bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of tissue factor (TF) in penile squamous cell carcinoma (PSCC) and enrichment in HPV-negative cases.
Authors: Johns Andrew , Jackson Jamaal Christopher , Campos Clemente Leticia , Solis Luisa Maren , Rao Priya , Manuel Christopher Matthew , Qiao Wei , Campbell Matthew T. , Chahoud Jad , Zacharias Niki Marie , Pettaway Curtis Alvin
Published: February 2025

10

Background:
Advanced/metastatic PSCC is an aggressive malignancy with limited treatment options. An antibody-drug conjugate (ADC) targeting TF is approved for treatment of advanced cervical cancer and may benefit patients with PSCC. We evaluated TF expression in PSCC which could support a future clinical trial of a TF-targeting agent for PSCC.
Methods:
We identified 33 pts with PSCC who underwent primary surgery at MD Anderson from 1999-2017 and had archived primary tumor tissue available for analysis. HPV-positive status was determined by either PCR testing or high-risk HPV in situ hybridization assay. A tissue microarray (TMA) was constructed with 3 cores per tumor. Anti-TF-1 antibody staining was performed by immunohistochemistry and mean H-scores for membrane and cytoplasm staining were assessed (range 0-300) for each tumor. Median H-scores were described and compared between HPV-positive and negative tumors. Percentage of pts with tumors staining positive for TF (≥10% of tumor cells with at least 1+ intensity in cytoplasm and/or membrane) was determined. Association of TF expression with tumor grade, presence of metastatic disease, lymphovascular invasion (LVI), perineural invasion (PNI), recurrence free survival (RFS), and overall survival (OS) was assessed.
Results:
17 pts (51.5%) had HPV-positive disease; 19 pts (57.6%) had metastatic disease. 27 tumors (81.8%) stained positive for tissue factor. Median overall membrane TF H-score was 47 (range 1-232). HPV-negative tumors had significantly higher membrane expression of TF (median H-score 70, range 1-232) than HPV-positive tumors (median H-score 19, range 1-123; p=0.004). While analyses were limited by small sample size, we did not find a significant association of TF H-score with tumor grade, presence of metastatic disease, LVI, PNI, RFS, or OS.
Conclusions:
TF expression was highly prevalent in this PSCC pt cohort. HPV-negative tumors had significantly higher TF expression than HPV-positive tumors; this finding requires further study. These data support further investigation of TF-targeted therapy, such as an ADC, for treatment of PSCC.

Variable
Overall population
HPV-positive(17 patients)
HPV-negative(16 patients)

Median (range) H-score

 Membrane
47 (1-232)
19 (1-123)
70 (1-232)

 Cytoplasm
29 (2-180)
18 (2-98)
59 (2-180)

Positive TF expression (Percent of patients with ≥1 core having ≥10% of tumor cells with at least 1+ intensity in either cytoplasm or membrane)
27/33 (81.8%)
12/17 (70.6%)
15/16 (93.8%)
Patterns of next-generation sequencing and associated next-line systemic therapy use in metastatic prostate cancer.
Authors: Shi Julia , Jiang Changchuan , Ghaderi Hamid , Yu James B. , Yang Daniel X.
Published: February 2025

105

Background:
Next-generation sequencing (NGS) testing is used for prognostication and to guide treatment choice in metastatic prostate cancer (mPC). While NGS testing is increasingly available, how its usage has impacted real-world selection of next line therapies including olaparib in mPC is unclear.
Methods:
We performed a retrospective observational study using the real-world nationwide U.S. Flatiron Health electronic health record-derived de-identified mPC database with patients diagnosed between January 1
st
, 2013, and July 30
th
, 2024. Due to limitations of follow-up, patients diagnosed with mPC in 2024 were excluded. Rates of patients with documented NGS testing within 6 months of metastatic prostate cancer diagnosis, short-interval changes in systemic therapy defined as initiation of a new therapy within 30 days after NGS testing, and olaparib initiation within 60 days of NGS testing were analysed.
Results:
A total of 24,222 mPC patients were included, of which 6282 (25.94%)had at least 1 documented NGS test and 1494 (23.78%) of those patients had more than 1 NGS test. NGS test documentation after metastatic diagnosis increased from 0.175% in 2013 to 22.8% in 2023. The median time from metastatic diagnosis to initial NGS testing was 413 days (IQR 76-993). The percentage of NGS tests associated with short-interval initiation of a new line of therapy increased from 14.29% of patients receiving NGS testing in 2014 to 24.19% of patients receiving NGS testing in 2023. The most common therapies initiated within 30 days after NGS testing were abiraterone (37.75%), enzalutamide (13.91%), and docetaxel (10.93%). Among patients with documented NGS testing, the percent who initiated olaparib within 60 days of an NGS test increased from 0.31% in 2015 to 17.34% in 2024, with the greatest year-on-year increase in 2020 corresponding to FDA approval for patients with homologous recombination repair gene alterations. Median time to olaparib initiation after metastatic diagnosis was 798 days (IQR 455-1383).
Conclusions:
There was a significant increase in rates of documented NGS test for patients diagnosed with mPC over the past decade. Furthermore, systemic therapy change appears to be more frequently influenced by NGS testing, with a significant increase in associated olaparib initiation as next-line therapy.
Association of androgen deprivation therapy and acute kidney injury in patients with prostate cancer: A systematic review and meta-analysis.
Authors: Carvalhal Gustavo Franco , Pires Iago , Sudo Renan Yuji Ura , Gobbo Marília Oberto da Silva , Filho Nilson Marquardt
Published: February 2025

