bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA methyl-transferases (DNMTs) as potential therapeutic vulnerability in prostate cancer.
Authors: Koul Hari K. , Vatanmakanian Mousa , Lima Ellen Nogueira , Chaturvedi Lakshmi S , Koul Sweaty K
Published: January 2024

339

Background: Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to resistance to current Androgen Receptor inhibitors, and emergence of CRPC-adeno, CRPC-NEPC and CRPC-DNPC phenotypes. There is an urgent and unmet need for developing new targets for CRPC especially CRPC-NEPC and CRPC-DNPC. Because cellular plasticity plays a central role in transition to NEPC and DNPC, molecular targets that are critical for prostate cancer cellular plasticity could serve as actionable targets in therapy resistance in prostate cancer. In this study we explored potential role of DNA methyl-transferases in prostate cancer therapy resistance. Methods: We analyzed publicly available clinical datasets to investigate expression of DNMTs (DNMT1, DNMT3a, and DNMT3b), and the association between expression of DNMTs, and prostate cancer progression, neuroendocrine features and overall survival. We evaluated effects of DNMT inhibitor [5-aza-2′-deoxycytidine (5AdC)] in short term experiments PCa cell lines to measure cell viability. We performed epigenetic reprograming by culturing PCa cells in sublethal doses of 5AdC over long term and measured cell migration and invasion. Results: Expression of DNMTs (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is a positive correlation between DNMT (DNMT1, DNMT3a, and DNMT3b) expression and tumor progression (increasing Gleason score) and NEPC score, and a negative correlation between DNMT expression and patient survival. DNMT1, DNMT3a and DNMT3b are expressed in androgen dependent as well as CRPC cell lines. All PCa cell lines were sensitive to DNMT inhibition (5AdC treatment). 5AdC was as effective as enzalutamide in limiting cell growth and proliferation in enzalutamide sensitive LNCaP cells, and sensitized these cells to enzalutamide. Moreover, 5AdC treatment also halted growth and proliferation of CRPC cell lines (PC3 and DU145) and epigenetic reprograming of these cells with 5AdC decreased cell migration and invasion. Conclusions: These results indicate DNMT expression is associated with prostate cancer progression. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer. Because DNMT inhibitors are currently approved for other malignancies, addition of these inhibitors to current treatment regiments could be readily explored in PCa.
Prevalence of variant of unknown significance (VUS) in men with prostate cancer who serve as a benchmark for enhanced screening and for personalized therapy.
Authors: Fasulo Vittorio , Lazzeri Massimo , Casale Paolo , Saita Alberto , Hurle Rodolfo , Paciotti Marco , Finocchiaro Alessio , Aljoulani Muhannad , Cavalli Pietro , Soldà Giulia , De Simone Ilaria , Colombo Piergiuseppe , Cieri Miriam , Maura Federica , Lughezzani Giovanni , Asselta Rosanna , Buffi Nicolò Maria
Published: January 2024

342

Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the other hand, there is the necessity to cautiously interpret VUS findings and to bolster VUS evaluations with additional evidence for pathogenicity. In this study, we aim to investigate the prevalence of germline VUS in men with PCa and their association with outcomes after robot-assisted radical prostatectomy (RARP). Methods: This is a nested cohort case study from an ongoing PCa screening, set to identify and screen men in the Italian population with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro project IG 2020 ID 25027). Cases for the current analysis were selected by “Adam's rib strategy” searching for germline DRG variant in men with a diagnosis of high-risk PCa who were scheduled for RARP. After informed consent was signed, a blood sample was obtained. A previously validated multigene panel test was used to assess the presence of germline variants. PVs and VUS were classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus criteria and International Agency for Research on Cancer guidelines. The primary endpoint was to describe the prevalence of VUS and the secondary to correlate VUS with pathological outcomes after RARP. Results: A total of 118 men with diagnosis of PCa who underwent RP were enrolled. The mean age at diagnosis of PCa was 65.9 (±6.42) years; pathological grade was ISUP 1-2 in 58.0% patients and 3-5 in 42.0%. Of the 76 men evaluated, 18 (23.7%) had a VUS and 1 (1.32%) a pathogenic germline variant in BRCA1 and PALB2. Among those with VUS younger men at diagnosis were more likely to carry a VUS than older at diagnosis mean (age 64 ± 6.41 vs. 66 ± 7.20 years). Additionally, 33.3% vs 16.2 % were carrier of VUS and N+ and required adjuvant androgen deprivation therapy. No difference between ISUP at final pathology and positive margin rate were found. Conclusions: Our findings showed a high prevalence of VUS germline mutations in PCa patients undergoing RARP. These mutations seem to be associated with worse pathological outcomes. Limitations includes short follow-up and absence of non-Caucasian patients.
Differences between whole body magnetic resonance imaging (WB-MRI) and chest/abdomen/pelvis computed tomography (CT)/bone scan (CT/B) in patients staged as having metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective comparative study within a single trust in the UK.
Authors: Hassan Mona , Anpalakhan Shobana , Maniam Akash , Ghose Aruni , Lokman Utku , Olejnik Tomasz , Banna Giuseppe Luigi
Published: January 2024

