bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes of sarcomatoid versus classic urothelial carcinoma of bladder.
Authors: Garje Rohan , Ozair Ahmad , Manoharan Meenakkshy , Prabhakar Pushan , Rubens Muni B. , Roy Mukesh , Saxena Anshul , Khosla Atulya Aman , Bastos Bruno R. , Ahluwalia Manmeet Singh
Published: June 2023

4588

Background: Sarcomatoid urothelial carcinoma (SUC), a rare bladder cancer variant, has both epithelial and mesenchymal differentiation along with frequent TERT C228T promoter mutations and has poorer prognosis. In this study, we compared survival outcomes of SUC with classic urothelial carcinoma (CUC) in patients with T2-T4, N0-N1 bladder cancer after definitive therapy. Methods: All cases meeting our inclusion criteria for SUC and CUC during 2004-2019 were identified from National Cancer Database. Sociodemographic and clinicopathological characteristics were analyzed via descriptive and comparative statistics. Propensity-score matching was performed to adjust for baseline differences between SUC and CUC. Overall survival (OS) was compared using Cox proportional-hazards modelling and visualized through Kaplan-Meier curves. Results: 30072 cases of CUC and 480 of SUC were identified. Propensity-score matching resulted in N = 478 patients in both groups. Matched cohorts had no baseline differences in age, sex, race, comorbidities, insurance status, income, distance to hospital, hospital location, rural versus urban residence, histological grade, and proportion getting regional lymph node surgery. Overall, there were 675 males and 281 females, 435 underwent surgery (Sx), and 521 surgery plus chemotherapy (Sx+Cx). For SUC, median survival with Sx vs Sx+Cx was 29.5 months (95%CI 20.0-50.6) vs 43.1 months (95%CI 25.3-64.4) respectively. For CUC, median survival was 56.1 (95%CI 53.7-58.6) vs 78.0 (95%CI 75.1-81.1) months with Sx vs Sx+Cx respectively. Conclusions: SUC has poorer prognosis than CUC. Perioperative chemotherapy along with surgery was associated with improved survival outcomes compared to surgery alone in patients with SUC. Further studies investigating novel immunotherapy agents are warranted to improve oncologic outcomes. [Table: see text]
Survival outcomes of micropapillary versus classic variant, loco-regional bladder cancer: A 2004-2019 National Cancer Database analysis.
Authors: Garje Rohan , Ozair Ahmad , Saxena Anshul , Roy Mukesh , Prabhakar Pushan , Rubens Muni B. , Khosla Atulya Aman , Muina Antonio F. , Millado Kristen F. , Bastos Bruno R. , Ahluwalia Manmeet Singh
Published: June 2023

4592

Background: Micropapillary (MP) is a rare histologic variant of urothelial cancer (UC) with luminal-type characteristics and p53-like gene expression, leading to chemotherapy resistance and poor prognosis. However, contemporary outcomes of MP variant T2-T4, N0-N1 loco-regional bladder UC after definitive therapy are underreported, which this work sought to determine. Methods: A retrospective review was performed of all eligible cases of MP and classic UC (CUC) available during 2004-2019 from National Cancer Database. Socio-demographic, pathological, and clinical attributes were analyzed via descriptive and comparative statistics. Propensity-score matching was performed to adjust for baseline differences between MP and CUC. Overall survival, being the primary outcome, was compared using multivariable Cox proportional-hazards modeling and visualized through Kaplan-Meier curves. Results: 30072 cases of CUC and 397 of MP were identified. After propensity-score matching, 395 patients remained in both groups, with matched cohorts having no baseline differences in age, sex, race, Charlson-Deyo comorbidity index (CCI), insurance status, income, distance to hospital, hospital location, rural versus urban residence, tumor pathological grade, proportion receiving radiotherapy, and proportion getting regional lymph node surgery. In both matched cohorts there were 313 males (79%) and 82 females (21%). Both cohorts had 334 (85%) T2 cases, 41 (10%) T3 cases, and 20 (5%) T4 cases. Both cohorts had 375 (95%) N0 cases and 20 (5%) N1 cases. MP variant was associated with inferior survival compared to CUC (HR 1.26, 95%CI 1.03-1.54, P=0.024). Older age (≥65 years) and higher CCI were also associated with inferior survival. Irrespective of histology, patients undergoing surgery (S) plus chemotherapy (C) had better survival compared to S alone (HR 0.77, 95%CI 0.62-0.94, P=0.012). Regional lymph node surgery resulted in improved survival (HR 0.59, 95%CI 0.42-0.83, P=0.002). Sex, race, insurance, income, and hospital type did not impact survival. Median and two-year OS are summarized. Conclusions: Survival outcomes of MP are poorer than CUC of bladder. Surgery combined with perioperative chemotherapy was associated with better survival compared to surgery alone in patients with MP and CUC. Studies evaluating novel immunotherapies and antibody drug conjugates in perioperative setting are needed to improve outcomes. [Table: see text]
CABOSUN II: Results from a phase 2, open-label, multi-center randomized study of cabozantinib (CABO) vs. sunitinib (SUN) for non-clear cell renal cell carcinoma (NCCRCC).
Authors: Johns Andrew , Campbell Matthew T , Msaouel Pavlos , Jonasch Eric , Hahn Andrew Warren , Gao Jianjun , Shah Amishi Yogesh , Goswami Sangeeta , Zurita Amado J. , Pagliaro Lance C. , Bilen Mehmet Asim , Venkatesan Aradhana M. , Rao Priya , Tamboli Pheroze , Sircar Kanishka , Slack Tidwell Rebecca , Tannir Nizar M.
Published: June 2023

