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PURPOSE: The purpose of this study was to assess prostate-specific antigen (PSA) testing rates in persons experiencing homelessness (PEH), identify factors associated with screening, and compare PSA screening rates in PEH with a matched cohort of persons not experiencing homelessness (non-PEH). MATERIALS AND METHODS: We identified 9,249 potentially eligible PEH cared for at a large metropolitan hospital system from an institutional registry of all patients who presented to the health care system as homeless from 2014 to 2021. Homelessness was defined by the presence of the Z-code for homelessness (Z59), the listed address matching to the address of a homeless shelter or other transitional housing or a positive screen for homelessness. A matched cohort of 10,000 non-PEH was generated for comparison. Univariate chi-square analysis and multivariate logistic regression were performed to evaluate variables associated with PSA testing. RESULTS: A total of 1,605 PEH and 3,413 non-PEH were eligible for PSA screening within the study timeframe. Half of PEH were Black (50%). Medicaid was the most common insurance (51%), followed by Medicare (18%). PEH were less likely to have a PCP (58% v 81%, P < .001) and had a significantly lower PSA testing rate (13% v 34%, P < .001) compared with non-PEH. Univariate analysis revealed that PSA testing was more common in PEH who were employed ( P < .001), had private insurance or Medicare ( P < .001), or had an established primary care provider (PCP; P < .001). Multivariate analysis confirmed that having a PCP (OR, 2.54; 95% CI, 1.62 to 4.00; P < .001) significantly increased the likelihood of PSA testing in PEH. CONCLUSION: PEH experience low rates of prostate cancer screening. Interventions to increase screening in this population, including increased PCP access, are needed.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

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Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island–associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers. Mol Cancer Res; 9(8); 1152–62. ©2011 AACR.

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Purpose:Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.Experimental Design:Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC).Results:Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.Conclusions:Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

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Figure S1, Supplementary Table, Figure S2, Figure S3, Figure S4, Figure S5

Purpose:Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth.Experimental Design:Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes.Results:In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors.Conclusions:A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

Objective: Pelvic lymph node metastasis (PLNM) at the time of radical prostatectomy (RP) portends an unfavorable prognosis in prostate cancer patients. Conventional and advanced imaging remains limited in its ability to detect PLNM. We sought to evaluate the combination of a genomic classifier Decipher with Prostate Imaging Reporting and Data System (PI-RADS) scores in improving the detection of PLNM. Methods: A retrospective review was performed of patients whom underwent RP, Decipher analysis, and pre-operative prostate MRI. Categorical variables were compared using Pearson chi-squareχ2 tests. Quantitative variables were assessed with Wilcoxon rank-sum tests. Multivariable logistic regression was used to identify predictors of PLNM on final pathology. Results: In total, 202 patients were included in the analysis, 23 of whom (11%) had PLNM. Patients with PLNM had higher median Decipher scores (0.73) than those without PLNM (0.61; p = 0.003). Patients with PLNM were more likely to demonstrate PI-RADS scores ≥ 4 (96%) than those without PLNM (74%; p = 0.012). Logistic regression demonstrated an interaction between Decipher score with PI-RADS score ≥4 (OR = 20.41; 95% CI, 2.10–198.74; p = 0.009) The combination demonstrated an area under the curve (AUC) of 0.73 (95% CI, 0.63–0.82; p < 0.001) for predicting PLNM. Conclusion: The combination of elevated Decipher genomic score (≥ 0.6) and clinically significant PI-RADS score (≥ 4) is associated with PLNM at the time of RP in a modern high-risk cohort of patients with PCaprostate cancer. Advances in knowledge: Prostate MRI and genomic testing may help identify patients with adverse pathology.

PURPOSE/OBJECTIVE(S) To determine if patients with unfavorable intermediate-risk (UIR), high-risk (HR), or very high-risk (VHR) prostate cancer (PCa) treated with 125I interstitial brachytherapy benefit from androgen deprivation therapy (ADT). MATERIALS/METHODS We reviewed our institutional database of patients with UIR, HR, or VHR PCa, per 2018 NCCN risk classification, treated with definitive 125I interstitial brachytherapy with or without ADT from 1998-2017. Outcomes including biochemical failure (bF), distant metastases (DM), and overall survival (OS) were analyzed with the Kaplan-Meier method and Cox proportional hazards regression. PCa-specific mortality (PCSM) was analyzed with Fine-Gray competing-risk regression. RESULTS Of 1033 patients, 262 (25%) received ADT and 771 (75%) did not. Median ADT duration was 6 months. By risk group, 764 (74%) patients were UIR, 219 (21%) HR, and 50 (5%) VHR. ADT was more frequently given to HR (50%) and VHR (56%) patients compared to UIR (16%; p

TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in TET2-mutant neoplasia. Significance: Loss-of-function somatic TET2 mutations are among the most frequent lesions in myeloid neoplasms and associated disorders. Here we report a strategy for selective targeting of residual TET dioxygenase activity in TET-deficient clones that results in restriction of clonal evolution in vitro and in vivo. See related video: https://aacrjournals.org/webinar-minimal-tet-activity-targetable-vulnerability-tet2-and-neomorphic-idh12-mutant

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance., Acquired resistance to cancer therapies reflects the ability of cancers to adapt to therapy-imposed selective pressures. Here, the authors elucidate the dynamics of developing resistance to ALK inhibitors in an ALK+ lung cancer cell line showing that resistance originates from drug-specific tolerant cancer cells and it develops as a gradual adaptation.

Cribriform (CF) and/or intraductal carcinoma (IDC) are associated with more aggressive prostate cancer (CaP) and worse outcomes.The transcriptomic features that typify CF/IDC are not well described and the capacity for clinically utilized genomic classifiers to improve risk modeling for CF/IDC remains undefined.We performed a retrospective review of CaP patients who had Decipher testing at a single high-volume institution. Index lesions from radical prostatectomy specimens were identified by genitourinary pathologists who simultaneously reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were grouped based on pathologic features, specifically the absence of CF/IDC (CF-/IDC-), CF positive only (CF+/IDC-), and CF/IDC positive (CF+/IDC+).Clinical, pathologic, and genomic categorical variables were assessed using the Pearson chi-square test, while quantitative variables were assessed with the Kruskal-Wallis test. Multivariable logistic regression was used to identify the predictors of high-risk Decipher scores (0.60). A gene set enrichment analysis was performed to identify genes and gene networks associated with CF/IDC status.A total of 463 patients were included. Patients who were CF+/IDC+ had the highest Decipher risk scores (CF+/IDC+: 0.79 vs CF+/IDC-: 0.71 vs CF-/IDC-: 0.56, p 0.001). On multivariate logistic regression, predictors of high-risk Decipher scores included the presence of CF, both alone (CF+/IDC-; odds ratio [OR]: 5.45, p 0.001) or in combination with positive IDC status (CF+/IDC+; OR: 6.87, p 0.001). On the gene set enrichment analysis, MYC pathway upregulation was significantly enriched in tumor samples from CF/IDC-positive patients (normalized enrichment score [NES]: 1.65, p = 0.046). Other enriched pathways included E2F targets (NES: 1.69, p = 0.031) and oxidative phosphorylation (NES: 1.68, =0 .033).This is the largest series identifying an association between a clinically validated genomic classifier and the presence of CF and IDC at radical prostatectomy. Tumors with CF and intraductal features were associated with aggressive transcriptomic signatures.Genomic-based tests are becoming readily available for the management of prostate cancer. We observed that Decipher, a commonly used genomic test in prostate cancer, correlates with unfavorable features in tissue specimens.

Purpose Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with non-metastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC. Materials and methods Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex, and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan Meier (KM) curves. Cox proportional hazards (PH) models were used to evaluate the primary and secondary study endpoints of overall survival (OS) and cancer-specific survival (CSS), respectively. Results A total of 601 patients with MIBC were included, where 247 had been treated with NAC and RC and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and CSS at three years was 7% and 5%, respectively. After controlling for clinicopathologic variables, non-luminal tumors had greatest benefit from NAC with 10% greater OS at 3 years (71% vs 61%) while luminal tumors had minimal benefit (63% vs 65%) for NAC vs. non-NAC, respectively. Conclusions In patients with MIBC, a commercially available molecular subtyping assay revealed non-luminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.

