bluuebunny/crossref_metadata_2025 huggingface dataset:
Fragmentomics of cell-free DNA from targeted panels in genitourinary malignancies.
Authors: Taylor Amy K , Helzer Kyle , Sharifi Marina Nasrin , Sperger Jamie M , Shi Yue , Annala Matti , Reese Shannon , Kaufmann Katherine , Schehr Jennifer L. , Sethakorn Nan , Kosoff David , Kyriakopoulos Christos , Armstrong Andrew J. , McKay Rana R. , Feng Felix Y , Wisinski Kari Braun , Emamekhoo Hamid , Wyatt Alexander William , Lang Joshua Michael , Zhao Shuang
Published: January 2024

199

Background: The detection of genomic alterations in cancer is critical for identifying clinically actionable alterations for treatment decisions. Tumor samples historically have been required, but obtaining tissue for molecular profiling is not always feasible, especially in the metastatic setting. The isolation and analysis of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) via blood-based “liquid” biopsies offers non-invasive sampling of the tumor. Recently, fragmentation patterns of cfDNA (i.e. “fragmentomics”) have emerged as a method for inferring epigenomic and transcriptomic information. However, these analyses use whole-genome sequencing, which lacks the necessary depth to cost-effectively assess genomic alterations, limiting the application of these techniques clinically. Methods: We developed a novel cfDNA fragmentomics machine learning approach for standard targeted cancer gene panels in order to identify genitourinary (GU) and non-GU cancers from two independent metastatic cancer cohorts: a published cohort from GRAIL (prostate cancer, non-GU cancers, normal samples, N=198) and an expanded institutional cohort from the University of Wisconsin (prostate adenocarcinoma, neuroendocrine prostate cancer (NEPC), renal cell carcinoma (RCC), bladder cancer, non-GU cancers, normal samples, n = 431). Results: In the GRAIL cohort, 10-fold cross-validation AUCs were 0.987 for identifying prostate cancer, 1.00 for normal samples, and ranged from 0.922-0.958 for the non-GU cancers. In the UW cohort, 10-fold cross-validation AUCs were 0.950 for bladder cancer, 0.982 for prostate cancer, 0.993 for NEPC, 0.925 for RCC, and 0.980 for normal samples, and ranged from 0.874-0.954 for non-GU cancers. Our assay can sensitively detect and accurately distinguish GU and non-GU malignancies despite a median ctDNA fraction of only 0.076 in the GRAIL cohort, and a median ctDNA fraction of only 0.022 in the UW cohort. Conclusions: Our enhanced machine learning approach for examining fragmentomics in standard cancer gene cfDNA panels unlocks the potential for these established assays to be utilized to answer critical clinical questions beyond somatic variant identification. The excellent performance of our innovative approach even in samples with low ctDNA fractions suggest potential applications such as multi-cancer early detection and minimal residual disease monitoring. This framework could dramatically expand the potential of already existing clinically used assays and minimizes barriers for continued biomarker development.
First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study.
Authors: Voss Martin H , Gurney Howard , Atduev Vagif , Suárez Cristina , Climent Miguel Ángel , Pook David William , Tomczak Piotr , Barthelemy Philippe , Lee Jae-Lyun , Nalbandian Taron , Stus Viktor , Ferguson Thomas , Wiechno Pawel , Gokmen Erhan , Lacombe Louis , Gedye Craig , Burgents Joseph E. , Sharma Manish , Cornell Jerry , Albiges Laurence
Published: January 2024

2

Background: Pembrolizumab (pembro) + lenvatinib (lenva) is approved for first-line treatment of advanced/metastatic RCC based on results of the phase 3 KEYNOTE-581/CLEAR study. Previously reported results from the phase 2 KEYNOTE-B61 (NCT04704219) study with a median follow-up of 15 months further support the use of pembro + lenva in the first-line setting specifically across nccRCC. We now report updated results from KEYNOTE-B61 with median follow-up of 23 months. Methods: Adults with previously untreated, advanced nccRCC (histology assessed by investigator) and measurable disease per RECIST v1.1 received pembro 400 mg IV Q6W for ≤18 cycles (~2 years) + lenva 20 mg orally once daily until intolerable toxicity, progressive disease, or patient (pt) withdrawal from the study. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DCR, DOR, and PFS per RECIST v1.1 by BICR, OS, and safety. Results: A total of 158 pts received pembro + lenva. Median age was 60 years (range, 24-87), and the most common histologic variants of RCC were papillary (n = 93; 59%), chromophobe (n = 29; 18%), and unclassified (n = 20; 13%). Median time from first dose to the data cutoff date of July 5, 2023, was 22.8 months (range, 16.6-27.6). 86 pts had discontinued treatment (most commonly due to progressive disease, n = 56 [35%]). In all pts, ORR was 51% (95% CI, 43-59; 13 CRs [8%]; 67 PRs [42%]) and DCR was 82% (95% CI, 75-88). Median DOR was 19.5 months (range, 15.3-not reached [NR]). An estimated 51% of responses had a duration of ≥18 months. ORR and DCR by histology are shown in the table. In all pts, median PFS and OS were 17.9 months (95% CI, 15.1-22.1) and NR (95% CI, NR-NR); estimated 18-month PFS and OS rates were 48% and 73%. Treatment-related AEs (TRAEs) occurred in 151 pts (96%), most commonly hypertension (56%), diarrhea (46%), hypothyroidism (41%), and proteinuria (30%). Grade 3-4 TRAEs occurred in 92 pts (58%), most commonly hypertension (25%), and diarrhea, proteinuria, and decreased weight (5% each). No deaths due to TRAEs were reported. Discontinuation due to TRAEs for pembro, lenva, or both pembro and lenva occurred in 15%, 13% and 4% of pts, respectively. Conclusions: Consistent with prior reports, pembro + lenva had durable antitumor activity and a manageable safety profile in pts with advanced nccRCC. These results continue to support pembro + lenva as a first-line treatment option for pts with variant histologies of nccRCC. Clinical trial information: NCT04704219 . [Table: see text]
The opposing effects of Class 1B and Class 2 FOXA1 mutations in prostate cancer.
Authors: Hwang Justin , Deshmukh Sachin , Wu Sharon , Elliott Andrew , Gandhi Nishant , Farrell Alex Patrick , Nabhan Chadi , McKay Rana R. , Heath Elisabeth I. , Baca Sylvan , Sartor Oliver , Dehm Scott , Antonarakis Emmanuel S.
Published: January 2024