111

Background:
Androgen deprivation therapy (ADT) has been associated with cardiovascular risk in prostate cancer patients. Thus, we performed a systematic review and meta-analysis to assess the incidence of acute kidney injury (AKI) in prostate cancer patients under ADT.
Methods:
PubMed, Embase, and Cochrane Library were searched from inception to October 2024. A random-effects model was employed to compute mean differences for continuous endpoints. Heterogeneity was evaluated by prediction interval and I-squared statistics. All statistical analysis was conducted using R software 4.4.1. GRADE approach rated the certainty of the evidence and the results were reported following the PRISMA statement guidelines.
Results:
Four studies involving 72,980 patients with a mean age of 73.5 years were included. Over a mean follow-up of 6.7 years, ADT was associated with an increase in the AKI incidence in prostate cancer patients compared to patients not receiving ADT (RR 1.34; 95% CI 1.13-1.58; p<0.001). Among patients who developed AKI while receiving ADT, the use of GnRH agonists was not associated with AKI incidence (RR 4.32; 95% CI 0.60-30.97; p=0.146). Similarly, when comparing AKI risk between patients on GnRH agonists alone and those without ADT, no statistically significant difference was found (RR 1.24; 95% CI 0.73-2.11; p=0.424). Orchiectomized patients had a lower AKI incidence than GnRH agonist users (RR 1.16; 95% CI 1.04-1.3; p=0.009). All studies were limited by retrospective designs, introducing potential selection and therapeutic bias.
Conclusions:
In this meta-analysis, ADT was associated with an increased risk of AKI. No statistical association was found between GnRH agonist use and AKI. Orchiectomy presented a lower AKI risk compared to GnRH agonists. Further investigations, including post hoc analysis of randomized controlled trials, are warranted to confirm these findings.

Characteristics of the included studies.

Study
Sample size (n)
Mean age (years)
ADT modality
Control group
AKI incidence (ADT)
AKI incidence (control)
Hazard ratio for GnRH use (95% CI) – sensitivity analyses
Follow-up (years)

Gandaglia 2014
31,408
78.6
GnRH agonist and Bilateral orchiectomy
No ADT
30.7%
24.9%
1.73 (1.62-1.85)
10

Cardwell 2021
10,751
69.2
GnRH agonists, GnRH antagonist, oral antiandrogens, estrogens and orchiectomy
No ADT
6.1%
5.2%
1.09 (0.88-1.34)
3.9

Sherer 2021
27,868
66
GnRH agonists, oral antiandrogens, and GnRH antagonist
No ADT +Radiotherapy
10.5%
7.9%

1.25 (1.13-1.37)
a

8.8

Lapi 2013
2,953
80.2
GnRH agonists, oral antiandrogens, GnRH agonists + oral antiandrogens, bilateral orchiectomy, estrogens, other combinations
No ADT
9.2%
4.5%

≈ 1.54 (1.17-2.15)
b
/ ≈ 1.04 (1.27-1.46)
c

4.1

a
Sensitivity analysis of all ADT modalities.

b
Adjusted analysis of current ADT modalities.

c
Adjusted analysis of past ADT modalities.
Safety profile of lutetium-177 in patients with impaired renal function: A retrospective analysis of adverse events in mCRPC treatment.
Authors: Seylani Allen , Zang Peter D. , Poku Erasmus , Kuo Phil , Yamauchi Dave , Dorff Tanya B.
Published: February 2025

123

Background:
Lutetium-177 vipivotide tetraxetan (Lu177) is the first FDA-approved radioligand therapy for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Not much is known regarding the safety of dosing of Lu177 in patients with creatinine clearance outside the range included in VISION trial (Sartor et al.) which was ≥50 mL/min. Using an institutional database of patients treated with Lu177, we sought to analyze whether there were increased incidences of adverse events (AEs) in patients with impaired renal function who received Lu177.
Methods:
We retrospectively identified 58 patients with mCRPC who received Lu177 from 2022 - 2024 at a single center (City of Hope). Impaired renal function was defined as an eGFR ≤ 60 mL/min prior to initiation of Lu177 and not confounded by acute renal injury. Statistical analysis was performed using R (v.4.4.1). A Fisher’s Exact test was used to determine whether impaired renal function was associated with increased frequency of AEs.
Results:
Among the 58 patients, 28 (48.28%) were Caucasian/White, 19 (32.76%) were Latino/Hispanic, 6 (10.34%) were African American/Black, and 5 (8.62%) were Asian/Pacific Islander. Median age was 68.5 years old (40-86 years old). There were 6 patients with low GFR (37 to 60 ml/min) and 36 patients with normal GFR >60 mL/min. Both groups received standard pluvicto doses. In terms of AEs, the most common AEs were anemia (41.54%), thrombocytopenia (12.31%), xerostomia (10.77%), and fatigue (10.77%). For G3/G4 AEs, the most common were anemia (56.25%) and thrombocytopenia (18.75%). Only one patient with prior impaired renal function (GFR <60 mL/min) experienced deterioration of renal function. There was no significant difference noted in incidence of AEs, incidence of anemia, and incidence of G3/G4 anemia between those with impaired renal function and those with normal function (p = 1, p = 0.7119, p = 0.6649 respectively).
Conclusions:
Patients with GFR < 60 mL/min did not identify an increased incidence of AEs, including anemia, when treated with Lu177. Patients with impaired GFR experienced a similar AE profile (anemia, thrombocytopenia, and xerostomia) as described in prior data sets. Our findings suggest that Lu177 may be safely dosed in patients with impaired renal function as low as eGFR 37 mL/min, without significantly increasing the risk of AEs.
Targeting the soluble epoxide hydrolase (sEH) enzyme to relieve painful docetaxel-induced peripheral neuropathy.
Authors: Mitsiades Nicholas , Wagner Karen M , Yang Jun , Hammock Bruce D.
Published: February 2025

