 9202 (median follow-up of 17.2 years, IQR [9.1, 19.6]), where 80% had at least one high/very high (H/VH) risk feature (cT3-4, Gleason 8-10, PSA &gt; 20, or primary Gleason pattern 5). Consistent with published results, LTADT significantly improved DM (subdistribution HR [sHR] 0.64, 95% CI 0.50-0.82, p &lt; 0.001) in the validation cohort. The AI biomarker was prognostic for DM (sHR 2.35, 95% CI 1.72-3.19, p &lt; 0.001). A significant biomarker-treatment interaction was observed (p = 0.04), in which AI-biomarker (+) men (n = 785, 66%) had reduced DM with LTADT (sHR 0.55, 95% CI 0.41-0.73, p &lt; 0.001), but no benefit was observed (sHR 1.06, 95% CI 0.61-1.84, p = 0.84) for AI-biomarker (-) men (n = 407, 34%). The 10-year DM rate difference between RT + LTADT vs RT + STADT was 13% in AI-biomarker (+) men vs 2% in AI-biomarker (-) men. Similar trends were observed for PCSM outcomes. Risk classification (NCCN intermediate [n = 221, 43% (+)] vs other H/VH risk [n = 954, 71% (+)]) was prognostic but not predictive of LTADT benefit. Conclusions: We have successfully validated the first predictive biomarker of LTADT benefit with RT in localized high-risk PC using an AI-derived digital pathology-based platform in the phase III NRG/RTOG 9202 trial. The predictive AI biomarker identified 34% of men that could derive similar benefit with STADT, avoiding the side effects of prolonged ADT, and 43% of intermediate risk men who would benefit from LTADT.

Classifying Malignancy in Prostate Glandular Structures from Biopsy Scans with Deep Learning

Histopathological classification in prostate cancer remains a challenge with high dependence on the expert practitioner. We develop a deep learning (DL) model to identify the most prominent Gleason pattern in a highly curated data cohort and validate it on an independent dataset. The histology images are partitioned in tiles (14,509) and are curated by an expert to identify individual glandular structures with assigned primary Gleason pattern grades. We use transfer learning and fine-tuning approaches to compare several deep neural network architectures that are trained on a corpus of camera images (ImageNet) and tuned with histology examples to be context appropriate for histopathological discrimination with small samples. In our study, the best DL network is able to discriminate cancer grade (GS3/4) from benign with an accuracy of 91%, F1-score of 0.91 and AUC 0.96 in a baseline test (52 patients), while the cancer grade discrimination of the GS3 from GS4 had an accuracy of 68% and AUC of 0.71 (40 patients).

Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy

AimsThis multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). Materials and methodsPatients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. ResultsAmong the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. ConclusionContemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.

MP11-12 DEVELOPMENT OF A RISK MODEL FOR TIME TO SECOND PROGRESSION IN PATIENTS WITH HIGH-RISK METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER TREATED WITH ABIRATERONE ACETATE AND ANDROGEN DEPRIVATION THERAPY