37

Background: Diagnostic imaging for metastases detection in HSPC varies across different countries with increasing use of WB-MRI and PSMA-PET. However, CT/B has still been the most used modality in the real world and recent registration clinical trials in this disease setting. Methods: We performed a cross-sectional retrospective descriptive study comparing WB-MRI with CT/B used as baseline staging modalities in patients diagnosed with mHSPC between February 2017 and August 2023 in two hospitals belonging to the same NHS trust in the UK routinely using one of the two. The study aimed at the detection of differences between the two modalities in the identification of metastatic sites and CHAARTED volume/LATITUDE risk, and the relative impact on patients’ received therapies and outcomes. Results: Of 213 patients diagnosed with mHSPC, 121 had baseline WB-MRI, 86 CT/B and 7 choline or PSMA PET. Compared to CT/B, patients staged by WB-MRI were diagnosed with significantly higher bone-only (47 vs 24%, p=0.002) and lower lymph-node only disease (11 vs 27%, p=0.005); higher high-volume (49 vs 21%, p<0.001) and -risk disease (48 vs 17%, p<0.001); higher de-novo metastatic disease (91 vs 66%, p<0.001); had previously received less radical surgery (2 vs 13%, p=0.003) or radiotherapy (7 vs 24%, p<0.001); received more frequently ADT plus Docetaxel (65 vs 44%, p=0.005). Treatment and outcome results in the overall cohorts’ populations and according to disease volume/risk will be presented. Conclusions: In a homogenous cohort of patients, we found a relevant discrepancy between the use of WB-MRI and CT/B in the identification of high-volume/risk and de-novo disease in mHSPC related to a higher detection rate of bone-only disease by the WB-MRI. This may prompt clinicians to offer different systemic therapies according to the disease burden and could also have a role in avoiding overtreatments for the under-staged disease.
Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic renal cell carcinoma with non-clear cell and/or sarcomatoid histologies.
Authors: Paffenholz Pia , Zschaebitz Stefanie , Casuscelli Jozefina , Rinderknecht Emily , Mattigk Angelika , Gür Melis , Ivanyi Philipp , Hilser Thomas , Darr Christopher , Mandal Subhajit , Schlack Katrin , Seidl Daniel , Handke Analena , Klee Melanie , Nestler Tim , Rehlinghaus Marc , Hijazi Sameh , Heidenreich Axel , Grünwald Viktor , Schostak Martin ,   GUARDIAN
Published: January 2024

392

Background: Papillary (pRCC), chromophob (chRCC) and predominantly sarcomatoid renal cell carcinoma (sRCC) as well as RCC with sarcomatoid features are rare cancers. We evaluated real-world treatment outcomes of 1st line treatment in these cohorts in Germany. Methods: We retrospectively analyzed patients with non-clear cell RCC treated at 17 German tertiary cancer centres. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to RECIST 1.1. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 189 patients with a median age of 63 years (IQR 54-72). Of these, 49% were pRCC, 12% chRCC, 12% sRCC. 17% of all RCC had a sarcomatoid features. 87% had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 15/54/31%. 74% received prior nephrectomy. Lymphatic (63%) and pulmonary (51%) metastases were the most common metastatic sites. 72% patients received first-line IO-combinations (IO-IO: 36%, TKI-IO: 64%) and 28% patients TKI-monotherapy, predominantly sunitinib. AE of all grades occurred in 86% and 72% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 46% or 36%, of which led to discontinuation of treatment in 42% or 29% of patients, respectively. ORR and survival outcomes with median follow-up of 17 months (IQR 9-30) are described in the table. Conclusions: IO-combinations are frequently applied in pRCC, chRCC and sRCC. Our data suggests that first-line IO-combinations yields higher ORR compared to single agent TKI in sRCC, but not in chRCC. However, the retrospective nature and small sample size are major limitations of our analysis. Additional analyses to tailor treatment strategies in patients with metastatic nccRCC or sRCC is warranted. [Table: see text]
Real-world metastatic renal cell carcinoma (mRCC) treatment trends in Mexico: A public vs private sector analysis.
Authors: González Espinoza Iván Romarico , Garcia Montes Lizbett Vanessa , Hernandez Flores Osvaldo , Remolina Bonilla Yuly Andrea , Sanchez-Trujillo Luis Arturo , Rios Mercado Maria del Socorro Isabel , Jaimes Diana
Published: January 2024

397

Background: Metastatic renal cell carcinoma (mRCC) treatment avenues have expanded, yet Mexico’s fragmented healthcare system could impact real-world setting, scarce information is available, and little is known regarding this issue. This study aims to characterize the treatment patterns for mRCC in Mexico’s public and private healthcare sectors. Methods: De-identified patient data collected from 180 oncologists (03/2022 to 02/2023) using Evidera LiveTracker were assessed. Data from adult mRCC patients outside clinical study protocols were included. Patients were categorized by healthcare sectors, and line of treatment (L). A descriptive analysis was conducted. Results: Of 651 patients, 182 (28.0%) were favorable risk-stratified, 332 (51.0%) intermediate, and 137 (20.0%) high-risk. Treatment in 1L involved 542 (83.3%), 96 (14.7%) in 2L and 13 (2.0%) ≥3L. Sectors were evenly split: 327 (50.2%) public and 324 (49.8%) private. Among patients in 1L, 60.7% underwent TKI monotherapy (72.8% public vs 48.1% private) mainly with sunitinib (49.8%) and pazopanib (20.9%). Immunotherapy (IO) combination IO+IO was indicated in 26.2% (17.0% public vs 35.7% private), and IO+TKI in 7.9% (5.4% public vs 10.5% private). similar disparities trends were observed in 2L, where TKI monotherapy increased to 70.8% (84.5% public vs 58.8% private), whereas 21.9% (13.3% public vs 29.4% private) and 4.2% (2.2% public vs 5.9% private) received IO monotherapy and IO+TKI, respectively (Table). Conclusions: Despite clinical practice guidelines favoring the use of IO for mRCC 1L treatment, many Mexican patients receive currently TKI monotherapy, particularly in public healthcare, and this is consistent in subsequent lines of treatment. Potential access barriers warrant further exploration. [Table: see text]
Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.
Authors: Selene Insija Ilyas , Lei Feitong , Huang Bin , Dhahri Amina , Heckman Patrick , Bardhan Roshmita , Jose Jemin , Myint Zin
Published: January 2024