126

Background:
Docetaxel is an important chemotherapeutic agent used for the treatment of several cancers, including metastatic prostate cancer. Unfortunately, it shares the side effect profile of other taxanes, including causing painful chemotherapy-induced peripheral neuropathy (CIPN). The pain of CIPN is notoriously difficult to treat, can lead to discontinuation of life-prolonging cancer treatments and can become a debilitating, chronic condition. Notably, African American (AA) cancer patients have increased (2-3-fold) risk and increased severity of CIPN. The enzyme soluble epoxide hydrolase (sEH) functions as a master regulator of inflammation, by converting epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding inactive or pro-inflammatory diols. As sEH inhibition has demonstrated efficacy in several models of neuropathy, here we assessed its potential to relieve and/or prevent docetaxel-induced CIPN specifically.
Methods:
We established a model of docetaxel-induced painful neuropathy in male Sprague Dawley rats, by administering 3 doses of docetaxel (10 mg/kg intraperitoneally, once weekly, for 3 doses). We tested the efficacy of the small molecule sEH inhibitor EC5026 (EicOsis, Inc, Davis, CA) both (1) as a single dose administered via oral gavage and (2) via chronic administration (1 mg/kg/day) in the drinking water started 1 week prior to and continuing during the period of docetaxel treatments. To examine the analgesic efficacy of EC5026, the rats were assessed for responses in nociceptive (von Frey assay and cold plate assay) and functional (open field test) behavior assays. Tail vein blood was sampled, and the blood concentration of docetaxel (measured by mass spectrometry) was compared between vehicle-treated and EC5026-treated cohorts.
Results:
Oral dosing of the sEH inhibitor EC5026 dose-dependently relieved docetaxel-induced painful neuropathy. Additionally, chronic treatment with EC5026 via the drinking water blocked both tactile allodynia and cold sensitivity compared to vehicle-treated rats. The open field assay revealed that EC5026 has no negative effect on motor skills. Moreover, EC5026 did not affect the blood levels of docetaxel in rats.
Conclusions:
sEH is a novel target for achieving pain relief in our CIPN model. Our results indicate robust response to therapeutic treatment of the CIPN model and additionally improved outcomes with prophylactic administration of the sEH inhibitor EC5026 in docetaxel-induced painful CIPN, without effect of EC5026 on animal motor skills or docetaxel pharmacokinetics.
PSA response to Lu177-PSMA-617 in patients experiencing xerostomia and ocular dryness in metastatic castration resistant prostate cancer.
Authors: Hassoun Rebecca , Tann Mark , Sims Justin , Auxier Ashleigh , Althouse Sandra K. , Salous Tareq , King Jennifer , Adra Nabil
Published: February 2025

127

Background:
Lu177-PSMA-617 (PSMA Lu177) therapy can cause dry mouth and/or eyes, as prostate specific membrane antigen (PSMA) is expressed in salivary and lacrimal glands. We evaluate the PSA response in pts with metastatic castration resistant prostate cancer (mCRPC) receiving PSMA-Lu177 who experienced dry mouth/eyes.
Methods:
The Indiana University Prostate Cancer database was queried for pts with mCRPC who were treated with PSMA Lu177. Adverse Events were documented throughout the course of treatment. PSA30 and PSA50 response were analyzed among subgroups of patients who had presence/absence of xerostomia and ocular dryness. Comparisons between the groups were based on the Chi Square test, or Fisher’s Exact test, if more appropriate.
Results:
144 pts with mCRPC were treated with PSMA Lu177 between November 2022 and October 2024. Included pts received at least 2 doses. Median age was 74 (53, 91). 126 pts had metastatic disease in bone, 80 in pelvic lymph nodes, 27 lungs, 20 liver, and 5 brain. 58 pts had 1 prior ARPI, 86 pts had ≥2 prior ARPI. 28 pts had no prior taxane regimen, 116 had at least 1 prior taxane. 23 pts had prior PARP inhibitor. Median follow-up from start of PSMA Lu177 was 9.77 months (1.38-26.9). 62 (43.1%) pts experienced dry mouth, 15 (10.4%) experienced dry eyes, and 13 (9%) experienced both. 92 (63.9%) pts achieved PSA30 response, and 81 (56.3%) achieved PSA 50 response.
Conclusions:
Patients with mCRPC treated with PSMA Lu177 who reported dry mouth were more likely to experience PSA responses.

Number and % of Pts Achieving PSA30 and PSA50 Response

Characteristic (N)

PSA30 response, N (%)

PSA30
p-value

PSA50 response, N (%)

PSA50
p-value

Dry mouth Present (N=62) Absent (N=82)
49 (79%)43 (52.4%)
0.0010
41 (66.1%)40 (48.8%)
0.0377

Dry eyes Present (N=15) Absent (N=129)
11 (73.3%)81 (62.8%)
0.4211
8 (53.3%)73 (56.6%)
0.8099

Dry eyes and/or dry mouth Present (N=64) Absent (N=80)
51 (79.7%)41 (51.3%)
0.0004
43 (67.2%)38 (47.5%)
0.0180
Impact of androgen deprivation therapy with postoperative radiotherapy after radical prostatectomy on health-related quality of life.
Authors: Westhofen Thilo , Buchner Alexander , Eismann Lennert , Rodler Severin , Berg Elena , Aydogdu Can , Askari Darjusch , Becker Armin , Stief Christian G. , Kretschmer Alexander
Published: February 2025

133

Background:
There is an ongoing debate on the use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) following radical prostatectomy (RP). While there have been conflicting results regarding oncological outcome, the effect of concomitant ADT on health-related quality of life (HRQOL) remains elusive. We aimed to assess the impact of adding ADT to postoperative RT on long-term HRQOL by providing PROM data from a large contemporary cohort of patients undergoing RT following RP with a systematic follow-up of up to 10 yrs.
Methods:
n=1124 patients who underwent RT after previous RP at a large tertiary care center between 2010 and 2021 were identified within a prospective institutional database. Patients with previous post-op ADT were excluded. Patients were stratified by concomitant ADT (no ADT n=682; ADT n=436). PROMs were prospectively assessed preoperatively, prior and post RT and at a maximum follow-up of up to 120mo, applying the validated EORTC QLQ-C30- and the prostate cancer-specific QLQ-PR25-questionnaires. Correlation analysis and multivariable regression models were used to estimate the impact of ADT with postoperative RT on HRQOL.
Results:
Median duration of ADT received within the ADT-cohort was 21mo. Prior RT, no significant difference in general HRQOL assessed by the global health status domain (GHS) was found between the ADT cohort (69.6) and the no ADT cohort (68.9; p=0.88). Post RT (65.1 vs. 69.9; p=0.038) and after median follow-up of 59 months (62.8 vs. 68.1; p<0.001) patients in the ADT cohort reported significantly worse general HRQOL. In multivariable regression analysis stratified by age, BMI, pT-stage, urinary continence and erectile functioning, concomitant ADT was confirmed as an independent predictor for worse general HRQOL (OR 0.68, 95% CI 0.47-0.96, p=0.03). Correlation analysis revealed a significant correlation between longer duration of ADT and worse long-term general HRQOL (p<0.001). In line, multivariable linear regression analysis revealed longer duration of ADT to independently predict worse general HRQOL (p=0.041) (Table).
Conclusions:
In patients with postoperative RT, concomitant ADT yields worse long-term general HRQOL. A longer duration of ADT furthermore leads to worse long-term general HRQOL. Those results support careful patient selection for ADT with postoperative RT after RP.