216

Background: PCa harbors recurrent FOXA1 alterations, yet distinct alteration types may drive divergent consequences. Here, we established several classes of FOXA1 alterations and evaluated their clinical outcomes, molecular correlates, and immunologic landscape in a large cohort of primary and metastatic PCa samples from Caris Life Sciences. Methods: We interrogated the Caris DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. FOXA1 alterations were annotated based on amino acid (a.a.) location and prior functional studies (Table). Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates. Gene set enrichment analyses (GSEA) was used to estimate signaling pathway activity. Immune-cell fractions were inferred from bulk RNA-seq using quanTIseq. All comparisons are made relative to FOXA1 WT cases. Results: The overall prevalence of FOXA1 alterations was 16%, with no enrichment in metastatic PCa samples (15.5%). Class 2 mutations were enriched in histologic NEPC, were associated with a classical NEPC mRNA signature, and showed poor survival with ADT (HR 5.6, 95% CI: 2.5–12.5, p<0.001). Conversely, metastatic PCa patients with Class 1B mutations had numerically improved survival with ADT (HR 0.76, 95% CI: 0.50–1.14, p=0.18). All FOXA1 alterations (except Class 2) resulted in increased FOXA1 transcripts, with 1B and 1C having the greatest effects (q<0.0001). Class 0 and 3 alterations had 2–5 fold higher frequency of TMB-high and MSI-high status (q<0.05). Conversely, Class 1B exhibited lower TMB and markedly fewer TP53 mutations (35.7% vs 20.3%, q<0.001) and TMPRSS2-ERG fusions (34.5% vs 4.6%, q<0.001). Class 1B was depleted of AR transcriptional signatures (q=0.01) but enriched of MYC signaling in GSEA analysis (FDR<0.001), and showed reduced expression of B7-H3. On immune-cell deconvolution analysis, Class 1B showed reduced dendritic cells, but increased B cells and neutrophils (DC: 1.96% vs 0.01%, B cell: 4.27% vs 5.29%, neutrophils: 5.05% vs 8.00%, each q<0.001). Conclusions: Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity. [Table: see text]
Cost-effectiveness of triplet therapies in metastatic hormone-sensitive prostate cancer used in PEACE-1 and ARASENS.
Authors: Lester-Coll Nataniel Hernan , Benjamin David Joseph , Ribault Hélène , Foulon Stéphanie , Fizazi Karim , Rezazadeh Arash
Published: January 2024

222

Background: Recent findings from the PEACE-1 and ARASENS trials have demonstrated survival benefits in men with newly diagnosed metastatic hormone-sensitive prostate cancer using different triplet therapies, including Abiraterone and Darolutamide added to Androgen Deprivation Therapy and Docetaxel. Given the rising costs of cancer care, this study aimed to assess the cost-effectiveness of these treatment regimens. Methods: Drug prices were obtained from drugs.com and assurance-maladie.ameli.fr at wholesale prices to evaluate both United States (US) and France payer perspectives. Survival and progression data were sourced from Kaplan-Meier curves of the PEACE-1 and ARASENS trials and fitted to Weibull distribution models in R. The parameters were imported into TreeAge Pro 2023 for partitioned survival analysis. Health states were classified as "Pre-Progression," "Post-Progression," and "Death," each assigned specific health utility values and costs. Outcomes including total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Uncertainty was addressed through one-way and probabilistic sensitivity analyses. The baseline willingness-to-pay (WTP) threshold was $100,000 per QALY. Euros were converted to US Dollars. Results: At the baseline WTP of 100,000, generic Abiraterone (US, France) in PEACE-1 and Darolutamide in ARASENS from the French perspective were cost-effective. Generic Abiraterone was dominant, associated with lower net costs (-1,347 to -333) and higher QALYs (0.16) and Darolutamide had an ICER of .7,001 per QALY. In contrast, other triplet therapies increased both net costs and QALYs. Abiraterone yielded ICERs of 408,074 (US) and 114,995 (France) per QALY. Darolutamide in the US had an ICER of $383,732 per QALY. On one-way sensitivity analyses, most drugs would need to be priced at less than ~4,000 a month to be cost-effective at WTP of 100,000 per QALY. On probabilistic sensitivity analyses, with WTP of 100,000 per QALY, generic Abiraterone (US) was the cost-effective drug (88% of simulations), while brand Abiraterone and Darolutamide (US) were the least cost-effective (0% of simulations). Conclusions: Cost-effectiveness of therapies in metastatic hormone-sensitive prostate cancer vary significantly based on pricing and country payer perspective. At a WTP threshold of $100,000, only generic Abiraterone (US, FRA) and Darolutamide (France) were cost-effective. [Table: see text]
Barriers and facilitators to first-line (1L) treatment intensification (TI) in metastatic castration-sensitive prostate cancer (mCSPC): The IMPLEMENT study.
Authors: Loeb Stacy , Agarwal Neeraj , El-Chaar Nader N. , de Ruiter Laura , Kim Janet , Mack Jessica , Bland Christopher S , Rich-Zendel Sarah , Joo Jin Su , Dyson Judith
Published: January 2024