403

Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.
Impact of renal function eligibility criteria in clinical trials and real-world survival outcomes among patients with metastatic renal cell carcinoma.
Authors: Miron Benjamin , Wang Xiaoliang , Hasler Jill S. , Royce Trevor Joseph , Geynisman Daniel M.
Published: January 2024

407

Background: Registration trials in metastatic renal cell carcinoma (mRCC) establishing the efficacy of first-line (1L) combination regimens employed strict renal function eligibility criteria (NCT02853331, NCT02811861, NCT03141177, NCT02231749); however, pharmacokinetics and safety of immune checkpoint inhibitors and anti-vascular endothelial growth factor therapies have been shown to be similar regardless of baseline renal function. Therefore, we aim to evaluate the impact of renal function eligibility criteria used in previous trials on real world outcomes. Methods: Data from the US nationwide Flatiron Health electronic health record-derived de-identified database included adult patients (pts) with mRCC who received any 1L systemic treatment on or after 4/16/2018 (first FDA combination regimen approval), had hemoglobin level ≥9 g/dL and ECOG performance status (ECOG) 0-1 at 1L. Renal function eligibility criteria at 1L (-60 days to +7 days) include serum creatinine (≤1.5 vs >1.5 x ULN), eGFR (≥30 vs <30 ml/min/1.73m2) and calculated CrCl (≥40 vs <40 ml/min) based on registration trial protocols. Outcomes include real world progression free survival (rwPFS), time to next treatment (rwTTNT), and overall survival (rwOS) from 1L. Inverse probability of treatment weighted (IPTW) Kaplan Meier methods and Cox proportional hazard models with multiple imputation were applied. Results: Of 2038 pts in this cohort, 1390 (68.2%) met all criteria for renal function (included), 140 (6.9%) met at least one criteria (relaxed), 46 (2.3%) met none (excluded), and 462 (22.7%) had unknown renal function. Compared to included pts, excluded pts were more likely to be older (median age: 74 vs 66), female (35% vs 27%), have recurrent disease (61% vs 53%), less likely to have ECOG 0 (24% vs 40%) and favorable IMDC risk (9% vs 14%). Excluded pts are also more likely to be Non-Latinx Black (13% vs 6%) and have lowest SES quintile (22% vs 15%) compared to included pts. Although, after weighting included pts had higher median rwPFS of 9.3 (95% CI 8.4 - 10.1) vs 6.9 (95% CI 3.7 - 9.9), rwTTNT 12.0 (95% CI 11.0 - 13.1) vs 9.1 (95% CI 5.5 - 16.4) and rwOS 38.5 mo (95% CI 35.9 - 44.5) vs 19.3 mo (95% CI 16.6 - 41.8) compared to relaxed/excluded pts, none of the hazard ratios (HRs) were statistically significant after multiple imputation (Table). Conclusions: In this real world study, we found that although only 68.2% of patients met all renal function eligibility criteria, survival outcomes were not different across pts groups. This suggests that mRCC patients with reduced renal function may benefit similarly to 1L treatment and should not be excluded from clinical trials. [Table: see text]
Health-related quality of life (HrQoL) of first-line treatments in metastatic renal cell carcinoma (mRCC): A network meta-analysis.
Authors: Abidoye Oluseyi , Naqvi Syed Arsalan Ahmed , Faisal Kunwer Sufyan , Imran Manal , Khakwani Kaneez Zahra Rubab , Raina Ammad , Tripathi Nikita , Abdul-Muhsin Haidar , Costello Brian Addis , Singh Parminder , Bryce Alan Haruo , Riaz Irbaz Bin
Published: January 2024