Multivariable linear regression for HRQOL.

Variable
B [regression coefficient]
Beta [standardized regression coefficient]
SE [standard error]
p value

Duration of ADT
-0.272
-0.191
0.132
0.041

Age
-0.127
-0.043
0.294
0.667

BMI
-0.588
-0.120
0.444
0.188

ICIQ-SF-Score
0.914
0.012
6.729
0.892

IIEF5-Score
0.661
0.165
0.403
0.103

R²
0.341

Adjusted R²
0.336
Survival outcomes of de novo mHSPC based on hemoglobin A1C and ARPI therapy.
Authors: Agarwal Rohan , Rohde Luke , Doherty Jason M , Schoen Martin W.
Published: February 2025

139

Background:
While there has been no prospective studies, enzalutamide (enza) has better overall survival, fewer adverse events, risk of progression, and PSA response compared to the abiraterone (abi) in real-world treatment of metastatic prostate cancer with androgen receptor pathway inhibitors (ARPI)s.

Diabetes (T2DM) is a major comorbidity in elderly patients, with worse glycemic control as a risk factor for and worse cancer outcomes. Studies analyzing the role of ARPIs in patients with diabetes have found enza associated with longer survival, less frequent acute hospitalizations, and likelihood of developing T2DM, compared to abi. However, there is little data in hormone sensitive population (mHSPC), where ARPIs are most commonly used.

This study analyzed the association between use of APRI treatment and survival in patients with controlled versus uncontrolled diabetes based off hemoglobin A1C (hgbA1C).
Methods:
1591 Patients with de novo mHSPC diagnosed between 2017-2023, treated with abiraterone or enzalutamide with 4 months of ADT, and hgbA1C within 1 year prior and up to 3 months after cancer diagnosis were retrospectively identified. Additional variables included age, BMI, base-line prostate specific antigen at diagnosis, Charlson Comorbidity Index score (CCI). Kaplan-Meier method was used to compare overall survival months based on hgbA1C and diabetes diagnosis. Cox proportional hazard modeling was performed to assess the relationship when adjusting for confounding variables.
Results:
The cohort included 1591 patients with de novo mHSPC, 1,196 who received abiraterone and 395 who received enzalutamide. Veterans treated with enza were older (mean 74.4 years vs. 73.0, p<0.001) with higher CCI (mean 2.6 vs. 2.0, p<0.001). Veterans with hgbA1C>6.5 were more likely to be prescribed enzalutamide (31.1% vs. 21.6%, p<0.001). Veterans with hgbA1C<6.5 had significantly longer survival compared to veterans with hgbA1C>6.5 (41.5 vs. 33.3 months, HR 0.79 95%, CI 0.68-0.91). Patients treated with abiraterone had a significant difference in survival based on hgbA1C (41.5 vs. 31.1, HR 0.79, CI 0.67-0.93). In patients treated with enzalutamide, there was no significant difference in survival (40.7 vs. 38.0, HR 0.80 95%, CI 0.60-1.07). A1C remained predictive of mortality (HR 1.27, 95CI 1.10-1.48) when controlled for PSA, BMI, ARPI, and age.
Conclusions:
In veterans with mHSPC who are treated with abiraterone, elevated hgbA1C is associated with shorter survival. No differences were seen in veterans treated with enzalutamide; however, these analyses may be underpowered. These results may help in treatment selection and support glycemic control when treating patients with mHSPC and comorbidities.

ARPI
A1C
Median OS (months)
HR
95 CI

Abiraterone
<6.5
41.5
0.79
0.67-0.93

6.5+
31.1

overall
39.2

Enzalutamide
<6.5
40.7
0.80
0.60-1.07

6.5+
38.0

overall
39.4
Analysis of gut microbiota profiles in patients with prostate cancer: The PROMISE-JAPAN study.
Authors: Hatano Koji , Oka Toshiki , Yamada Takuji , Matsushita Makoto , Fujimoto Saizo , Hata Junya , Tsujimura Akira , Obara Wataru , Takao Tetsuya , Takada Shingo , Yachida Shinichi , Nonomura Norio , Fujita Kazutoshi ,   PROMISE-JAPAN Study Group
Published: February 2025

