bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of whole blood mRNA expression and overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Lewis Akeem Ronell , Sosa Carlos , Bobek Olivia , Hillman David W. , Costello Brian Addis , Quevedo Fernando , Pagliaro Lance C. , Weinshilboum Richard M. , Cairns Junmei , Wang Leiwei , Kalari Krishna Rani , Kohli Manish , Tan Winston , Giridhar Karthik
Published: March 2023

201

Background: Previous studies have evaluated peripheral whole blood mRNA to identify prognostic biomarkers in metastatic prostate cancer, with no consistent genes of prognostic significance between studies and sample collection done at various points of therapy. We aim to identify the prognostic value of 20 previously identified genes in patients mCRPC from a prospective clinical trial. Methods: Between June 2013 and August 2015, whole blood was prospectively collected in PAXgene RNA tubes from 92 men with mCRPC (NCT01953640). Gene expression from samples with RIN > 4.0 were quantified using a customized NanoString CodeSet of 20 candidate genes (C1QA, MCM2, STOM, GABARAPL2, R10K3, HMBS, TFDP1, CDKN1A, ITGAL, TMCC2, TERF2IP, MMP9, SNCA, TIMP1, SLC4A1, SELENBP1, TMEM66, SEMA4D, PROS1, CD22). The raw data from the nCounter Analysis system were normalized to the positive controls and log2 transformed. Univariable Cox proportional hazards models were performed on each target gene sufficiently above negative control (5 times the maximum value of the negative control) to evaluate associations with overall survival (OS). For each gene we considered a linear, quadratic, or categorical model with quantile cutpoints. Categorical models with cutpoints at the 25th percentile for the genes CD22, GABARAPL2, R10K3, and STOM were used as there was a nonlinear relationship between gene expression and death hazard. The remaining genes were modeled with a linear model. Findings were considered statistically significant based on p-values adjusted using the Holm-Bonferroni correction. Results: 18/20 genes were identified and passed quality control (QC) measures, which excluded C1QA and MCM2. 72/92 men had an evaluable pretreatment specimen that passed QC. The median age was 72 years. The study cohort was evenly balanced in terms of Gleason score ( < = 7 v. > 7) and 60% had high volume disease. The median follow-up time was 5.73 years (IQR: 5.39, 6.49) and 58 patients had died. Of the 18 genes evaluated, STOM (Stomatin) [hazard ratio (HR) 3.00, adjusted p = 0.007] and GABARAPL2 (GABA Type A Receptor Associated Protein Like 2) [HR 2.62, adjusted p = 0.033] were significantly associated with overall survival in univariate analysis. In multivariate analysis, after adjusting for volume of metastatic disease and Gleason score, STOM [HR 2.89, adjusted p = 0.014] was significantly associated with overall survival. Conclusions: Elevated whole blood mRNA expression of STOM is adversely associated with OS in mCRPC. Further studies investigating elucidating the molecular significance of STOM in mCRPC are planned. Clinical trial information: NCT01953640 .
Distinct genomic features and evolutionary relationships between concurrent intraductal carcinoma and adenocarcinoma of the prostate.
Authors: Zhu Sha , Zhao Jinge , Nie Ling , Zhang Mengni , Zheng Linmao , Xu Nanwei , Shen Pengfei , Chen Ni , Zeng Hao , Sun Guangxi
Published: March 2023

215

Background: Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally co-exists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared to concomitant adenocarcinoma. Till now, the genomic characteristics of IDC-P remain largely unknown. Methods: To explore the genomic features and evolutionary relationships between concurrent IDC-P and PAC, we isolated IDC-P, concurrent invasive high-grade PAC lesions, and adjuvant normal prostate tissues from 22 radical prostatectomy specimens. Whole-exome, RNA, and DNA-methylation sequencing were performed on the acquired tumoral and normal samples. The biological characteristics of IDC-P and concurrent PAC were compared at different molecular levels. Results: Three evolutionary patterns between concurrent IDC-P and PAC were identified. Tumors with clonally distant and early divergent evolutionary patterns showed higher genomic and pathological heterogeneities between concurrent IDC-P and PAC than those with the late-divergent pattern. Compared to co-existing PAC, increased adverse prognosis-associated genes were overexpressed in IDC-P. Besides, IDC-P was similar to Gleason pattern 5 PAC on the transcriptome profile. Survival analysis based on an independent cohort supported IDC-P resembled Gleason pattern 5 tumors. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Conclusions: Our findings provide a molecular groundwork for the aggressive behavior of IDC-P and contribute to developing potential therapies for tumors with IDC-P.
Characterization of ctDNA findings at the end of life in patients with prostate cancer.
Authors: Gupta Kanika , Caputo Sydney , Casado Crystal , Jang Albert , Sweeney Patrick L , Lanka Sree M , Pocha Olivia , Hawkins Maddie , Lieberman Alexandra , Schwartz Jennifer , Miller Patrick , Jaeger Ellen B. , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver
Published: March 2023

