bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of gene expression signatures in prostate cancer prior to liver metastases.
Authors: Watson Joshua , You Sungyong , Bhowmick Neil , Posadas Edwin Melencio
Published: February 2025

206

Background:
It has been recognized that as a prostate cancer (PCa) metastasizes to bone, it begins to express bone-specific proteins such as osteopontin, bone sialoprotein, and osteocalcin. This process is known as osteomimicry. Liver metastases (LM) are associated with the poorest clinical outcomes and affect 25% of PCa patients at autopsy. We hypothesized that PCa that metastasize to the liver express liver-specific genes prior to liver metastasis – a process we have named “hepatomimicry”.
Methods:
We have curated a list of 23 putative genes that are both primarily expressed in the liver and found in RNA-seq data from over 3000 PCa samples. Initial sources included the PCa transcription atlas (n = 2115), West Coast/SU2C Dream Team (n = 210), neuroendocrine PCa from cBioPortal (n = 49), and TEMPUS RNA-seq data generated specifically for Cedars-Sinai (n = 88). In each dataset, for the 23 hepatomimicry genes, we used recursive feature elimination and a t-test to discriminate between PCa LM and non-liver visceral metastases. In datasets with count-level data, we performed differential gene expression analysis with DeSeq2 and gene set enrichment analysis (GSEA) on identified differentially expressed genes.
Results:
In three different datasets, MAT1A, ELF3, and WEE1 were found to be either optimal genes for discriminating between these two groups or significantly different by t-test and were more highly expressed in LM. 270 genes were downregulated and 437 genes were upregulated in liver metastases (FDR q-value < 0.05, log2 fold change > 1 for upregulated and < -1 for downregulated). Subsequent GSEA found that liver-specific gene sets are highly enriched in the genes upregulated in LM, and endothelial cell genes are strongly downregulated.
Conclusions:
The initial results indicate that a three-gene subpanel of our initial set have predictive power for LM against other visceral metastases in PCa.While hepatocyte infiltration may impact the characterization of these samples by yielding a strong signal for liver-specific gene expression signature, confirmation of this finding remains important. Ongoing work is directed at confirming this signature in single-cell RNA-seq from PCa LM. Our work may be adaptable to developing diagnostic technologies such as liquid biopsies that may enhance the identification of patients who may have occult LM or that may develop LM as part of their natural history so that interventions may be enacted in a more timely manner.
Analysis of distinct genomic, transcriptomic, and immune landscapes driven by alterations in androgen production, uptake, and conversion (APUC) genes in metastatic prostate cancers.
Authors: Lacuna Kristine Peregrino , Ishani Khalid , Boytim Ella , Abida Wassim , Morris Michael J. , Antonarakis Emmanuel S. , Hwang Justin , Ryan Charles J.
Published: February 2025

209

Background:
Prostate cancer (PC) progression is driven by aberrant activity of the androgen receptor (AR) or its associated ligands - androgens. Dysregulation of genes that regulate androgen production, uptake, and conversion (APUC) may impact the efficacy of hormone therapies for PC. In our recent study of primary (n=2593) or metastatic PC (n=4490) biopsies, 6 APUC genes (
HSD3B1
,
HSD3B2
,
CYP11A1
,
CYP11B1
,
CYP17A1
,
CYP3A43
) showed strong clustering in prostate adenocarcinoma. Tumors with high APUC expression (APUC-6 high) had low AR alterations/signaling activity and showed prolonged overall survival. Here we examined the genomic, transcriptomic, and immune cell-fraction compositions in APUC-6 high versus AR-high tumors. Given improved outcomes in APUC-6 high tumors, we hypothesize reduced features of tumor aggressiveness or a favorable immune milieu in these specimens.
Methods:
Metastatic PC samples in the SU2C/PCF dataset (n=208) were annotated as APUC-6 high or AR-high based on gene expression quartiles, with the upper quartile defining “high” status. Additional stratification was performed to ensure that no samples classified as both APUC-6 high and AR-high were included in either group. This stratified two groups of tumors (n= 41, each). Transcriptomic, genomic, and clinical features between the two groups were compared. Gene Set Enrichment Analysis was used to identify upregulated gene-expression hallmark pathways, and CIBERSORT was used to infer fractions of 22 immune cell types.
Results:
APUC-6 high tumors exhibited fewer
AR
genomic alterations,
AR
gene expression, and AR-V7 detection. APUC-6 high and AR-high groups harbored significant differences in mutation alteration frequencies of 4 genes:
AR, EDN2, EDA2R,
and
OPHN1
(q < 0.05). There were no differences in the frequency of poor-prognosis mutations such as in
TP53, PTEN,
or
RB1.
APUC-6 high tumors were enriched in several hallmark inflammatory pathways and epithelial to mesenchymal transition (EMT) (NES>1.5, FDR<0.05). APUC-6 high tumors contained a higher fraction of naïve CD4 T-cells (224-fold, q = 0.0226), and also exhibited numerically higher levels of activated natural killer cells and neutrophils (1.35-fold and 2.11-fold, q = 0.081, 0.051, respectively), relative to AR-high tumors.
Conclusions:
APUC-6 high tumors, characterized by a favorable prognosis, are associated with upregulation of inflammatory pathways and EMT, and a distinct immune cell repertoire despite no difference in aberrations of canonical drivers of aggressiveness, such as
TP53, PTEN
, or
RB1
status. The more inflamed tumor microenvironment observed in APUC-6 high tumors warrants further exploration of distinct clinical approaches to this distinct phenotype. Validation of these findings in larger cohorts is ongoing.
The prognostic significance of circulating tumor DNA in prostate cancer: A systematic review and meta-analysis.
Authors: Liu Haolin
Published: February 2025