212

Background:
Prostate cancer (PCa) is clinically associated with dietary habits such as high-fat diets. The gut microbiota is strongly influenced by dietary habits and is involved in the host immune response and metabolic pathways. Recently, the gut microbiota has been shown to influence a variety of diseases, including PCa. We have found that the gut microbiome and its metabolite, short-chain fatty acids (SCFA), promote cancer growth in PCa mouse models. To clarify the association between gut microbiota and PCa in humans, we conducted a study of PCa, gut microbiome, and lifestyle in Japan (PROMISE-JAPAN). In this study, we evaluated the gut microbiota profiles in PCa patients with a particular focus on differences between non-metastatic PCa (nmPCa) and metastatic PCa (mPCa).
Methods:
This multicenter, prospective, observational study enrolled 869 Japanese patients between 2020 and 2022. Eligibility criteria were men with suspected PCa who underwent prostate biopsy, and rectal swab samples were collected before prostate biopsy. Men who had taken antibiotics within 6 months before sample collection or whose previous antibiotic use was unknown were excluded. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. The raw sequencing data was processed by the QIIME2 pipeline. The Mann-Whitney U tests were used to compare characteristics between groups.
Results:
A total of 723 participants were eligible for analysis, including 262 men without cancer and 461 men with PCa, including 56 men with mPCa. The composition of the gut microbiota differed significantly between the non-cancer and the PCa group, with PCa having more Lachnospiraceae, which produce SCFA. The mPCa group had a higher abundance of Ruminococcaceae (UCG-005 and NK4A214), which belong to the Firmicutes pylum, compared to the nmPCa group. The mPCa group had a lower abundance of Prevotella, which belongs to the Bacteroidota pylum, compared to the nmPCa group. In mPCa compared to nmPCa, 19 gut microbiota pathways were significantly altered. In particular, the androstenedione degradation pathway was significantly increased in the mPCa group (p=0.0287).
Conclusions:
The composition of the gut microbiota differed between the non-cancer, the nmPCa and the PCa group. The gut microbiome associated with androgen metabolism was more common in mPCa patients. Clinical trial information:
UMIN000043489
.
Chromosomal instability in tumor suppressor genes–altered prostate cancer.
Authors: Garcia de Herreros Marta , Jiménez Natalia , Padrosa Joan , Reig Òscar , Fernandez-Mañas Laia , Ferrer-Mileo Laura , García-Esteve Samuel , Font Pous Albert , Ruiz de Porras Vicente , Mellado Begoña
Published: February 2025

226

Background:
Metastatic prostate cancer (PC) accumulates significant genomic alterations as the disease progresses, exhibiting the highest levels of chromosomal instability (CIN) among all metastatic tumors (Bakhoum, Nature 2018). Furthermore, tumor suppressor genes (TSG;
RB1
,
PTEN
and
TP53
) are frequently altered in metastatic PC and are associated with adverse outcomes. Here, we aim to investigate CIN in metastatic hormone-sensitive PC (mHSPC) harbouring alterations in TSG.
Methods:
TSG and whole transcriptome gene expression was assessed by nCounter platform (N=354) and RNA-seq (N=60) in mHPSC samples, respectively. TSG
low
was considered when ≥2 out of 3 TSG presented low expression of a previously stablished cut-off, and TSG
wt
in the remaining cases. Differential gene expression analysis between TSG
low
vs TSG
wt
tumors of our RNA-seq cohort (N=60) and TCGA cohort (N=333) was performed. Differential expressed genes (DEGs) were considered if FDR <0.05 and log2FoldChange (LFC)>0.5. DEGs were correlated with castration-resistance PC-free survival (CRPC-FS) and overall survival (OS) by Cox analysis. CIN gene signatures were obtained from literature and the rest of Hallmark signatures from MSigDB.
Results:
In our cohort of mHSPC patients treated with androgen deprivation therapy + docetaxel, TSG
low
tumors (16.7%) displayed higher levels of CIN compared with TSG
wt
(CIN25 normalized enrichment score [NES] 2.13, p<0.001 and CIN70 NES 2.54, p<0001). Cell cycle and DNA-repair signatures were also overexpressed in TSG
low
tumors, contrasting with a low expression of androgen receptor pathway. Results were validated in the TCGA cohort, where TSG
low
presented also overexpression of CIN signatures. In our RNA-seq cohort, we found 22 DEGs associated with CIN (29.3% of the total DEGs) in TSG
low
tumors compared with TSG
wt
. 51 genes were significantly correlated with CRPC-FS in a multivariate analysis and 16 of them (31,3%) were CIN-associated genes. Among these genes, 5 encode proteins that are targetable for metastatic PC, with specific inhibitors already developed:
BUB1
(LFC 1.06, FDR 0.034),
CDC7
(LFC 12.4 FDR 0.003),
KIFC1
, (LFC 11,7, FDR 0.01),
PLK1
(LFC 1.08, FDR <0.001) and
WEE1
(LFC 0.79, FDR 0.011).
Conclusions:
TSG-altered mHSPC tumors harbor high levels of CIN, and differentially expressed CIN-associated genes could potentially be targets in mHSPC.
Transcriptional profiling of patients with metastatic hormone-sensitive prostate cancer to uncover specific signatures linked to the transition from androgen-dependent to androgen-independent phenotype.
Authors: Pecoraro Giovanna , Esposito Daniela , Belli Stefania , Di Costanzo Fabrizio , Migliaccio Fortuna , Messina Francesca , Pepe Felice , Varricchio Silvia , Caruso Marco , Scagliarini Sarah , Rossetti Sabrina , Crocetto Felice , Conteduca Vincenza , Sanguedolce Francesca , Malapelle Umberto , Imbimbo Ciro , Servetto Alberto , Bianco Roberto , Formisano Luigi
Published: February 2025

