bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of a multigenomic liquid biopsy (PROSTest) for prostate cancer detection.
Authors: Modlin Irvin Mark , Kidd Mark , Drozdov Ignat A. , Boegemann Martin , Bodei Lisa , Kunikowska Jolanta , Malczewska Anna , Bernemann Christof , Rahbar Kambiz
Published: March 2023

252

Background: A crucial requirement in prostate cancer (PCa) management is an accurate, easily measurable, liquid biopsy that can define the molecular pathology of an individual PCa. We report the development and clinical validation of a novel PCa-specific, multi-genomic biomarker. Methods: We identified candidate mRNA biomarkers in PCa-Adeno transcriptomes ( n=1,159) using several strategies: co-expression networks, differential expression, and functional enrichment. mRNA transcripts were screened in an independent tumor tissue ( n=50) set and validated as biomarkers in the TCGA-PRAD ( n=500) dataset. An amalgam of Random Forest, Gradient Boosted Machines and Support Vector Machines, all standard machine learning classifiers, was used to develop a classification algorithm and probability score in a peripheral blood gene expression test cohort ( n=430). This multigene biomarker was validated in two independent clinical blood sample sets (Set I: PCa n=77, controls n=54; Set II: PCa n=132, controls/BPH n=99) to determine as PCa-specificity and diagnostic efficacy Clinical utility was evaluated versus Gleason scores, T-staging and PSA ( n=209) and in a prostatectomy cohort ( n=47). Results: The pipeline identified 27 of PCa gene markers in the tumor tissue set and TCGA-PRAD dataset. Gene expression was significantly correlated ( r=0.72, p<0.0001) in matched tissue/blood samples. The PROSTest (scale: 0-100) ensemble algorithm (developed in blood) had a sensitivity for PCa of 92.2% (95% CI: 83.8-97.1%; Set I) and 95.0% (95% CI: 89.9-98%. Set II). The specificity was 100% for Set I (95% CI: 93.4-100%) and 100% for Set II (95% CI: 96.3-100%). PCa scores were significantly ( p<0.0001) lower for controls (Set I: 17±4; Set II: 18±4) and BPH (19±6) to PCa; 82±19 (Set I) and 80±19 (Set II). The AUROC was 0.98±0.01. PROSTest scores were elevated ( p<0.05) in T2-4 and were significantly correlated with Gleason ( r=0.93, p<0.02). In contrast, PSA from matched samples was not associated ( p=NS) with clinically significant disease (Gleason 7-10 or T2-4 tumors). In head-to-head comparisons, the PROSTest was considerably more accurate than PSA for detecting significant disease (z-statistic: 2.43, p=0.015). In the R0 prostatectomy cohort, all scores were elevated (72±7) and significantly decreased post-surgery (26±8, p<0.0001, n=37). Individuals with residual disease ( n=10) exhibited elevated (60±4) post-surgical scores. Conclusions: The PROSTEst is a multigenomic blood-based PCR tool that accurately (>90%) identifies prostate cancer. It is significantly more accurate than PSA for the detection and stratification of clinically significant prostate disease. A multigenomic liquid biopsy for PCA provides a real-time, non-invasive method for detection of a PCa and may facilitate the early identification of residual/recurrent disease.
Evaluation of ctDNA in patients with CRPC with pathogenic germline mutations in BRCA2.
Authors: Huang Minqi , Jaeger Ellen B. , Caputo Sydney , Casado Crystal , Jang Albert , Sweeney Patrick L , Lanka Sree M , Gupta Kanika , Lieberman Alexandra , Schwartz Jennifer , Pocha Olivia , Hawkins Maddie , Miller Patrick , Layton Jodi Lyn , Lewis Brian E. , Barata Pedro C. , Ledet Elisa M. , Sartor A. Oliver
Published: March 2023

253

Background: Approximately 3-5% of advanced prostate cancer patients have pathogenic BRCA2 mutations in germline tests. In this study, we examine the relationship between pathogenic germline BRCA2 mutation and somatic changes in ctDNA. Methods: Germline screenings were performed by Invitae multi-cancer gene panel which includes 50-84 genes. ctDNA alterations were detected by Guardant 360 assays which report somatic changes in 70-83 genes. All ctDNA samples were collected in post-abiraterone and/or enzalutamide (in CRPC patients). Any pathogenic/likely pathogenic somatic alterations in the ctDNAs with more than 0.1% of allelic fraction were included in this cohort. The type of mutation detected in ctDNA was also assessed (truncating, point, etc.). Statistical significance for comparison is calculated with Fischer Exact Probablity Test and Chi-Square Test. Results: A total of 11 patients had germline BRCA2 pathogenic mutations and ctDNA assays; 267 patients had no germline DNA pathogenic alterations and ctDNA assays. Compared to germline normal patients, the germline BRCA2 mutations were less likely to have AR alterations on ctDNA (OR=0.2133, 95% C.I. [0.087, 0.525], p-value = 0.0003). BRCA2 germline positive patients were also more likely to have a mutated BRCA1, BRCA2, and TP53 ctDNA (OR=7.899, 95% C.I. [1.2745, 48.9548], p=0.055), (OR=7.899, 95% C.I. [1.7529, 16.059], p=0.008), and (OR=6.442, 95% C.I. [2.449, 16.946], p=0.00001), respectively. All other ctDNA assessed genes were mutated at a similar frequency between germline BRCA2 mutated and “normal” germline patients. BRCA2 germline mutations patients are less likely to have copy number alterations (CNVs) (OR=0.3992, 95% C.I. [0.2168, 0.7352], p=0.0031) and more likely to have frameshift mutations (OR=2.3182, 95% C.I. [1.169, 4.5972], p=0.0183). Conclusions: The ctDNA testing in this CRPC population (after abiraterone and/or enzalutamide) was less likely to find AR alterations and more likely to find pathogenic mutations for BRCA1, BRCA2, and TP53 in BRCA2 germline positive patients. In addition, BRCA2 germline positive CRPC patients were more likely to have frameshift mutations and less likely to have CNVs than those with an intact germline. Characterizing the mutational landscape in BRCA2 germline mutated patients may help to better define underlying disease biology. Those with BRCA mutated germline may be less likely to have AR driven tumors. More study is needed to better understand patients with underlying DNA repair defects.
Natural killer cell activity in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Zedan Ahmed , Nederby Line , Volmer Lone , Madsen Christine Vestergaard , Sørensen Bente E. , Hansen Torben
Published: March 2023