412

Background: Previously we have reported comparative effectiveness data regarding survival of first line (1L) treatment options in mRCC. However, it is not known how the life-prolonging frontline combinations compare to patient-reported outcomes. Methods: Electronic databases including MEDLINE and EMBASE were searched from each database’s inception through July 1st 2023. Phase III randomized controlled trials (RCTs) assessing 1L immune-checkpoint inhibitor (ICI) combination therapies for mRCC and reporting HrQoL were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global, physical, functional, and emotional QoL. Positive SMD indicated an improvement. A network meta-analysis was conducted to assess the comparative HrQoL across different treatment options. P-scores were computed to assess relative treatment rankings. Results: Of 5770 citations identified, five trials (nine references) were included in this analysis. Patient-reported outcomes have not been reported in the JAVELIN Renal 101 or COSMIC-313 trials yet. Global QoL was significantly improved with cabozantinib-nivolumab (CaboNivo) as compared to Nivo-ipilimumab (SMD 2.74, 95% CI 2.54; 2.93), lenvatinib-pembrolizumab (LenPem; 2.79, 2.53; 3.06), sunitinib (2.87, 2.72; 3.03), Pem-axitinib (PemAxi; 3.09, 2.89; 3.30) and atezolizumab-bevacizumab (AteBev; 3.24, 3.04; 3.45). Global QoL improvement was also observed with NivoIpi compared to sunitinib (0.14, 0.02; 0.25), PemAxi (0.36, 0.18; 0.54) and AteBev (0.51, 0.33; 0.68). Physical QoL improvement were consistent with CaboNivo. Likewise, LenPem significantly improved QoL compared to sunitinib (0.26, 0.04; 0.47), PemAxi (0.38, 0.13; 0.64) and NivoIpi (0.51, 0.27; 0.76). Significant functional QoL benefits were only observed with CaboNivo (0.32, 0.17; 0.48) and NivoIpi (0.19, 0.08; 0.31) compared to sunitinib. No significant mixed treatment comparisons were observed for emotional QoL, however, currently available data suggests that LenPem (rank 1) may potentially improve QoL (Table). Conclusions: CaboNivo and NivoIpi as 1L therapy may offer an improved overall HrQoL compared to other contemporary treatment options in mRCC. [Table: see text]
UNICAB: Cabozantinib in locally advanced or metastatic non‐clear cell renal cell carcinoma post immunotherapy or in those unsuitable for immunotherapy (ANZUP 1802).
Authors: Pook David William , Harris Carole A. , Link Emma , Goh Jeffrey C. , Parnis Francis , Gurney Howard , Kichenadasse Ganessan , Underhill Craig , Torres Javier , Roncolato Felicia , Inderjeeth Andrisha Jade , Conduit Ciara , McJannett Margaret Mary , Davis Ian D. , Gedye Craig ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: January 2024

428

Background: Rare variant non-clear cell renal cell cancer (nccRCC) have diverse biology and therapeutic response. Immune checkpoint immunotherapy (ICI) can benefit some people with nccRCC, but many experience progression. We sought to test cabozantinib (C) in people with nccRCC refractory to, or unsuitable for ICI. Methods: Eligible participants (pts) had advanced/metastatic nccRCC with good ECOG PS (<2) and either prior treatment with ICI or were unsuitable for ICI due to a contraindicating autoimmune disorder. Pts with urothelial or collecting duct tumour were excluded. Eligible pts started C at 60mg per day with dose modifications as required. Clinical cycles were 28 days and radiological assessment occurred 8-weekly for 12 months. Pts could then continue C via an access program. Results: 33 pts with nccRCC were recruited from Mar 2019 to Dec 2022. Recruitment was influenced by the COVID19 pandemic. Two pts were found ineligible (brain metastasis, concurrent CYP3A4 inducer). Pts tumour histology included papillary type 1 (10), chromophobe (7), papillary type 2 (4), Xp11 translocation (3) and other histologies (7). 24 pts had received prior ICI, mostly nivolumab alone (17) or anti-PD1-antibodies in combination with other agents (anti-CTLA4, anti-TIGIT). Median duration of therapy was 9 cycles. 17 pts ceased for unacceptable toxicity or disease progression and 12 pts completed the 12 months of treatment, with 2 remaining on trial treatment at time of analysis. A partial response was seen 7/31 (22%) pts overall, including 7/24 pts with prior ICI and 0/7 pts unsuitable for ICI. Median treatment duration was 7.5 cycles (range 2-12) in pts with prior ICI treatment, and 11 cycles (range 2-12) in pts unsuitable for ICI. 90% of pts required dose reduction, most often due to fatigue, hypertension, diarrhoea and hand-foot syndrome, with a mean C dose of 46mg/day. No new safety signals were observed. Conclusions: C is an active treatment for people with nccRCC previously treated with ICI, with similar toxicity to previous reports in other cancers. Pts unsuitable for ICI may have poorer outcomes for C therapy in nccRCC. Further follow-up will determine duration of response and overall survival. Clinical trial information: NCT03685448 .
Hypoxia-inducible factor-2 alpha (HIF-2α) target activation and clinical outcomes in 942 patients with clear cell renal cell carcinoma.
Authors: Doshi Sahil D , Kuo Fengshen , Knezevic Andrea , Kotecha Ritesh R , Motzer Robert J. , Hakimi A. Ari , Voss Martin H
Published: January 2024