224

Background: Despite evidence of benefits and guideline recommendations for first-line treatment intensification (ie, androgen-deprivation therapy with chemotherapy, novel hormonal therapies, or both) in mCSPC, it is underutilized. We examined barriers and facilitators that US urologists and oncologists face with treatment intensification for mCSPC and identified behavior change techniques to address these through an implementation science approach. Methods: We conducted 36 double-blind, semi-structured, virtual interviews with practicing US urologists and oncologists who manage mCSPC using an interview guide based on the theoretical domains framework. Saturation was met when no new themes emerged. Physician statements were coded into 11 domains and themes to identify barriers and facilitators. To confirm codebook reliability, 10% of transcripts were double coded independently (k=0.77). Key domains and the associated barriers and facilitators were analyzed for frequency, perceived potential to impact behavior, and presence of disagreement. Top domains were cross-referenced with a taxonomy of validated behavior change techniques. Results: 36 interviewed physicians (20 low intensifiers[≤50% of patients get treatment intensification]; 16 high intensifiers [>50% of patients get treatment intensification]), 14 (39%) were from academic centers. Five impactful domains and the associated barriers and facilitators were identified along with behavior change techniques to overcome them (Table). Conclusions: Underutilization of treatment intensification in US is multifactorial. Poor knowledge, habit, anticipated regret, costs, and reserving treatment intensification for later use were prominent barriers. These can be addressed through behavior change techniques to improve mCSPC care. [Table: see text]
The utility of ChatGPT in subspecialty consultation for patients (pts) with metastatic genitourinary (GU) cancer.
Authors: Srivastava Ayana , Galarza Fortuna Gliceida , Chigarira Beverly , Dal Emre , Hage Chehade Chadi , Gebrael Georges , Narang Arshit , Agarwal Neeraj , Swami Umang , Li Haoran
Published: January 2024

227

Background: Cancer management requires a multidisciplinary approach, often requiring medical consultation from subspecialists. With the advent of artificial intelligence (AI) technologies like ChatGPT, it is hypothesized that these tools may help expedite the consultation process. This study aimed to assess the efficacy of ChatGPT in providing guideline-based sub-speciality recommendations for managing pts with metastatic GU cancer. Methods: In this single-institution, IRB-approved, retrospective, proof-of-concept study, pts with metastatic GU cancer over the past 3 years were screened. Those with at least one consultation referral to subspecialty clinics were randomly selected. ChatGPT 3.5 was given the most recent clinic note that triggered sub-specialty consultation. The AI tool was then asked to provide an assessment and plan. Two physicians independently assessed the accuracy of diagnoses made by ChatGPT and subspecialty physicians. The primary outcome was the consistency of ChatGPT recommendations with those of subspecialty physicians. Secondary Outcomes included potential time saved by using ChatGPT and comparison of medical decision-making (MDM) complexity levels between ChatGPT and subspecialty physicians. Results: A total of 39 pts were included. Their primary diagnoses included prostate cancer (51.3%), bladder cancer (23.1%) and kidney cancer (15.4%). The referred subspecialty clinic included cardiology (33.3%), hematology (17.9%), hepatology (2.6 %), hospice (10.3%), neurology (12.8%), pulmonary (15.4 %), and rheumatology (7.7%). The average waiting time for pts to be seen in subspecialty clinics was 44.9 days (SD = 42.4). Of 39 patient’s charts reviewed by ChatGPT, 30/39 (76.9%) had the same diagnosis with consultant sub-specialties. The average diagnoses made by ChatGPT were 8.2, compared with 3.4 made by sub-specialty physicians (p < 0.0001). The accuracy of diagnoses made by ChatGPT was the same, higher, and lower than human physicians in 10 (33.3%), 3 (10%), and 17 (56.7%) cases, respectively. Consistency of treatment plans between ChatGPT and physicians was found in 18 cases (46.2%). ChatGPT recommended additional workup in 32 cases (85.1%). The average number of words written in consultation notes by ChatGPT was 362.7 (SD = 72.9), which was significantly greater than subspecialty physicians (n = 224.7, p < 0.0001). Conclusions: These hypothesis-generating data suggest the potential utility of ChatGPT to assist medical oncologists in managing increasingly complex pts with metastatic cancer. Further studies are needed to validate our findings.
ERBB3 expression in racially diverse patients with castration-sensitive prostate cancer and its association with a unique AR activity signature.
Authors: Vellky Jordan , Vander Griend Donald , Reizine Natalie Marie
Published: January 2024