4597

Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]
Associations of diet with survival of patients (pts) with metastatic cancer of the urothelium (mUC) and renal cell carcinoma (mRCC) on immune checkpoint blockade (ICB).
Authors: Guercio Brendan John , Ratna Neha , Gavrilov David , Duzgol Cihan , Akhlaq Mahnoor , Teo Min Yuen , Regazzi Ashley M , Kotecha Ritesh R , Funt Samuel A , Aggen David H , Voss Martin H , Carlo Maria Isabel , Laccetti Andrew Leonard , Feldman Darren R. , Shah Neil J. , Motzer Robert J. , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa , Lee Chung-Han
Published: June 2023

4598

Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]
Gender and postoperative surgical margin status in MIBC: An analysis of the National Cancer Database.
Authors: Gordon Olivia French , Whalen Michael Joseph
Published: June 2023

4599

Background: Women with muscle-invasive bladder cancer (MIBC) continue to experience persistent disparities in health outcomes despite accounting for less than 1/3 of newly diagnosed bladder cancer cases. Multiple studies have acknowledged the aggressive profile of female bladder cancer. This study aims to identify tangible areas to intervene and improve the delivery of oncologic care. Methods: The National Cancer Database (NCDB) was queried from 2004-2017 to conduct a retrospective cohort analysis of men and women with MIBC (cT2a-T4). N=41,037 patients with MIBC were reviewed, (30,313 male; 10,724 female). The primary endpoints were OS and surgical margin status. Logistic regression was performed to determine whether female sex conferred differential impact on surgical margin status when controlling for baseline clinical stage, age, receipt of neoadjuvant chemotherapy (NAC), Charleson-Deyo Comorbidity Classification (CDCC), and facility type. Cox proportional hazards assessed the impact of age, gender, margin status, CDCC and NAC on OS. Results: Logistic regression showed that sex, age, baseline clinical stage, CDCC, facility type and NAC were significant predictors of surgical margin status (p<.001). Female sex was found to have a 14.4% higher probability of having positive residual margins (HR 1.144 (95% CI: 1.07-1.23), p<.001). When adjusting for age, margin status, CDCC and NAC, Female gender (OS HR 1.063 (95% CI: 1.03-1.09), p<.001), positive microscopic margins (OS HR 2.0 (95% CI: 1.90-2.10), p<.001) and positive macroscopic margins (OS HR 2.62 (95% CI: 2.40-2.90), p<.001) independently portended poorer OS and necessitated increased adjuvant XRT (p<.001). Unexpected demographic findings included a significantly greater number of females than expected with a median household income <$38,000 (p= 0.047) and a greater number of females in the upper quartile of patients without a HS diploma (p<.001). The median days from diagnosis to definitive surgical treatment was significantly lower compared to males (58 vs 67 days; p<.001). Conclusions: Women with MIBC faced obstacles to getting treatment (less education and lower median income). Despite these hurdles they may be more proactive with their health as seen by a shorter time from diagnosis to the surgical table. However, this proactivity has yet to pay off as women undergoing surgical treatment for MIBC were significantly less likely to have clear margins post-operatively. The urologic community must mirror female patient’s proactivity and further investigate the gender disparity in surgical treatment of MIBC. [Table: see text]
Primary retroperitoneal lymph node dissection (RPLND) in seminoma stage IIA-IIC ≤3cm: Combined results of the SWENOTECA (Swedish Norwegian Testicular Cancer Group) and Cologne.
Authors: Tandstad Torgrim , Kjellman Anders , Almås Bjarte , Grenabo Bergdahl Anna , Cohn-Cedermark Gabriella Elisabeth , Gerdtsson Axel , Glimelius Ingrid , Halvorsen Dag L. , Haugnes Hege Sagstuen Sagstuen , Hedlund Annika , Karlsdottir Asa , Larsen Signe Melsen , Negaard Helene F. S. , Pfister David , Stahl Olof , Thor Anna , Wahlquist Rolf , Heidenreich Axel , Paffenholz Pia , Seelemeyer Felix ,   SWENOTECA
Published: June 2023