214

Background:
Circulating tumor DNA (ctDNA) has attracted increasing interest as a biomarker in multiple cancers. This study aimed to perform a systematic review and meta-analysis to evaluate the prognostic value of ctDNA in prostate cancer (PCa).
Methods:
An electronic search of PubMed, Embase, and the Cochrane library was conducted to identify eligible studies. Hazard ratios (HRs) and corresponding 95% confidence intervals (95%CIs) for progression-free survival (PFS) and overall survival (OS) were extracted for pooled analysis. Data were pooled using a fixed-effects or random-effects models based on the study heterogeneity. Subgroup analyses were performed according to disease status, study design, treatment regimen, and sequencing method. R software (version 4.2.2) was used for statistical analysis.
Results:
A total of 13 studies comprising 1946 patients with PCa were included. The pooled analysis showed that higher baseline ctDNA levels were associated with shorter PFS (HR 2.88, 95%CI 1.98-4.19, P<0.001) and OS (HR 2.57, 95%CI 1.66-3.97, P<0.001) in overall PCa patients. Subgroup analysis further indicated that the prognostic value of ctDNA levels remained consistent across different study designs, systemic treatment regimens, and sequencing methods. Additionally, elevated ctDNA levels were significantly correlated with shorter PFS (HR 2.56, 95%CI 1.69-3.87, P<0.001) and OS (HR 2.76, 95%CI 1.76-4.33, P<0.001) in the metastatic castration-resistant prostate cancer (mCRPC) setting.
Conclusions:
Our systematic review and meta-analysis demonstrated that higher ctDNA levels were associated with poorer survival outcomes in patients with PCa, suggesting that ctDNA may serve as a valuable prognostic biomarker in PCa.
Late onset of apalutamide-related skin toxicity in Black men with advanced prostate cancer: A diverse real-world analysis.
Authors: Yong Chen H , Aly Alaa Ahmed Genidy , Josephs Debra Hannah , Enting Deborah , Smith Kate , Crawley Danielle , Abdelfattah Nabil Mahmoud , Pintus Elias
Published: February 2025

23

Background:
Apalutamide (APA)- related skin toxicity is a common adverse reaction of varying incidence by ethnicity
1
. We have limited data on APA-related skin toxicity in Black men due to under-representation in clinical trials
2
. This real-world analysis evaluates APA-related skin toxicity and its differential impact across Black and White men in an ethnically diverse population at two high-volume cancer centers in London, United Kingdom.
Methods:
We investigated 120 prostate cancer patients treated with APA between 2021 and 2023. Skin toxicity incidence and grading, time to onset and drug discontinuation rates were examined. Adverse event causality was attributed by treating physicians and graded by the Common Terminology Criteria for Adverse Events v5.0 based on body surface area involvement. The cumulative incidence of APA-related skin toxicity and APA discontinuation rates were estimated by Gray’s method.
Results:
111 patients were included in our analysis, represented by 35 (31.5%) Black and 76 White men (68.4%). 18 men (16.2%) had pre-existing autoimmune or skin disease. 108 men (97%) commenced APA at 240 mg. At 24-month follow up, APA-related skin toxicity of any grade and Grade 3, were seen in 23 (23%) and 12 men (12%) respectively. There was no significant difference in skin toxicity incidence or severity between Black and White men (Table). The median time to skin toxicity was 179 and 84 days in Black and White men respectively, with late onset (>6 months) events more commonly seen in Black men. APA discontinuation rate due to skin or other Grade 3 toxicity was similar (24-month, 11.4% in Black vs 9.2% in White men). Based on multivariable competing risk analysis, skin or autoimmune disease, or eosinophil count at baseline had no significant impact on incidence or severity of skin toxicity.
Conclusions:
Late onset of APA-related skin toxicity is seen more commonly in Black men, thus requires clinical vigilance and monitoring. There is no significant ethnicity disparity in incidence or severity for APA-related skin toxicity. No significant risk factors for incidence and severe skin toxicity were identified.

Cumulative incidence of APA-related skin toxicity at 6 and 24 months.

Skin Toxicity
Ethnicity
6-months
24-months
p-value

Any grade

0.851

White

14%

21%

Black

11%

25%

Grade 3

0.954

White

9.2%

11%

Black

2.9%

13%
Adrenal androgens and overall survival (OS) in men with castration-resistant prostate cancer (CRPC) treated with enzalutamide without (ENZ) or with abiraterone and prednisone (ENZ/AAP) (Alliance).
Authors: Sharifi Nima , Kim Hyotae , Alyamani Mohammad , Diaz Robert , Beltran Himisha , Armstrong Andrew J. , Morris Michael J. , Halabi Susan , Ryan Charles J.
Published: February 2025

230

Background:
DHEA, testosterone (T) and androstenedione (AD) are adrenal androgens that can drive CRPC.
HSD3B1
encodes for 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) and has 2 common missense-encoding germline variants: the more active adrenal-permissive allele and the less active adrenal-restrictive allele that are associated with greater and lesser non-gonadal androgen biosynthesis from DHEA. A single adrenal-permissive
HSD3B1
(1245C) allele is sufficient to confer more rapid development of CRPC and homozygous inheritance (about 7-10% of men) is the most common monogenic link to prostate cancer mortality. Alliance A031201 (NCT01949337) is a phase 3 trial of ENZ versus ENZ/AAP for metastatic CRPC. This analysis combines clinical outcomes associated with adrenal androgens and
HSD3B1
as the gene encoding the enzyme that uses dehydroepiandrosterone (DHEA).
Methods:
Germline DNA was genotyped for
HSD3B1
in 929 men from A031201 (469 ENZ and 460 ENZ/AAP). Baseline DHEA, T and AD were assessed in 922 men (464 ENZ and 458 ENZ/AAP) using mass spectrometry. The Cox proportional hazards model was used to determine the prognostic significance of DHEA, T and AD categorized as tertiles in predicting OS.
Results:
In the combined treatment arms, median (95% CI) OS for men in low, medium and high DHEA tertiles was 27 (25, 31), 36 (33, 42) and 39 (37, 47) months (Table). In the ENZ arm, men with inheritance of 0, 1 and 2 adrenal-permissive alleles had median OS of 34 (30, 39), 34 (29, 39) and 28 (23, 37) months.
Conclusions:
DHEA is the most informative adrenal androgen. Men with the lowest tertile for this substrate of 3βHSD1 have the shortest OS. These data are consistent with prior analyses demonstrating poor prognosis for men with low adrenal androgens. Outcomes for men homozygous for the adrenal-permissive
HSD3B1
allele treated with ENZ are consistent with prior retrospective studies.