You have accessJournal of UrologyCME1 Apr 2023MP11-12 DEVELOPMENT OF A RISK MODEL FOR TIME TO SECOND PROGRESSION IN PATIENTS WITH HIGH-RISK METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER TREATED WITH ABIRATERONE ACETATE AND ANDROGEN DEPRIVATION THERAPY Shintaro Narita, Takafumi Yanagisawa, Shingo Hatakeyama, Kenichi Hata, Hiromi Sato, Ryuichiro Sagehashi, Yuya Sekine, Mizuki Kobayashi, Taketoshi Nara, Kazuyuki Numakura, Mitsuru Saito, Chikara Ohyama, Takahiro Kimura, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Takafumi YanagisawaTakafumi Yanagisawa More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Kenichi HataKenichi Hata More articles by this author , Hiromi SatoHiromi Sato More articles by this author , Ryuichiro SagehashiRyuichiro Sagehashi More articles by this author , Yuya SekineYuya Sekine More articles by this author , Mizuki KobayashiMizuki Kobayashi More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Chikara OhyamaChikara Ohyama More articles by this author , Takahiro KimuraTakahiro Kimura More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Evidence on risk stratification in patients treated with doublet therapy with abiraterone acetate is limited. In this study, we developed a risk stratification model in patients with de novo high-risk mCSPC who received abiraterone acetate plus androgen deprivation therapy based on clinical risk factors. METHODS: Medical records of 224 high-risk patients with de novo mCSPC treated with abiraterone acetate plus androgen deprivation therapy at 11 centers between 2015 and 2022 were retrospectively reviewed. Castration-resistant prostate cancer (CRPC)-free, progression-free survival 2 (PFS2), and overall survival (OS) were estimated using the Kaplan–Meier method. The association of pretreatment clinical risk factors with PFS2 was evaluated by Cox proportional hazard models and survival outcomes were classified according to the number of risk factors. RESULTS: Median PFS2 was 43 months; second-progression occurred in 76 (34.2%) patients. On multivariable analysis, the following four risk factors were identified as independent predictors of PFS2: primary Gleason pattern 5 (HR 1.97, 95% CI 1.20–3.22), presence of liver metastasis (HR 2.05, 95% CI 1.02–4.13), extent of disease score ≥3 (HR 2.25, 95% CI 1.16–4.34), and abnormal hemoglobin (HR 1.73, 95% CI 1.02–2.92). Significant differences in PFS2 were observed among the three risk groups (low vs. intermediate; p=0.006, intermediate vs. high; p<0.001). Median PFS2 and OS of high-risk patients were significantly worse in the low- and intermediate-risk groups. The median PFS2 of low-risk patients with no or one factor was not reached, whereas that of intermediate-risk patients with two or three factors and high-risk patients with four factors were 42 months and 16 months, respectively. Median OS was 24 months in high-risk patients, whereas it was not reached in low- and intermediate-risk patients. CONCLUSIONS: We successfully classified patients with high-risk mCSPC treated with abiraterone acetate based on four clinical risk factors. Risk-adapted treatment may be beneficial for selected patients with mCSPC in this triplet therapy era. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e128 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita More articles by this author Takafumi Yanagisawa More articles by this author Shingo Hatakeyama More articles by this author Kenichi Hata More articles by this author Hiromi Sato More articles by this author Ryuichiro Sagehashi More articles by this author Yuya Sekine More articles by this author Mizuki Kobayashi More articles by this author Taketoshi Nara More articles by this author Kazuyuki Numakura More articles by this author Mitsuru Saito More articles by this author Chikara Ohyama More articles by this author Takahiro Kimura More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...

Patient-level data meta-analysis of a multi-modal artificial intelligence (MMAI) prognostic biomarker in high-risk prostate cancer: Results from six NRG/RTOG phase III randomized trials.

299 Background: Recently, an MMAI prognostic biomarker, ArteraAI Prostate, was trained and validated in localized prostate cancer to more accurately risk stratify patients for multiple endpoints compared to NCCN risk groups (Esteva et al., 2022). Prognostication within an NCCN risk group remains clinically important given the multiple treatment decisions required within each risk group (e.g., radiotherapy dose or hormone therapy use). Herein, we validated the MMAI biomarker in high-risk prostate cancer where an increasing number of therapeutic decisions is required. Methods: This study leveraged histopathology image and clinical data from patients with at least one high-risk feature (HRF; cT3-cT4, Gleason 8-10, PSA &gt; 20 ng/mL, primary Gleason pattern 5) from six NRG/RTOG phase III randomized trials (n=1,088). Patients from two trials not part of the initial MMAI biomarker training/validation (RTOG 0521 [n=344] and 9902 [n=318]) and the MMAI validation cohort (RTOG 9202, 9408, 9413, and 9910 [n=426]) were included. Fine-Gray, cumulative incidence, and time dependent area under the curve (tdAUC) analyses were performed for time to distant metastasis (DM) and prostate cancer-specific mortality (PCSM) for standard clinicopathologic variables (age, PSA, Gleason score, T-stage, number of HRFs) and the MMAI model, as a continuous score (per standard deviation increase) and categorically by quartile. Death from other causes were treated as competing risks. Results: The analyzed cohort had a median follow-up of 10.4 years. Median PSA was 21 ng/mL, 60% had Gleason 8-10 disease, 37% had cT3-T4 disease, and 20% were African American. On univariable analysis, the MMAI model was significantly associated with DM (subdistribution hazard ratio [sHR] 2.05, 95% CI 1.74-2.43, p&lt;0.001) and PCSM (sHR 2.04, 95% CI 1.73-2.42, &lt;0.001). On multivariable analysis, the MMAI model, adjusting for either age, PSA, Gleason score, T-stage, or number of HRFs, was the only variable significantly associated with DM. TdAUC was highest for the MMAI biomarker for both 5-year DM (0.71), compared to PSA (0.56), Gleason score (0.61), T-stage (0.63), or number of HRFs (0.64), and for 5-year PCSM (0.75), compared to clinicopathologic variables (range 0.53-0.63). The estimated 10-year DM and 15-year PCSM rates for MMAI quartile 1 vs 4 were 8% vs 31% and 8% vs 34%, respectively. Conclusions: Our novel MMAI prognostic biomarker was successfully validated across six phase III randomized trials with long-term follow-up to be independently prognostic over standard clinical and pathologic variables for men with high-risk prostate cancer. Despite all patients having high-risk disease, the MMAI biomarker identified those with highly variable risks for DM and PCSM. This tool can help enable personalized, shared decision making for patients and providers.