Background: Chemotherapy or radiotherapy have been standard treatment for stage II seminomas with excellent survival but are associated with significant long-term treatment-related toxicities. Several prospective trials have shown primary retroperitoneal lymph node dissection (RPLND) to be an effective and safe alternative. The current SWENOTECA treatment program recommends primary RPLND in seminoma stage IIA to IIB ≤ 3 cm with 1-2 metastatic nodes as the standard treatment modality. We present preliminary results combined with data from Cologne. Methods: Within SWENOTECA, RPLND is centralized to 5 hospitals and Cologne is a tertiary centre for patients recruited from different parts of Germany. Both patients with recurrence after initial stage I disease and patients with primary stage IIA and IIB at diagnosis were included. We collected information on operation time, bleeding, peri- and postoperative complications. We also analyzed histologic outcome and whether adjuvant chemotherapy was given. We followed the patients for any recurrence of disease. Results: We have included 94 patients operated from May 2018 to November 2022. The number of operations per site varied from 4 to 28. The mean age of patients at time of RPLND was 41.8 years (range 21-79). Overall, 54 patients had recurrence after initial stage I disease and 40 patients had primary stage IIA/IIB disease at diagnosis (one missing data). At time of RPLND 62 patients had IIA-disease and 31 stage IIB-disease (one missing data). The histology from RPLND showed seminoma in 83 patients, benign/necrosis in eight patients, vital non-seminomatous GCT in one patient, teratoma only in one patient and lymphoma in one patient. Mean number of resected nodes was 19, and mean number of positive nodes were 1.5. Twenty-six patients (28%) were operated with robotic laparoscopic technique. Ten patients (10.6%) had a Clavien-Dindo postoperative complication > 2. Twenty-three of the patients were given adjuvant oncological treatment after RPLND, most of them one course of BEP. The patients have been followed for in median 18 months (range 2-59). Nine patients (9.6 %) have had recurrences, all but one in the first year after RPLND. Conclusions: Our early results of primary RPLND of seminomas IIA-IIB ≤ 3 cm are promising. Longer follow-up is required to ensure this as a safe treatment option.
Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.
Authors: Hadaschik Boris A. , Eiber Matthias , Weber Manuel , Ravi Kumar Aravind , Calais Jeremie , Czernin Johannes , Ilhan Harun , Saad Fred , Kretschmer Alexander , Brookman-May Sabine D. , Mundle Suneel , Small Eric Jay , Smith Matthew Raymond , Perez Rivera Paola M. , Hope Thomas A. , Herrmann Ken , Hofman Michael S , Fendler Wolfgang P.
Published: June 2023

5010

Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in >50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p>0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p>0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p>0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (>5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]
Do bone scans over-stage disease compared to PSMA PET? An international multicenter retrospective study with blinded independent readers.
Authors: Fendler Wolfgang P. , Hope Thomas A. , Jiang Fei , Thompson Daniel , Barbato Francesco , Juarez Roxanna , Hernandez Pampaloni Miguel , Auerbach Martin S. , Gupta Pawan , Benz Matthias R. , Calais Jeremie
Published: June 2023