Objective To explore relationships between dose to periprostatic anatomic structures and erectile dysfunction (ED) outcomes in an institutional cohort treated with prostate brachytherapy. Methods The Sexual Health Inventory for Men (SHIM) instrument was administered for stage cT1-T2 prostate cancer patients treated with Pd-103 brachytherapy over a 10-year interval. Dose volume histograms for regional organs at risk and periprostatic regions were calculated with and without expansions to account for contouring uncertainty. Regression tree analysis clustered patients into ED risk groups. Results We identified 115 men treated with definitive prostate brachytherapy who had 2 years of complete follow-up. On univariate analysis, the subapical region (SAR) caudal to prostate was the only defined region with dose volume histograms parameters significant for potency outcomes. Regression tree analysis separated patients into low ED risk (mean 2-year SHIM 20.03), medium ED risk (15.02), and high ED risk (5.54) groups. Among patients with good baseline function (SHIM ≥ 17), a dose ≥72.75 Gy to 20% of the SAR with 1 cm expansion was most predictive for 2-year potency outcome. On multivariate analysis, regression tree risk group remained significant for predicting potency outcomes even after adjustment for baseline SHIM and age. Conclusion Dose to the SAR immediately caudal to prostate was predictive for potency outcomes in patients with good baseline function. Minimization of dose to this region may improve potency outcomes following prostate brachytherapy.

We assessed the impact of cribriform pattern and/or intraductal carcinoma on Gleason 7 prostate cancer treated with external beam radiotherapy.We evaluated men with Gleason 7 (Grade Groups 2 and 3) prostate cancer treated with dose escalated external beam radiotherapy with or without androgen deprivation. We reviewed biopsies for the presence of cribriform pattern and/or intraductal carcinoma. Study end points included biochemical recurrence-free, distant metastasis-free and disease specific survival.In the 237 patients median followup was 117 months (range 3 to 236). According to National Comprehensive Cancer Network® risk groups 24% of patients were at favorable intermediate risk, 53% were at unfavorable intermediate risk and 23% were at high risk. The rate of cribriform pattern without intraductal carcinoma, cribriform pattern with intraductal carcinoma, intraductal carcinoma without cribriform pattern and none of these morphologies was 36%, 13%, 0% and 51%, respectively. On multivariable analysis cribriform pattern with intraductal carcinoma (HR 4.22, 95% CI 2.08-8.53, p0.0001), prostate specific antigen 10 to 20 ng/ml (HR 1.97, 95% CI 1.03-3.79, p=0.04) and prostate specific antigen greater than 20 ng/ml (HR 2.26, 95% CI 1.21-4.23, p=0.01) were associated with worse biochemical recurrence-free survival. On multivariable analysis only cribriform pattern with intraductal carcinoma was associated with inferior distant metastasis-free survival (HR 4.18, 95% CI 1.43-12.28, p=0.01) and disease specific survival (HR 14.26, 95% CI 2.75-74.04, p=0.0016). Factors associated with cribriform pattern with or without intraductal carcinoma included Grade Group 3, high risk group and 50% or more positive biopsy cores. When stratified by neither morphology present, cribriform pattern without intraductal carcinoma and cribriform pattern with intraductal carcinoma the differences in biochemical recurrence-free, distant metastasis-free and disease specific survival were statistically significant (p=0.00042, p=0.017 and p0.0001, respectively).Cribriform pattern with intraductal carcinoma was associated with adverse outcomes in men with Gleason 7 prostate cancer treated with external beam radiotherapy while cribriform pattern without intraductal carcinoma was not so associated. Future studies may benefit from dichotomizing these 2 histological entities.

Long-term outcomes with hypofractionated radiation therapy for prostate cancer are limited. We report 10-year outcomes for patients treated with intensity modulated radiation therapy (IMRT) for localized prostate cancer with 70 Gy in 28 fractions at 2.5 Gy per fraction.The study included 854 consecutive patients with localized prostate cancer treated with moderately hypofractionated IMRT and daily image guidance at a single institution between 1998 and 2012. Patients with a single intermediate risk factor were considered to have favorable intermediate-risk (FIR) disease, and those with multiple intermediate risk factors were considered unfavorable (UIR). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival were analyzed using Kaplan-Meier analysis. Prostate cancer-specific mortality (PCSM) was analyzed using competing risk regression. All grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 4.03, and cumulative incidence rates of GU and GI toxicity were calculated.The median follow-up was 11.3 years (maximum, 19 years). For patients with low-risk (LR), FIR, UIR, and high-risk (HR) disease, the 10-year biochemical relapse free survival rates were 88%, 78%, 71%, and 42%, respectively, (P .0001). The 10-year clinical relapse free survival were 95%, 91%, 85%, and 72% for patients with LR, FIR, UIR, and HR, respectively, (P .0001). For all patients, the 10-year actuarial overall survival rate was 69% (95% confidence interval, 66%-73%), and the 10-year PCSM was 6.8% (95% confidence interval, 5.1%-8.6%) overall. For patients with LR, FIR, UIR and HR disease, the 10-year PCSM rates were 2%, 5%, 5%, and 15%. Long-term grade ≥3 GU or GI toxicity remained low with 10-year cumulative incidences of 2% and 1%, respectively.High-dose moderately hypofractionated IMRT with daily image guidance for localized prostate cancer demonstrates favorable 10-year oncologic outcomes with a low incidence of toxicity. This fractionation schedule appears to be acceptable for patients across all risk groups.