23

Background: Despite successful clinical management of castration sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. This number is even more striking in the context of racial disparities where prostate cancer mortality rates for Black/African American (AA) men are two to four times higher than those in every other racial and ethnic group in the US. Identification of molecular expression and activity patterns that vary by racial group may provide a key to addressing outcomes related to survival disparities, as current treatments have not been developed with attention to the inclusion of diverse patient populations. Developing a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide intelligent intensification of therapeutic strategies and improve survival, particularly in high-risk patient populations. Methods: Targeted deep sequencing was performed as routine care for treatment naïve patients in the UI cohort (n=30), and immunostaining was performed in racially diverse tissue microarray (n=149). Bioinformatics analyses were utilized to identify signaling pathways associated with biomarker overexpression in the UI cohort, consolidated publicly available RNA-seq datasets (n=664), and a racially diverse Gene Expression Omnibus dataset (n=68). Results: We identified ERBB3 overexpression (OE) in racially diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/AA men. Bioinformatics analyses showed a positive correlation between ERBB3 expression and the Androgen Response pathway despite low intraprostatic androgen and stable expression of androgen receptor (AR) transcript in Black/AA men. Clinically, ERBB3 OE is associated with high pre-treatment serum PSA in Black/AA men and is positively correlated with a clinically adaptable AR signature score. Preliminary outcomes data suggest Black/AA men with ERBB3 OE have a shorter time to disease progression. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling and serum PSA despite low intraprostatic androgen, suggesting ERBB3 OE as a prospective biomarker for ligand-independent AR activation. In this context, ERBB3 OE could stratify patients for intensification of therapy in castration-sensitive disease and emphasizes the importance of biomarker-directed clinical trials with diverse populations.
Evolving trends in prostate cancer: Disparities across income levels and global regions (1990-2019).
Authors: Jani Chinmay , Dudipala Harshitha , Tran Eli , McKay Rana R.
Published: January 2024

25

Background: Prostate Cancer, the third most commonly diagnosed cancer in 2020 and the fifth leading cause of cancer mortality worldwide, has exhibited significant disparities in global prevalence and impact over recent decades. This study assesses the trends in incidence, mortality, and disability-adjusted life years from prostate cancer in the World Bank regions based on country income levels from 1990 to 2019. Methods: The Global Burden of Disease Study database was used to extract Age-standardized incidence rates (ASIR), age-standardized (ASDR), and life years (DALYs) for prostate cancer from different World Bank regions based on income levels from 1990 to 2019. Annual percentage change was also acquired. Mortality-to-incidence ratios (MIR) were then computed. Trends were assessed using Joinpoint regression. Results: Between 1990 and 2019, ASIRs increased across all income levels, with the greatest growth in the upper middle income (+64.7%). While ASDRs decreased in high income, upper middle income, and lower middle income levels, they notably increased in low income levels (+14.3%). DALYs decreased in high income and upper middle income levels, primarily in the high income (-25.7%), and increased in lower middle and low income levels, primarily in the low income (+13.8%). MIRs decreased in all countries, with the largest decrease in high income levels (-50%). In the last 30 years, high income countries have consistently observed the highest ASIR (2019: 77.5/100,000). However, in 1990 high income countries also had the highest ASDRs and DALYs. Interestingly, by 2019 this pattern shifted, with low income surpassing high income countries in both. Conclusions: Over the last 30 years, the incidence of prostate cancer has been rising regardless of income level. Despite the universal decrease of MIRs implying improved outcomes, screening, and therapeutical strategies, the contrasting trends in ASDRs and DALYs across income levels underscore the disparities in health outcomes. Higher income countries experienced highest cancer incidence but also the highest decrease in the mortality rates while lower income countries faced the opposite challenges with lower increase but higher mortality rates. [Table: see text]
Patient-provider rurality and outcomes in older men with prostate cancer.
Authors: Stabellini Nickolas , Jiang Stephanie , Patel Vraj , Datta Biplab , Nain Priyanshu , Seth Lakshya , Kunhiraman Harikrishnan Hyma , Malik Sarah , Patel Sagar A. , Rupji Manali , Ward Kevin C , Switchenko Jeffrey M. , Moore Justin , Weintraub Neal L , Guha Avirup
Published: January 2024