255

Background: Metastatic castration resistant prostate cancer (mCRPC) is the lethal stage for most patients with prostate cancer (PCa). The need for more reliable prognostic and predictive markers for the management of mCRPC is still unmet. The aim of this study was to elucidate the correlation between Natural Killer cell activity (NKA) and treatment outcome in mCRPC patients. Methods: Blood samples were collected prospectively from 87 patients with mCRPC who were treated by enzalutamide as first line treatment. Samples were collected, in NK Vue tubes, at baseline, and prior to each treatment cycle until treatment change. Tubes were placed in an incubator at 37°C within 15 minutes of sampling. Following 20-24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured, by ELISA (NK Vue) as a surrogate for NKA. Outcomes data were included as endpoints. Results: At the time of biochemical response, plasma IFNγ decreased significantly compared to levels detected at baseline (z-score= 2.334, p=0.019). Additionally, the level of IFNγ was significantly lower at radiological response compared to values at biochemical progression (z-score=2.168, p=0.030). Regarding outcome data, the whole cohort was divided into four groups. In group 1 (n=41) the IFNγ level remained within a normal range (>250 pg/mL), while in group 2 (n=8) it increased from an abnormal (<250 pg/mL) to a normal level. In group 3 (n=13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n=17). There was a significant difference between patients in group 2 and patients in the other three groups regarding both overall survival, radiological free survival and time to next treatment (HR= 3.98, p= 0.012, HR= 6.10, p=< 0.001 and HR= 6.521, p= < 0.001, compared to group 1 respectively). Conclusions: An inverse correlation between NKA and both treatment response and outcome was observed, suggesting a unique role of NK cells in late stage PCa treated with enzalutamide.
Single and multi-hit PIK3CA short variant (SV) genomic alterations (GA) in clinically advanced prostate cancer (CAPC): A genomic landscape study.
Authors: Miguel Carla , Bratslavsky Gennady , Jacob Joseph M , Grivas Petros , Spiess Philippe E. , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Graf Ryon , Vasan Neil , Ross Jeffrey S.
Published: March 2023

258

Background: Tumors harboring 2 or more PIK3CA Short variants (SV) (“Multi-hit”) have been described in breast cancer as linked to enhanced clinical outcome from anti-PIK3CA targeted therapies including alpelisib and investigational agents in clinical trials. The landscape and clinical implications of multi-hit PIK3CA alterations in other tumors, including in CAPC, are underexplored. Methods: 19,978 CAPC samples underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of GA and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, signature and loss of heterozygosity (gLOH). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 18,741 (93.8%) CAPC were PIK3CA wild type (WT), 1,155 (5.8%) featured a single PIK3CA SV and 82 (0.4%) featured multi-hit PIK3CA SVs. The median ages of CAPC patients with single hit (69.1 yrs) or multi-hit (68.7 yrs) PIK3CA SV were older than the PIK3CA WT (67.6 yrs) CAPC (p<.0001 for both). At 14.0%, African ancestry was more frequent in PIK3CA WT CAPC than in single-hit (10.4%; p=.001) and multi-hit (10.2%; not significant). Single-hit (81.4%; p<.0001) and multi-hit (85.2% p=.05) PIK3CA SV CAPC featured significantly more MMR trinucleotide genomic signatures than PIK3CA WT (64.8%). Single-hit (2.7%; p=.02) and multi-hit (5.8% p=.05) PIK3CA SV CAPC featured significantly more POLE trinucleotide genomic signatures than PIK3CA WT (0.4%). MSI high status was significantly more common in both PIK3CA single-hit (12.4% vs 2.5%; p<.0001) and multi-hit (35.4% vs 2.5%; p<.0001). Mean TMB was also significantly higher in single-hit PIK3CA (11.1 vs 3.5 mut/Mb; p<.0001) and multi-hit (42.9 vs 3.5 mut/Mb; p<.0001). Noteworthy differences in GA of potential importance for CAPC pts included significantly higher frequencies of GA in BRCA2 in multi-hit vs WT (18.3% vs 8.5%; p=.019), ATM in multi-hit vs WT (13.4% vs 5.6%; p=.02) and PTEN in single-hit vs WT (40.2% vs 30.1%; p<.0001) and lower frequencies of GA in CDK12 (3.6% vs 5.6%; p=.009) and SPOP (7.4% vs 9.8%; p=.012) in single-hit vs WT. There were no differences in gLOH or PD-L1 expression among the 3 groups. Conclusions: Although uncommon, the identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique subtype of this disease that may be associated with enhanced responsiveness to anti-PIK3CA targeted therapy strategies.
A cohort study evaluating the clinical, environmental and genetic profiles of men with early-onset, aggressive prostate cancer.
Authors: Fenton Sarah Elizabeth , Kocherginsky Masha , VanderWeele David James , Morgans Alicia K. , Palmbos Phillip Lee , Meeks Joshua J , Benning James , Kenny Siobhan , Martone Brenda K. , Szymaniak Brittany , Hussain Maha H. A.
Published: March 2023