230

Background: Somatic alterations change over time in response to treatment and disease progression in patients with prostate cancer (PCa). We report ctDNA findings of patients who died from PCa within 3 months of a ctDNA assessment to better characterize patients with fatal disease. Methods: A total of 118 patients with PCa specific mortality who had been treated at Tulane Cancer Center and had ctDNA assessments between 2015 and 2022. The ctDNA was assessed by Guardant360 (Guardent Health, Inc) assays to identify alterations, pathogenic mutations and/or copy number alterations (CNAs) in cancer-related genes. Clinical annotation including treatment history, genetics, and staging were also obtained. Statistical analyses included Fischer’s Exact and Wilcoxon tests. Results: Of the 118 patients with PCa specific mortality, 42% (49/118) had a ctDNA assessment <3 months from death. Of 49 CRPC patients tested within 3 months of death, the median number of life extending therapies (LET) at death was 5 (2-9). Patients had a median of 2 (0-6) LET prior to first ctDNA screening and 3 (0-7) LET in between first and last ctDNA assessment. Of the total gene alterations detected on ctDNA analysis, within 3 months of death, the most common alterations detected were 65.3% (32/49) TP53, 44.9% (22/49) AR, 28.6% (14/49) EGFR, 24.5% (12/49) PIK3CA, 22.4% (11/49) MYC, and 20.4% (10/49) CDK6. In a paired analysis(n= 45) of first and last ctDNA screening, AR (OR= 2.35, 95% C.I. (0.99, 5.62), p= 0.05), CDK6 (OR= 4.00, 95% C.I. (1.02, 15.68), p= 0.04), FGFR1 (OR= 9.51, 95% C.I. (1.14, 79.61), p= 0.03), and EGFR (OR= 9.71, 95% C.I. (2.06, 45.83), p= 0.0009) were significantly more likely to be detected in ctDNA screening within 3 months of death. In addition, ctDNA alterations in general were significantly more likely to be detected at the end-of-life (p=< 0.00001). Other ctDNA gene mutations did not have statistically significant increases. Conclusions: An analysis of patients with PCa mortality showed most frequent gene alterations in TP53, AR, EGFR, PIK3CA, MYC, and CDK6. When comparing patients’ first and last ctDNA, alterations were significantly more likely by time of death in AR, CDK6, EGFR, FGFR and there was a significant increase in overall detection of somatic alterations in ctDNA. These analyses are limited to the genes assessed on the ctDNA panel and may or may not reflect all of the functionally relevant alterations. Further the CNAs reported herein may reflect broad genomic changes rather than specific gene alterations.
Characterizing changes in tumor mutational burden (TMB) by serial circulating tumor DNA (ctDNA) testing in patients with advanced prostate cancer (aPC).
Authors: Childs Daniel S , Kwon Eugene D. , Ahmed Mohamed E. , Mahmoud Ahmed , Rodrigues Pessoa Rodrigo , Nabavizadeh Reza , Tsai Jill , Drusbosky Leylah , Bucheit Leslie
Published: March 2023

239

Background: In part, TMB guides therapeutic decisions on the use of immune checkpoint inhibitors (ICIs) in aPC. Most patients (pts) with aPC do not have high TMB (TMB-H) at the time of initial assessment. However, TMB changes over time (from treatment pressure) as pts progress through lines of therapy (LOT) has not been extensively explored in aPC. We describe real world data on changes to blood TMB (bTMB) in pts with aPC exposed to several LOT. Methods: Genomic results from pts with aPC who had ≥1 ctDNA test(s) with TMB analyzed (Guardant360, Guardant Health, Inc) as part of clinical care from Oct 2020 – Jun 2022 were retrospectively queried. Clinical factors were extracted from test requisition forms; pts from Mayo Clinic had additional factors, including intervening treatment, extracted from medical records. High bTMB (TMB-H) was defined as ≥13.4 mut/Mb, as previously reported. Proportions were compared using Fisher’s Exact Test. Results: 316 patients with a median age of 72 (range: 44-91) were analyzed. Initial median TMB for the entire cohort was 8.18 mut/Mb (range: 0.01-268.3). On subsequent test, TMB decreased in 122(40%), increased in 173(55%), of whom 29 (17%) became TMB-H; 21 (7%) had unchanged TMB. Median time between tests was 182 days (range: 21-578). 101 patients with 262 tests and a median age of 71 years (range: 46-87) were clinically annotated in the Mayo cohort of whom 58 had >2 consecutive TMB scores: 25 (43%) had TMB increase, of whom 4 (16%) became TMB-H, 23 (40%) had TMB decrease, 10 (17%) had dynamic changes with increases and decreases. Numeric but not statistically significant differences in clinical factors were observed between groups (p>0.05). Conclusions: In this real world cohort, variation in TMB is seen with increasing LOT. Importantly, nearly 1 in 5 patients with increasing tumor mutational burden develop TMB-H, which may be a clinically actionable finding as these pts become eligible for ICI. Findings underscore the importance of repeat genetic testing with time and LOT. [Table: see text]
Evaluation of ctDNA in patients treated with lutetium-177-PSMA-617.
Authors: Lanka Sree M , Jang Albert , Sweeney Patrick L , Gupta Kanika , Caputo Sydney , Casado Crystal , Huang Minqi , Pocha Olivia , Hawkins Maddie , Lieberman Alexandra , Schwartz Jennifer , Jaeger Ellen B. , Miller Patrick , Layton Jodi Lyn , Barata Pedro C. , Lewis Brian E. , Ledet Elisa M. , Sartor A. Oliver
Published: March 2023