5011

Background: PSMA positron emission tomography (PET) has a higher accuracy than computed tomography (CT) and bone scans to stage patients with prostate cancer. However, we do not understand how to apply clinical trial data based on conventional imaging to patients staged using PSMA PET. Therefore, we aim to evaluate the ability of bone scans to detect osseous metastases using PSMA PET as a reference standard. Methods: In this multicenter retrospective diagnostic study, 167 patients with prostate cancer, who were imaged with bone scan and PSMA PET performed within 100 days were included for analysis. Each study was interpreted by three blinded readers, and the results of the PSMA PET were used as the reference standard. Endpoints were positive predictive value (PPV), negative predictive value (NPV) and specificity for bone scans. Additionally, inter-reader reproducibility, positivity rate, uptake on PSMA PET, and number of lesions were evaluated. Results: 167 patients were included in the study, with 77 at initial staging, 60 in the BCR/CSPC setting and 30 in the CRPC setting. BS findings for metastatic disease validated by PSMA PET were tabulated. In all patients, the PPV, NPV and specificity for bone scans were 0.73 [0.61,0.82], 0.82 [0.74,0.88] and 0.82 [0.74,0.88]. In patients at initial staging, the PPV, NPV and specificity for bone scans were 0.43 [0.26,0.63], 0.94 [0.85,0.98], and 0.80 [0.68,0.88]. At initial staging 13/23 (57%) of positive bone scans were false positive. Inter-reader agreement for bone disease was moderate for bone scans (Fleiss k, 0.51) and substantial for the PSMA PET reference standard (Fleiss k, 0.80). Conclusions: In this multicenter retrospective study, the PPV of bone scans was low in patients at initial staging with majority of positive bone scans being false positives. This suggests that a large proportion of patients considered low volume metastatic by bone scan actually have localized disease. [Table: see text]
Final results from phase I study of PSCA-targeted chimeric antigen receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Blanchard Suzette , Martirosyan Hripsime , Adkins Lauren , Dhapola Gaurav , Shishido Stephanie , Wagner Jamie R , Stiller Tracey , D'Apuzzo Massimo , Kuhn Peter , Forman Stephen J. , Priceman Saul
Published: June 2023

5019

Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We are completing a phase I study of PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on other prior treatments. The primary objective was to define the dose limiting toxicities (DLT) as well as to describe preliminary bioactivity and activity. CAR T persistence and cytokine levels were evaluated by flow cytometry and Luminex. Circulating tumor cells (CTC) were measured by an unselected assay (Kuhn). Results: 14 pts were treated, median age 69, median baseline PSA 88. 12(86%) had previously been treated with chemotherapy; 9 received two taxanes and 3 docetaxel only. 79% of screened pts had PSCA expression >2+ in >80% of cancer cells. Two of 6 pts encountered DLT (grade 3 cystitis) at 100M + lymphodepletion (LD) chemotherapy. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3. No DLTs occurred in 5 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), best response by RECIST, CAR T cell expansion and persistence are presented by dose level in the table. CAR T expansion was greater with LD than without. PSA declines were seen, as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Cytokine peaks were higher in patients with anti-tumor effect noted. CTC decreases in both marrow and peripheral blood were seen, associated with PSA declines. Conclusions: PSCA-CAR T cells have anti-cancer activity in mCRPC with DLT of cystitis. LD was required for greater expansion and activity; lower dose LD improved toxicity without clear negative impact on expansion. Clinical trial information: NCT03873805 . [Table: see text]
Longitudinal transcriptome profiling of localized hormone-sensitive tumors in treatment-naïve ENACT patients with prostate cancer with and without enzalutamide (ENZA).
Authors: Ross Ashley , Shore Neal D. , Davicioni Elai , Zhao Xin , Elsouda Dina , Liu Yang , Proudfoot James A. , Hairston John , Russell David , Iwata Kenneth K. , Schaeffer Edward M.
Published: June 2023

5026

Background: The ENACT trial (NCT02799745) randomized men with low- or intermediate-risk prostate cancer to 12 months of ENZA monotherapy followed by active surveillance (AS) for 12 months or to AS alone. Men were followed longitudinally, including by serial genome-wide expression profiling. Of 258 genomic signatures evaluated from baseline samples, increased Decipher genomic classifier score was prognostic for progression on AS; androgen receptor activity (AR-A) and PAM50 subtypes were associated with clinical benefit from ENZA, as previously reported. Here we present transcriptomic changes over time for men undergoing AS and those treated transiently with ENZA. Methods: Gene-expression profiling was performed via the Decipher GRID platform (Veracyte, Inc.) on 131 ENACT patient samples (ENZA, n=57; AS, n=74) collected at prespecified time points (screening, 12 months, and 24 months). Predefined GRID signatures were assessed for correlation with biological and clinical characteristics, including immune activity, treatment sensitivity, metastatic risk, and molecular subtypes. Statistical analysis was conducted by Cox proportional hazards models and logistic/linear regression; longitudinal changes were assessed by linear mixed-effects models. Results: Analysis of 12-month longitudinal samples showed significant transcriptomic changes in patients treated with ENZA, including markers of AR-A downregulation, decreased regulatory T-cell suppression, and increased immune activation. Many of the transcriptomic signature changes that occurred during ENZA treatment, including immune marker changes, were transient and returned to baseline values by 24 months following ENZA treatment discontinuation at 12 months. Conclusions: This exploratory biomarker analysis provides valuable data on transcriptomic changes in patients undergoing AS and those exposed to ENZA followed by cessation of treatment. Longitudinal analysis data provided insights into progression of early disease in the AS arm and possible strategies for extending ENZA activity beyond progression. Immune modulation with ENZA treatment may provide further insights for exploration of immunotherapy strategies. Clinical trial information: NCT02799745 .
Predicting absolute benefit in risk of metastasis of androgen deprivation therapy added to radiation therapy in patients with newly diagnosed prostate cancer using Prolaris.
Authors: Tward Jonathan David , Lenz Lauren , Gutin Alexander , Clegg Wyatt , Finch Rob , Cohen Todd
Published: June 2023