We sought to evaluate the correlation between MRI phenotypes of prostate cancer as defined by PI-RADS v2 and the Decipher Genomic Classifier (used to estimate the risk of early metastases). This single-center, retrospective study included 72 nonconsecutive men with prostate cancer who underwent MRI before radical prostatectomy performed between April 2014 and August 2017 and whose MRI registered lesions were microdissected from radical prostatectomy specimens and then profiled using Decipher (89 lesions; 23 MRI invisible [PI-RADS v2 scores ≤ 2] and 66 MRI visible [PI-RADS v2 scores ≥ 3]). Linear regression analysis was used to assess clinicopathologic and MRI predictors of Decipher results; correlation coefficients (r) were used to quantify these associations. AUC was used to determine whether PI-RADS v2 could accurately distinguish between low-risk (Decipher score

4593 Background: Upper tract urothelial carcinoma (UTUC) is a rare and heterogeneous disease accounting for approximately 5-10% of UC. While tumor grade and stage are known prognostic factors, data on other factors affecting outcomes in UTUC patients (pts) undergoing surgery is scant. We studied effect of various clinical factors and treatment on outcomes in UTUC. Methods: This is a single-institution retrospective study of 607 pts with UTUC undergoing surgery (nephroureterectomy (NU) or ureterectomy (U)) between Jan 2000 and Dec 2020. We studied effect of demographics, clinicopathological features, tumor location, preoperative Neutrophil-to-Lymphocyte ratio (NLR) and Albumin-to-Globulin ratio (AGR) and use of neoadjuvant or adjuvant chemotherapy on overall survival (OS) and recurrence free survival (RFS). Results: Of the 607 pts 401 (66.06%) were males and 355 (58.48%) were > 70 yrs; 232 pts (38.22%) had UTUC of renal pelvis, 242 (39.87%) of ureter and 133 (21.91%) of both. 542 pts (89.29%) underwent radical NU and 65 (10.71%) segmental U; 328 patients (54.04%) were diagnosed with muscle invasive UC (MIUC) ( > / = pT2) and 276 (45.47%) with non-MIUC ( < / = pT2). Only 51 (8.4%) pts had lymph node positive (N+) disease. Lymphovascular invasion (LVI) was identified in 163 (26.85%) and carcinoma- in-situ (CIS) in 163 (26.85%) pts. Surgical margins were positive in 92 pts (15.16%). Median NLR cutoff was 3.25 and AGR cutoff was 1.25 (dichotomized based on literature). 44 pts (7.2%) received Neoadjuvant chemotherapy and 49 pts (8%) received adjuvant chemotherapy. Tumor recurrence occurred in 216 pts (35.58%) of which 65% were at urothelial and 35% at non-urothelial sites. With median follow up of 35.2 mos, median OS was 82.69 mos and 5-yr OS rate was 60%; median RFS was 29.47 mos and 5-yr RFS rate was 40%. High grade, age > / = 70 yrs, high NLR, low AGR, presence of LVI, positive margins, CIS, MIUC, N+ disease were associated with worse outcomes. Pts with only renal pelvis involvement had better OS. Conclusions: In this large, long term follow-up series of UTUC pts, we identified several prognostic factors besides grade and stage that impact outcomes. These findings warrant further validation for use in clinical practice. [Table: see text]