243

Background: Lutetium-177- PSMA-617 (Lu-177) is a radioligand therapy that delivers radiation to PSMA-expressing cells in patients with advanced prostate cancer. In this study, we aimed to analyze ctDNA in responders and non-responders after Lu-177 treatments. Methods: Data was retrospectively collected on 31 heavily pre-treated metastatic CRPC patients who received Lu-177 treatment at Tulane Cancer Center. All patients fulfilled VISION criteria for treatment and all had ctDNA assessment with Guardant 360 within 30 days prior to first treatment with Lu-177. Of the 31 patients, 7 had paired ctDNA assessment both prior initiation of treatment and at the end of treatment. Clinical data such as PSA response (PSA decline 50% or more) to Lu-177, initial diagnosis, pathology, treatment history, and relevant germline genetic data were collected. Results: Of the 31 patients who received Lu-177 treatment, 18 had PSA response to Lu-177 (responders) and 13 did not (non-responders). In ctDNA mutational analyses, there were no significant differences detected prior to treatment between responders and non-responders. There was, however, a significant increase in the presence of copy number amplifications in non-responders (n= 11/13) when compared to responders (n= 7/18) (OR= 8.64, 95% C.I. [1.46, 51.25)], p = 0.0250). Amplification was detected in 10 genes in non-responders, whereas responders only had amplifications in AR (7/18) and EGFR (1/18). The most frequently amplified genes in non-responders were AR (8/13), CCNE1 (6/13), EGFR (4/13), and FGFR1 (4/13). Furthermore, in analysis of the 7 patients with paired ctDNA assessments, amplifications increased during treatment with Lu-177. Conclusions: Radioligand therapy with Lu-177 has been shown to prolong life and reduce disease progression. Our analysis of the cohort of Lu-177 treated patients showed that the presence of gene amplifications in ctDNA may play a role in predicting resistance to treatment with Lu-177.
Pathogenic BRAF mutations in prostate cancer: Frequency and distribution.
Authors: Ledet Elisa M. , Mauer Elizabeth , Chao Calvin Y. , Sartor A. Oliver
Published: March 2023

257

Background: Human cancers are known to harbor mutations in BRAF, a rare but clinically significant finding. BRAF p. V600E is the most common hot spot mutation and has been well described, however other activating mutations are less well studied. Herein we evaluate the landscape of BRAF pathogenic/likely pathogenic (P/LP) variations in prostate cancer patients. Methods: De-identified records from patients with primary prostate cancer who underwent NGS with Tempus xF (ctDNA, 105 genes) or xT (tissue, DNAseq of 648 genes, 500× coverage, full transcriptome RNAseq for a subset of patients) were analyzed from a real-world dataset. Results: There were 5,902 patients identified with prostate cancer who underwent any Tempus xT testing, of whom 85 (1.4%) harbored a P/LP BRAF mutation. Of these 85 patients, the most prevalent BRAF mutation identified was BRAF K601E (Lys601Glu) (36% of total), followed by Gly469Ala (18%) and Leu597Arg (8%, Table) There were 4,177 patients identified with primary prostate cancer who underwent any Tempus xF testing, of whom 50 (1.2%) harbored a P/LP BRAF mutation. Similarly, the most prevalent BRAF mutation identified was BRAF K601E (26%). Conclusions: This study presents the first large-scale genomic characterization of BRAF mutations in patients with prostate cancer using both tissue and ctDNA NGS analysis. Among thousands of samples from prostate cancer patients, K601E was the most common BRAF mutation. This confirms findings of smaller studies and has implications for developmental therapeutics. Further studies should document the natural history of BRAF K601E in prostate cancer. [Table: see text]
The impact of genomic biomarkers on a validated clinical risk prediction model for upgrading/upstaging among men with low-risk prostate cancer.
Authors: Braun Avery , Cowan Janet E. , Chan June M. , Neuhaus John , Carroll Peter , Cooperberg Matthew R.
Published: March 2023

262

Background: While active surveillance (AS) is the preferred management strategy for men diagnosed with low-risk prostate cancer (PCa), the inability to distinguish indolent from aggressive tumors in clinically low-risk patients complicates decision-making. Genomic classifiers (GCs) were introduced to improve risk stratification, based on their ability to predict the risk of upgrading or upstaging (UG/US) in this setting. We assessed the impact of GCs on UG/US risk prediction added to a rich clinical model to better guide management decision-making for low-risk patients. Methods: We used multivariate logistic regression and receiver operating characteristic (ROC) curves to develop a prediction model for UG/US in men with low-risk, low-volume intermediate-risk PCa who were potential candidates for AS. The model was developed among 864 men and validated in an independent cohort of 2,267 men with similar risk profiles. After computing areas under the ROC curve (AUC) from these probabilities, we tested the model’s predictive ability with the addition of a series of GCs (OncoType Dx Genomic Prostate Score, Decipher score, and selected Decipher GRID scores) using the logistic model constructed for the development cohort to estimate the predicted probability of UG/US. Results: The prediction model for the development cohort included five diagnostic variables that were significantly associated with risk of UG/US: diagnostic grade (OR 5.83, 95% CI 3.73-9.10), PSA (OR 1.10, 95% CI 1.01-1.20), percent positive cores (OR 1.01, 95% CI 1.01-1.02), TRUS prostate volume (OR 0.98, 95% CI 0.97-0.99), and age (OR 1.05, 95% CI 1.02-1.07). The pooled AUC was 0.72 for 10 iterations of the model. When the addition of GCs was applied to this model, Genomic Prostate Score was independently associated with risk of UG/US (OR 1.42, 95%CI 0.016-0.066, p=0.017). However, the pooled AUC was 0.71, indicating comparable predictive performance to the risk prediction model. Conclusions: The addition of GCs to a validated rich model incorporating detailed clinical variables, when applied to favorable-risk PCa patients, did not substantially improve prediction of UG/US. Our findings suggest that widespread use of biomarkers to guide management or the intensity of follow up may not be supported in men with low-risk, low-volume disease pursuing AS.
Association of exposure of Camp Lejeune contaminated water and prostate cancer outcomes.
Authors: Deshler Leah N. , Morgan Kylie M. , Duran Elizabeth A. , Nelson Tyler J. , Guram Kripa , Rose Brent S
Published: March 2023