266

Background: The frequency of young men with aggressive prostate cancer (PC) at diagnosis is increasing. Clinical, environmental, and genetic drivers of this change have not been well characterized. Methods: This multi-institutional study evaluated two cohorts; Cohort 1 completed enrollment and is reported here. Eligible patients (pts) had early-onset (age ≤ 60 years) PC with metastasis (N+ or M+) at diagnosis, or within 5 years of curative intent local therapy. Data were collected to define clinical, environmental, and genetic profiles, including ctDNA and whole genome and transcriptome sequencing using Tempus xE. Standard descriptive statistics were used. Results: 46 pts were enrolled. Median age at diagnosis was 55 (range 41-60 years); 85% were White, 15% were Black; 4% served in the military and 4% reported biochemical exposure. 85% reported a family history of cancer, 46% had family history of PC. Median PSA at diagnosis was 19 (range 1-534 ng/mL), 56% had a Gleason score of 9-10, and 56% had de novo metastatic PC. 46% had prior local therapy. Genetic data is available for 40 pts. The most frequent clinically significant mutations (≥10% for somatic, ≥2.5% for germline) are summarized. 23 unique germline and over 1,000 unique somatic mutations were identified. Germline mutations associated with hereditary PC were found in 15%, all were associated with DNA damage repair (DDR). Somatic mutations in DDR genes were found in 10%. Co-mutations in TP53 and BRAF were seen in 30%. Interestingly, there were also incidental germline mutations identified that are associated with cardiac ( MYBPC, MYH7) and vascular ( MYH11, ACTA2) conditions, among others. Conclusions: In this cohort study we identified an unexpectedly high frequency of family histories that were positive for cancer (85%), and specifically PC (46%). However, rates of germline mutations associated with hereditary PC were similar to previous studies (15%), suggesting the possibility that other novel hereditary mutations driving increased PC risk may be present. Increased rates of somatic mutations in BRAF (35%) were also seen. The high frequency of BRAF mutations, particularly those that co-occur with TP53 mutations, may be driving more aggressive disease. We also found enrichment of mutations associated with non-cancer hereditary syndromes, including hypertrophic cardiomyopathy. These are not usually included in cancer-focused genetic studies, suggesting broader testing that includes potentially actionable incidental findings should be considered. More work is needed to define characteristics of this high-risk population and optimize management. [Table: see text]
Racial differences in survival and healthcare resource utilization among Medicaid-insured adults with metastatic castration-resistant prostate cancer.
Authors: DerSarkissian Maral , Gupta Deepshekhar , Ivanova Jasmina , Niyazov Alexander , Zanardo Enrico , Guo Tracy , Wang Jingru , Duh Mei Sheng , Freedland Stephen J.
Published: March 2023