Overall survival and adrenal androgens.

Serum Androgen
Median OS in months (95% CI)
Multivariable Hazard Ratio (95% CI)

DHEA 1
st
Tertile (Low) DHEA 2
nd
Tertile (Medium) DHEA 3
rd
Tertile (High)

27 (25, 31)36 (33, 42)39 (37, 47)
AC vs. AA 0.97 (0.82,1.14)CC vs. AA 1.08 (0.81,1.44)DHEA: Med vs High 1.17 (0.97,1.42)DHEA: Low vs. High 1.65 (1.37,2.00)

AD 1
st
Tertile (Low) AD 2
nd
Tertile (Medium) AD 3
rd
Tertile (High)

32 (27, 36)36 (34,43)34 (31, 39)
AC vs. AA 0.96 (0.82,1.13)CC vs. AA 1.08 (0.81, 1.44)AD: Med. vs. High 0.89 (0.73,1.07)AD: Low vs. High 1.16 (0.97,1.40)

T 1
st
Tertile (Low) T 2
nd
Terile (Medium) T 3
rd
Tertile (High)

28 (26, 35)37 (34, 41)36 (32, 41)
AC vs. AA 0.95 (0.81,1.12)CC vs. AA 1.07(0.80,1.43)T: Med vs. High 1.01 (0.83,1.22)T: Low vs. High 1.28 (1.06,1.54)
Validation of PAM50 for predicting progression in active surveillance: Results from the Miami MAST prospective clinical trial.
Authors: Lee David J , Mahal Brandon A. , Punnen Sanoj
Published: February 2025

238

Background:
Active surveillance (AS) has emerged as an increasingly common management strategy for men with low- to favorable intermediate-risk prostate cancer. Although rates of prostate cancer mortality and metastasis remain low, some men experience cancer progression that necessitates treatment. Tools that improve the prediction of progression can enable more risk-adapted and timely treatment. We evaluated a PAM50 molecular classification profile for predicting cancer progression in men undergoing AS for prostate cancer.
Methods:
A total of 205 men enrolled in the Miami MAST trial who underwent a follow-up protocol involving serial multiparametric MRI and biopsies, including MRI-targeted and systematic biopsies. The highest-grade cores from each targeted and systematic biopsy were sent to Veracyte for genomic profiling. Patients were categorized into three groups based on the PAM50 genomic profile from the Decipher GRID. Time to progression, mutation analysis, and other prognostic signatures available on the Decipher GRID were compared across the three PAM50 classifier groups. Statistical analysis was performed using ANOVA and the rank-sum test, with significance defined as p<0.05.
Results:
Among the 205 patients enrolled in the trial, 128 had successful genomic profiling for baseline PAM50 classification. 46 were classified as Luminal A, 26 as Luminal B, and 56 as Basal subtypes. The Luminal B subtype demonstrated the highest risk of progression (77%), while the Basal subtype showed the lowest risk (45%) (p=0.011). Median time to progression was shorter in the Luminal B subtype (1.7 years) compared to the Luminal A and Basal subtypes (2.9 years each) (p=0.005). Decipher scores were lowest in the Luminal A group, followed by the Basal group, and highest in the Luminal B group (p=0.0015). Intra-patient variability based on subtyping of different cores within the same biopsy was observed in 37.1% of cases. Transcriptome analysis revealed distinct enrichment profiles for each PAM50 subtype, and mutation pattern analysis highlighted differences in mutation associations, with Luminal B showing a stronger association with SPOP and PTEN mutations.
Conclusions:
PAM50 shows promise as a molecular classification tool for predicting the risk of progression in prostate cancer. Given its stronger association with SPOP and PTEN mutations, as well as associations with higher progression risk, shorter progression times, and higher Decipher scores, the Luminal B subtype indicates a poorer prognosis compared to the Luminal A and Basal subtypes. This is the first study to validate PAM50 for predicting cancer progression in a prospective cohort of men undergoing active surveillance for prostate cancer. Clinical trial information:
NCT02242773
.

Progression rates among different PAM50 subtypes.

PAM50 Group
Non-progressor (%)
Progressor (%)
P VALUE

BASAL
31 (55)
25 (45)
0.011

LUMINAL A
26 (57)
20 (43)

LUMINAL B
6 (23)
20 (77)
Integrating aggressive variant prostate cancer–associated tumor suppressor genes (AVPC-TSG) status to refine prognosis and predict androgen-receptor pathway inhibitors (ARPI) response in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Pedrani Martino , Salfi Giuseppe , Merler Sara , Testi Irene , Agrippina Clerici Chiara Maria , Castelo-Branco Luis , Tortola Luigi , Turco Fabio , Vogl Ursula , Theurillat Jean-Philippe , Gillessen Silke , Pereira Mestre Ricardo
Published: February 2025