265

Background: There is evidence that exposure to contaminated water while serving at Camp Lejeune is associated with the development of genitourinary cancers including kidney and bladder; however, there is a lack of literature regarding prostate cancer (PC). We investigated disease severity at diagnosis, overall survival, and cumulative incidence of metastases for PC patients within the Veterans Health Administration (VHA) who served at Camp Lejeune. Methods: The cohort included men diagnosed with PC between 1999 and 2022 within the VHA Database. Patients who were housed at or had one or more Military Service Episodes between August 1, 1953 and December 31, 1987 at Camp Lejeune were considered to have exposure. Camp Lejeune exposure status and baseline characteristics were ascertained through the VHA electronic health records. Logistic regressions were used to analyze associations between Camp Lejeune exposure and adverse diagnostic characteristics, adjusted for demographic covariates. The outcome of metastases was identified through natural language processing from cancer or radiology documents. Time to metastases was defined as the time from PC diagnosis to metastases, with other causes of death considered as competing risks. The hazard ratio for the association between Camp Lejeune exposure and metastatic disease was calculated with a Cox regression model, controlling for covariates. The difference in overall survival was assessed with the Kaplan-Meier method and log-rank test. Results: The cohort included 6,918 men with PC, 1,635 (23.6%) of which had Camp Lejeune exposure and 5,283 (76.4%) without. Median age at diagnosis was 65 years. Logistic regression models indicated patients with Camp Lejeune exposure have similar odds of having Gleason Score ≥8 at diagnosis (odds ratio (OR) 0.97, p=0.62) and metastasis at diagnosis (OR 1.00, p=0.997), and slightly lower odds of PSA >20 ng/mL at diagnosis (OR 0.78, p=0.02).There were 803 patients with metastatic disease, 159 of which had Camp Lejeune exposure in comparison to the 644 that did not. The 10-year cumulative incidence of metastases for those with Camp Lejeune exposure was 11.9% (CI: 9.9-13.9%), while for those without exposure it was 14.0% (CI: 12.8-15.1%). The Cox proportional hazards model indicated that those with Camp Lejeune exposure had a similar risk of developing metastases (hazard tatio (HR) 0.93, p=0.43) compared to those without exposure. The 10-year overall survival was similar for those with Camp Lejeune exposure (83.3% [CI: 80.7-85.9%]) compared to those without exposure (82.5% [CI: 81.1-83.9%]) (p=0.2). Conclusions: In contrast to kidney and bladder cancers, Camp Lejeune exposure is not associated with worse outcomes for PC. Further research should be conducted to test whether Camp Lejeune exposure affects the risk of developing PC. However, these data do not support Camp Lejeune exposure playing a large role in PC outcomes.
Oncologist-driven development of an electronic health record (EHR) clinical data visualization tool for prostate cancer.
Authors: Ganta Teja , Anker Jonathan Forrest , Miller Eric James , Kannry Joseph , Bhardwaj Aarti Sonia , Tsao Kai , Oh William K.
Published: March 2023

267

Background: Clinical information management is a burdensome process for oncology providers owing to the complexity of modern cancer data. The results that a clinician needs to review are often spread across several areas within the EHR, making it cumbersome to sense a broad overview of patient status. The purpose of this study is to describe a framework for oncologist-driven development of a data visualization tool to trend cancer biomarkers and assess the feasibility of this tool to query and display EHR data relevant for the treatment of prostate cancer. Methods: A clinical sponsor is selected to identify data elements necessary to make treatment decisions for patients receiving therapy for prostate cancer and to provide rapid feedback for the clinical tool interface. The commercial EHR database is queried to determine identifying codes for relevant laboratory tests, medications, and procedures. Data elements are assembled using the EHR platform for clinical synopsis and the clinical tool is made available to five genitourinary medical oncologists for initial pilot. Results: Oral prostate cancer medications were queried based on medication therapeutic and pharmaceutical class. In addition, androgen deprivation therapy (ADT) injections were separately identified based on route of administration. Prostate specific antigen (PSA) and testosterone result values were queried using laboratory base and/or common name codes. However, many duplicate entities are found varying by hospital/laboratory site and test assay. The assembled clinical data visualization tool can overlay temporal trends in PSA and testosterone over medication start/stop dates to convey treatment response and signs of early medication resistance. The clinician also has the option to overlay vital signs or other laboratory information to visualize treatment related adverse events (ex. weight gain related to ADT, anemia related to PARP inhibitor therapy, etc.) Lastly, the tool can also highlight the dates of the patient’s last imaging tests to allow clinicians to determine if the patient is due for any follow up imaging. Conclusions: The EHR can support novel data visualization tools for cancer biomarkers that can reasonably support clinical workflows. Development requires an intimate knowledge of EHR data but may still be limited by duplicate or erroneous codes for laboratory results. This issue may be addressed by using standard nomenclature for laboratory results such as LOINC codes but is not currently supported by the commercial EHR. Future work in this area will include formal usability testing from the perspective of oncology providers and patients.
Racial impact (Asian vs. White) on the prognosis of patients with de novo mCSPC: An analysis on LATITUDE, SEER and NCDB.
Authors: Ni Xudong , Luu Michael , Ma Weiwei , Freedland Stephen J. , Daskivich Timothy , Yao Zhu
Published: March 2023