445

Background: Von Hippel Lindau ( VHL) gene function is uniformly lost in clear cell renal cell carcinoma (ccRCC) with consequent accumulation of hypoxia inducible factor 2 alpha (HIF-2α). HIF-2α inhibitors have entered the clinical arena as a new class of agents, alone and in combinations. While VHL loss is thought to result in broad increase of HIF-2α activity, preclinical data suggests that HIF-2α target activation varies across patients. Xenograft response to HIF-2α inhibition helped define an RNA-based HIF-2α target signature (SIG) comprising 277 genes downregulated with treatment (Courtney et al. CCR 2020). We applied this signature in our analysis of two large cohorts. Methods: Retrospective analyses were conducted using two cohorts: 533 tumors from the Cancer Genome Atlas Project (TCGA) with emphasis on early-stage disease and 409 archival tumors collected from patients receiving pazopanib or sunitinib on the phase 3 COMPARZ trial in metastatic RCC. Using single-sample gene set enrichment analysis (ssGSEA), enrichment scores were calculated for HIF-2α-SIG and a previously validated 6 gene tumor angiogenesis SIG (McDermott et al. Nat Med 2020). Individual patients were classified as “high” vs “low” for each (enrichment scores < vs ≥ median). We tested associations of HIF-2α and angiogenesis scores with overall survival (OS) using the Kaplan Meier Method and log-rank comparison. Results: In the TCGA cohort, patients with “high” HIF-2α-SIG had inferior median OS compared to those with “low” levels (69 months [95% CI 53-117] vs 'not reached', log-rank p<0.0001). In the metastatic COMPARZ cohort, “high” HIF-2α-SIG associated adversely with median OS (27 months [95% CI 21-32] vs 36 months [95% CI 28-not reached], log-rank p=0.0240) while angiogenesis scores associated favorably. In both cohorts the majority of HIF-2α “high” patients categorized “low” for angiogenesis and vice versa. Associations amongst HIF-2α-SIG, angiogenesis-SIG, and OS are summarized below (Table). Conclusions: HIF-2α target activation was adversely associated with survival in early and late stage ccRCC while angiogenesis scores correlated favorably. HIF-2α targets other than VEGF appear to have clinical impact and should be explored. HIF-2α-SIG may prove helpful for clinical development of targeted HIF-2α inhibitors and deserves further study.[Table: see text]
Preclinical testing of a novel PD-L1 inhibitor for the treatment of renal cell carcinoma.
Authors: Hsu Michelle , An Zesheng , Gicobi Joanina , Xu Tianxiao , Harrington Susan , Zhang Henan , Pavelko Kevin , Hirdler Jacob , Lohse Christine M. , Nabavizadeh Reza , Pessoa Rodrigo , Sharma Vidit , Thompson Houston R. , Leibovich Bradley C. , Dong Haidong , Lucien Fabrice
Published: January 2024

458

Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis has revolutionized the therapeutic landscape of patients with advanced and locally advanced renal cell carcinoma (RCC). However, complete response rates remain low and there is a need for novel therapeutic options for ICI-resistant and refractory RCC. Our group has generated a novel humanized anti-PD-L1 antibody, called H1A, that induces PD-L1 degradation preventing not only its interaction with PD-1 but also inhibiting pro-tumorigenic intracellular signaling. In this study, we compared the antitumor activity of H1A with FDA-approved ICI using patient-derived immune cells and humanized mouse tumor models. Methods: In vivo antitumor activity of H1A and atezolizumab (ATZ) was compared in three humanized PD-1/PD-L1 mouse tumor models with different immunogenicity (E0771:high, MC38:moderate, B16-F10:poor). Peripheral blood mononuclear cells (PBMC) were isolated from 14 RCC patients undergoing with nephrectomy. PBMC were treated with H1A, nivolumab (NIV), atezolizumab (ATZ) and pembrolizumab (PEM) to evaluate their efficacy in inducing tumor cell death in an ex-vivo cytotoxicity assay. Mass cytometry was employed to determine the impact of H1A and atezolizumab on the PBMC profile. Results: MC38 tumors showed moderate response to both H1A and ATZ which was abrogated by CD8 T cell depletion. In E0771 tumors, higher percentage of complete responders was observed with H1A compared to ATZ and E0771 rechallenge revealed memory antitumor immunity with complete rejection of tumors. Patient-derived PBMC treated with H1A showed superior tumor cell killing compared to NIV, PEM and ATZ (p<0.01). While H1A treatment of PBMC induced expansion of effector NK and CD8 T cells (GZMB+ T-bet+), ATZ treatment led to enrichment of Tregs (CD25+,Foxp3+) expressing inhibitory markers PD-1 and LAG-3. Conclusions: H1A demonstrated superior antitumor activity compared to FDA-approved ICI which lays the ground for clinical testing of H1A as a next-generation immune checkpoint inhibitor for the treatment of renal cell carcinoma.
IL-6 and PIM1 expression in renal cell carcinoma.
Authors: Meza Kimberly Stephanie , Seymour Kimberly , Graff Stephanie L. , Nabhan Chadi , Elliott Andrew , Holder Sheldon L.
Published: January 2024

470

Background: Renal cell carcinoma (RCC) is a top ten malignancy in the U.S. Overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in RCC patients. PIM1 is a constitutively active serine/threonine kinase promoting cell proliferation, apoptosis resistance, invasion, and migration. The mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine that activates the JAK/STAT signaling cascade. High serum IL-6 levels are associated with the poor prognosis of RCC patients and may contribute to RCC invasion and metastasis. STAT3/5 binds directly to the PIM1 promoter inducing PIM1 expression. An IL-6/STAT3/PIM1 axis exists in pancreatic and breast cancer. We previously reported that PIM1 is overexpressed in a panel of human RCC cell lines relative to renal proximal tubule epithelial cells. We also identified that RCC cells secrete IL-6. Our prior studies suggest that differential expression of PIM1 may be linked to autocrine IL-6 signaling. We thus hypothesize that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in RCC. Methods: Retrospective review of DNA (592-gene or whole exome) and RNA (whole transcriptome) NGS data from real-world patient samples profiled at a CLIA-certified lab (Caris Life Sciences). Pathway analysis of differentially expressed genes was assessed using GSEA. Overall survival was calculated from insurance claims data. To understand how IL-6 signaling through the JAK/STAT pathway may regulate PIM1 expression in RCC cells, we examined whether IL-6 blockade using anti-IL-6 antibody or tocilizumab, would modulate PIM1 expression. Similarly, we assessed whether ruxolitinib, and LLL12, a STAT3 inhibitor could regulate PIM1 expression. Results: Transcriptome analyses show that PIM1 expression is significantly increased in metastatic RCC relative to primary RCC. Survival curves demonstrate that PIM1 overexpression is associated with decreased overall survival for RCC patients, independent of treatment received. IL-6 expression was up to 6.5-fold higher in RCC patients with PIM1 overexpression. In RCC cell lines, IL-6 blockade through either anti-IL-6 antibody or tocilizumab was sufficient to decrease PIM1 protein levels. Treatment with ruxolitinib leads to a dose and time-dependent decrease in PIM1 levels. Incubation with a STAT3 inhibitor also resulted in decreased PIM1 levels in RCC cells. Conclusions: These results suggest that differential expression of PIM1 in RCC may be linked to autocrine IL-6 signaling. Furthermore, poor survival in PIM1-overexpressing RCC patients is independent of treatment received, and therefore necessitates use of targeted therapies against this axis. Multiple FDA-approved agents are available that target this pathway. Further investigation is required to determine the efficacy of these agents in pre-clinical models and clinical trials.
Circulating tumor DNA in the surveillance of patients with oligometastatic renal cell carcinoma treated with stereotactic ablative radiation.
Authors: Kwon Young Suk Suk , Pop Laurentiu , Stein Maggie Janell , Christie Alana , Manna Subrata , Garant Aurelie , Yang Daniel X. , Desai Neil B , Brugarolas James , Timmerman Robert D. , Hannan Raquibul
Published: January 2024