Modified the 8th AJCC staging system for patients with advanced prostate cancer: a study based on SEER database

BackgroundThe American Joint Committee on Cancer (AJCC) 8th staging system of prostate cancer may be insufficient in predicting the prognosis of some staged patients. This study aimed to modify the AJCC 8th staging system in patients with advanced prostate cancer.MethodsData of patients with advanced prostate cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016 were enrolled in this cohort study. All patients were divided into the training set and the testing set with a ratio of 6:4. Multivariate Cox survival model was utilized to obtain the nomogram score for each stage variable. The modified staging system was based on the total nomogram score. The C-index and Kaplan-Meier (K-M) curves were used to show the prognostic prediction effect of patients with different staging systems.ResultsA total of 28,006 patients were included for analysis. T stage, N stage, M stage, primary Gleason pattern score, secondary Gleason pattern score, and PSA level were included as stage variables. Patients with AJCC stage III C [hazard ratio (HR) = 4.17, 95% confidence interval (CI), 3.39–5.13] and AJCC stage IV B (HR = 3.19, 95%CI, 1.79–5.69) were associated with worse prognosis compared with those of AJCC stage III B, while no statistical significance was found in patients with stage IV A (P > 0.05). In terms of the modified staging system, patients with modified stage III C (HR = 2.06, 95%CI, 1.46–2.92), modified stage IV A (HR = 6.91, 95%CI, 4.81–9.94), and modified stage IV B (HR = 21.89, 95%CI, 14.76–32.46) were associated with a poorer prognosis compared with patients with modified stage III B. The prognostic ability (C-index) of the modified staging system (0.789; 95%CI, 0.777–0.801) was better than that of the AJCC 8th edition system (0.762; 95%CI, 0.748–0.776) (0.789 vs. 0.762, P = 0.004). The K-M curves indicated that the modified staging system may be distinguished prognostic differences in patients with different stages.ConclusionModified staging system may be better than AJCC 8th staging system for predicting prognosis in prostate cancer patients. The AJCC 8th staging system should be further optimized.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis

Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT+BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT+BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. Among the entire cohort, 270 underwent EBRT and 101 EBRT+BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT+BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P=.42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P=.45) between EBRT+BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P=.42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P=.38). In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT+BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Radical prostatectomy for patients with high-risk, very-high risk, or radiographic suspicion for metastatic prostate cancer: Perioperative and early oncologic results from the MUSIC statewide collaborative.

High-risk (HR) prostate cancer (CaP) patients are at greatest risk for occult metastases and disease progression. Radical prostatectomy (RP) provides benefit, but remains of unknown oncologic value compared with other options. We investigated outcomes of RP for HR, very-high-risk (VHR), or metastatic CaP. Included are 1,635 patients undergoing RP between January 2012 and December 2018 (prior to widespread availability of CaP-specific PET imaging). VHR CaP was defined as having ≥2HR features, >4cores of biopsy Gleason ≥4+4, or primary Gleason pattern 5. Metastatic CaP was defined by radiographic evidence of N1 and/or M1 CaP and grouped as cN1Many and cN0M1. Pre-treatment, perioperative, and early oncologic data were compared. Patient/tumor characteristics were compared according to risk groups using Chi-squared and Wilcoxon rank-sum tests. Kaplan-Meier analysis of cancer progression and multivariable analyses were performed. Length of stay >2days and readmission following RP was 10.8% and 5.5% for patients with HR or higher CaP. Median time to progression was 3.9 months (IQR:1.6-13.9), and 2-year progression-free probability was 67% for HR, 53% for VHR, 51% for cN1Many, and 58% for cN0M1. In multivariable analysis, VHR (hazard ratio:1.70; P < 0.0001) and cN1Many (1.96, P < 0.0001) were highly significant predictors of progression, while cN0M1 was not (P = 0.54), compared with non-metastatic HR CaP. Limitations include selection biases and imprecision of imaging methodologies. Most patients with HR or higher CaP remain progression-free 2 years after RP, with acceptable perioperative outcomes. Progression-free survival was similar in cN1 and VHR patients, better with non-metastatic HR CaP, and between these for cN0M1 patients indicating the imprecise clinical staging occurring with conventional imaging modalities alone.