29

Background: Prostate cancer (PC) disproportionately affects Black or African American (BAA) men in the United States (US), but racial disparities in outcomes are not well understood. This study analyzed racial disparities in OS, healthcare resource utilization (HRU), and PC treatments in Medicaid-insured metastatic castration resistant PC (mCRPC) patients. Methods: This retrospective longitudinal cohort study evaluated de-identified data from the Centers for Medicare and Medicaid Services 100% Medicaid data files from 01/01/2010 – 12/31/2018. The study included adult patients with a diagnosis of PC and metastasis, and a claim for at least one of the following drugs prior to 9/30/2018, which is specific to mCRPC (date defined index): ≥1 claim for cabazitaxel, mitoxantrone, enzalutamide, radium-223, or sipuleucel-T, ≥1 claim for abiraterone acetate before June 2017, ≥1 claim for docetaxel at least 90 days after initiation of hormone therapy, or evidence of castration resistance. Patients were required to be continuously enrolled for ≥6 months pre-index (i.e., baseline period) and ≥3 months post-index. Outcomes were assessed from the index date to the earliest of end of continuous enrollment, data availability, or death. A multivariable Cox proportional hazards model of OS, and a multivariable Poisson model of HRU were implemented and controlled for age, plan type, region, median state income, residence in a state with Medicaid expansion, index year, Charlson comorbidity index, baseline HRU, baseline PC treatments, and clinical characteristics. Results: The study included 1,095 mCRPC patients (320 [29%] White [W], 278 [25%] BAA, 190 [17%] Hispanic [H], 307 [28%] Other races [O]). H had the highest mean age of 69 years, followed by 68 years for O, and 63 years for both W and BAA. Median unadjusted OS was 46.7 months in H, 40.5 months in BAA, 35.3 months in O, and 32.3 months in W. After adjustment, H had significantly lower risk of death vs. W (hazard ratio [95% confidence interval (CI)]: 0.62 [0.42, 0.90]) and BAA had comparable survival to W (0.85 [0.62, 1.16]). BAA had significantly fewer PC-related outpatient (OP) visits vs. W (adjusted incidence rate ratios [IRR] [95% CI]: 0.67 [0.48, 0.93]), but significantly more PC-related emergency room (ER) visits (5.03 [2.03, 12.47]) per patient per year. Race cohorts differed in the proportions of patients treated with novel hormonal therapy (70% W, 63% BAA, 58% H, 67% O) and chemotherapy use (29% BAA, 26% H, 24% W, 19% O). Conclusions: Among Medicaid-insured adult mCRPC patients, H were more likely to live longer than W patients, while BAA and W patients had similar OS. BAA patients had a higher rate of PC-related ER visits but fewer PC-related OP visits as compared to W, showing differential use of PC-related healthcare resources.
Genomic profiling between Hispanic Americans (HA) and non-Hispanic (NHW) with advanced prostate cancer: A retrospective analysis of tissue, liquid, and germline testing.
Authors: Dhaliwal Armaan , Taylor Megan Kathleen , Bertolo Aaron , Estrada-Mendizabal Ricardo J. , Saboda Kathylynn , Roe Denise , Chipollini Juan , Heimark Ronald , Batai Ken , Boiles Alejandro Recio
Published: March 2023

30

Background: Genomic testing through the employment of somatic and germline testing has become increasingly relevant in determining the prognosis and targeted therapies for advanced prostate cancer patients. Prostate cancer health disparities resulting in worse presentations and clinical outcomes have been observed in HA compared to NHW. Understanding the prevalence of different genomic alterations is paramount to bridge the gap between the two ethnic groups. Methods: This is a retrospective analysis of 190 metastatic prostate adenocarcinoma patients with 24.2% HA who presented to the University of Arizona Cancer Center from 2015 to 2022. Patients in both groups may have undergone more than one type of testing. Homologous recombination repair (HRR) included ATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCA/L, HDAC2, PALB2, RAD-51B/1C/51D, or 54L. Tissue-agnostic therapy approvals are dMMR, MSI-H, TMB-High, BRAF V600E, and NTRK/RET fusion. The proportion of HA and NHW was determined, and the statistical significance of the differences was reported using Chi2 or Fisher’s Exact test. Results: 43.6%, 34.7%, and 38.9% of patients had somatic tissue, liquid, and germline testing, respectively analyzed for pathogenic variants. TMB-High >10 (30% vs 3.6%, p=0.02), PD-L1 CPS>5 (9.4% vs 0%, p=0.03) and TMPRSS2-ERG fusion (37.5 vs 7.8%, p=0.0009) had higher proportion in HA compared to NHW. No test showed a difference in BRCA 1/2 or another HRR deficiency actionable mutation between the two ethnicities. There were no other statistically significant differences in common mutations or variants of unknown significance among groups. Conclusions: Liquid and tissue biopsies indicated a difference in proportions for tissue-agnostic and immune-oncology therapeutic indications, being more prevalent in HA. TMPRSS2-ERG fusions have differences in PC development and progression by race and now potentially by ethnicity, as shown by our study. Our review revealed increased germline and somatic testing over time according to targeted therapies approval and guideline recommendations, although, there remains a critical need for advancing genomic sequencing efforts for underrepresented HA. The Hispanic Americans Prostate Cancer Comprehensive Genomic Profiling Study's (THAPCA-GPS) future investigations aim to delineate the pathogenetic differences between HA and NHW and may reduce healthcare disparities and improve clinical outcomes in HA patients. [Table: see text]
Persistent need for systematic biopsy for those on active surveillance for early-stage prostate cancer.
Authors: Fakunle Mary , Cowan Janet E. , Washington Samuel L. , Nguyen Hao G , Cooperberg Matthew R. , Carroll Peter
Published: March 2023