Purpose/Objective(s) To determine if hypofractionated post-operative prostate bed radiotherapy (HYPORT) does not increase patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity over conventionally fractionated post-operative radiotherapy (COPORT). Materials/Methods Eligibility criteria were: 1) an undetectable PSA ( Results Between July 2017 and July 2018, 298 patients were screened and 296 were randomized: 144 to HYPORT and 152 to COPORT. Compliance with the EPIC was 100% at baseline, 83% at the end of RT, 77% at 6 months, 78% at 12 months, and 73% at 24 months. At the end of RT, the HYPORT and COPORT mean GU change scores were neither clinically significant nor significantly different and remained so at 6 and 12 months. The mean GI change scores for HYPORT and COPORT were both clinically significant and significantly different at the end of RT (HYPORT mean GI = -15.0 vs COPORT mean GI = -6.8 P ≤ 0.01). However, both the HYPORT and COPORT mean GI change scores clinically and statistically significant differences were resolved at 6 and 12 months. The 24-month mean GU and GI change scores for HYPORT and COPORT remained neither clinically nor statistically significant (HYPORT mean GU = -5.2 vs COPORT mean GU = -3.0, P = 0.81; HYPORT mean GI = -2.2 vs COPORT mean GI = -1.5, P = 0.12). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT versus COPORT for biochemical failure defined as a PSA ≥ 0.4 ng/mL followed by a value higher than the first by any amount (2-yr actuarial, 12% vs 8%, P = 0.29) or local failure (2-yr actuarial, 0.7% vs 0.8%, P = 0.35). Conclusion HYPORT is non-inferior to COPORT in terms of late patient-reported GU or GI toxicity. More follow-up is needed to appropriately assess disease control endpoints. In some clinic scenarios, HYPORT may be considered an acceptable practice standard.

Endocrine-driven malignancies, including breast and prostate cancer, are among the most common human cancers. The relationship between sex steroid hormones (eg, androgen, estrogen, and progesterone), their cognate receptors, and genomic stability lie at the center of endocrine-driven cancer development, progression, and therapeutic resistance. A variety of direct and indirect mechanisms have been described that link steroid hormone signaling to the loss of genomic integrity that drives early carcinogenesis. These effects are often enriched within endocrine receptor cistromes, accounting for the high proportion of mutations and rearrangements in the region of hormone response elements. In other cases, the effects are generalized and rely on a complex array of genetic, epigenetic, and metabolic interactions. Both androgen and estrogen receptors directly modulate the DNA damage response by trans-activating DNA damage response genes and redirecting the cellular repair machinery in the wake of genotoxic stress. Here we review the key mechanistic underpinnings of the relationship between sex steroid hormone receptors and genomic stability. In addition, we summarize emerging research in this area and discuss important implications for cancer prevention and treatment.

Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70–80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

Purpose Research in radiation oncology (RO) is imperative to support the discovery of new uses of radiation and improvement of current approaches to radiation delivery and to foster the continued evolution of our field. Therefore, in 2016, the American Society of Radiation Oncology performed an evaluation of research grant funding for RO. Methods and Materials Members of the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) were asked about funded and unfunded grants that were submitted by their departments between the fiscal years 2014 and 2016. Grants were grouped according to broad categories defined by the 2017 American Society of Radiation Oncology Research Agenda. Additionally, active grants in the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools database were collated using RO faculty names. Results Overall, there were 816 funded (44%) and 1031 unfunded (56%) SCAROP-reported grants. Total grant funding was over $196 million. The US government funded the plurality (42.2%; 345 of 816) of grants compared with nonprofit and industry funders. Investigators from 10 institutions accounted for >75% of funded grants. Of the funded grants, 43.5% were categorized as “genomic influences and targeted therapies.” The proportion of funded to unfunded grants was highest within the category of “tumor microenvironment, normal tissue effects, and reducing toxicity” (53.4% funded). “New clinical trial design and big data” had the smallest share of SCAROP grant applications and the lowest percent funded (38.3% of grants). NIH grants to RO researchers in 2014 to 2016 accounted for $85 million in funding. From the 31 responding SCAROP institutions, there was a 28% average success rate for RO proposals submitted to the NIH during this period. Conclusions Though RO researchers from responding institutions were relatively successful in obtaining funding, the overall amount awarded remains small. Continued advocacy on behalf of RO is needed, as well as investment to make research careers more attractive areas for emerging faculty.

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets. Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody–drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most “normal-like” pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most “metastasis-like” pattern had the shortest OS (P = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (P = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