IJU this issue

This issue of International Journal of Urology contains 11 Original Articles, two Urological Notes, two Letters to the Editor, two Author’s reply, and three Editorial Comments. Partial nephrectomy for totally endophytic renal tumor is a surgical challenge and even if under robotic assistance, off-clamp partial nephrectomy is considered a risky procedure. Tuderti et al. (Rome, Italy) reported 56 consecutive patients with totally endophytic renal masses treated with off-clamp robotic partial nephrectomy (RAPN) in their institution. Preoperative super-selective delivery of a lipiodol-indocyanine green mixture into arterial branches feeding the renal mass provides a quick guide to identify tumor location without intraoperative ultrasound. Furthermore, it gives us a straight access to surgical area with minimal opening of Gerota’s capsule. Trifecta achievement was 91% in their patients with low operative complication rates. As Pandolfo et al. (Viriginia, USA) described in the Editorial Comment, the Editor also thinks that this procedure sacrifices visibility due to increased bleeding during the procedure. Moreover, it needs an extra step (preoperative super-selective delivery of a lipiodol-indocyanine green mixture) before surgery, which makes the procedure more complicated. With the technical advancement and accumulation of experience, the debate “on-clamp versus off-clamp” RAPN for completely endophytic renal masses will be settled in the near future. Gleason pattern 5 has been considered an independent unfavorable prognostic factor in localized and advanced prostate cancer. Morozumi et al. (Miyagi, Japan) retrospectively conducted multicenter analysis of outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) with a Gleason score (GS) ≥8. They revealed that in high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival (OS), while both Gleason pattern 5 and primary Gleason pattern 5 were not significant predictive factors after multivariate analysis. On the contrary, in the low-volume (LV) metastatic groups, only Gleason pattern 5 was an independent unfavorable predictive factor for OS after the analysis. Although there are several limitations, such as a lack of central pathology, they concluded that only in LV mHSPC patients with GS ≥8, primary Gleason pattern 5 should be considered as an unfavorable factor for the treatment strategy. As a homeostatic system, bladder storage function keeps the micturition interval constant by increasing bladder capacity during the diuretic phase, which is known as vesical adaptation response to diuresis (VARD). Matsuoka et al. (Fukushima, Japan) analyzed 94 male patients older than 65 years with lower urinary tract symptoms (LUTS). They found that 48 patients (51%) had VARD but in 46 patients (49%), VARD was lacking. Interestingly, absence of VARD was significantly associated with overactive bladder and benign prostate enlargement after adjusting for confounders. Although there are several limitations in their study, understanding of the pathophysiology underlying VARD might contribute a novel strategy for the treatment of bladder storage dysfunction in patients with LUTS. Immune checkpoint inhibitors (ICIs) therapy has become a key therapy against advanced urothelial carcinoma (UC), but there are no definitive data available for the association of the oncological outcome to first-line chemotherapy to subsequent ICIs therapy. Ozaki et al. (Hirosaki, Japan) reported their retrospective analysis of 218 patients with advanced UC who received systematic, platinum-based first-line chemotherapy. Focusing upon OS between patients treated with or without second-line ICIs therapy who had no progressive disease (PD) within four or few cycles of first-line chemotherapy (the non-PD ≤4 group), there was significant difference in the median survival (63 vs 26 months). On the contrary, in patients who had PD within four or few cycles of first-line chemotherapy (the PD ≤4 group), there was no significant difference in OS whether they were treated with ICI or not. These results suggest that the favorable response to the first-line chemotherapy was significantly associated with longer survival in patients with subsequent ICIs therapy than those without. Although we do not know the precise mechanisms of the results of the article, Miyake (Nara, Japan) commented in this issue that platinum derivatives could induce immunogenic cell death, which might enhance the antitumor activity of dendritic cells and T cells, which results in modulation of the expression of immune checkpoint molecules. Moreover, we still do not have the answer to how many first-line chemotherapy cycles will be appropriate before ICIs therapy. Consideration of introduction of antibody-drug conjugate, enfortumab vedotin for advanced UC treatment, we should accumulate more data about appropriate timing of changing armaments against this difficult disease. Unfortunately, the limited space restricts me to introduce the other excellent articles in this issue. I hope that the articles in this issue will help you in daily clinical practice. None declared.

Looking for a Simplified Diagnostic Model to Identify Potentially Lethal Cases of Prostate Cancer at Initial Diagnosis: An ImGO Pilot Study.