227

Background:
Metastatic hormone-sensitive prostate cancers (mHSPC) are generally sensitive to androgen deprivation therapy (ADT). However, resistance often occurs, leading to disease progression. Understanding the transcriptomic changes underpinning the shift to antiandrogen resistance is crucial for identification of novel therapeutic vulnerabilities.
Methods:
Sixty patients with mHSPC undergoing ADT
plus
androgen receptor pathway inhibitors (ARPI) were enrolled. We defined non-responder (NR) patients (13/60) with biochemical/ radiological progression within 6 months of treatment and responder (R) (47/60) as those with stable disease or partial/complete response and eventually disease progression after 6 months. Total RNA was extracted from archived Formalin-Fixed Paraffin-Embedded (FFPE) basal prostate biopsies tissue samples using Maxwell RSC RNA FFPE Kit, and RNA was profiled using NanoString Tumor Signaling 360 Panel.
Results:
To identify gene signatures associated with response to ADT + ARPI, we analyzed differentially expressed genes between NR and R patients, through Rosalind platform Gene Set Analysis. Notably, NR patients exhibited significant upregulation of genes linked to cell cycle progression and DNA replication. The mitotic kinases
AURKB
and
PLK1
were the most markedly upregulated genes in NR versus R samples (p=0.02 and p=0.01, respectively), suggesting enhanced cell cycle progression despite antiandrogen therapy. Coherent with these results, hyper-expression of
KIF23
and
CDC20
in NR
vs
R samples further confirmed aberrant cell cycle progression. Importantly, NR biopsies also exhibited increased expression of metastasis-promoting genes, such as
HGF
(p= 6.53
e-3
), which may influence therapy response. Kaplan-Meier survival analysis reinforced the clinical significance of these findings, revealing that patients with hyper-expression of AURKB, KIF23, or CDC20, had shorter progression-free survival (PFS) compared to those with lower expression levels (p=0.0037, p=0.0007 and p=0.0289, respectively). These results underscore the potential of these molecular markers as predictive tools for resistance to ADT + ARPI and as potential targets for future therapeutic interventions.
Conclusions:
This study provides new insights into the transcriptomic landscape of mHSPC and identifies key gene signatures responsible for resistance to standard-of-care. Validation in larger cohorts is essential to confirm the predictive value of these genes and to identify patients eligible for novel combinatory treatments aimed at delaying this critical phenomenon.
Hydroxychloroquine effects on tumor suppressor PAR-4 levels in patients with oligometastatic prostate cancer: Results from a phase-2 trial.
Authors: Kim Joon Kyung , James Andrew Callaway , Burikhanov Ravshan , Huang Zhengyan , Myint Zin , Cohen Don , Yan Donglin , Adu Akosua , Faul Leigh Anne , Li Ning , Wang Peng , Strup Stephen , St. Clair William H , Rangnekar Vivek , Hensley Patrick J.
Published: February 2025

233

Background:
In oligometastatic prostate cancer (OMPC), delaying time to initiation of androgen deprivation therapy (ADT) may have oncologic and quality of life benefits. Additionally, there is an emerging role for metastatic/primary tumor site-directed therapy for patients with OMPC. Prostate apoptosis response-4 (PAR-4) is a potent tumor suppressor, facilitating apoptosis in prostate cancer cells. Hydroxychloroquine (HCQ) has been identified to be a potent inducer of PAR-4 secretion and downstream tumor inhibition in preclinical models and Phase I trials. We present a single institution Phase II trial assessing induction of PAR-4 levels in the plasma of patients in response to HCQ administration in combination with radiation therapy (RT) for OMPC.
Methods:
Men with OMPC (≤5 synchronous metastatic lesions) following primary tumor treatment were eligible. Patients received 400 mg HCQ daily for 2 weeks prior to metastatic site-directed RT and 400 mg HCQ daily for 90 days post-radiation. Plasma samples were collected on Day 0, 14, 30, 60, and 90. The primary endpoint was induction of ≥50% serum PAR-4 expression above baseline level within 90 days of treatment initiation. We hypothesized that over half of patients would exhibit ≥50% induction of serum PAR-4 expression.
Results:
Nineteen participants met inclusion criteria and were treated with 90 days of HCQ and RT to oligometastatic lesions. Median age was 68 years (range 55-77), the majority of patients were Caucasian (94%) and the median baseline PSA was 6.30 ng/ml (range 0.99 to 27.80). Prior primary tumor treatment included radiation therapy in 26%, radical prostatectomy in 32%, and radical prostatectomy with radiation in 42%. Eleven patients (58%) showed ≥50% increase in plasma PAR-4 above baseline levels (p=0.0006). This was associated with a concomitant PSA decline at 6-months (mean -0.98 ng/ml, 95% CI -6.61 to 4.65) and 12-months (mean -7.21 ng/ml, 95% CI -12.45 to -1.97). At 12-month follow-up, seven patients (37%) were free from ADT and median progression-free survival was 9.3 months (95% CI 6.4 to N/A). Twelve patients (63%) reported at least one adverse event, with 2 patients (11%) experiencing grade 3 toxicity.
Conclusions:
Oral administration of HCQ is well tolerated and effectively induces plasma expression of the potent tumor suppressor PAR-4 in patients with OMPC. Given the promising findings, further investigation into possible radiosensitizing and anti-tumor benefits of HQC in a larger cohort of OMPC is necessary. Clinical trial information:
NCT04011410
.
HSD3B1
and overall survival (OS) in high-risk non-metastatic (M0) and metastatic (M1) prostate cancer starting androgen deprivation therapy (ADT) in the enzalutamide (ENZ) and abiraterone acetate plus prednisolone (AAP) STAMPEDE phase 3 trial.
Authors: Sharifi Nima , Kayani Mahaz , Murphy Laura , Diaz Robert , Grist Emily , Kote-Jarai Zsofia , Eeles Ros A. , Leone Gianmarco , Clarke Noel W , Parmar Mahesh K. B. , Brown Louise C. , James Nicholas David , Attard Gerhardt
Published: February 2025