322

Background: Serial biopsy is a mainstay of surveillance for patients on active surveillance for prostate cancer. mpMRI targeting has become a standard for targeting lesions during biopsy as it allows for better identification of the dominant lesion (grade and/or volume). It is unclear whether “targeted biopsy” alone reliably identifies the dominant lesion on serial biopsy, thereby obviating the need for systematic biopsy. The aim of this study was to assess whether targeting alone can consistently identify the dominant lesion on serial biopsies for active surveillance. Methods: Participants enrolled in active surveillance with early-stage prostate cancer (PSA <20, cT1-2, GG1 and 2) at diagnosis and underwent two or more MR fusion biopsy sessions that include both systematic and targeted sampling. Timing and frequency of Gleason upgrading were assessed. Grade and sextant location within the prostate were compared between the systematic and targeted cores to determine concordance. Results: Of 619 men who had multiple MR targeted biopsies, 80% were GG 1 at time of diagnosis and 20% were GG 2. Fifteen percent had their first MR fusion biopsy as their diagnostic, 41% on confirmatory biopsy, and 44% on subsequent surveillance biopsy. The highest grade was sampled by MR targeting from 70% to 91% of the time. In a subset of 106 men with GG1 at first MR fusion biopsy and a subsequent MR fusion biopsy within 36 months, Gleason upgrading was detected in 47 men (44%) on the 2nd MR fusion biopsy. When comparing upgrading between systematic and MRI targeting, 20 men (42%) upgraded inside the target only. Twenty-one men (45%) upgraded on both systematic and MR targeted biopsy. And 6 men (13%) upgraded on systematic biopsy only. Conclusions: In those with serial MR-targeted biopsies, targeting alone identified a majority of upgrading. However, it missed a portion of with upgrading outside the target. This suggests that those on active surveillance, with MR targets, still benefit from systematic biopsies.
Impact of MRI and targeted biopsy on oncological outcomes of prostate cancer after treatment.
Authors: Debnath Neha , Tayebi Shima , Tobler Juliana , Verma Sadhna , Sidana Abhinav
Published: March 2023

323

Background: To determine the impact of pre-biopsy prostate MRI followed by a targeted biopsy (TBx) approach for initial diagnosis on oncological outcomes after prostate cancer (PCa) treatment. Methods: We performed a retrospective review of all patients who underwent prostate biopsy followed by radiation therapy (RT) or radical prostatectomy (RP) as their first treatment from 2014-2020. Patients were separated into two cohorts based on the diagnostic approach: pre-biopsy prostate MRI during the initial evaluation and those who did not receive MRI. Patients with positive MRI findings underwent a combination of TBx and systematic biopsy (SBx) to confirm the diagnosis, while those without MRI underwent SBx only. Patients with PSA >20 were excluded. Kaplan-Meier curve analysis was used to compare biochemical recurrence (BCR, defined as PSA > 0.2ng/ml after RP or a rise of 2ng/ml after RT) between cohorts. Cox proportional hazard analysis was done to determine the predictors of the BCR. Results: 366 patients (174 diagnosed by SBx only, and 192 diagnosed by pre-biopsy MRI and TBx) with a median follow-up of 40 months were included in the study. 245 men (67%) had RP as their first treatment. Median age and PSA were 64.7 and 7.9, respectively in the SBx cohort and 65.0 and 8.3, respectively in the TBx cohort. There was a significant difference in BCR rate between the TBx (7.98%) versus SBx (19.28%, p<0.05 by log-rank). After adjusting for age, race, PSA, biopsy path, DRE, and family hx, pre-biopsy the MRI and TBx approach for diagnosis was found to be an independent negative predictor (p=0.001); with patients diagnosed with the above approach 71% less likely to have BCR during the study period. Conclusions: Our study shows that patients undergoing pre-biopsy MRI followed by TBx have lower rates of biochemical recurrence compared to men diagnosed without pre-biopsy MRI. To our knowledge, this study is the first to show the positive impact of pre-biopsy MRI on oncological outcomes, likely due to its role in risk stratification, treatment selection, surgical staging, and planning. Further longitudinal studies are needed to discern the true long-term benefits of pre-biopsy MRI on oncological outcomes.
Real-world clinical outcomes of patients with localized prostate cancer (LPC) treated with external beam radiation therapy (EBRT).
Authors: Karsh Lawrence Ivan , Du Shawn , He Jinghua , Waters Dexter , Muser Erik , Shore Neal D.
Published: March 2023

330

Background: Patients (pts) with localized prostate cancer (LPC) or locally advanced prostate cancer (PC) have several treatment options, including external beam radiation therapy (EBRT) and radical prostatectomy, which can be curative in some pts. However, limited real-world evidence exists on the long-term clinical outcomes of these pts, particularly those with high-risk LPC (HRLPC). This study examines real-world clinical outcomes for HRLPC and low/intermediate risk LPC (LIRLPC) pts treated with EBRT in the US. Methods: A retrospective study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked registry-claims data from 2012−2019 included LPC pts aged ≥65 treated with EBRT as initial definitive therapy. Baseline demographic and clinical characteristics were summarized for HRLPC and LIRLPC pts. Clinical outcomes of interest (overall survival, metastasis-free survival [MFS] and time to initiation of advanced PC treatment) were compared using Kaplan-Meier (KM) and Cox proportional hazards (PH) models. Results: Of 11,127 LPC pts treated with EBRT within 6 months of LPC diagnosis, ~40% (n=4,414) were HRLPC and ~60% (N=6,713) were LIRLPC. Patient characteristics for both groups appeared similar, with mean age at EBRT initiation >70 years, 86% white, and mean follow-up time >40 months. ADT was used with EBRT in 78% HRLPC and 34% LIRLPC. Median (IQR) duration of ADT therapy (via KM analysis) was 9.9 (5.8, 21.5) months for HRLPC and 7.2 (5.3, 9.8) months for LIRLPC. A higher proportion of HRLPC vs LIRLPC pts experienced metastasis, death, and progression to advanced PC therapies (medians were not reached). Unadjusted Cox PH survival analyses showed higher risk of mortality, metastasis, and advanced PC therapy use for HRLPC vs LIRLPC pts. Conclusions: This real-world study of clinical outcomes in pts with HRLPC and LIRLPC treated with EBRT suggested substantial additional disease burden in pts with HRLPC and highlights the need for additional strategies and treatments to improve clinical outcomes in pts with HRLPC. [Table: see text]
Survival outcomes in metastatic castration-resistant prostate cancer in the up-front treatment era.
Authors: Kamijo Shunsuke , Naito Yushi , Kato Masashi , Yamamoto Akiyuki , Tsuzuki Toyonori
Published: March 2023