5030

Background: Most patients would defer using androgen deprivation therapy (ADT) with radiation therapy (RT) when the number-needed-to-treat (NNT) exceeds 25 persons to prevent 1 from developing metastasis, corresponding to an absolute benefit of 4%.1 However, no tools for estimating personalized NNT or absolute benefit from ADT exist. We aimed to quantify personalized absolute benefit and NNT for persons receiving ADT added to single modality RT. Methods: The clinical cell-cycle risk (CCR) score combines the University of California, San Francisco’s Cancer of the Prostate Risk Assessment and the cell cycle progression molecular score to accurately assess prostate cancer aggressiveness. The effect of ADT added to RT was modeled using a 10-year risk of metastasis as a function of continuous CCR score for patients treated with RT alone. The relative benefit of ADT added to RT to reduce distant metastasis was modeled using published data from The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) which utilized several prospectively randomized RT±ADT trials.2 The average absolute benefit was calculated for patients with CCR scores above and below a prespecified multimodality treatment threshold (MTT) using the distribution of scores in a cohort of patients commercially tested by Myriad Genetics. Results: The commercially tested cohort consisted of 56,485 patients spanning all National Comprehensive Cancer Network risk categories (33.7% very low/low risk, 29.8% favorable intermediate risk, 25.6% unfavorable intermediate risk, 11.0% high/very high risk), with 87.2% having CCR scores at or below the MTT and 12.7% with CCR scores above the threshold. The average absolute benefit of ADT treatment was 0.86% (NNT=116) for patients with CCR scores below the MTT and 8.2% (NNT=12) for patients with CCR scores above the MTT. Patients with CCR scores at precisely the MTT had a predicted absolute benefit of 3.7% (NNT=27). Conclusions: The Prolaris test can accurately predict an individual's benefit of adding ADT to RT, and the risk threshold is consistent with patient attitudes about when to use or omit ADT. 1. Spratt DE, Tward JD: IJROBP 108:899-902, 2020. 2. Kishan AU, Sun Y, Hartman H, et al. Lancet Oncol 23:304-316, 2022.
Prevalence of mismatch repair deficiency in a large prospective prostate cancer cohort.
Authors: McNevin Ciara S. , Mohammed Nur Mutaz , O'Brien Cathal , McGovern Brianan , McFadden Julia , Baird Anne-Marie , Cadoo Karen Anne , Barr Martin P , Gray Steven G. , Keogh Anna P. , Sheils Orla , Sutton Lesley Ann , Flanagan Sinead , Mucci Lorelei A , Stopsack Konrad H. , Finn Stephen P.
Published: June 2023