243

Background:
Alterations in AVPC-TSG (TP53, RB1, PTEN) are related with androgen insensitivity and aggressive disease. However, their role in mHSPC prognosis and treatment guidance is unclear. This retrospective study assesses the value of AVPC-TSG alterations in refining prognosis and predicting ARPI benefit in mHSPC.
Methods:
We included 158 mHSPC patients with available genomic tumor sequencing analysis undergoing treatment between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (defined by ≥1 alterations in the TP53 gene, RB1 gene, or PTEN/PI3K/AKT pathway genes) to those without (AVPC-TSGwt tumors). Cox analyses were performed for progression-free survival (PFS) and overall survival (OS).
Results:
AVPC-TSGwt status was associated with improved PFS and OS in both univariate and multivariate (MV) analyses (MV PFS: HR 0.58, p=0.012; MV OS: HR 0.48, p=0.025). AVPC-TSGalt mHSPC patients seemed to derive no PFS benefit (PFS: HR 1.13, p=0.721) from the addition of an ARPI to ADT, while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, p=0.029). Integrating AVPC-TSG status with CHAARTED volume criteria enhanced prognostic and predictive discrimination in mHSPC. Three distinct subgroups were identified: "good-risk" (AVPC-TSGwt and low-volume), "intermediate-risk" (either AVPC-TSGalt or high-volume), and "poor-risk" (AVPC-TSGalt and high-volume) with median PFS of 46.8, 28.2, and 15.7 months, respectively. Among them, only the "intermediate-risk" subgroup seemed to derive PFS benefit (HR 0.36, p=0.002) from addition of an ARPI.
Conclusions:
Integrating AVPC-TSG status with clinical prognostic variables refines prognostication and may predict PFS benefits from the addition of an ARPI in patients with mHSPC. Patients with AVPC-TSGalt mHSPC should be considered for clinical trials exploring alternative treatments, as they may not benefit from current standard approaches.

Patient characteristics.

AVPC-TSGaltn=63(39.9%)
AVPC-TSGwtn=95(60.1%)
p-value

mHSPC treatmentADT aloneADT+ARPIADT+DocetaxelADT+ARPI+Docetaxel
23(36.5%)28(44.5%)8(12.7%)4(6.3%)
32(33.6%)49(51.6%)7(7.4%)7(7.4%)

p=0.64
1

De Novo disease
43(68.3%)
57 (60%)

p=0.29
1

CHAARTED High Volume
36(57.1%)
52(54.7%)

p=0.77
1

AVPC-TSG 1 altAVPC-TSG 2-3 alt
56(88.9%)7(11.1%)
00

p<0.012
1

median PFS (months)median OS (months)
20.568.2
39.6NR

p=0.010
2

1
Pearson,
2
Log-rank test.
Molecular evolution of HRR gene alterations in metastatic prostate cancer: A ctDNA-based study.
Authors: Jani Chinmay , Tran Eli , Zhang Nicole , Tsai Jill , Dong Jianjie , Pan Elizabeth , Panian Justine , McKay Rana R.
Published: February 2025

255

Background:
Homologous recombination repair (HRR) genes, including DNA repair genes, are increasingly recognized for impacting treatment resistance and prognosis of metastatic prostate cancer (mPC). Next-generation sequencing of circulating tumor DNA (ctDNA) enables non-invasive, longitudinal monitoring of molecular alterations in patients (pts) undergoing systemic therapies. This study explores the dynamic changes in ctDNA profiles in mPC, particularly focusing on the HRR alterations.
Methods:
We utilized GuardantINFORM, a clinical-genomics database containing de-identified ctDNA test results and commercial payer-claims data. Eligible pts had a diagnosis of mPC and underwent ctDNA testing pre (within 3 months before initiation) and post (within 3 months of discontinuation before initiating subsequent treatment) Androgen Receptor Pathway Inhibitors (ARPi), poly ADP-ribose polymerase inhibitors (PARPi), and taxane chemotherapy. Mann-Whitney test assessed the differences in mutations. We also examined the association between ctDNA burden and overall survival (OS).
Results:
From a database of 21,682 pts with mPC, 145 had ctDNA collected pre/post-ARPi, 54 pre/post PARPi and 115 pre/post taxane chemotherapy. Pre-to-post-ARPI, individual HRR alterations increased from 21 to 34, with the most common (%pre/%post) genes to be altered, including ATM (5.5/7.6), BRCA2 (3/6) and CDK12 (3/2). In the PARPi group, the most prevalent (%pre/%post) genes to be altered were ATM (28/22), BRCA2 (28/20) and BRCA1 (4/6). Although overall BRCA2 prevalence declined, 11 new unique alterations were detected post-PARPi, along with an increase in unique BRCA1 (2 to 4) and BRCA2 (16 to 21) alterations. Three of 25 patients (12%) who underwent serial testing pre- and post-PARPi exhibited BRCA reversion mutations. In the taxane group, notable (%pre/%post) HRR genes to be altered included ATM (4/3), BRCA1 (1/3), and BRCA2 (1/3). Patients with higher ctDNA burden in pre-treatment samples exhibited worse OS.
Conclusions:
This study reveals dynamic changes in HRR gene alterations in mPC using ctDNA profiling. We observed increased unique alterations in ATM, BRCA1, and BRCA2 post-treatment, along with BRCA reversion mutations, indicating potential treatment resistance mechanisms. These findings underscore the importance of tailoring therapeutic approaches based on HRR gene profiles in mPC.
Application of radiomics as a risk stratification tool in node positive penile cancer.
Authors: Fazili Adnan Nazir , Morse Brian , Ahmed Abraham , Kim Jongphil , Jeong Daniel , Spiess Philippe E. , Chahoud Jad
Published: February 2025