336

Background: Several studies have shown that the survival outcome of patients with metastatic prostate cancer after progression to metastatic castration-resistant prostate cancer (mCRPC) appears to be independent of a variety of prognostic factors, suggesting that prolonged time-to-CRPC is important for overall survival. However, the findings of these studies are based on data before the clinical application of up-front therapies such as docetaxel, abiraterone, enzalutamide, and apalutamide for hormone-sensitive metastatic prostate cancer (mHSPC), and the survival of patients with mCRPC with disease progression on up-front treatment has not been fully investigated. Methods: We retrospectively identified 318 patients diagnosed with treatment-naïve mHSPC between March 2014 and January 2022 from our database of 13 affiliated institutions. The patients included in this study were those who received the first-line treatment for mHSPC and progressed to mCRPC and received a second-line treatment. We defined the up-front group as patients who received abiraterone, apalutamide, or enzalutamide in addition to androgen deprivation therapy (ADT) as the first-line treatment for mHSPC, and the vintage group as patients who received ADT alone or bicalutamide or flutamide in addition to ADT. We compared the time-to-CRPC in each group, i.e., the time from diagnosis of mHSPC to progression to mCRPC. We also compared the overall survival (OS) after CRPC and the progression-free survival (PFS) after CRPC, calculated from the diagnosis of castration resistance, between the up-front group and the vintage group. To minimize selection bias, we performed propensity score matching between the up-front group and vintage group and adjusted for covariates such as age, metastatic burden, and Gleason score. Results: Of the 318 patients, 100 were in the up-front group and 218 in the vintage group. Fifteen of the up-front group and 205 of the vintage group progressed to mCRPC within the observation period and received second-line treatment. Fourteen patients from each group were extracted for the analysis of survival after CRPC by propensity score matching, and the clinicopathologic variables in each group were well balanced. In the analysis of the propensity score-matched cohort, time-to-CRPC was significantly prolonged in the up-front group compared to the vintage group (median, not-reached vs. 10.7 months; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.12-0.28; p<0.001), while OS after CRPC (median, 18.2 months vs. not-reached; HR, 13.80; 95% CI, 1.52-125.10; p=0.019) and PFS after CRPC (median, 4.7 months vs. not-reached; HR, 7.73; 95% CI, 2.05-229.19; p=0.003) were significantly shortened in the up-front group. Conclusions: Although overall survival of mHSPC has improved in the up-front therapy era compared to the vintage hormonal therapy era, survival after disease progression to mCRPC may be shortened.
Impact of psychological distress on emergency room utilization and mortality among prostate cancer survivors.
Authors: Jiang Changchuan , Chidester Kaitlin , Sanders Alexandra , Perimbeti Stuthi , Deng Lei , Jatwani Karan , Roy Arya Mariam , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

343

Background: The population of prostate cancer (PCa) survivors has grown over the recent decades, with many reporting long-term treatment-related physical, emotional, and financial adverse effects resulting in greater psychological distress compared to males without a history of PCa. This study analyzes the prevalence of psychological distress among PCa survivors and its impact on emergency room (ER) utilization and overall survival. Methods: We identified a cohort of 3,453 PCa survivors from the 2000-2018 National Health Interview Survey (NHIS) linked to the National Death Index Mortality Files through Dec 31, 2019. Deaths that occurred during the first two years of follow-up were excluded from analyses to minimize the likelihood of reverse causation. The Kessler Psychological Distress Scale (K6) was used to quantify psychological distress. Severe, moderate, and none/low mental distress have been validated for thresholds K6≥13, 13> K6 ≥5, and 5> K6 ≥0. Its association with self-reported ER utilization during the 12 months preceding the survey and all-cause mortality was estimated using weighted multivariable logistic regression and Cox proportional hazards regression, respectively. Models were adjusted for age, sex, race, educational attainment, comorbidities, region, year of survey, smoking status, health insurance, functional limitations, and time since cancer diagnosis. Results: Among the 3,453 PCa survivors (mean [SD] age 68.5 [7.2] years; 2479 (77.9%] non-Hispanic White, 655 (14.1%) non-Hispanic Black; median time since cancer diagnosis:5 years), 435 (11.3%) and 96 (2.4%) reported moderate and severe psychological distress respectively. PCa survivors with psychological distress tend to be younger, less educated, single, and with multiple comorbid conditions, and functional limitations. 812(22.8%) of PCa survivors visited the ER during 12 months preceding the survey. During a median follow-up of 81 months, 937(25.5%) of survivors died of all causes. After adjusting for covariates, PCa survivors with severe psychological distress were at a higher risk of ER utilization and all-cause mortality than those with moderate or no distress. Conclusions: Psychological distress was associated with increased risk of ER utilization and all-cause mortality among PCa survivors. Greater efforts are needed to understand, recognize, and alleviate such distress, as well as to enhance social and mental/physical health support in this rapidly growing community of vulnerable cancer survivors. [Table: see text]
Preclinical evaluation of teleglenastat (CB-839) in prostate cancer.
Authors: Lam Elaine T. , Su Lih-Jen , Salzmann-Sullivan Maren , Nordeen Steven K. , Flaig Thomas W.
Published: March 2023