477

Background: Oligometastatic renal cell carcinoma (oRCC) patients receiving stereotactic ablative radiation (SAbR) are in need of effective biomarkers beyond imaging to identify those most likely to fail rapidly and therefore would benefit from systemic therapy. Detection of minimal residual disease (MRD) using circulating tumor (ctDNA) is a promising tool to guide decisions in the management of solid tumors. Herein, we investigate the utility of longitudinal ctDNA monitoring to identify high-risk patients. Methods: Patients with oRCC on surveillance after previous SAbR were enrolled in a prospective registry study and longitudinal quantitative ctDNA testing were performed using a tumor-informed commercial ctDNA assay (Signatera). Disease progression was assessed using standard-of-care clinical / radiographic exams and compared to the ctDNA levels that were obtained within the median 32.5 days (IQR 18.5-59) of radiographic exams. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated. Results: The cohort encompassed 17 patients with oRCC (16/17 metachronous >1 year after nephrectomy) who underwent 42 ctDNA measurements between September 2022 and August 2023 with a median of 3 (range 2-6) ctDNA time points per patient. Median follow up after start of ctDNA monitoring was 10.3 months. Seven patients developed radiographic progression at new sites including 6 who received additional SAbR and one who started systemic therapy with interleukin-2. At most recent follow up, 13/17 patients had no radiographic evidence of disease. Out of the 42 ctDNA time points, 11 had detectable ctDNA and 17 had clinical/radiographically detectable metastasis. The sensitivity, specificity, PPV, and NPV were calculated to be 64.7%, 100.0%, 100.0%, and 80.6% respectively. Out of 6 patients who underwent had ctDNA testing on SAbR, 5 had undetectable levels and the only patient that had detectable ctDNA levels showed a robust decline in ctDNA levels post SAbR. In the interleukin-2 treated patient, detectable levels of ctDNA became undetectable post treatment which also correlated with a complete radiographic response. Conclusions: This study highlights the utility of ctDNA as a prognostic biomarker in the surveillance of oRCC patients who were previously treated with SAbR. A high SPE and PPV suggests that rising ctDNA levels may harbinger radiographic progression requiring systemic therapy intervention. A larger study is warranted to further validate the findings of this study and to optimally integrate ctDNA kinetics to direct subsequent treatment choices for the oRCC patients.
Treatment efficacy implications of incorrect utilization of tumor marker levels and risk group assignment according to the International Germ Cell Consensus Classification (IGCCCG).
Authors: Nestler Tim , Paffenholz Pia , Ruf Christian , Che Yue , Seidel Christoph Alexander , Heinzelbecker Julia , Schmelz Hans , Matthies Cord , Albers Peter , Bokemeyer Carsten , Heidenreich Axel , Pichler Martin , Majewski Matthaeus ,   German Testicular Cancer Study Group
Published: January 2024

505

Background: Patients withmetastatic germ cell tumors of the testis (GCTs) are risk-stratified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system for further therapy decision. This risk classification is based on metastatic load as well as tumor marker levels of AFP, HCG and LDH assessed pre-chemotherapy after orchiectomy treatment. An incorrect classification is possible when pre-orchiectomy marker levels are used, possibly resulting in over- or undertreatment of patients. Therefore, the aim was to investigate the potential frequency and clinical relevance of incorrect risk stratification using pre-orchiectomy tumor marker levels. Methods: Patients with metastasized nonseminomatous GCT (NSGCT)were included in a multicenter registry analysis which was conducted by investigators of the German Testicular Cancer Study Group (GTCSG). Based on the marker levels at different timepoints, IGCCCG risk groups were calculated. The agreement was tested using Cohen’s kappa. Results: A total of698 of 1983 (35%) patients were diagnosed with metastatic NSGCTs, and 546 (78%) had sufficient data for 232 follow-up data points. By using pre-orchiectomy tumor marker levels, 111 patients (20%) would have been incorrectly classified. Seventy-five patients (14%) were classified into a higher risk category, and 36 patients (6%) were classified into a lower risk category. Cohen’s kappa was 0.69 (p < 0.001), showing a strong agreement between the use of both marker timepoints. The treatment of misclassified patients would have resulted in an overtreatment of 75 patients or undertreatment of 36 patients. Conclusions: The use of pre-orchiectomy tumor marker levels may lead to an incorrect risk classification and might subsequently lead to under- or overtreatment of patients. Part of these data were published in: Majewski et al. Cancer Med. 2023.
Association of DAZL expression with risk of recurrence in clinical stage 1 testicular germ cell tumors.
Authors: Tewari Alok , Hamid Anis , Huang Jiaming , Zhong Caiwei , Xie Wanling , Rothmann Emily , Nicholls Peter , Walk Nathan , Brcic Iva , Terbuch Angelika , Van Allen Eliezer Mendel , Sweeney Christopher
Published: January 2024