234

Background:
The
HSD3B1
gene encodes for the 3βHSD1 enzyme which regulates the rate-limiting step in potent androgen synthesis from non-gonadal precursors. The missense-encoding adrenal-permissive form of
HSD3B1
generates a hyperactive 3βHSD1 enzyme compared to the adrenal-restrictive form. We aimed to test associations with OS for
HSD3B1
genotyped patients randomized 1:1 to ADT vs. ADT+ENZ+AAP in the STAMPEDE platform protocol.
Methods:
HSD3B1
genotype was performed in germline DNA using a validated melting assay. We included patients who donated saliva or white blood cells for translational studies and were not planned for “triplet therapy with” docetaxel. Association between
HSD3B1
gene and overall survival was estimated using Cox survival models adjusted for randomised group, age at randomization, WHO performance status, regular aspirin or NSAID use, planned radiotherapy and metastatic disease status. Predictive effect was estimated with the addition of an interaction term. We pre-specified M1 low volume as of primary interest given prior associations in the CHAARTED trial.
Results:
Germline
HSD3B1
genotype was obtained for 259 men in the ADT arm and 335 men in the ADT+ENZ+AAP arm (594 total). 319 (54%) men were adrenal-permissive and 275 were adrenal-restrictive. Adrenal-permissive
HSD3B1
was associated with shorter OS (HR, 1.32 [1.04-1.67, p=0.025]), which by pre-specified sub-group analysis was most strongly prognostic in low volume (N=185, HR 1.70 [1.12-2.59], p=0.012) versus M0 (N=248, HR 1.21 [0.74-1.96], p=0.442) or M1 high volume (N=161, HR 1.14 [0.78-1.67] p=0.490) Although, there was no evidence of an interaction between treatment arm and genotype (p=0.800, 0.231 and 0.480 for M0, M1 LV and M1 HV, respectively), the treatment effect in the M1 LV restrictive group was 0.37 [0.19, 0.71] versus 0.7 [0.41, 1.21] in the permissive group.
Conclusions:
Adrenal-permissive
HSD3B1
inheritance is associated with increased risk of death in men starting long-term ADT ± ENZ+AAP in STAMPEDE. This result is consistent with prior analyses of the CHAARTED trial and prostatectomy cohorts. This effect is most notable in M1 LV and not overcome by addition of ENZ+AAP to ADT.
Gene expression signatures in biopsy cores as predictors of coexisting higher-grade disease in Gleason group 1 prostate cancer: Results from the Miami MAST prospective clinical trial.
Authors: Lee David J , Mahal Brandon A. , Punnen Sanoj
Published: February 2025

239

Background:
Despite several improvements in Active Surveillance (AS), pathologic reclassification remains frequent. Therefore, we examined if gene expression signatures in biopsy cores with Gleason Group (GG) 1 cancer can predict coexisting higher-grade disease elsewhere in the prostate among participants of the Miami Active Surveillance Trial (MAST).
Methods:
MAST enrolled 205 men with low and favorable intermediate-risk prostate cancer undergoing AS. Participants underwent an MRI and confirmatory biopsy at enrollment, and annually thereafter for three years. Positive cores underwent expression profiling with the whole-transcriptome Decipher genomic classifier (DGC). Derived Genomic Prostate Score (dGPS) and Cell Cycle Progression (dCCP) signatures were obtained. The primary objective was to compare signature scores in GG1 cores from prostates with (positive) vs. without (negative) coexisting GG2+ cancer elsewhere. The three signatures were also compared for coexisting GG3+ cancer elsewhere, and a sub-analysis using only the highest-volume GG1 core from each biopsy session was performed.
Results:
There was no significant difference between groups in DGC or dCCP scores regarding the primary objective, whereas median (IQR) dGPS was 0.14 (0.08–0.24) in positive vs. 0.10 (0.07–0.16) in negative groups (p=0.018). For coexisting GG3+ elsewhere, DGC or dCCP scores again did not differ, while dGPS was 0.24 (0.19–0.29) vs. 0.10 (0.07–0.16) in positive and negative groups, respectively (p=0.005). In a sub-analysis using only the highest volume GG1 core from each biopsy, as is the usual standard of care when using genomic testing on biopsy tissue, there was no significant difference in score between the groups for any of the signatures.
Conclusions:
Neither Decipher GC, dCCP, nor dGPS signatures showed clinically significant differences between GG1 cores with vs. without coexisting higher-grade cancer elsewhere when using the highest volume GG1 core for genomic testing. Our findings suggest that prostate cancer foci are heterogeneous and genomically independent. Clinical trial information:
NCT02242773
.
Genomic characteristics of patients with metastatic hormone-sensitive prostate cancer treated with ARPI-based therapy: A single-center analysis.
Authors: Maiorano Brigida Anna , Cigliola Antonio , Mercinelli Chiara , Tateo Valentina , Pastorino Giovanni Luigi , Colecchia Maurizio , Pavlick Dean , Ross Jeffrey S. , Necchi Andrea
Published: February 2025

244

Background:
The addition of androgen receptor pathway inhibitors (ARPI) to androgen deprivation therapy (ADT) has improved survival in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), both as doublets and as triplets with docetaxel. The prognostic role of genomic alterations (GA) is of growing interest in this setting. We evaluated the GA profiling of a population treated with ARPI-based therapy in a single-center institution.
Methods:
Our retrospective analysis included patients with mHSPC treated at IRCCS San Raffaele Hospital between 2020 (when ARPI were authorized for mHSPC in Italy) and 2023 (when triplets of ARPI + ADT + docetaxel were authorized). Included patients had a diagnosis of mHSPC, tissue biopsy available for genomic profiling, and were treated with ARPI plus ADT (plus or minus docetaxel) within 120 days of initial diagnosis. Comprehensive genomic profiling (CGP) using a commercial hybrid capture-based system (Foundation Medicine) was performed on all pts to evaluate all classes of GA, homologous recombination score (HRDsig), genomic ancestry, and signature. The log-rank test and Cox proportional hazards models compared GA between responders (Rs: defined as non-progressive pts) and not-responders (NRs: pts developing a progressive disease). Kaplan Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS).
Results:
28 patients were included in our analysis. Among them, 25 pts received ARPI + ADT, 3 ARPI + ADT + docetaxel. The median age was 71.8 years (range 53.1-83.9). After a median follow-up of 55.1 months, there were no differences in median PFS (mPFS) between patients treated with triplets and doublets (55.42 vs. 78.0 mos - HR = 1.12; 95%CI, 0.13-9.87; p = 0.92). The median OS (mOS) was not reached in both subgroups, without significant differences in survival rates (HR = 0.32; 95%CI, 0.01-7.33; p = 0.48). The overall response rate was 71.4%, and the disease-control rate was 85.7%. Comparing the CGP profiling between responders and progressive-pts,
SPOP
mutations were more frequent among Rs than NRs to ARPI (25% vs 0%; p = 0.183).
TMPRSS2
-
ERG
fusions, which tend to be less frequent in
SPOP
mutated cases, were less frequent in Rs (12.5%) than NRs (20.0% - p = 0.648). There was a similar incidence of other GAs between the two groups of pts, such as
PTEN
,
BRCA1/2
,
ATM
, and
CDK12
(all 12.5% vs. 10.0%; all p > 0.05).
Conclusions:
In a real-world setting, response to ARPI-based therapy may be associated with characteristic genomic features, such as
SPOP
mutations, or
TMPRSS2
/
ERG
fusions, both in doublets and in triplet regimens. These findings underscore the importance of larger cohorts to further validate this hypothesis and inspire future research in the treatment selection for mHSPC pts.
ctDNA characterization in mCRPC patients with pathogenic germline variants.
Authors: Nguyen Tivoli , Habibian Nicholas , Opeoluwa Akerele , Pocha Olivia , Bhandari Priya , Johnson Courtney , Huang Minqi , Lieberman Alexandra , Schwartz Jennifer , Layton Jodi Lyn , Lewis Brian E. , Sartor Alton Oliver , Ledet Elisa Marie
Published: February 2025