5031

Background: Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer. Methods: This study included men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The highest-grade/index lesions of tumor tissue from radical prostatectomy (95%) or transurethral resections of the prostate were mounted in triplicate on tissue microarrays. Immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed, with scoring as MMR-deficient requiring a visible staining in a non-tumor internal positive control of the same case. For validation, a polymerase chain reaction-based MSI assay (Idylla MSI Test, Biocartis) was performed on tumor DNA of MMR-deficient cases and a selection of MMR-intact cases. Results: The study included 1016 men with prostate cancer. Tumor stage was predominantly pathologically localized (71% stage pT1/2, 18% T3a/b) with a full distribution of Gleason scores, including 20% Gleason score 6 (grade group 1), 36% 3+4 (grade group 2), 23% 4+3 (grade group 3), 8% 8 (grade group 4) and 13% 9-10 (grade group 5). MMR tumor scoring could be performed for MLH1 in 747 cases (75% of those with tumor tissue), for MSH2 in 903 cases (90%), for MSH6 in 708 cases (74%), and for PMS2 in 703 cases (72%). The remaining tumors were unevaluable due to lack of non-tumor tissue necessary as an internal positive control. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence 0.4%, 95% confidence interval [CI] 0.2–1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence 0.4%, 95% CI 0.1–1.2%). No tumor had loss of MLH1 or PMS2. The MMR-deficient tumors had Gleason scores of 3+4, 8 (two cases), and 9–10. Tumor DNA of 1 of the 4 MMR-deficient tumors met the manufacturer’s cut-off for MSI-high; two additional MMR-deficient cases had non-zero repeats, with good reproducibility between tumor cores and technical replicates. One MSH2-deficient tumor and 6 DNA samples from 3 MMR-intact cases had repeat scores of zero. Conclusions: In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. This low prevalence contrasts with hospital-based studies of MMR deficiency and MSI that may have represented tumors with certain clinical features. The low prevalence and the need for an internal positive control for reliable scoring calls into question to what extent immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies, is routinely feasible.
Sequential metastasis-directed therapy (MDT) for oligometastatic prostate cancer (Oligo PCa) assessed by PET-based imaging.
Authors: Carretero-González Alberto , Kwon Daniel , Shakhnazaryan Nonna , Hong Julian C. , Mohamad Osama , Feng Mary Uan-Sian , de Kouchkovsky Ivan , Borno Hala , Bose Rohit , Chou Jonathan , Desai Arpita , Fong Lawrence , Friedlander Terence W. , Koshkin Vadim S , Feng Felix Y , Aggarwal Rahul Raj , Hope Thomas A. , Small Eric Jay
Published: June 2023

5032

Background: Prostate specific membrane antigen (PSMA) and F-18-Fluciclovine PET imaging have high sensitivity for the detection of prostate cancer (PCa) metastases. MDT with stereotactic body radiation therapy (SBRT) to PET-detected Oligo PCa has been shown to improve progression free survival (PFS) and delay androgen deprivation therapy (ADT). However, in those patients (pts) who ultimately develop oligoprogressive disease following MDT, the utility of subsequent courses of MDT has not been well defined. Methods: A single institution retrospective review was undertaken to describe outcomes following ≥2 courses of PET-guided SBRT in pts with Oligo PCa. Pts included in this analysis had undergone initial SBRT for ≤5 PCa lesions detected on PSMA or Fluciclovine PET, and subsequently underwent ≥1 additional course of SBRT at progression. Baseline data collected included stage, PSA level, Gleason Score, tracer type, and concurrent systemic therapy. Endpoints collected for each SBRT course included PSA decline ≥50% (PSA50), PFS, and systemic therapy change free survival (RxFS) (initiation of ADT, or for pts already on ADT, addition of an androgen signaling inhibitor). Association of factors with PFS after SBRT2 were analyzed using multivariable Cox proportional-hazards models. Results: 34 pts underwent ≥2 courses of MDT (SBRT1, SBRT2). At SBRT2, progression was identified by PSMA-PET in 26 (77%) pts, and by Fluciclovine-PET in 8 (23%). With SBRT2, 18 (53%) had a concurrent systemic therapy change; 10 (29%) did not receive any systemic therapy. 12 pts subsequently underwent SBRT3. Progression was detected by PSMA PET in 9 (75%) and Fluciclovine PET in 3 (25%). Clinical outcomes are summarized in the table. In the multivariable analysis, predictors associated with PFS following SBRT2 were 1) PSA decline at SBRT1 (HR 1.10, 95% CI 1.05-1.16, P<0.001) and 2) PSA doubling time (PSADT) < 12 months at the time of SBRT2 (HR 11.52, 95% CI 1.36-97.38, P 0.025). Overall, from SBRT1 to last follow-up (median 25.2 months), 23 (68%) pts remained ADT-free (14 after SBRT2; 9 after SBRT3). Conclusions: Serial MDT for Oligo PCa detected on PSMA or Fluciclovine PET is feasible and results in PSA declines, independent of change in systemic therapy. There is a persistent but diminishing benefit of MDT over successive courses. Overall, 2/3 of pts were able to postpone the use of ADT. PSA decline at SBRT1 and PSADT at SBRT2 may be biomarkers for SBRT2 benefit. Despite the retrospective nature of this study and cohort heterogeneity, these data provide a rationale for serial SBRT in Oligo PCA, and the need for larger, prospective studies of this strategy. [Table: see text]
Genetic ancestry associations with somatic mutations in a real-world cohort of over 3,000 patients with prostate cancer.
Authors: De La Vega Francisco M , Rhead Brooke , Pouliot Yannick , Guinney Justin , Craig David W , Carpten John D.
Published: June 2023