3

Background:
The risk level of lymph node metastasis in penile cancer is determined using the Graafland criteria which determines how patients are treated. These imaging-based criteria have critical implications on patient care yet have not been extensively validated. The purpose of this study was to validate the Graafland criteria and to assess the use of radiomics analysis of CT scans to standardize risk stratification.
Methods:
Thirty-eight patients with squamous cell penile cancer with CT scans prior to regional lymphadenectomy were included in this retrospective cohort. Patients with prior chemotherapy for PSCC or any inguinal and pelvic radiotherapy were excluded. All CT scans were performed using IV contrast with axial slice thickness of 3mm. CT scans were analyzed by two experienced oncologic radiologists using Graafland criteria. The largest inguinal lymph node in each patient was segmented and radiomics features were extracted and compared to pathologic evidence of high-risk disease. 308 radiomic features were identified. Features with poor predictive value (i.e. AUC <0.5) were excluded. Pearson’s correlation coefficient was used to find the clusters of features (absolute value of correlation of ≥0.95), and the most predictive feature of each cluster was selected.199 features with best predictive value were selected for analysis. Two logistic regressions were performed using stepwise selection and LASSO approach.
Results:
In 38 subjects, 16 of 38 patients were identified as harboring lymph node metastasis on surgical pathology. Applying Graafland criteria had an inter-reader concordance of 89.5% (34/38), an accuracy of 86.8% (95%CI: 71.9% - 95.6%); AUC: 0.869 (95% CI: 0.758– 0.981); Sensitivity 87.5%; and Specificity 86.4% in predicting high-risk disease. CT radiomics analysis yielded a model including two features F54 (compactness) and F279 (3D wavelet_P1_L2_C1) which is a multi-order texture-based feature. The logistic regression with stepwise selection included two features (F54 and F279) and had an (AUC = 0.921 ± 0.096) after five-fold cross validation.
Conclusions:
Graafland criteria accurately predicted the presence of high-risk nodal disease on pre-operative CT scans when assessed by expert radiologists. Radiomic analysis shows promise in further refining and standardizing the detection of high-risk nodal disease with the advantage in ease of training and/or clinical application.
Differences in incidence and clinicopathologic features of secondary bladder cancer after long-term follow-up of brachytherapy and radical prostatectomy for localized prostate cancer.
Authors: Obayashi Kotaro , Kimura Go , Hasegawa Hiroya , Mikami Hikaru , Akatsuka Jun , Takeda Hayato , Endo Yuki , Toyama Yuka , Muramatsu Hiroyuki , Maebayashi Katsuya , Kumita Shinichiro , Kondo Yukihiro
Published: February 2025

381

Background:
Although there studies have been reported that brachytherapy (BT) for prostate cancer is associated with an increased incidence of metachronous urinary bladder cancer (MBC), few studies have clarified differences in the clinicopathological features (CPF) of MBC between BT and prostatectomy (RP). We studied the risk and clinicopathological CPF of MBC between RP and BT groups in our hospital after long-term follow-up.
Methods:
Five hundred four patients treated with BT and 471 referred patients treated with RP between 2006 and 2017 in our hospital were reviewed. We compared the incidence of MBC and the CPF including the tumor number, location within the bladder, histology, and time from BT or RP to the MBC occurrence between BT and RP. The differences between the two groups were analyzed. Furthermore, in the BT group, the radiation dose distribution within bladder was estimated.
Results:
A total of 11 cases of MBC occurred in the BT group (2.2%) and 7 in the RP group (1.5%) after a median follow-up time of 107 months (13-209). The median time from initial treatments to the occurrences of MBC was 65 months (12-121) in BT and 100 months (4-126) in RP (p=0.469). Average tumor number was not significantly different between the groups (BT:1.4, RP:1.9, p=0.589). The tumor locations of MBC within the bladder for BT vs. RP were 9 vs. 1 in the lateral wall, 0 vs. 4 in the posterior wall, 0 vs. 3 in the dome, and 1 vs. 0 in the trigone. The incidence in the lateral wall was significantly higher in BT than in RP (p=0.001). Their median radiation dose of right wall (15.7±7.74Gy) and left wall (13.0±5.85Gy) showed no significant difference compared to the BT patients without MBC. There were 3 muscle-invasive cases in BT and 1 in RP (p=0.60). High-grade urothelial carcinoma occurred significantly more in BT (10 cases) than in RP (1 case) (p=0.001). According to the criteria, six MBC were judged as radiation-induced secondary bladder cancer.
Conclusions:
Long-term follow-up showed that the risk of MBC after BT was similar to that after RP. MBC after BT occurred significantly more frequently in the lateral wall and had a higher grade compared to those after RP.
Efficacy and safety of immune checkpoint inhibitors (ICI) for the treatment of metastatic penile squamous cell carcinoma (mPSCC).
Authors: Cheng Tiewei , Schieber Timothy J. , Clennon Anna , Bertken Katie , Cai Sunny Shengyuan , Wulff-Burchfield Elizabeth Marie , Abbasi Saqib , Parikh Rahul Atul , Li Haoran
Published: February 2025

4

Background:
Metastatic penile squamous cell carcinoma (mPSCC) is a rare and aggressive malignancy with limited treatment options. Standard systemic therapies include paclitaxel, ifosfamide, cisplatin (TIP), fluorouracil and cisplatin (5-FU + cis), paclitaxel monotherapy and cetuximab. These regimens were evaluated as small single-arm studies. The HERCULES trial, a single-arm phase 2 clinical study, demonstrated the safety and efficacy of combining immunotherapy with chemotherapy, signaling a potential benefit of immunotherapy. Our retrospective analysis evaluates the safety and efficacy of single-agent immunotherapy at the University of Kansas and Aurora St. Luke’s Medical Center.
Methods:
We conducted a multicenter retrospective, IRB-approved study of mPSCC patients treated with single-agent immunotherapy from 2015 to 2023. Objective response rates were assessed per RECIST version 1.1, and progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events were graded per CTCAE version 5.0, with only grade 3+ immune-related adverse events being recorded.
Results:
Nine patients with mPSCC were included, with a median age of 75 years (range, 50-92). Over half (n=5) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more, and most (n=8) had visceral metastasis. Single-agent immunotherapy was administered as first-line (n=3), second-line (n=4), and third-line or beyond (n=2). Pembrolizumab was used in six patients, with two receiving nivolumab and one cemiplimab. The objective response rate was 33.3% (n=3), including one complete response. Median PFS was 2.82 months (range, 1.0-14.3), and median OS was 4.3 months (range, 1.0-24.9). Patients who responded had PFS exceeding 12 months, with two still ongoing at data cutoff. No grade 3 or higher treatment-related adverse event has been observed during the treatment period. Additional analyses to correlate the response with HPV positivity are ongoing.
Conclusions:
Our findings suggest that single-agent immunotherapy can yield favorable response rates and durations in older and/or frail mPSCC patients. While our sample size is small and retrospective, response rates are comparable to those in the HERCULES trial (33.3% vs. 39.4% with chemoimmunotherapy). Notably, grade 3+ treatment-related adverse events were lower in our study compared to 51.4% of HERCULES patients. This underscores the potential of single-agent immunotherapy as a safe and effective option for this rare malignancy. Further prospective studies are needed to optimize treatment strategies for mPSCC.
Molecular insights of low-PSA–expressing high-risk prostate cancer.
Authors: Chakraborty Goutam , Zaman Nabila , Pedraza Adriana M , Kyprianou Natasha , Tewari Ashutosh K.
Published: February 2025