247

Background:
Approximately 10% to 15% of men with metastatic castration-resistant prostate cancer (mCRPC) harbor germline mutations. Circulating tumor-derived DNA (ctDNA) as non-invasive approach to characterizing somatic alterations. In this study, we report longitudinal ctDNA assessments in mCRPC patients who have undergone germline testing.
Methods:
A total of 238 patients, who had undergone both germline testing and ctDNA assessment from Tulane Cancer Center were included in this study. Germline testing was conducted using a multi-gene cancer panel from Invitae, covering 50-86 genes, while somatic alterations in ctDNA were tested through Guardant 360, including 70-83 genes. Somatic alterations with <0.1%, synonymous, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test.
Results:
From 2015-2024, 17.2% (41/238) had pathogenic or likely-pathogenic (P/LP) germline mutations. The most common pathogenic germline mutations were in BRCA2 (17.1%; 7/41), BRCA1 (9.8%; 4/41), and CHEK2 (9.8%; 4/41). In ctDNA, germline positive patients were more likely to have frameshift mutations (OR= 1.75, 95% C.I. [1.09, 2.81], p=0.02) and less likely to have copy number amplifications (OR= 0.58, 95% C.I. [0.36, 0.93], p= 0.03) compared to germline negative patients. Among mCRPC patients with germline HRR P/LP mutations, frameshift alterations were significantly more frequent (OR=5.03, 95% CI [2.03, 13.23], p-value=0.0008). mCRPC patients with germline P/LP mutations were more likely to have somatic mutations in BRCA2 (OR=2.85; 95% CI: [1.62, 4.93]; p=0.0002) and GATA3 (OR=3.37, 95% CI: [1.26, 8.51]; p=0.016) detected ctDNA and less likely to have EGFR alterations (mutations and/or amplifications) (OR=0.46; 95%CI: [0.25, 0.80]; p=0.0094). BRCA2 somatic mutations are also more likely to be detected in patients with germline P/LP mutations in HRR genes (OR=0.11, 95% CI [0.03, 0.33], p=0.00004).
Conclusions:
mCRPC patients with pathogenic germline mutations are more likely to have frameshift and less likely to have copy number amplifications compared to germline negative mCRPC patients. Frameshift mutations are more likely to be detected in patients with germline P/LP in HRR genes. Patients with germline P/LP mutations are more likely to have somatic mutations BRCA2 and GATA3 and less likely to have mutations and/or amplifications in EGFR.
A high omega-3, low omega-6 diet with fish oil for men with prostate cancer on active surveillance: The CAPFISH-3 randomized clinical trial.
Authors: Aronson William , Grogan Tristan , Liang Pei , Jardack Patricia , Liddell Amana , Perez Claudia , Lerman Mikayla , Elashoff David , Said Jonathan W. , Cohen Pinchas , Marks Leonard S. , Henning Susanne M
Published: February 2025

312

Background:
Men on active surveillance for prostate cancer are extremely interested in dietary changes or supplements to prevent progression of their disease. There are presently no prospective trials supporting such changes. We sought to determine if a high omega-3, low omega-6 fatty acid diet with fish oil capsules (D+FO) decreases proliferation (Ki-67) in prostate biopsies in men with prostate cancer on active surveillance over a 1-year time period.
Methods:
In this Phase II, prospective randomized trial, men (N=100) with grade group 1 or 2 prostate cancer that elected active surveillance were randomized to the D+FO or a control group. Same site prostate biopsies were obtained at baseline and 1-year tracked using an image-fusion device. The primary endpoint was the change in Ki-67 index from baseline to 1-year from same site biopsies compared between the groups. Ki-67 index was determined using multiplex immunofluorescence analysis. Secondary outcomes included compliance, grade group, maximum tumor length, the Decipher 22 gene score, serum PSA, lipid levels, and adverse events.
Results:
The Ki-67 index decreased in the D+FO group by approximately 15% from baseline to 1-year (1.34% at baseline, 1.14% at 1-year) and increased in the control group by approximately 24% from baseline to 1-year (1.23% at baseline, 1.52% at 1-year) resulting in a statistically significant difference in the change of Ki-67 index between the groups (95% CI 2%, 52%, p=0.043). There was no significant difference in the secondary outcomes grade group, tumor length, decipher genomic score or PSA between the two groups. There was a significant decrease in serum triglyceride (p=0.016) and serum colony stimulating factor-1 (p=0.017) in the D+FO group compared to control. Four patients in the D+FO group were withdrawn from the trial due to adverse events related to the FO.
Conclusions:
A high omega-3, low omega-6 diet with FO for 1-year resulted in a significant reduction in Ki-67 index (compared to the control group), a biomarker for prostate cancer progression, metastasis and death. These findings support future Phase III trials incorporating this intervention in men on active surveillance. Clinical trial information:
NCT02176902
.