265

Background: The impact of rural residence status as a social determinant of health on prostate cancer (PC) outcomes, considering both patient and provider location, remains unexplored. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to identify males aged ≥66 with new primary PC diagnoses (2009-2017). Patients' rurality was defined using the 2013 SEER Rural Urban Continuum Code. Provider rurality was defined by matching the provider to Core Based Statistical Area Codes with the 2013 National Center for Health Statistics Urban–Rural Classification scheme for counties. The primary outcome was All-cause mortality. Given proportional hazard violation, adjusted extended Cox models were performed for the primary outcome. Secondary outcomes were PC-specific mortality (PCSM) and cardiovascular mortality (CVDm). Adjusted Fine-Gray models, accounting for competing risks (other causes of mortality), were applied to assess PCSM and CVDm. Results: We included 75,291 PC patients, with a median age of 72 years (interquartile range 69-76), of whom 8.9% received androgen deprivation therapy (ADT). Among them, 91.7% originated from and received treatment in metropolitan areas, 7% were from urban areas but were served by metropolitan providers, 0.8% lived in rural areas and were served by metropolitan providers, and 0.5% resided in rural areas and were served by non-metropolitan providers. All-cause mortality risk was 44% higher in patients who hailed from rural areas and had a provider from a non-metropolitan area [adjusted hazards ratio = 1.44 (95% confidence interval = 1.15-1.79); Table]. Conclusions: Patients from rural areas with non-metropolitan providers face a higher risk of all-cause mortality, underscoring the role of rurality as a contributing factor to disparities in this PC outcome.[Table: see text]
Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial.
Authors: Tannir Nizar M. , Escudier Bernard , McDermott David F. , Burotto Mauricio , Choueiri Toni K. , Hammers Hans J. , Plimack Elizabeth R. , Porta Camillo , George Saby , Powles Thomas , Donskov Frede , Atkins Michael B. , Kollmannsberger Christian K. , Grimm Marc-Oliver , Tomita Yoshihiko , Rini Brian I. , Jiang Ruiyun , Desilva Heshani , Lee Chung-Wei , Motzer Robert J.
Published: January 2024

363

Background: First-line NIVO+IPI has provided substantial long-term survival benefits over SUN in patients (pts) with aRCC in CheckMate 214. We report survival, response per independent radiology review committee (IRRC) and safety after 6 y minimum (80 mo median) follow-up in all randomized pts, by IMDC risk and in pts with overall survival (OS) ≥ 6 y (long-term survivors; LTS). Longer follow-up data (minimum, 7.5 y) will be presented. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO 3 mg/kg Q2W vs SUN 50 mg QD for 4 wk on, 2 wk off. Endpoints: OS, progression-free survival (PFS) and objective response rate (ORR; both per IRRC using RECIST v1.1) in IMDC intermediate/poor risk (IP; primary), intent-to-treat (ITT; secondary) and favorable risk (FAV; exploratory) pts. Exploratory outcomes in LTS pts were assessed post hoc. Results: OS with NIVO+IPI vs SUN remained superior in ITT (HR 0.72) and IP (HR 0.68) pts; OS benefits were similar between arms in FAV pts (HR 0.87; Table). Median PFS was consistent with previous reports. ORR per IRRC was higher with NIVO+IPI vs SUN, with more ongoing responses in ITT (60% vs 50%) and IP (60% vs 50%) pts. In FAV pts, ORR was lower with NIVO+IPI vs SUN, yet more responses were ongoing (59% vs 52%, respectively). Median duration of response (DOR) was longer and complete response (CR) rate was higher with NIVO+IPI vs SUN regardless of IMDC risk. Incidence of any and grade 3-4 treatment-related adverse events remained largely unchanged. No new drug-related deaths occurred in either arm since the previous database lock. In the LTS subgroup (NIVO+IPI, n = 208; SUN, n = 151), ORR was higher (66% vs 53%), more pts had a CR (27% vs 9%) and fewer progressed (4% vs 11%) with NIVO+IPI vs SUN. Median DOR was longer with NIVO+IPI (n = 137) vs SUN (n = 80) among LTS with confirmed response (76 vs 40 mo). Updated survival, response and safety data with 7.5 y minimum follow-up, along with additional subgroup analyses, will be presented. Conclusions: NIVO+IPI demonstrated long-term survival and more durable response benefits vs SUN in ITT and IP pts. CR rates were higher and median DOR was longer with NIVO+IPI vs SUN regardless of IMDC risk group, and in LTS pts. No new safety signals emerged. Clinical trial information: NCT02231749 . [Table: see text]
Real-world efficacy and toxicity of ipilimumab and nivolumab as first line treatment of metastatic renal cell carcinoma (mRCC) in a subpopulation of elderly and poor performance status patients.
Authors: Beltran-Bless Ana-Alicia , Shani Shrem Noa , Ghosh Sunita , Tajzler Camilla , Wood Lori , Kollmannsberger Christian K. , Basappa Naveen S. , Graham Jeffrey , Fallah-rad Nazanin , Heng Daniel Yick Chin , Soulieres Denis , Lalani Aly-Khan A. , Breau Rodney H. , Finelli Antonio , Tanguay Simon , Bhindi Bimal , Bjarnason Georg A. , Pouliot Frederic , Canil Christina M.
Published: January 2024