Purpose For patients with localized pancreatic cancer (PC) with vascular involvement, prediction of resectability is critical to define optimal treatment. However, the current definitions of borderline resectable (BR) and locally advanced (LA) disease leave considerable heterogeneity in outcomes within these classifications. Moreover, factors beyond vascular involvement likely affect the ability to undergo resection. Herein, we share our experience developing a model that incorporates detailed radiologic, patient, and treatment factors to predict surgical resectability in patients with BR and LA PC who undergo stereotactic body radiation therapy (SBRT). Methods and materials Patients with BR or LA PC who were treated with SBRT between 2010 and 2016 were included. The primary endpoint was margin negative resection, and predictors included age, sex, race, treatment year, performance status, initial staging, tumor volume and location, baseline and pre-SBRT carbohydrate antigen 19-9 levels, chemotherapy regimen and duration, and radiation dose. In addition, we characterized the relationship between tumors and key arteries (superior mesenteric, celiac, and common hepatic arteries), using overlap volume histograms derived from computed tomography data. A classification and regression tree was built, and leave-one-out cross-validation was performed. Prediction of surgical resection was compared between our model and staging in accordance with the National Comprehensive Care Network guidelines using McNemar’s test. Results A total of 191 patients were identified (128 patients with LA and 63 with BR), of which 87 patients (46%) underwent margin negative resection. The median total dose was 33 Gy. Predictors included the chemotherapy regimen, amount of arterial involvement, and age. Importantly, radiation dose that covers 95% of gross tumor volume (GTV D95), was a key predictor of resectability in certain subpopulations, and the model showed improved accuracy in the prediction of margin negative resection compared with National Comprehensive Care Network guideline staging (75% vs 63%; P Conclusions We demonstrate the ability to improve prediction of surgical resectabiliy beyond the current staging guidelines, which highlights the value of assessing vascular involvement in a continuous manner. In addition, we show an association between radiation dose and resectability, which suggests the potential importance of radiation to allow for resection in certain populations. External data are needed for validation and to increase the robustness of the model.

Introduction Prostate hypertrophy, median lobe hypertrophy, and pubic arch interference (PAI) are relative contraindications to brachytherapy because of potential morbidity and technical considerations. GnRH analogs or non-steroidal anti-androgens are currently utilized to achieve prostatic downsizing prior to brachytherapy. However, such agents have been associated with effects on body habitus, metabolism, and quality of life. In contrast, 5-alpha reductase inhibitors (5-ARI) are far less frequently associated with these morbidities. Methods and materials Patients with large gland size, median lobe hypertrophy, or PAI were offered 5-ARI therapy. Repeat transrectal ultrasound was performed at 3 or 4 months, followed by brachytherapy if resolution was achieved. If downsizing was inadequate, patients were offered continuation of 5-ARI for additional 3 months, gonadotropin-releasing hormone analog (GnRH) agonist or antiandrogen therapy, or other curative treatment. Results Of 59 patients with follow-up available, 42 (71%) were deemed to have adequate downsizing; 37 (63%) after 3 to 4 months of 5-ARI and 5 (8%) after 7 to 8 months. Seventeen patients (29%) received other treatments because of inadequate effect. Median volume reduction was 20%. Of 41 patients undergoing brachytherapy, 4 (9.7%) required temporary catheterization because of obstruction. Median follow-up after implantation was 25 months (range, 1-64). Median time for return to International Prostate Symptom Score ≤5 of baseline score was 7 months (interquartile ratio, 6-13). All but 1 patient who received brachytherapy remain biochemically controlled. Conclusion 5-ARI monotherapy is an alternative for downsizing in patients with hypertrophy or PAI, with more than 70% achieving adequate downsizing without use of GnRH analogs or antiandrogens. Patients who received brachytherapy experienced typical rates of postimplant urinary morbidity.

Purpose Interest in prostate dose reduction or focal treatment exists due to expected reductions in treatment morbidity. Prior analyses have not generally corroborated relationships between prostate or urethral dose and urinary toxicity after brachytherapy, but such analyses have been performed on cohorts all receiving the same prescribed dose. We analyzed patients treated to differing prescription doses to assess acute urinary morbidity with dose reduction. Methods and Materials Patients treated with Pd-103 to either 125 Gy or 90–100 Gy were compared using the International Prostate Symptom Score (IPSS) at 1-month postimplant. Patients in the 90–100 Gy cohort began external beam radiation therapy after their 1-month assessment; thus, toxicities were measured before contribution from external beam radiation therapy. Patient/treatment characteristics were compared to verify subgroup homogeneity. Dose and change in IPSS 1 month after treatment were assessed using a multivariate linear regression model. Results One hundred ninety-one and 41 patients were treated with 125 Gy versus 90–100 Gy, respectively. Preimplant and postimplant prostate volumes and initial IPSS were similar between groups. Higher prescription dose and increased pretreatment IPSS were independent predictors of increased 1-month IPSS. In addition, every 10 percentage point additional prostate volume receiving a given dose was associated with increase in IPSS after treatment for the same level of pretreatment IPSS. Conclusion Lower prescription dose and decreased volume of high-dose regions to the prostate correlated with reduced acute urinary morbidity after brachytherapy. Our findings suggest that focal treatment approaches with modest dose reductions to subregions of the prostate may reduce acute morbidity and potentially expand the number of patients eligible for brachytherapy.