5034

Background: Disparities in incidence and outcomes of prostate cancer among racial groups have been reported. Black men have a higher incidence of prostate cancer compared to White men and are more likely to be diagnosed at a later stage, resulting in poorer outcomes. These differences are likely due to a combination of genetic, socioeconomic, and healthcare access factors. Furthermore, evidence has revealed racial differences in molecular profiles of prostate cancer, such as a higher incidence of ERF mutations and increased transcriptional activation of the androgen receptor signaling and inflammatory pathways in tumors derived from Black men compared to White men, suggesting that underlying biology may contribute to these disparities. Here, we aimed to identify differences in the mutational profiles of prostate cancers by race and genetic ancestry in a de-identified real-world cohort of 3,804 patients that underwent the Tempus xT 648-gene NGS tumor profiling test. Methods: We used 654 ancestry-informative markers to estimate continental ancestry likelihoods for five regions: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We imputed Asian (ASN, n=122), Hispanic/Latino/Native American (HLN, n=300), Non-Hispanic Black (NHB, n=619) and Non-Hispanic White (NHW, n=2,679) categories using genetic ancestry thresholds based on literature and validated with available metadata. Associations between either race/ethnicity categories or continental ancestry proportions and somatic variants (copy number alterations (CNAs), small nonsynonymous, OncoKB L1/2 & R1, and predicted driver somatic mutations) were assessed for 109 prostate cancer-related genes using logistic regression models. Likelihood ratio tests were used to compare models with and without race/ethnicity or ancestry terms, and the Benjamini-Hochberg method was used to adjust p-values and control the FDR at 5%. Results: NHB and ASN men had lower odds of having a PTEN CNA compared to NHW men (OR=0.58 and 0.40, p=0.0001 and 0.009, respectively). Confirming this finding was a positive association between EUR ancestry and PTEN CNAs (OR=1.07 per doubling of EUR ancestry proportion, p=0.0007). NHB men were also less likely to have actionable OncoKB somatic mutations in the PIK3CA gene when compared to NHW men (OR=0.48, p=0.03). Increased AFR ancestry was associated with the presence of nonsynonymous predicted driver mutations in SPOP (OR=1.04, p=0.04), while both EAS and SAS ancestries were associated with fewer such mutations in TP53 (OR=0.95 in both cases, p=0.02 and 0.003). Conclusions: Analysis of a large real-world cohort leveraging genetic ancestry inferred from NGS data confirms previously known associations between the presence of somatic alterations in prostate cancer genes and race/ethnicity, and identifies novel associations of potential precision therapeutic relevance.
Association of plant-based diet index with quality of life in patients with prostate cancer.
Authors: Loeb Stacy , Hua Qi , Bauer Scott , Kenfield Stacey A. , Morgans Alicia K. , Mucci Lorelei A
Published: June 2023

5037

Background: Plant-based diets have many health benefits including a lower risk of fatal prostate cancer. Less is known about the relationship between diet and functional outcomes among prostate cancer survivors. We hypothesized that greater consumption of plant-based food after prostate cancer diagnosis is associated with improved quality of life (QOL). Methods: This prospective cohort study included 3,505 participants in the Health Professionals Follow-up Study with non-metastatic prostate cancer (1986-2016). Overall and healthful Plant-based Diet Indices were calculated from food frequency questionnaires with cumulative updating. QOL scores were calculated using the Expanded Prostate Cancer Index Composite. Generalized estimating equations were used to examine associations between Plant-based Diet Indices and 5 QOL domains, adjusted for clinical and demographic factors. Results: Higher Plant-Based Diet Index was associated with improved scores for sexual function, urinary irritation/obstruction, and urinary incontinence among men with prostate cancer. Consuming more healthful plant-based foods was also associated with better scores for bowel function and hormonal/vitality in the age-adjusted models. Results were similar in sensitivity analyses excluding patients with pre-existing erectile dysfunction or lower urinary tract symptoms, and adjusting for use of sexual or urinary medications. A limitation is that no participants followed a strict vegan diet. Conclusions: This prospective study suggests that greater consumption of healthful plant-based foods is associated with modest improvements in QOL domains among patients with prostate cancer. [Table: see text]
64Cu-SAR-bisPSMA (PROPELLER) positron emission tomography (PET) imaging in patients with confirmed prostate cancer.
Authors: Lengyelova Eva , Wong Veronica , Lenzo Nat , Parker Michelle , Emmett Louise
Published: June 2023