Simple SummarySeveral genetic anomalies are recurrent in prostate cancer (PC) and allow this disease to be classified into distinct molecular subtypes; however, these anomalies have no predictive role and have limited relevance for clinical practice. Within this pilot study, metastatic castration-resistant PC (mCRPC) and metastatic castration-sensitive PC (mCSPC) were used for identifying and understanding lethal prostate tumor clones, from a genomic point of view. Some elements, such as a high Gleason Score and the presence of a cribriform pattern or intraductal carcinoma were evaluated as phenotypic markers of potentially lethal PC. Our results provide hypothesis-generating data, as the idea of evaluating mCSPC and mCRPC as a phenotypic/biologic model able to be translated in clinical practice. The confirmation of a high incidence of TP53 and BRCA2 mutations in larger trials may find a therapeutic implication through the choice of whether or not to use “more” therapy in respect to “selective” treatments approaches.The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as “phenotypic” markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a BRCA2 mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of TP53 and BRCA2 mutations in de novo mCSPC may also have a therapeutic implication.

Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer

Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.

Clinical strategy of repeat biopsy in patients with atypical small acinar proliferation (ASAP)

Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30–40% of patients with ASAP have biopsy detectable prostate cancer (PCa) within 5 years. Current guidelines recommend a repeat biopsy within 3–6 months after the initial diagnosis. The aim of the present study was to examine the association between ASAP and subsequent diagnosis of clinically significant PCa (csPCa). The need for immediate repeat biopsy was also evaluated. We identified 212 patients with an ASAP diagnosis on their first biopsy at our institution between February 2006 and March 2018. Of these patients, 102 (48.1%) had at least one follow-up biopsy. Clinicopathologic features including rates of subsequent PCa and csPCa were assessed. Thirty-five patients subsequently underwent radical prostatectomy (RP). Their pathologic results were reviewed. csPCa was defined as the presence of Gleason score (GS) ≥ 3 + 4 in ≥ 1 biopsy core. Adverse pathology (AP) was defined as high-grade (primary Gleason pattern ≥ 4) or non-organ-confined disease (pT3/N1) after RP. Of 102 patients, 87 (85.3%), 13 (12.7%), and 2 (2.0%) had one, two, and three follow-up biopsies, respectively. Median time from the initial ASAP diagnosis to the 2nd follow-up biopsy and the last follow-up biopsy were 21.9 months (range 1–129 months) and 27.7 months (range 1–129 months), respectively. Of these patients, 46 (45.1%) were subsequently diagnosed with PCa, including 20 (19.6%) with csPCa. Only 2 (2.0%) patients had GS ≥ 8 disease. Five (4.9%) patients had number of positive cores > 3. Of 35 patients who subsequently underwent RP, seven (20%) had AP after RP and 17 (48.6%) showed GS upgrading. Of these 17 patients, the vast majority (16/17, 94.1%) had GS upgrading from 3 + 3 to 3 + 4. 45.1% of patients with an initial diagnosis of ASAP who had repeat prostate biopsy were subsequently diagnosed with PCa and 19.6% were found to have csPCa. Our findings add further evidence that after a diagnosis of ASAP, a repeat biopsy is warranted and that the repeat biopsy should not be postponed.

Risk of adverse pathological features for intermediate risk prostate cancer: Clinical implications for definitive radiation therapy.

Intermediate risk prostate cancer represents a largely heterogeneous group with diverse disease extent. We sought to establish rates of adverse pathological features important for radiation planning by analyzing surgical specimens from men with intermediate risk prostate cancer who underwent immediate radical prostatectomy, and to define clinical pathologic features that may predict adverse outcomes. A total of 1552 men diagnosed with intermediate risk prostate cancer who underwent immediate radical prostatectomy between 1/1/2005 and 12/31/2015 were reviewed. Inclusion criteria included available preoperative PSA level, pathology reports of transrectal ultrasound-guided prostate biopsy, and radical prostatectomy. Incidences of various pathological adverse features were evaluated. Patient characteristics and clinical disease features were analyzed for their predictive values. Fifty percent of men with high risk features (defined as PSA >10 but <20 or biopsy primary Gleason pattern of 4) had pathological upstage to T3 or higher disease. The incidence of upgrade to Gleason score of 8 or higher and the incidence of lymph node positive disease was low. Biopsy primary Gleason pattern of 4, and PSA greater than 10 but less than 20, affected adverse pathology in addition to age and percent positive biopsy cores. Older age and increased percentage of positive cores were significant risk factors of adverse pathology. Our findings underscore the importance of comprehensive staging beyond PSA level, prostate biopsy, and CT/bone scan for men with intermediate risk prostate cancer proceeding with radiation in the era of highly conformal treatment.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features

The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.