523

Background: One model for testicular germ cell tumor (TGCT) formation posits that these tumors arise from a failure of germ cell determination characterized by persistent pluripotency and apoptotic escape. Risk assessment for relapse in clinical stage 1 (CS1) TGCT is dictated by clinical factors; molecular biomarkers to improve patient stratification for post-orchiectomy care are lacking. In this study, we examined the relationship between protein expression of pluripotency and apoptosis factors and risk of relapse in clinical stage 1 TGCT. Methods: Orchiectomy specimens from 73 patients treated for clinical stage 1 TGCT at one institution (27 seminoma, 46 non-seminoma) were subjected to immunohistochemistry (IHC) to assess protein expression of DAZL, POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Samples were dichotomized as negative or positive for target protein expression. Patients with CS1 TGCT managed with surveillance were annotated for baseline clinical characteristics and whether they experienced relapse within two years of orchiectomy. Exact logistic regression estimated odds ratios (OR) and 95% confidence intervals were calculated for the association between protein expression and relapse. Results: At two years, 17% of patients in our cohort experienced relapse. DAZL expression (score > 0) was detected in 43% of seminoma samples and 13% of embryonal carcinomas. After adjusting for histology, tumors negative for DAZL expression were more likely to recur within two years (adjusted OR for recurrence 0.08, 95% CI 0 – 0.81, p = 0.03). The direction of this relationship was consistent in seminoma when adjusted for tumor size (adjusted OR 0.14, 95% CI 0-1.83, p = 0.18) and non-seminoma after adjustment for embryonal predominance and lymphovascular invasion (adjusted OR 0.53, 95% CI 0-3.10, p = 0.30). No notable findings were observed for POU5F1, BAK1, DDX4, NANOG, and PMAIP1. Validation studies in two independent cohorts from other institutions are ongoing. Conclusions: The absence of DAZL expression by IHC is associated with a greater risk of relapse in CS1 TGCT. As DAZL promotes germ cell commitment by suppressing the pluripotency program, absence of DAZL expression may promote an oncogenic germ cell phenotype and more aggressive tumor behavior. Validation in larger patient cohorts is required to credential DAZL as a biomarker for clinical stage 1 relapse on surveillance.
Prostate-specific antigen (PSA) response among patients with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or abiraterone acetate (ABI) in real-world urology practices.
Authors: Brown Gordon Andrew , Khilfeh Ibrahim , Du Shawn , Rossi Carmine , Diaz Lilian , Kinkead Frederic , Muser Erik , Korsiak Jill , Lefebvre Patrick , Pilon Dominic , Ellis Lorie , Lowentritt Benjamin H.
Published: January 2024

53

Background: Recently approved oral therapies APA and ABI (plus prednisone) are effective mCSPC treatments. Prior real-world evidence showed that, relative to ABI, patients who initiated APA had significantly higher rates of PSA decline ≥90% (PSA90), which has been associated with longer overall survival. The objective of this study was to compare PSA90 response among an enhanced cohort of patients with mCSPC initiated on APA or ABI. Methods: Electronic medical records from PPS Analytics including data from US community urology practices were linked with administrative claims from the Komodo Health Solutions Research Database. Androgen receptor signaling inhibitor (ARSI)-naïve patients with mCSPC with ≥12 months of pre-index clinical activity were selected into the APA or ABI cohort based on their first paid claim/dispensation on or after 17 Sep 2019 (index date). Patients were followed to earliest of index ARSI discontinuation or switch, radiopharmaceutical use, end of insurance or clinical activity, or end of data availability (30 Sep 2022). Inverse probability treatment weighting (IPTW) was used to reduce potential pre-index confounding, controlling for age, race, region, insurance payer, index year, time from metastasis to index date, time from first prostate cancer (PC) diagnosis to index date, metastasis locations, de novo PC, use of androgen deprivation therapy, first-generation antiandrogens or chemotherapy, most recent PSA and testosterone levels, and most recent Gleason score. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to pre-index (most recent value within 13 weeks). The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: A total of 917 APA and 632 ABI patients were identified. Patient characteristics were balanced with IPTW (Table). By 6 months post-index, 80.9% of APA and 72.8% of ABI patients had a PSA measurement. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ABI patients (P < 0.001; Table). Median time-to-PSA90 was 3.5 months for APA patients and 8.8 months for ABI patients. Conclusions: This real-world study supports previous findings that a greater percentage of patients with mCSPC in the US initiating APA achieved deep PSA response compared to those initiating ABI. [Table: see text]
Predictive value of dynamic changes in ctDNA and baseline biomarkers with neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.
Authors: Young Matthew Nicholas , Szabados Bernadett , Assaf Zoe , Jackson-Spence Francesca , Nally Elizabeth , Wells Connor , Suárez Cristina , Castellano Daniel , Powles Thomas , Banchereau Romain
Published: January 2024