416

Background:
Despite advances in molecular genetics and genome sequencing, identifying lethal and non-lethal forms of prostate cancer in the early stages of the disease remains challenging. A significant number of prostate cancer patients have high-risk tumors that produce low levels of prostate-specific antigen (PSA) at the time of diagnosis. There is an indication that the therapeutic outcome of these patients, may be considered unfavorable as they may not respond as well to ADT or androgen receptor pathway inhibitors (ARPI). Consequently, this type of high-risk prostate cancer with low PSA secretion may be associated with a unique subtype of the disease that has not been fully characterized.
Methods:
From 2013 to 2023, 3,619 patients diagnosed with prostate cancer underwent robotic-assisted radical prostatectomy (RARP) performed by a single experienced surgeon (AKT). The patients were classified into four groups based on their PSA levels: very low (<2.5 ng/ml), low (2.6-5.0 ng/ml), medium (5.1-8.0 ng/ml), and high (>8.0 ng/ml). We conducted an ANOVA analysis to compare various clinical characteristics across these groups. Additionally, we explored the gene expression profiles from the Cancer Genome Atlas (TCGA) prostate cancer cohort, specifically examining differential PSA/KLK3 mRNA expression within cancer cells. Furthermore, we selected and expanded single-cell clones from the LNCaP parental population to investigate the molecular landscape of low PSA expressing prostate tumor cells.
Results:
We observed that patients with high-risk prostate cancer and a very low PSA level (<2.5 ng/ml) had higher rates of biochemical recurrence compared to those with high-grade cancer but PSA levels (>2.5 ng/ml). Additionally, we noticed a significantly high presence of seminal vesicle (p= 1.058e-05) and neurovascular invasion (p=0.0047) in both the very low and high PSA groups compared to the other two groups. Importantly, the very low PSA group exhibited a higher rate of lymph node invasion (p= 0.00095) compared to the other three groups. Our transcriptomic analysis in the TCGA cohort revealed that genes which are upregulated in the very low PSA group compared to the high PSA group are significantly (p<0.001) enriched in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, our study on LNCaP-derived clones revealed an increased migration potential and elevated expression of mesenchymal markers in LNCaP-PSA
Low
clones compared to the clones expressing high PSA.
Conclusions:
Our research identifies a distinct subtype of localized prostate cancer, demonstrating that low-PSA, high-risk prostate cancer is significantly invasive and leads to potentially lethal disease. This highlights the need for further investigation to better understand the biology of this poorly defined but aggressive subtype of localized prostate cancer.
Temporal trends and socioeconomic determinants of cytoreductive nephrectomy (CN) utilization for metastatic renal cell carcinoma (mRCC) in the United States (US).
Authors: Esagian Stepan M. , Msaouel Pavlos , Karam Jose A. , Gartrell Benjamin , Makrakis Dimitrios
Published: February 2025

447

Background:
The evolving treatment landscape in mRCC since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of CN unclear. We sought to quantify CN utilization in the US over the past two decades and assess factors that affect equitable access to CN.
Methods:
We performed an analysis of the National Inpatient Sample database, using ICD-9 and ICD-10 diagnostic and procedure codes to identify mRCC patients undergoing CN from 2006 to 2021. We calculated annual CN utilization rates, stratified by demographic and socioeconomic factors. We then performed univariable and directed acyclic graph-guided multivariable logistic regression analyses to determine the effect of demographic, socioeconomic, and clinical factors on CN utilization rates.
Results:
There has been a significant decrease in CN utilization in 2021 compared to 2006 (8.7% vs. 15.8%; OR 0.51, 95% CI 0.42-0.61), consistent across all demographic and socioeconomic groups. Factors associated with decreased CN utilization include Black race (OR 0.70, 95% CI 0.64-0.76), Hispanic race (OR 0.87, 95% CI 0.80-0.95), female gender (OR 0.94, 95% CI 0.90-0.98), being a Medicare (aOR 0.69, 95% CI 0.64-0.73) or Medicaid beneficiary (aOR 0.59, 95% CI 0.54-0.64), lowest income quartile (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI, 0.74-0.93), and treatment in small-sized (aOR 0.57, 95% CI 0.51-0.63) or rural hospitals (aOR 0.33, 95% CI 0.27-0.40). CN utilization has significantly decreased during the ICI era compared to the TKI era (OR 0.69, 95% CI 0.64-0.75).
Conclusions:
CN utilization has steadily declined across the US over the past two decades, reflecting the uncertainty surrounding its role in mRCC management as new systemic therapies emerge. Access to CN is marked by significant demographic and socioeconomic disparities. Defining the evolving role of CN in the current mRCC treatment era and addressing these disparities is crucial to optimize patient outcomes.