367

Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) and response rates compared to sunitinib in the pivotal Checkmate 214 trial of intermediate/poor risk mRCC. A subgroup analysis showed no significant difference in OS for ipi/nivo in pts 65 to 75 years old (yo), as well as pts >75 yo. In another subgroup analysis, Karnofsky performance status (KPS) <70 was associated with worse median OS compared with pts with KPS ≥ 70. We evaluated efficacy and toxicity of ipi/nivo in an older and frailer population in a real-world cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N=378) treated with ipi/nivo as first line treatment from the Canadian Kidney Cancer Information System (CKCis) database from January 2011 to March 2022. Median follow-up was 14.3 m (range 0 to 87.6). A comparison was made between outcomes and toxicity in pts ≥ versus (vs) <70 yo, ≥ vs <75 yo, KPS < vs ≥70, and ≥70 yo with KPS <70 vs <70 yo with KPS >70. Toxicity was graded as per CTCAE v4.03 or any toxicity that resulted in a dose/schedule change. OS, progression free survival (PFS) and time to treatment failure (TTF) were calculated by Kaplan-Meier analysis. Log rank tests were used for comparison between groups. Multivariate analysis was done including IMDC for all outcomes. Results: Median OS was worse in older patients at 30.0 m in pts ≥ 70 yo vs 45.4 m in pts < 70 yo (p=0.060), and 19.0 m in the pts ≥ 75 yo vs 45.5 m in pts < 75 yo (p=0.003) despite similar disease control rates and toxicity. Median PFS was similar in younger and older pts: < vs ≥ 70 yo (p=0.560) and < vs ≥ 75 yo (p=0.296). Median TTF was comparable in < 70 yo and ≥ 70 yo (p=0.106) and < 75 and ≥ 75 yo groups (p-value=0.733). Median OS, PFS and TTF were comparable in pts KPS < 70 vs pts KPS ≥ 70 and in pts ≥70 yo with KPS < 70 vs pts < 70 yo with KPS >70. Adjusted and unadjusted analysis showed no difference in OS and PFS between groups. Conclusions: Use of ipi/nivo in mRCC in older patients was associated with inferior OS, while decreased performance status had equivalent OS. Both groups had equivalent TTF and PD without higher toxicity. We believe that ipi/nivo is a reasonable treatment option for older and low performance status patients. [Table: see text]
Impact of 18F-flotufolastat PET on management of patients with recurrent prostate cancer: Data from the SPOTLIGHT study.
Authors: Twardowski Przemyslaw ,   SPOTLIGHT Study Group
Published: January 2024

38

Background: 18F-Flotufolastat (18F-rhPSMA-7.3) is a newly approved high affinity PSMA-targeting PET radiopharmaceutical for diagnostic imaging in patients with prostate cancer (PCa). SPOTLIGHT (NCT04186845) evaluated 18F-flotufolastat in patients with recurrent PCa. Here, we report available SPOTLIGHT data to assess the impact of 18F-flotufolastat on planned treatment after curative-intent primary therapy. Methods: Patients underwent PET 50–70 min after IV administration of 296 MBq 18F-flotufolastat. The protocol instructed onsite investigators to record patients’ management plans (MP) before and after 18F-flotufolastat PET. These MP were compared and categorized as: ‘no change’, ‘major change’, ‘other change’, ‘additional information required’ or ‘intended plan not valid’. A ‘major change’ was defined as a change to treatment modality (e.g., salvage radiation therapy [RT] to systemic therapy), while ‘other change’ represented a change within a modality (e.g., modified RT field). Plans categorized as ‘no change’, ‘major change’ or ‘other change’ were considered evaluable. All imaging data were subsequently submitted for blinded image evaluation (BIE) by 3 central readers. Results: Of 389 patients who had 18F-flotufolastat PET, 97 had sufficient MP data for evaluation. These 97 patients were comparable to the overall population in terms of prior treatment (84% vs 79%, respectively, were post-prostatectomy), Gleason Score (63% vs 60% had Score 7), and median baseline PSA (0.8 vs 1.1 ng/mL). Moreover, BIE data show the detection rate in this subgroup (81/97; 84%) to be equivalent to that in the overall population (322/389; 83%). Most patients, 86/97 (89%) had a change to their MP post-scan. A ‘major change’ was noted for 78 (80%) patients, while 8 (8.2%) had an ‘other change’ (Table). Onsite imaging reads show that both positive and negative 18F-flotufolastat scans influenced MP. While 88% of revisions occurred after a positive scan, 75% of those whose MP were revised to watchful waiting (WW) had negative scans. All patients with MP revised from salvage therapy to non-curative systemic therapy had distant/extrapelvic 18F-flotufolastat-avid lesions. Conclusions: 18F-Flotufolastat located recurrence sites in the majority of patients with recurrent PCa, frequently resulting in major changes to MP. Treatment based on visualization of 18F-flotufolastat-avid lesions may facilitate optimal targeting of recurrence sites and avoid futile salvage therapy. Future studies of the outcome of such MP changes are warranted. Clinical trial information: NCT04186845 . [Table: see text]
Treatment options and outcome of patients with metastatic renal cell carcinoma with brain or bone metastases: Real world evidence from a German retrospective multi-center analysis.
Authors: Paffenholz Pia , Ivanyi Philipp , Casuscelli Jozefina , Stelmach Ramona , Guer Melis , Schlack Katrin , Darr Christopher , Rinderknecht Emily , Hilser Thomas , Flegar Luka , Klee Melanie , Seidl Daniel , Handke Analena , Nestler Tim , Mattigk Angelika , Augustin Marinela , Hijazi Sameh , Rehlinghaus Marc , Heidenreich Axel , Gruenwald Viktor ,   GUARDIAN
Published: January 2024