378

Background: Glutaminase (GLS) levels are upregulated in prostate cancer [PMID: 28138303, 16897757]. The androgen receptor signaling pathway enhances the expression of SLC43A1, SLC1A4 and SLC1A5 (amino acid and glutamine transporters) in prostate cancer cells [PMID: 22007000, 24052624, 28507054]. We evaluated prostate cancer data from The Cancer Genome Atlas and found that GLS expression correlates with Gleason sum. We performed in vitro and in vivo experiments to evaluate the effect CB-839, a glutaminase inhibitor (GLS1 > GLS2), as monotherapy and in combination with other agents. Methods: We evaluated glutamine dependence of 3 prostate cancer cell lines [parental LNCaP (P0, hormone-sensitive), LNCaP-derived castrate resistant (CRPC) variant (P1, PMID: 34575033), and PC-3 (CRPC)] using media with and without glutamine, as well as clonogenic assays in regular media with BPTES (GLS1 inhibitor as a control) and CB-839. Combinatorial treatment and dose response studies were performed with CB-839 plus enzalutamide (ENZ), everolimus (EVE), or olaparib (OLA). We used NOD SCID female nude mice carrying P1 and PC3 prostate tumor xenografts to evaluate effects of CB-839 monotherapy, CB-839 + EVE, and EVE monotherapy. Results: P0, P1, and PC-3 all exhibited glutamine dependence. In glutamine-deplete media, all tested cell lines formed < 50% of colonies from baseline. Clonogenic assays with BPTES showed IC50 of 2-6 uM. CB-839 showed single agent activity in vitro with IC50 = 1 uM (P0), IC50 = 2 (P1), and IC50 < 0.1 uM (PC-3). The IC50 of CB-839 + ENZ in P1 cells was < 4uM CB-839 + 2uM ENZ. CB-839 + OLA showed no additive effect as OLA alone was very active (IC50 < 100 nM) in P1 cells. CB-839 + EVE showed single agent and synergistic effect (IC50 < 4 uM CB-839 + 0.05 uM EVE) in both P1 and PC-3 cells. In P1 tumor xenografts, treatment response was seen in CB-839 monotherapy, EVE monotherapy, and CB-839 + EVE treatment arms. In PC-3 xenografts, treatment response was seen in all groups, with greater effect in the EVE monotherapy and CB-839 + EVE treatment groups compared with CB-839 monotherapy. Conclusions: CB-839, EVE, and CB-839 + EVE all demonstrated activity in P1 and PC-3 castrate resistant prostate cancer tumor xenografts. Additive or synergistic activity was difficult to assess with combination therapy since each drug was effective as monotherapy. Additional studies are needed to evaluate the role of EVE monotherapy or CB-839 + EVE in prostate cancer. Research Sponsors: NCI CTEP UM1 Supplement CA186688-04, NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30. [Table: see text]
A phase 2 study of ibrutinib as neoadjuvant therapy in patients with localized prostate cancer.
Authors: Nawaf Cayce Ben , Peng Bo , Reimers Melissa Andrea , Weimholt Cody , Slane Kathryn , Oppelt Peter John , Frankel Jason , Figenshau Robert S. , Kim Eric H , Andriole Gerald L. , Fong Lawrence , Pachynski Russell Kent
Published: March 2023