534

Background: Circulating tumour DNA (ctDNA) is being explored in the neoadjuvant setting in multiple prospective trials. Dynamic changes may be a surrogate marker of pathological complete response. ABACUS was a multi-centre, single-arm phase II trial investigating two cycles of atezolizumab before cystectomy in patients with muscle-invasive urothelial cancer who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy (NCT02662309). Results of primary and secondary endpoints have been previously published. Here we perform exploratory biomarker analysis using different definitions of ctDNA response and assess correlation with tissue response at time of cystectomy in the ABACUS trial. We also assess how these definitions of response correlate with baseline biomarker expression. Methods: Patients with baseline PDL-1, CD8, TMB and sequential ctDNA measurements (baseline and at cystectomy) were included. ctDNA analysis was performed using the Signatera assay, PD-L1 positivity was defined as ≥5% of immune cell staining, TMB was assessed using the FoundationOne CDx assay and CD8 measurement was performed via immunohistochemistry analyses. Two definitions of ctDNA response were used—ctDNA clearance and a 50% reduction (or greater) in ctDNA variant allele frequency (VAF). Results were correlated with pathological complete response (pCR) rate at time of cystectomy and relapse-free survival. Results: The 2-yr DFS and OS rates in ABACUS were 68% and 77%, respectively (N=95). 40 patients had sequential DNA analysis. 43% (17/40) had pathological complete response and 20% (8/40) experienced relapse. 63% (25/40) patients were ctDNA+ at baseline, with 40% (10/25) having ctDNA response of 50% VAF reduction and 8% (3/40) achieving ctDNA clearance. 30% (3/10) of patients who had VAF reduction experienced relapse and 40% (4/10) achieved pCR. All patients with ctDNA clearance achieved pCR none relapsed. There was no association between VAF reduction of 50% and tissue response (pCR) (p=0.24). Additional analysis showed no association between a ctDNA reduction of 75% (rather than 50%) and pCR (p=0.24). Baseline PDL-1, TMB and not predictive of pathological complete response (p=0.18, p=0.77, p=0.10, respectively) or ctDNA response (p=0.54, p=0.77, p=0.74) to neoadjuvant atezolizumab. There was no difference in relapse rates between ctDNA/PD-L1+ve vs ctDNA+ve/PD-L1-ve patients (16% vs 16%, respectively). Conclusions: ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse. This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint. Combining immune tissue based biomarkers with ctDNA does not appear to improve biomarker accuracy.
Outcomes in patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV) after switch maintenance avelumab (MAv) in the UNITE study.
Authors: Nizam Amanda , Jindal Tanya , Jiang Cindy Y. , Alhalabi Omar , Bakaloudi Dimitra Rafailia , Talukder Rafee , Davidsohn Matthew P. , Nguyen Charles B , Oh Eugene , Taylor Amy K , Lemke Emily , Kilari Deepak , Hoimes Christopher J. , Emamekhoo Hamid , Gupta Shilpa , Bellmunt Joaquim , Grivas Petros , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: January 2024

537

Background: MAv is approved in pts with aUC without progression (PD) on 1L platinum-based therapy (PBT). As pts in the pivotal EV trials had not received MAv after PBT, data on outcomes with EV post-MAv are limited. We examined outcomes with EV post-MAv in the multicenter retrospective UNITE study. We hypothesized that outcomes would be similar to published EV data. Methods: Pts who received sequential PBT, MAv, then EV monotherapy were included. Investigator-assessed observed response rate (ORR) was assessed for evaluable pts with scans after ≥ 1 cycle EV using χ2 test and logistic regression. Progression-free and overall survival (PFS, OS) were measured from EV start and assessed using ΚΜ method and Cox proportional hazards model. Results: Among 633 pts at 16 US sites, 49 received PBT and MAv then EV. Median age 72; 63% men; 96% Caucasian; 82% ECOG PS 0/1, 71% lower tract tumor; 65% pure urothelial histology; 71% visceral or bone mets; 33% Bellmunt score (BS) 2-3. In terms of PBT, 67% had cisplatin-based (cis); 26% carboplatin-based (carbo); 6% both cis- and carbo-based therapy. Best response to PBT was CR/PR/SD for 12% / 59% / 29% pts, respectively. Median time from PBT start to EV start was 8.5 months (mo) (3.9-21.2). Median follow up from EV start was 8.5 mo (95%CI 6.7-15.0). ORR to EV was 54%; median PFS and OS were 7.0 mo (95%CI 5.8-13.3) and 13.3 mo (95%CI 10.8-NR). Median PFS2 measured from PBT start until PD after starting EV or death was 17.5 mo (95%CI 15.2-22.5). Median OS from PBT start was 22.5 mo (95%CI 18.6-NR); 29% of pts remained on EV at data cutoff; 43% received subsequent therapy (Tx) after EV with median time to next therapy 6.4 mo (1.8-15.9). Outcomes did not differ among subgroups, except for improved PFS and OS in pts with BS 0-1 vs BS 2-3 (Table). Conclusions: Pts with aUC treated with EV after MAv had outcomes consistent with data for EV in PBT- and checkpoint inhibitor-refractory aUC. These data support the use of EV as third-line Tx after progression on MAv but should be validated in larger cohorts. [Table: see text]