5039

Background: Prostate cancer (PC) is the second most frequent malignancy in men globally. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is overexpressed in PC. Recently, several new 68Ga- and 18F-based PSMA-targeted PET agents have been approved by the FDA to detect PC, which offer improved sensitivity and specificity compared to traditional imaging. Methods: PROPELLER (NCT04839367) investigated 64Cu-SAR-bisPSMA in 30 men with untreated, histopathologically proven, primary PC with intermediate- to high-risk features. At screening, patients completed 68Ga-PSMA-11 PET/CT at 1h post dose. Following enrollment, patients received either 100MBq, 150MBq or 200MBq of 64Cu-SAR-bisPSMA, followed by PET/CT at 2-4h post dose. Safety was evaluated before and after 64Cu-SAR-bisPSMA dosing. The 68Ga-PSMA-11 and 64Cu-SAR-bisPSMA PET/CT scans were evaluated by 2 independent, blinded central readers for image quality, PC detection, and intensity of tracer uptake in lesions (SUVmax and Tumor-to-Background Ratio [TBR]). Results: A single, Grade 1 64Cu-SAR-bisPSMA-related AE was reported in the 200MBq cohort. Both readers scored 200MBq of 64Cu-SAR-bisPSMA as the dose providing the highest image quality. In this cohort, 64Cu-SAR-bisPSMA and 68Ga-PSMA-11 was able to detect primary PC in 100% and 77.8% of patients for Reader 1 and 85.7% and 83.3% of patients for Reader 2, respectively. In the 200MBq cohort, Reader 1 identified 41 lesions with 64Cu-SAR-bisPSMA vs 36 lesions with 68Ga-PSMA-11, while Reader 2 identified 31 lesions with 64Cu-SAR-bisPSMA vs 22 lesions with 68Ga-PSMA-11. In the 200MBq cohort, 64Cu-SAR-bisPSMA consistently showed higher uptake compared to 68Ga-PSMA-11 (SUVmax: Reader 1 median [IQR]: 31.40 [27.45] vs 10.08 [13.92], p < 0.001, Reader 2 median [IQR]: 41.00 [46.09] vs 14.58 [14.98], p < 0.001); TBR: Reader 1 median [IQR]: 49.07 [67.69] vs 21.91 [35.71], P = 0.0015), Reader 2 median [IQR]: 76.34 [66.37] vs 23.90 [33.05], p < 0.001). Conclusions: 64Cu-SAR-bisPSMA was safe and effective for detecting PSMA-expressing lesions. 200 MBq of 64Cu-SAR-bisPSMA was determined as the optimal dose for future trials. 64Cu-SAR-bisPSMA PET/CT showed a greater number of lesions and lesions exhibited significantly higher uptake when compared to 68Ga-PSMA-11 in men being with intermediate- to high-risk PC. Further studies to evaluate 64Cu-SAR-bisPSMA as an imaging agent in patients with biochemical recurrence of PC are underway. Clinical trial information: NCT04839367 .
Prognostic factors for relapse in patients with clinical stage I testicular seminoma: A nationwide, population-based cohort study.
Authors: Wagner Thomas , Toft Birgitte Grønkær , Lauritsen Jakob , Bandak Mikkel , Christensen Ib Jarle , Engvad Birte , Jessen Michael Kreiberg , Agerbaek Mads , Dysager Lars , Rosenvilde Josephine , Berney Daniel , Daugaard Gedske
Published: June 2023

5041

Background: Approximately 20% of patients with clinical stage I testicular seminoma will relapse after orchiectomy. No robust prognostic factors for relapse exist which challenges risk assessment and counselling for patients. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We therefore assessed prognostic factors for relapse in a large unselected nationwide population-based setting with centralized pathology review. Methods: Patients with clinical stage I seminoma diagnosed in Denmark between 2013 and 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, microscopic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified clinical and histopathological prognostic factors and relapse were assessed by use of Cox regression analysis. Potential prognostic factors included age, pre-orchiectomy values of β-human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH), tumor size, tumor multifocality, tumor necrosis, lymphovascular invasion, pagetoid rete involvement, and invasion of rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea, and tunica vaginalis. Results: In total, 924 patients were included. During a median follow-up of 6.3 years, 148 (16%) patients relapsed. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated pre-orchiectomy levels of β-hCG and LDH were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors, to 64% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the model had an overall concordance statistic of 0.70. Conclusions: The provided prognostic factors allow a long-awaited opportunity to make more informed treatment decisions about post-orchiectomy management in patients with clinical stage I seminoma. These should replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies. [Table: see text]