27

Background: Little is known about the impact of race (Asian or White) on the long-term survival outcomes of men with de novo mCSPC treated with different methods. Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. Methods: This multiple-cohort study included individual patient-level data of men with de novo mCSPC from the following 3 cohorts: LATITUDE clinical trial data (LATITUDE [n=1199]); Surveillance, Epidemiology, and End Results (SEER [n=5496]); and the National Cancer Database (NCDB [n=10366]). Key efficacy outcomes were overall survival (OS) in LATTITUDE and NCDB as well as OS and cancer-specific survival (CSS) in SEER. Kaplan-Meier analysis with propensity score matching (PSM) was used for survival analysis. Hazard ratios were calculated using a multivariate Cox proportional-hazard model. Results: Across all three cohorts, Asian patients diagnosed with de novo mCSPC had better OS and CSS than White patients. In LATITUDE, median OS was significantly longer in Asian than in White men in the ADT+Abiraterone+Prednisone group (not reached vs. 43.8 months, HR 0.47, 95%CI 0.28–0.77, P=0.003 for Cox analysis) as well as in the ADT+placebo group (57.6 months vs. 32.7 months, HR 0.49, 95%CI 0.32–0.75, P=0.001 for cox analysis). In SEER, among all patients diagnosed with de novo mCSPC, median OS was significantly longer in Asian than in White men (53 months vs. 42 months, HR 0.76, 95%CI 0.68–0.85, P<0.001 for Cox analysis). When analyses were restricted to patients who received chemotherapy, Asian men again had longer OS (67 months vs. 41 months, HR 0.70 95% CI 0.51–0.95, P=0.02 for Cox analysis). Using CSS data in SEER resulted in similar conclusions as OS. In NCDB, Asians also had longer OS than White men (whole cohort: 38 months vs. 26 months, HR 0.73, 95%CI 0.63–0.84, P=0.02 for Cox analysis; ADT subgroup: 41 months vs. 26 months, HR 0.75, 95%CI 0.63–0.89, P<0.001 for Cox analysis; Chemotherapy subgroup: 34 months vs. 27 months, HR 0.80, 95%CI 0.69–0.94, P=0.005 for Cox analysis). Conclusions: Asian men had better OS and CSS than White men with mCSPC across different treatment regimens in all datasets examined and should be considered as an independent prognostic factor. This racial difference should also be considered when designing multiregional clinical trials. Further studies including biological analyses are needed to understand the etiology of the apparent survival advantage for Asian men. [Table: see text]
Radiographic-pathologic concordance in the workup of locally radiorecurrent prostate cancer.
Authors: Valle Luca Faustino , Calais Jeremie , Marks Leonard S. , Raman Steven , Reiter Robert Evan , Rettig Matthew , Shen John , Czernin Johannes , Weiner Adam B , Steinberg Michael L. , Nickols Nicholas George , Chang Albert J , Boutros Paul Christopher , Ye Huihui , Hotta Masatoshi , Huang Rong Rong , Kishan Amar Upadhyaya
Published: March 2023

313

Background: Advanced molecular PET/CT (mPET) studies are increasingly being utilized in conjunction with multiparametric MRI (mpMRI) to evaluate the burden of radiorecurrent disease in men who develop a biochemical recurrence following definitive radiotherapy (RT) for prostate cancer (PCa). However, radiographic concordance with pathologic confirmation of radiorecurrent disease in this setting is poorly described. We sought to conduct a patient-level analysis comparing concordance of radiographic and pathologic findings between mpMRI and mPET. Methods: Men who had previously undergone definitive RT for PCa and subsequently experienced treatment failure defined by the Phoenix definition were enrolled in a prospective registry study wherein radiographically identified local PCa recurrences were biopsied using mpMRI or mPET fusion (Artemis) with real-time ultrasound. Prior to biopsy, men underwent diagnostic imaging with mpMRI, advanced mPET (68Ga-PSMA-11 or 18F-FACBC), or both in order to identify a biopsy target. At least one imaging modality had to reveal a recurrent lesion based on PIRADS or PROMISE imaging classifications in order to prompt biopsy. Radiographic and pathologic findings were classified as either “treatment effect” or “recurrent disease”. Using biopsy as the reference standard, positive predictive value (PPV) was evaluated for mpMRI and mPET modalities separately. Results: Of 28 patients with radiographic recurrence on mpMRI or mPET, 10/28 (35.7%) exhibited treatment effect without evidence of active cancer on biopsy confirmation. Prostate adenocarcinoma was identified in 17/28 patient biopsies, whereas small cell prostate cancer was present in 1 patient. All 28 men underwent mpMRI prior to biopsy and 23/28 (82.1%) additionally underwent mPET; 19/23 (82.6%) underwent 68Ga-PSMA-11 and 4/23 (17.4%) were imaged with 18F-FACBC. Concordance in the assessment of recurrent disease between mpMRI and mPET was achieved in 12/23 (52.2%) men who underwent both imaging modalities. Among the 28 men who underwent mpMRI, PPV was 0.84, whereas PPV for the 23 men who underwent mPET was 0.70. Conclusions: In patients for whom clinical suspicion of radiorecurrence was high enough to warrant a biopsy, pre-biopsy mpMRI outperforms mPET in terms of PPV for detecting pathologically confirmed locally radiorecurrent PCa. Used in tandem, mpMRI and mPET might better select appropriate candidates for biopsy than either radiographic modality alone. While advanced mPET remains promising for detecting distant recurrences at the time of RT failure, biopsy confirmation following radiographic detection of local radiorecurrence remains essential for evaluating the true burden of local recurrence.
A national questionnaire survey of Japanese urologists on the treatment perspective for elderly patients with prostate cancer.
Authors: Kato Takuma , Tohi Yoichiro , Honda Tomoko , Matsuda Iori , Osaki Yu , Naito Hirohito , Matsuoka Yuki , Okazoe Homare , Taoka Rikiya , Ueda Nobufumi , Sugimoto Mikio
Published: March 2023