387

Background: Brain (BM) and bone metastases (BOM) in renal cell carcinoma (RCC) are associated with poor outcome. We evaluated real-world treatment paradigms of RCC patients with BM and BOM. Methods: We retrospectively analyzed RCC patients with BM and/or BOM treated at 18 German tertiary cancer centres from 2003 to 2023. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to local standard. Overall survival (OS) was calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 453 patients with a median age of 64 years (IQR 56-71). 93% of all patients had BOM, 15% BM and 8% both. Most patients (79%) had clear cell RCC, 7% of all patients had sarcomatoid differentiation. 82% of patients had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 20/56/24%. 64% received prior nephrectomy. Patients with BOM received first-line IO-combinations in 61% (IO-IO: 38%, TKI-IO: 62%), TKI-monotherapy in 39%, while patients with BM received IO-combinations in 68% (IO-IO: 37%, TKI-IO: 63%) and TKI in 32%. IO-based first-line therapy increased from 2003 to 2023. AE of all grades occurred in 87% and 69% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 42% or 25%. Best ORR and survival outcomes with median follow-up of 23 months (IQR 9-42) are described in table 1. 56% and 58% of all patients with BOM and BM received second-line treatment, with Cabozantinib (34%; 34%) and Nivolumab (17%, 23%) being the most common treatment options. In the subgroup of RCC with sarcomatoid features (n=36), 34 patients had BOM and 7 had BM, of which were treated with IO-combinations in 88% (BOM; IO-IO: 41%, TKI-IO: 59%) or 66% (BM; IO-IO: 50%, TKI-IO: 50%) and TKI-monotherapy in 12% (BOM) or 34% (BM) of all patients. Response rates (ORR/SD/PD) were 48%/28%/24% for IO-based therapy and 0%/50%/50% for TKI-monotherapy in RCC with sarcomatoid features, mOS was 41 months (95% CI 16.7-65.3). Conclusions: RCC patients with BOM and BM are increasingly treated with IO-combinations but lead to higher rates of AE grade ≥ 3. In patients with BOM, IO-TKI revealed higher ORR compared to IO-IO combination, but not in patients with BM. However, the small sample size and retrospective design are major limitations of our analysis. Prospective studies evaluating treatment options for BOM and BM in patients with RCC is critical. [Table: see text]
The role of cytoreductive nephrectomy (CN) in the immune checkpoint inhibitor (ICI) era of metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 2319 patients.
Authors: Makrakis Dimitrios , Msaouel Pavlos , Karam Jose A. , Esagian Stepan M.
Published: January 2024

425

Background: The combination of CN and systemic therapy has been established as one of the mainstay treatments for mRCC during the targeted therapy era. However, the role of CN in the ICI era remains unclear. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing the combination of CN + ICI vs. ICI alone in mRCC. Using published Kaplan-Meier overall survival (OS) curves, we reconstructed IPD and then performed one-stage and two-stage meta-analyses with both parametric and non-parametric effect estimates. To account for immortal time bias, we performed 6-month and 12-month landmark analyses. We also performed a subgroup analysis according to ICI line of treatment. The risk of bias was assessed using the ROBINS-I tool. Results: We identified eight retrospective cohort studies fulfilling our inclusion criteria. Only two out of eight studies adjusted for immortal time bias and none of them adequately adjusted for all predetermined confounding factors. A total of 2319 (1264 CN + ICI and 1055 ICI only) patients were included in our analysis. Patients in CN + ICI group were younger (median age 58.2 vs. 62.8), had lower proportions of non-clear cell histology (8.8% vs. 15.2%), ≥2 metastatic sites (60.0% vs. 68.5%), liver metastases (9.0% vs. 21.9%), and poor IMDC risk score (21.7% vs. 43.9%), but had higher proportions of sarcomatoid histology (15.6% vs. 10.6%) and ≥2nd line treatment (38.1% vs. 17.1%). The combination of CN + ICI was associated with superior OS in the one stage (HR: 0.45, 95% CI 0.38–0.52), 6-month landmark (HR: 0.45, 95% CI 0.37–0.54), 12-month landmark (HR: 0.50, 95% CI 0.31–0.50) and two-stage (HR: 0.38, 95% CI 0.29–0.49) meta-analyses. Similarly, the combination of CN + ICI was associated with superior OS in the subgroup of patients receiving first-line ICI (HR 0.39, 95% CI: 0.30–0.48). Conclusions: The combination of CN + ICI for mRCC may be associated with superior OS compared to ICI alone, but currently available data are subject to selection bias. More studies, including well-designed randomized controlled trials, are needed to determine the role of CN in the ICI era. [Table: see text]
Effect of dipeptidyl protease 4 (DPP4) inhibitors on progression-free survival in patients with metastatic renal cell carcinoma: A single-center retrospective analysis.
Authors: Ali Soham , Fortune Kathryn , Masur Jack , Viscuse Paul Vincent , Devitt Michael Edward , Dreicer Robert , Skelton William Paul
Published: January 2024