268 Background: Invasive cribriform and intraductal carcinoma (CF/IDC) portends an unfavorable prognosis for patients diagnosed with prostate cancer (CaP). Limited studies with small sample sizes have explored whether genomic classifiers are associated with IDC and/or CF status. We investigated the correlation between Decipher genomic risk score and IDC/CF status and assessed PCa transcriptomic features. Methods: We performed a retrospective review of CaP patients who had Decipher testing at a single high volume center between 2009-2020. The highest grade index lesion from radical prostatectomy specimens was identified by GU pathologists and used for Decipher testing. Genitourinary pathologists reviewed prostatectomy specimens for the presence of CF and IDC features. Patients were divided into three groups based on pathologic features, absent CF/IDC (CF-/IDC-), CF positive only (CF+/IDC-), and CF/IDC positive (CF+/IDC+). Categorical clinical, genomic, and pathologic variables were assessed using the Pearson Chi-Square test, quantitative with the Kruskal-Wallis test. Multivariable logistic regression was used to identify predictors of high-risk Decipher GC scores. The Kaplan-Meier method with log-rank was used to compare biochemical recurrence free survival. Differential gene expression and gene network analysis was used to identify genes and pathways associated with IDC/CF features. Results: 463 patients were included with a median follow-up of 25 months. Patients who were CF+/IDC+ had higher GC scores (CF+/IDC+: 0.77 vs. CF+/IDC-: 0.71 vs. CF-/IDC-: 0.61, p3 (CF+/IDC+: 79% vs. CF+/IDC-: 52% vs. CF-/IDC-: 52%, p3 (OR: 1.58, p=0.04). Transcriptomic analysis revealed that the hallmark androgen response pathway was significantly upregulated in CF+/IDC+ patients (Log fold change: 15.7, p

Background: TET-dioxygenases (TET1, TET2, and TET3) are key epigenetic regulators, which require molecular oxygen, αKG, and Fe 2+ to progressively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to the demethylation of mCpGs at promoter and enhancer, a key step for mounting an efficient transcription profile and thereby differentiation. Loss of function TET2 mutation (TET2 MT) is frequently observed in myeloid neoplasms (MN). Despite extensive studies of the biochemical mechanisms underlying distorted myeloid differentiation and neoplastic evolution of TET2 MT HSPCs, targeted therapies are lagging. Here, we report the therapeutic utility of preferential targeting of TET2 mutant and TET-dioxygenase deficient cells either by restoring the lost activity to induce differentiation and death or by inhibiting the residual activity to induce synthetic lethality. Methods: Genetic as well as pharmacologic in vitro and in vivo models of AML were used to validate specific targeting of TET2 mutant cells. Knockout and over-expression in the isogenic background of different cells were used to understand the pro-survival and proliferative mechanism of TET2 loss in myeloid cells. The efficacy of small molecule pharmacophore targeting TET-dioxygenase was evaluated in vitro in cell free and cell culture as well as in vivo in a mouse competitive transplant model to demonstrate the proof of therapeutic concept. Result: Ascorbate, used as an activator of αKG/Fe 2+ dependent dioxygenase including TETs, functions via maintaining the redox state of iron (II) in the dioxygenase catalytic site with a half-maximal effective concentration of 13.8 ± 1.3 µM for enhancing TET2activity as measured by an ELISA for 5hmC. However, the reported intracellular cellular concentrations of ascorbate in human remains in the millimolar range, well above the saturating concentration required for TET-dioxygenases activation. Interestingly, ascorbate failed to activate TET in primary mononuclear cells isolated from myeloid neoplasia patients with TET2 mutations. Consistent with the in-vitro observation, we found that ascorbate treatment in physiologically relevant doses has no significant effect in syngeneic murine models (p=0.1). TET-inactivation is a complex phenomenon that is controlled by context-dependent post-translational modifications including lysine acetylation by acetyltransferases and class I and II deacetylases. Therefore, the anti-leukemic effect of the supraphysiological doses of ascorbate in humans and mice leukemia models may not be dependent on TET activation by ascorbate. On the other hand, a comprehensive analysis of the configurations of TET2 MT in myeloid neoplasia (n= 2617) demonstrated a remarkable exclusivity with 2-hydroxyglutarate (2-HG) producing neomorphic IDH1/2 MT. Ectopic inducible expression of IDH1/2 MT induced synthetic lethality of malignant TET2 MT cells. Therefore, themutual exclusivity of TET2 MT and neomorphic IDH1/2 MT is due to synthetic lethality caused by 2-HG production. In addition, we demonstrate that sequential deletion of TET1 and TET3 leads to growth arrest in cellular models, which has never been observed in any myeloid malignancies. Altogether, these observations suggest that malignant TET2 mutant myeloid cells may be vulnerable to inhibition of residual TET-activity coming from TET1 and TET3. Therefore, we synthesized TET-specific inhibitor on 2HG scaffold using iterative computer-aided design, characterized in cell-free as well as cell culture model systems, and selected TETi76 with no cytotoxic effect in normal bone marrow-derived CD34 + cells. TETi76 selectively inhibits TET-dioxygenase activity with IC50 of 1.5, 9.4, and 8.8 μmol/L for TET1/2/3, and it restricts clonal outgrowth of TET2 MT both in vitro and in vivo in malignant and nonmalignant clonal hematopoiesis of indeterminate potential (CHIP). Conclusion: Taken together, here we demonstrated that anti-cancer activity of ascorbate may not come from its role as a TET activator and that a minimum level of TET-dioxygenase activity is required for cell survival, rendering TET2 -mutant malignant cells selectively vulnerable to inhibitors of TET-function. Disclosures Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy.