327

Background: Physicians' attitudes toward elderly prostate cancer patients in Japan remain unknown. So, we conduct a national questionnaire survey of Japanese urologists from a treatment perspective for elderly patients with prostate cancer. Methods: A questionnaire was sent to 922 Japanese urological association teaching base hospitals. The following items were included: years of experience as a urologist, gender, workplace, treatment equipment owned, specialty area of daily practice, specialty area of urological cancer, reference items for treatment of the elderly, upper age limit for radical treatment, medication, and two hypothetical cases of Gleason grade Group 2 prostate cancer with or without oligometastasis. For examined the correlation between experience for urological practice and the answer, “not considering the upper age limit”, Cochran-Armitage trend test was used. For comparison of the rate of answering with “not considering the upper age limit” between variables, z-tests were conducted repeatedly and Bonferroni adjustments were made. In this analysis, the statistical significance was set at a P-value <0.05. Results: Altogether, 1,732 questionnaires were analyzed. The responses were almost equally distributed among all age groups. Workplaces included general hospitals (49.4%), university hospitals (40.3%), and cancer centers (4.2%). Performance status was the most frequently referenced item in treating the elderly, followed by the presence of comorbidities and cognitive function. Furthermore, 13.3% of respondents used the geriatric assessment. There was no upper age limit for total prostatectomy, brachytherapy, and external radiation therapy. Antiandrogens, androgen receptor-axis-targeted agents, chemotherapy, PARP inhibitors, and immune-checkpoint inhibitors were selected by 6.8%, 35.6%, 47.3%, 89%, 62.8%, 24.7%, 41.9%, and 41.7% of the respondents, respectively. The answers for the administration of hormone therapy for hypothetical cases of Gleason grade Group 2 prostate cancer with or without oligometastasis were 96.8% and 61.2%, respectively. The answers for the administration of hormone therapy for hypothetical cases of Gleason grade Group 2 prostate cancer with or without oligometastasis were 96.8% and 61.2%, respectively. Conclusions: Fewer than 10% of urologists used geriatric assessments. Many urologists responded that they would set age limits for highly invasive radical and systemic therapies. [Table: see text]
Awareness of genetic risk for prostate cancer (PCa) in men from families with germline mutations in DNA-repair genes.
Authors: Lazzeri Massimo , Fasulo Vittorio , Buffi NicolòMaria , Lughezzani Giovanni , Casale Paolo , Benetti Alessio , Saita Alberto , Hurle Rodolfo , Guazzoni Giorgio Ferruccio , Chiarelli Giuseppe , Asselta Rosanna , Soldà Giulia
Published: March 2023

328

Background: Although one of the most important risk factors for prostate cancer (PCa) is a family history of the disease, there is a poor awareness of genetic risk. The aim of the current study is to investigate the awareness of genetic risk for PCa in men belonging to female families with germline variants in DNA-repair genes (DRGs). Methods: Data were extracted by a prospective observational study designed to select men with germline pathogenic variants (PVs) and offer them a dedicated PCa screening. The selection of probands was performed by genetic counseling and testing of male grade I relatives of female patients with a PVs. Male candidates were identified after reviewing the genealogical trees of all women who had received the diagnosis of breast and/or ovarian cancer and tested positive for a PVs. All the probands, 35-69 yrs old, who resulted positive for PVs were offered to participate to a specific PCa screening based on annually digital rectal examination (DRE), detection of PHI, which is a blood test including total PSA, free PSA, free/total PSA and -2proPSA, and multiparametric MRI. The primary outcome was the “willing to be tested”, defined as a proxy for male awareness of PCa risk. The secondary endpoint was the acceptance rate to be screened. Results: We reviewed the genealogical trees of breast/ovarian cancer female patients from January 2017 to December 2021 and we identified, over 1256 families, 139 positive cases for PVs in DRGs. Among 139 families, we identified 378 “healthy” 35-69 yrs old men, who were offered a genetic counseling, and if they agree a genetic testing. Overall 117/378 (31%) healthy males declared to be interested to be tested. Out of the 51 new tests (66 men already tested out of the study), we found 30 (58.8%) positive men. All the new positive tested men accepted to attend the PCa screening. Living in Northern Italy, having at least one child and higher (degree) level of education were the strongest predictors of willing for testing (p<0.01). Conclusions: Our data reveals a limited will to be tested, but all men tested positive for PVs accepted to participate to the PCa screening. These findings strongly support the urgent need to implement awareness of genetic risk for PCa.
Real world prospective evaluation of clinical outcomes in patients with non-metastatic castrate resistant prostate cancer treated with darolutamide.
Authors: Challapalli Amarnath , Renninson Emily , White Paul , Elumalai Thiraviyam , Parikh Omi , Vickers Alexander , Birtle Alison Jane , Brocklehurst Andrew , Bhana Rajanee , Wickramasinghe Kanchana , Jayaprakash Kamalram Thippu , Gray Emma , Sephton Matthew , Bowzyk Al-Naeeb Anna , Foulstone Emily , Soundy Alexandra , Ashurst Lauren , Bahl Amit
Published: March 2023

