bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]