Characteristic
Univariable analysis(OR [95% CI])

p
-value

Multivariable analysis(aOR [95% CI])

p
-value

Black race (ref. White)
0.70 (0.64-0.76)
<0.001
-
-

Hispanic race (ref. White)
0.87 (0.80-0.95)
0.001
-
-

Female gender (ref. male)
0.94 (0.90-0.98)
0.008
-
-

1
st
quartile income (ref. 4
th
quartile)

0.79 (0.73-0.85)
<0.001
0.84 (0.78-0.90)
<0.001

Medicare (ref. private insurance)
0.55 (0.53-0.58)
<0.001
0.69 (0.64-0.73)
<0.001

Medicaid (ref. private insurance)
0.58 (0.54-0.63)
<0.001
0.59 (0.54-0.64)
<0.001

Southern US (ref. Northeastern US)
0.82 (0.73-0.92)
0.001
0.83 (0.74-0.93)
0.002

Small hospital (ref. large hospital)
0.56 (0.50-0.62)
<0.001
0.57 (0.51-0.63)
<0.001

Rural hospital (ref. urban teaching hospital)
0.32 (0.27-0.38)
<0.001
0.33 (0.27-0.40)
<0.001
Survival of patients with metastatic renal cell carcinoma with or without brain metastases.
Authors: Hurwitz Michael E. , Considine Bryden , Hasson Nitzan , Savion Gaiger Noam , Nelson Melanie , Chiang Veronica , Kluger Harriet M. , Braun David A. , Schoenfeld David Aaron , Sznol Mario , Leapman Michael
Published: February 2025

476

Background:
Brain metastasis (BM) is an adverse prognostic indicator and associated with poor survival for patients with metastatic renal cell carcinoma (mRCC). Although immune checkpoint inhibitor (ICI) therapy has significantly improved survival in patients with metastatic renal cell carcinoma, the prognostic significance of BM in the ICI era is unclear.
Methods:
We performed a retrospective cohort study of patients diagnosed with clear cell RCC (ccRCC) between 2012-2023 at the Yale Cancer Center. We examined the association between brain metastasis and overall survival among patients by treatment type (with or without ICI in any line of therapy). We compared overall survival (mOS) using Kaplan-Meier analyses and multivariable Cox proportional hazards models.
Results:
We identified 338 patients diagnosed with metastatic ccRCC between 2012 and 2023, of whom 96 (28.4%) had BM, 39 of which were detected by screening versus 57 detected by symptoms. BM detected on screening MRI were smaller than those identified for cause (mean 13.9 versus 20.8 mm, respectively, p=0.002). The mOS from the time of metastatic ccRCC diagnosis was 54.0 months (95%CI 41-76) in patients without BM versus 37.0 (27-52) months in patients with BM (p=0.03). Among patients who received ICI therapy, mOS was 66 months (95% CI, 50-91) in those without BM versus 37 months (95% CI, 29-63) in those with BM (p=.01). In patients who did not receive ICI therapy, mOS was 31.5 months (95% CI, 23-80) in those without BM versus 17 months (95% CI, 14-NR) in those with BM (p=0.4). Among patients with BM, the mOS from the development of BM was 17.0 months (95% CI, 13-30). Median overall survival was 62 (95% CI: 17-NR months) versus 12 months (95% CI: 5-25 months) from the time of metastatic cancer diagnosis for those who underwent screening versus those who did not (p=0.0001).
Conclusions:
In our ccRCC population, there is a higher prevalence of brain metastases than previously thought. Overall survival for patients with metastatic ccRCC and brain metastases has improved in the era of ICI therapy. Brain metastases remain associated with poor prognosis and were frequently detected during asymptomatic screening. Patients with brain metastases discovered on screening had improved overall survival compared to those with brain metastases discovered because of symptoms.
Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic papillary renal cell carcinoma: A GUARDIANS project.
Authors: Hilser Thomas , Aydogdu Can , Zschaebitz Stefanie , Rinderknecht Emily , Mattigk Angelika , Volk Anna-Lisa , Ivanyi Philipp , Wiegmann Jonas , Darr Christopher , Mandal Subhajit , Schlack Katrin , Seidl Daniel , Handke Analena , Klee Melanie , Nestler Tim , Rehlinghaus Marc , Hijazi Sameh , Heidenreich Axel , Grünwald Viktor , Paffenholz Pia
Published: February 2025

496

Background:
Papillary (pRCC) renal cell carcinoma is a rare cancer. We evaluated real-world treatment outcomes of 1st line treatment in these cohorts in Germany.
Methods:
Data were collected retrospectively from 13 GU cancer centres in Germany. Patients (pts) with advanced or metastatic pRCC were eligible. Adverse events (AEs) were reported according to CTCAE 5.0. ORR was accessed according to local standard. Progression Free Survival (PFS) were calculated from start of treatment to progression or death. Descriptive statistics and KM-plots were utilized, where appropriate.
Results:
131 suitable pts (82% male) with median age of 63 years (range 22-86) were included. ECOG 0-1 was 70%, nephrectomy was performed in 78%. IMDC scores were: 0 in 18%, ≥ 1 in 53%, missing in 29%. The most common sites of metastasis were lymphatic (66%) and pulmonary (41%) metastases. 52% patients received first-line IO-combinations (IO-IO: 18%, TKI-IO: 34%) and 40% patients TKI-monotherapy, predominantly sunitinib. AEs (all grades) with IO‐based or TKI mono therapy, were reported in 86% and 74%, CTCAE grade ≥ 3 in 46% and 22%, dose modifications were required in 35% and 26.0%. ORR and survival outcomes with median follow-up of 19 months (IQR 9-35) are described in the table.
Conclusions:
TKI-based therapy are frequently applied in pRCC. Our data support the use of IO+ TKI as a first-line standard for patients with pRCC. Major limitations were the retrospective data capture and short follow-up of our study. Additional analyses to tailor treatment strategies in patients with metastatic pRCC is warranted.

ORR and survival outcomes of study population.