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Background: The RECORD Study is a real world data, prospective evaluation of clinical outcomes in patients with nmCRPC treated with Darolutamide. This study will increase the understanding of treatment response and management and in particular inform regarding use of next generation imaging in this setting. Methods: Patient data from 9 UK centres was collected based on the recommendation of NICE for Darolutamide as an option for the treatment of non-metastatic castrate resistant prostate cancer (nmCRPC) from November 2020. Data cut-off was 15 September 2022. The study is ongoing. Results: 87 patients were analysed with a median age of 78 (range 61-92). Median pre-treatment PSA and PSA doubling time (PSAdT) were 13 (range 1.99-110.6) mg/L and 5.05 (range 0.6 - 10) months. 42 patients (49.4%) had pre-treatment PSAdT of <6 months and 43 (50.6%) patients had PSAdT of ≥6 months (2 patients had no pre-treatment PSAdT data). 6 patients (6.90%) had next generation imaging prior to initiation of Darolutamide. Median duration of treatment on Darolutamide was 17 months for patients with pre-treatment PSAdT <6 months but median duration had not been reached for patients with pre-treatment PSAdT ≥6 months after 24 months of treatment, a significant difference p=0.018 (HR=0.385, 95% CI 0.17-0.88). 30 patients have come off treatment so far (34.5%); 21 (70%) for disease progression, 5 (16%) for a medical cause unrelated to the drug (e.g. COVID infection, reduced performance status secondary to pre-existing Parkinson's), 3 (10%) for unacceptable toxicity (rash, Grade3 fatigue, muscle aches, memory issues), and 1 patient died (unrelated). Conclusions: In the RECORD study, predominantly the diagnosis of nmCRPC is based on conventional imaging. The majority of patients respond and tolerate Darolutamide well, comparable with the ARAMIS trial. There is a significant difference between time on Darolutamide for those with pre-treatment PSAdT of <6 months compared with ≥6 months. Further long-term toxicity, MFS and OS data will continue to be collected prospectively within the study.
Sexual function after primary external beam radiation therapy (EBRT) for prostate cancer in a large cohort of men with long-term follow-up.
Authors: Escobar Domenique , Wang Lufan , Banton Jasmin , Cowan Janet E. , Washington Samuel L. , Mohamad Osama , Carroll Peter
Published: March 2023

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Background: Clinically localized prostate cancer can be treated with prostatectomy, radiation or focal therapy, with known impacts on sexual function. We sought to characterize long term sexual function in a large cohort of men treated with primary EBRT and to differentiate between those who have high vs low sexual function scores at baseline. Methods: Patients enrolled in CaPSURE, a national registry of men diagnosed with prostate cancer, from 1995 - 2017 with clinically localized prostate cancer (cN0M0/X, PSA < = 50) and treated with primary EBRT were included. Sexual function (SF) was self-reported using the UCLA Prostate Cancer Index (PCI). We performed repeated measures mixed models to evaluate SF after EBRT, stratified by baseline SF and adjusted for age, BMI, comorbidities, smoking, clinical risk, receipt of brachytherapy and/or hormonal therapy, and type of clinical site. Results: 1193 patients were included for analysis. Mean age was 70, mean number of comorbidities was 2, and median PSA was 7.5 at diagnosis. Baseline PCI scores were available for 43% of the cohort (data not collected before 1998). The mean PCI score was 38 out of 100 at baseline and after EBRT, declined gradually to 16 by 10 years. When only those men with good SF at baseline were assessed (scores 80 – 100), the initial rate of decline was more severe, but the nadir in this group was higher than those with lower baseline scores. Unadjusted mean PCI scores showed a similar decline amongst both groups, although those with good baseline SF consistently had better scores. 63% of patients were treated for erectile dysfunction (PDE5 inhibitors, intracavernosal injections or both), 13% of whom started therapy before EBRT. In the repeated measures mixed models analysis, we found that SF changed significantly over time and scores differed significantly by age, comorbidities, baseline SF, receipt of brachytherapy boost and concurrent ADT. Conclusions: SF after EBRT declines and persists. The most affected are those who had better PCI scores at baseline, although their overall PCI scores are consistently higher compared to those with baseline scores less than 80. Among both groups however, there was a similar decline that was statistically significant.
Major adverse cardiovascular events after androgen deprivation therapy in patients with prostate cancer with hypercholesterolemia.
Authors: Twardowski Przemyslaw , Henry Jacqueline , Atkinson Stuart
Published: March 2023

348

Background: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) may experience major adverse cardiovascular events (MACE). It is unclear how much of MACE is caused by ADT itself. High cholesterol has been associated with lower MACE risk in older men, not on statin therapy. This study evaluates MACE risk after ADT initiation for patients with and without hypercholesterolemia using real-world data. Methods: US electronic medical records (2010-2020) of PCa patients (n=45,059) receiving LHRH agonist/antagonist injections were analyzed to calculate the risk of MACE since ADT initiation in patients with and without hypercholesterolemia. Hypercholesterolemia was defined as having taken hypercholesterolemia medication or diagnosis with hypercholesterolemia prior to the first MACE event after ADT start. Exclusion criteria included lack of ADT initiation date or MACE within six months prior to ADT initiation. MACE was defined as myocardial infarction, stroke, and death from any cause. Kaplan-Meier event-free survival curves and cox regression were used to compare MACE risk between patients with and without hypercholesterolemia. Results: The dataset contained 178,388 LHRH injection entries and 7,681 MACE. MACE risk was only 1.8% lower (19.0% vs 20.8%) after 4 years for patients with hypercholesterolemia compared to those without (across 10 years, unadjusted: HR=0.88, 95% CI [0.83, 0.92] and adjusted: HR=0.85, 95% CI [0.77, 0.94]). Conclusions: Patients with hypercholesterolemia appear to have slightly lower MACE rates. This may be due to the use of statins, which can reduce the incidence of CV events in a general population. Our analysis of data over the most recent decade from ~45,000 PCa patients is likely an accurate reflection of the real world. Clinicians should monitor PCa patients with underlying CV risk factors and help educate them on lifestyle changes that could impact treatment outcomes.
Major adverse cardiovascular event risk following androgen deprivation therapy initiation by personal history of cardiovascular events.
Authors: Lee Andrew , Henry Jacqueline , Atkinson Stuart
Published: March 2023