387

Background: Treatment of localized prostate cancer (PCa) with surgery or radiotherapy remains suboptimal with failure rates of 35-40%. Bruton’s Tyrosine Kinase (BTK) is seen elevated in PCa tissues compared to normal prostate tissue. Malignant B-cell density has been correlated with higher risk of aggressive PCa and mitigating that through the BTK has been proposed in mouse models. Ibrutinib is a potent BTK inhibitor which targets B-cell signaling pathways, has an established safety profile, and has been shown to inhibit in vivo prostate tumor growth pre-clinically. Therefore, we hypothesized that ibrutinib will augment anti-tumor immune responses through inhibiting tumor-intrinsic growth via blocking BTK B-cell signaling pathways, while also inducing favorable T-cell profiles in localized PCa. Methods: We performed a neoadjuvant clinical trial (NCT02643667) studying ibrutinib in PCa. Eligible patients had localized PCa with no prior treatment, and deemed suitable for undergoing a radical prostatectomy. Patients received 840mg/day oral ibrutinib for 28 days followed by a radical prostatectomy 7-12 days later. Patients were assessed 4 weeks after surgery. The primary objectives are to assess safety of ibrutinib and characterize B and T cell infiltration. Correlative pre- and post- treatment tissue and blood samples were collected; BTK and PD-L1 expression in tumor and immune-infiltrating immune cells will be examined, and BCR and TCR clonality and diversity will be evaluated. Results: 22 patients were registered and underwent treatment to date. 4 patients had early termination of ibrutinib treatment with 3 due to adverse effects and 1 due to discovery of surgically unresectable disease. A total of 21 of 22 patients received radical prostatectomies. There were no intra-operative complications attributed to ibrutinib. The treatment was generally well tolerated with 7.1% grade 3 treatment related adverse effects. 2% experienced a grade 4 treatment adverse effects of hepatic dysfunction. The most common grade 1-2 adverse effects were diarrhea (8.2%), fatigue (7.1%), and anemia (6.1%). The median follow-up time was 23.9 months. Median overall survival and median failure free survival have not been reached and the two-year milestone is 100%. Sample collection is complete and immune correlative analyses are ongoing. Safety/tolerability, clinical outcomes, and preliminary correlative data will be reported. Conclusions: This is the first clinical trial of ibrutinib in PCa, and lays the foundation for larger future studies. Clinical trial information: NCT02643667 .
Biochemical recurrence (BCR) surrogacy for clinical outcomes after radiotherapy for adenocarcinoma of the prostate (BCRSCRAP): A meta-analysis from MARCAP Consortium.
Authors: Roy Soumyajit , Romero Tahmineh , Steigler Allison , Denham James William , Joseph David John , Michalski Jeff M. , Feng Felix Y , Bolla Michel , de Reijke Theo M. , Maingon Philippe , Sydes Matthew R. , Dearnaley David P. , Incrocci Luca , Heemsbergen Wilma , Nabid Abdenour , Souhami Luis , Zapatero Almudena , Sun Yilun , Spratt Daniel Eidelberg , Kishan Amar Upadhyaya
Published: March 2023

391

Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R2=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.
Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
Authors: Spiess Philippe E. , Li Roger , Grivas Petros , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Ross Jeffrey S. , Jacob Joseph M , Bratslavsky Gennady
Published: March 2023

4

Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: <10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and >20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) >1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB >10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
Comparison of serum miR-371a-3p assay performance by digital droplet PCR and reverse transcriptase quantitative PCR in patients with malignant germ cell tumor.
Authors: Nuno Michelle , Lafin John T. , Scarpini Cinzia , Savelyeva Anna , Wang Zhaohui , Gagan Jeffrey , Jia Liwei , Lewis Cheryl , Murray Sarah , Cheng Yun , Margulis Vitaly , Woldu Solomon L. , Strand Douglas , Coleman Nicholas , Amatruda James F. , Frazier Lindsay Lindsay , Murray Matthew , Bagrodia Aditya
Published: March 2023

426

Background: MicroRNAs have shown promise as potential germ cell tumor (GCT) biomarkers. In particular, previous work has shown miR-371a-3p alone may serve as a biomarker for GCTs, demonstrating higher sensitivity than current biomarkers. Quantitative reverse transcriptase PCR (RT-qPCR) has been commonly used to measure circulating levels of miR-371a-3p. More recently, miR-371a-3p has also been measured using digital droplet PCR (ddPCR), which has the potential advantage of absolute quantification. Here, we compared the performance of miR-371a-3p as quantified by RT-qPCR and ddPCR. Methods: Patient samples from the University of Texas Southwestern (UTSW) Medical Center and the University of Cambridge (UoC) were evaluated using both RT-qPCR and ddPCR, as per current protocols (RT-qPCR) or as per standard manufacturer’s recommendations (ddPCR). A range of clinical scenarios (pre-orchiectomy, chemotherapy-naïve RPLND) were intentionally selected. We compared the performance of the two assays using receiver operating characteristic (ROC) curves and area under the curve (AUC) values. We also determined an optimal threshold for each procedure by maximizing the Youden Index and compared the corresponding estimated sensitivity and specificity. Results: Data were available for 69 patients. Among these patients, 35 (50.7%) had malignant GCT (MGCT) and 34 (49.3%) had either non-MGCT (n=26) or no tumor (n=8). Patients with non-MGCT or with no tumor were considered controls. Cq values were generally lower among patients with MGCT and the number of positive droplets was higher compared with controls. The AUC was 0.96 when using RT-qPCR and 0.82 when using ddPCR to classify patients based on circulating miR-371a-3p. The optimal threshold for ddPCR was determined to be 17.5 positive droplets with a corresponding estimated sensitivity of 71% and 100% specificity. For RT-qPCR, the optimal threshold was determined to be Cq=28.52, with a corresponding estimated sensitivity of 83% and specificity of 100%. Conclusions: RT-qPCR was more sensitive in identifying MGCT patients in our current cohort when compared with ddPCR. Further investigations are required to optimize PCR methodology, particularly for ddPCR, and determine whether e.g., tumor volume and/or clinical context affects ddPCR performance. [Table: see text]