Parameter
All therapiesN=131
IO-ION=23
IO-TKIN=45
TKI monoN=51
OtherN=12

ORR (CR+PR)
34%
35 %
40 %
31 %
8%

SD
29%
17 %
33 %
29 %
17%

PD
23%
35 %
13 %
29 %
17%

unknown
14%
13%
13 %
10 %
58 %

mOS, months,95%-CI
32 .1 (24.4-39.9)
15.6(7.5-23.7)
Not reached
27.6(19.7-35.7)
32.1(21.15-42.7)

mPFS, months,95%-CI
8.5(6.5-10.4)
4.9(0.5-9.4)
9.2(3.5-15.0)
9.0(6.9-11.1)
8.5(0.0-22.8)
Role of liquid biopsy in the detection of homologous recombination repair gene mutations (HRRm) in metastatic prostate cancer (mPC).
Authors: Labidi Soumaya , Fallah Parvaneh , Salehi Aida , Rajan Raghu , Alameldine Mona , Brimo Fadi , Foulkes William D. , Papadakis Andreas I , Spatz Alan , Ferrario Cristiano , Saleh Ramy , Rose April A. N.
Published: February 2025

51

Background:
The treatment landscape of mPC is rapidly evolving to include more precision therapies for patients with actionable genomic alterations. Specifically, deleterious aberrations in HRR genes (HRRm) confer sensitivity to PARP inhibitors (PARPi) which have demonstrated survival benefit in this context. Therefore, accurate identification of potentially actionable HRRm is indicated. Somatic testing for HRRm in archival tissue is inadequate due to poor DNA quality or lack of tissue availability in 30-40% of cases. We evaluated whether circulating tumor DNA (ctDNA) testing using liquid biopsies is associated with an increased rate of HRRm detection.
Methods:
This was a multi-institutional retrospective cohort study of mPC patients (pts) treated at the Jewish General Hospital or the McGill University Health Center, Montreal Canada, between 2021-23. Molecular data and treatment information was abstracted from chart review. Fisher’s exact test and Wilcoxon test were used to assess differences between groups.
Results:
We identified 282 mPC pts, mostly castration resistant (n=181, 64.2%). Median age was 67 years (43-92). Somatic and germline testing for HRRm was performed in 78.3% (n=224) and 23.4% (n=66) pts, respectively. Somatic testing was performed on tissue (n=164, 73.2%) or ctDNA from liquid biopsies (n=17, 7.5%) or both (n=43, 19.3%). Pathogenic somatic HRRm were detected in 37 pts (13.2%): BRCA2 (n=13), ATM (n=8), CHEK2 (n=4), PALB2 (n=4), CDK12 (n=4) and BRCA1 (n=2). Amongst pts with germline testing 10/66 (15.1%) had pathogenic HRRm, mostly BRCA2 (n=9) and 4/10 had detectable HRRm in tissue. The somatic HRRm detection rate was 14.6% (24/164) on tissue and 11.7% (2/17) in ctDNA, respectively. Pts who had both tissue and liquid biopsy experienced a higher detection rate (25.5%, 11/43) vs. either modality alone (P=0.064). Inconclusive results were less frequent in pts who had both liquid and tissue testing vs. tissue alone (2.3% vs 7.3%). Amongst the 10 pts who had discordant results between liquid and tissue tests, HRRm were more frequently identified in ctDNA (n=7) vs. tissue (n=3). Pts who had HRRm detected only in ctDNA, had significantly older tissue samples (median 5.1 years) compared to those who had HRRm detected only in tissue (median 0.2 years, P=0.0156).
Conclusions:
Our data highlight a potential role of implementing liquid biopsy to improve the detection rate of HRRm. We are currently conducting a multi-center prospective study to determine if liquid biopsy increases the rate of detection of HRRm compared to routine tissue testing, and therefore allows to identify more patients who are eligible to receive precision therapies.
Lenvatinib's efficacy in heavily pre-treated metastatic renal cell carcinoma: Insights from a European multicenter study.
Authors: Gavira Javier , Auclin Edouard , Rey-Cárdenas Macarena , Roy Pritha , Tapia Jose C. , Nay Paula , Vinceneux Armelle , Nannini Simon , Randis Adela , Borchiellini Delphine , de Velasco Guillermo , Barthelemy Philippe , Negrier Sylvie , Oudard Stephane , Frazer Ricky Dylan , Flippot Ronan , Albiges Laurence
Published: February 2025

510

Background:
Lenvatinib-based therapy has shown efficacy in the frontline treatment of metastatic renal cell carcinoma (mRCC). However, there is uncertainty about the role of Lenvatinib (LEN) in subsequent lines of treatment, particularly after immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). This study aimed to describe the real-world clinical outcomes of patients (pts) with mRCC treated with LEN-based therapies beyond first-line treatment.
Methods:
Retrospective multicenter study including all pts with mRCC treated with LEN-based therapies beyond first-line at seven European centers from October 2020 to August 2024. Data on patient characteristics, treatments, and outcomes were collected. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included disease control rate (DCR), overall survival (OS), and safety. This study was approved by a centralized institutional review board (Gustave Roussy).
Results:
A total of 115 pts were included, 80% males, with a median age of 60.0 years. Of them, 80.9% had clear-cell subtype. Lenvatinib was mainly used after a median of 3 previous lines of treatment (range 2-8), either alone (41.7%) or in combination with everolimus (35.7%), pembrolizumab (PEM) (20.0%), or investigational agents (2.6%). Most of the pts had previously received ICI (88.7%) or TKI (96.5%), including cabozantinib (89.6%). The ORR was 28.2% and DCR was 65.5%. With a median follow-up time of 13.5 months (mo), the median PFS was 6.0 mo (95% CI 4.3-8.4 mo). Previous Cabozantinib (HR 4.3, p=0.02), bone metastases (HR 2.1, p=0.002) and the intermediate (HR 3.4, p=0.009) or poor IMDC risk (HR 7.7, p<0.001) significantly impacted PFS in the multivariate analysis. Median OS was 10.1 mo (95% CI 6.9-12.4 mo). Multivariate Cox models identified poor IMDC risk (HR 7.4, p<0.001) and bone metastases (HR 2.3, p=0.002) as negative independent prognostic factors for OS. On the contrary, LEN-PEM treatment (HR 0.3, p=0.017) had a positive impact on OS. Up to 38.3% of the pts started LEN with a dose adjustment (<18mg per day). On treatment, dose modifications were required in 33.9% of pts, with 9.6% discontinuing due to toxicities.
Conclusions:
In our cohort, LEN demonstrated meaningful clinical activity in heavily pretreated mRCC pts. The safety profile was manageable. These findings provide evidence to support its utilization in pretreated pts with mRCC.