351

Background: Associations between androgen deprivation therapy (ADT) and increased cardiovascular (CV) risk in prostate cancer (PCa) patients have been reported; however, how many of these major adverse CV events (MACE) are caused by ADT itself has been debated. One risk factor for increased CV risk is a prior history of CV events; an analysis found that each new CV event increased the probability of a future event. This study aims to evaluate the incidence of MACE after ADT initiation for patients with and without a prior medical history of MACE. Methods: Analyses of US electronic medical records (2010 to 2020) of PCa patients (n=45,059) receiving LHRH agonist and antagonist injections were conducted to evaluate MACE incidence after ADT initiation in patients with and without MACE history. Exclusion criteria included lack of ADT initiation date or myocardial infarction (MI)/stroke within 6 months prior to ADT initiation. MACE was defined as MI, stroke, and death from any cause. Kaplan-Meier event-free survival curves were constructed, and Cox regression was used to compare the MACE hazard rates between patients with and without a personal history of MACE. Multivariate Cox regression adjusted for agonists vs antagonist, increasing age per year, BMI (<18.5 vs ≥18.5 kg/m2), race (White vs Black), family MACE history, ethnicity (Hispanic vs non-Hispanic), urology vs oncology setting, history of hypertension, and history of hypercholesterolemia. Results: Overall, MACE incidence was 3.9% and 19.6% for the cohort at one year and four years after ADT initiation, respectively. MACE risk following ADT initiation was higher for patients with history of prior MACE (unadjusted: (HR=2.76, 95% CI [2.49, 3.06], p<0.001); adjusted: HR=2.29, 95% CI [1.93, 2.71], p<0.001). When MACE was divided into component events, the risks of myocardial infarction and stroke were higher for patients with a prior MACE history compared to those without (8 vs. 1% and 8 vs. 2%, respectively), and the risk of any-cause death was similar (13 vs. 14%). Conclusions: MACE incidence in PCa patients in the first year of ADT was consistent with previous publications.(3). When MACE risk was analyzed in detail, ADT patients with a personal history of stroke or myocardial infarction (MI) had a 4- and 8-fold greater risk of a subsequent stroke and MI, respectively, compared to those without a history of stroke or MI. Given the large sample size (~45,000 PCa patients) of this data set over the recent past decade, these results likely reasonably reflect the real world. Urologists and oncologists should work with cardiologists, cardio-oncologists, and primary care practitioners to ensure the highest quality CV care is delivered.
Oncological outcomes with wide resection in robot-assisted radical prostatectomy as primary treatment for very high-risk prostate cancer.
Authors: Miura Noriyoshi , Hashine Katsuyoshi , Watanabe Ryuta , Noda Terutaka , Nishimura Kenichi , Fukumoto Tetsuya , Miyauchi Yuki , Kikugawa Tadahiko , Tacho Takatoshi , Yanagaki Takahiro , Oka Akihiro , Takeda Hajime , Watanabe Yuichi , Ninomiya Iku , Shirato Akitomi , Saika Takashi
Published: March 2023

357

Background: Patients with very high-risk prostate cancer (VHRPCa) have earlier biochemical recurrences (BCRs) and higher mortality rates. It remains unclear whether extended robot-assisted radical prostatectomy (eRARP) with intended wide resection can improve the outcomes of VHRPCa patients. We aimed to compare the oncological outcomes of eRARP versus standard RALP (sRARP) for primary treatment of VHRPCa. Methods: We retrospectively evaluated 168 patients classified by the National Comprehensive Cancer Network (NCCN) as very high-risk who were treated with RARP without neoadjuvant/adjuvant therapy between September 2011 and December 2020. eRARP was performed using the extra-fascial approach as reported by Gandaglia G et al. (Eur Urol. 71:249-256, 2017). We performed 1:1 propensity score matching to account for potential differences between eRARP and sRARP. Kaplan-Meier analysis and Cox regression models were used to test the effect of eRARP on the biochemical progression-free survival (bPFS). This observational study was approved by the Institutional Review Board. Results: There were 93 patients in the eRARP group and 75 in the sRARP group. The eRARP group had a worse clinical stage than the sRARP group ( p< 0.001). Age, pretreatment prostate specific antigen (PSA), and pretreatment Gleason score were similar in the two groups. All patients in the eRARP group underwent pelvic lymph node dissection, compared with 89% in the sRARP group. The propensity-adjusted 3-year biochemical recurrence-free survival rates was 31.4% in the sRARP group and 67.4% in the eRARP group(p=0.001), respectively. The adjusted Cox regression analysis showed that the eRARP group had a significantly longer bPFS than the sRARP group (hazard ratio 0.415, p=0.0047). Conclusions: In patients with VHRPCa, eRARP was associated with a reduce risk of biochemical recurrence. These results suggest that eRARP may improve oncological outcomes in VHRPCa.