PURPOSE Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. MATERIALS AND METHODS A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. RESULTS We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. CONCLUSIONS The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

Bladder-sparing therapies for the treatment of nonmetastatic muscle-invasive bladder cancers are included in both American and European guidelines. Numerous treatment approaches have been described, including partial cystectomy, radiation monotherapy, and radical transurethral resection. However, the most oncologically favorable and well-studied regimen employs a multimodal approach that consists of maximal transurethral resection of the bladder tumor followed by concurrent radiosensitizing chemotherapy and radiotherapy. This sequence, referred to as trimodal therapy (TMT), has been evaluated with robust retrospective comparative studies and prospective series, although a randomized trial comparing TMT with radical cystectomy has not been performed. Despite promising reports of 5-year overall survival rates of 50% to 70% in well-selected patients, relatively few patients qualify as ideal candidates for TMT. Specifically, contemporary series exclude patients who have clinical stage T3 disease, multifocal tumors, coexisting carcinoma in situ, or hydronephrosis. Herein, we review all forms of bladder-preserving therapies with an emphasis on TMT, highlighting the rationale of each component, survival outcomes, and future directions.

To validate the 2019 NCCN subgroups of favorable- and unfavorable-intermediate risk (IR) prostate cancer among patients treated with brachytherapy, who are underrepresented in the studies used to develop the 2019 NCCN classification.We included all 2,705 men treated with I-125 LDR brachytherapy monotherapy at a single institution, and who could be classified into the 2019 NCCN risk groups. Biochemical failure and distant metastasis rates were calculated using cumulative incidence analysis.Of 1,510 IR patients, 756 (50%) were favorable-IR, and 754 (50%) were unfavorable-IR. Median follow up was 48 months (range, 3-214). As compared to favorable-IR, the unfavorable-IR group was associated with significantly higher rates of biochemical failure (HR, 2.87; 95% CI, 2.00-4.10; p0.001) and distant metastasis (HR, 3.14; 95% CI, 1.78-5.50, p0.001). For favorable-IR vs. unfavorable-IR groups, 5-year estimates of biochemical failure were 4.3% (95% CI, 2.6-6.1%) vs. 17.0% (95% CI, 13.6-20.5%; p0.001), and for distant metastasis were 1.6% (95% CI, 0.5-2.6%) vs. 5.4% (95% CI, 3.3-7.4%; p0.001), respectively. Patients with one unfavorable-intermediate risk factor (unfavorable-IRF; HR, 2.27; 95% CI, 1.54-3.36; p0.001) and 2-3 unfavorable-IRFs (HR, 4.42; 95% CI, 2.89-6.76; p0.001) had higher biochemical failure rates; similar findings were observed for distant metastasis (1 unfavorable-IRF: HR, 2.46; 95% CI, 1.34-4.53, p = 0.004; 2-3 unfavorable-IRFs: HR, 4.76; 95% CI, 2.49-9.10, p0.001).These findings validate the prognostic utility of the 2019 NCCN favorable-IR and unfavorable-IR prostate cancer subgroups among men treated with brachytherapy. Androgen deprivation was not beneficial in any subgroup. Alternative treatment intensification strategies for unfavorable-IR patients are warranted.