426

Background: Dipeptidyl peptidase IV (DPP4) is a cell surface receptor with exopeptidase activity that is expressed on most cell types, and possesses numerous substrates including growth factors, chemokines, and vasoactive peptides. These effects have implicated DPP4 in tumor growth and metastasis. Prior SEER-Medicare and retrospective studies have suggested an association between DPP4 inhibition and increases in both progression-free survival (PFS) and overall survival (OS) in patients with colorectal and lung cancers. Similar studies have shown no associated OS benefit from DPP4 inhibition in breast or pancreatic cancers, and increased OS but not PFS in prostate cancer. However, no studies to date have explored the impact of DPP4 inhibitors (DPP4i) in renal cell carcinoma (RCC). Thus, in this study we present a first-time analysis examining the impact of DPP4i use on PFS in patients with metastatic RCC and type 2 diabetes mellitus. Methods: We performed a single-center retrospective analysis of patients with diabetes and metastatic RCC at University of Virginia. The control group included patients who were on metformin, a sulfonylurea or SGLT2 inhibitor during treatment for metastatic RCC, while the study group included those who were taking a DPP4i with or without metformin and other diabetes medications during treatment. The primary and secondary endpoints of this study were PFS and OS, respectively. Results: Fifty-nine patients were eligible for the study, 11 of whom were taking a DPP4i with or without other diabetic medications during RCC treatment, while 48 were taking metformin with or without other non-DPP4i medications. Cancer progression occurred in 81.8% of patients in the DPP4i group compared to 66.7% of patients in the control group with an odds ratio of 1.58 (95% CI: 0.672-3.71), p = 0.57. No statistically significant difference on PFS (HR: 1.60; 95% CI: 0.75-3.43; p = 0.24) or OS (HR of death: 0.73; 95% CI: 0.27-1.97; p = 0.52) was found in this study. Conclusions: This retrospective study explored the effect of DPP4i on outcomes in patients with metastatic RCC and diabetes. While DPP4i have been shown in previous SEER-Medicare and retrospective studies to have favorable effects on PFS and OS in certain cancers such as colorectal and lung, the results of this study suggest that DPP4i do not confer clinical benefit in patients with RCC, similar to pancreatic and breast cancers. Given the small sample size in this study, larger studies are warranted to better elucidate the effect of DPP4i in metastatic RCC as well as the mechanisms underlying differential tumor response to these agents.
Utility of PSMA PET/CT for imaging ductal carcinoma of the prostate.
Authors: Mahmoud Ahmed M. , Navin Patrick , Muniz Miguel , Quevedo Fernando , Orme Jacob , Andrews Jack R. , Kase Adam McLain , Mosalem Osama M , Bryce Alan Haruo , Riaz Irbaz Bin , Burkett Brian J. , Kendi Ayse T. , Johnson Geoffrey , Ravi Praful , Kwon Eugene D. , Sartor Oliver , Childs Daniel S
Published: January 2024

49

Background: Ductal carcinoma (DC) is the second most commonly encountered histologic variant of prostate cancer. Previous studies have described its molecular features and aggressive behavior, but few have explored the performance of PSMA PET/CT in the initial staging and follow-up of DC. Methods: To address this gap, we performed a single-institution retrospective analysis using the Mayo Clinic PSMA PET database. All patients receiving a PSMA PET/CT scan in the interval of January 1, 2021, to December 31, 2022, were eligible for inclusion. Cases were filtered and categorized by histology at the time of diagnosis to select for pure DAC and mixed ductal variants. Trained research personnel annotated disease- and treatment-related variables. A board-certified radiologist performed tumor burden segmentation with calculations of SUV max, total lesion SUV mean and volume, and total lesion uptake, and ascribed a miPSMA expression score. Results: We queried 1792 patients from our PSMA PET/CT registry and identified 32 (1.8%) patients with a pathologically confirmed DC, including 8 (25%) patients with pure ductal and 25 (75%) patients with mixed histology. The indication for PSMA PET/CT was biochemical progression or restaging for 29 (91%) patients and initial staging for 3 (9%) patients. The median (IQR) time from prostate cancer diagnosis to PSMA PET scan was 41.6 (11.5-64.7) months, during this time 50% (n= 16) of patients developed CRPC. At the time of the PSMA PET/CT scan, the median age was 70 years, the median (IQR) PSA was 0.5 ng/mL (0.2-2.6). The distribution of metastatic spread and quantitative imaging parameters from PSMA PET are shown in the Table. Conclusions: Despite low PSA at the time of imaging, PSMA PET/CT frequently detected high volume osseous and/or visceral metastases in patients with DC. However, it is noteworthy that more than 50% of patients with DC had a low miPSMA score (0-1). Additional studies are needed to better understand the performance of novel imaging modalities when evaluating variant prostate cancers. [Table: see text]
Identification of a panel of microRNA biomarkers for the management of patients with refractory germ cell tumor of the testis.
Authors: Chen Jim Zhongning , Aydin Ahmet , Gokden Neriman , Langford Timothy , Tu Shi-Ming
Published: January 2024

521

Background: In 1946, nearly 90% of patients diagnosed with metastatic Testicular Germ Cell Tumor (TGCT) succumbed to the disease within a year. In the present day, over 90% of such patients are successfully cured. However, there is a remaining 10% of patients have tumors that consist of chemotherapy-resistant forms of TGCT, such as yolk sac tumors and teratomas. This underlines the need for developing biomarkers that can guide the choice between additional chemotherapy and surgical intervention. MicroRNAs (miRNAs), non-coding RNA molecules that control post-transcriptional modifications, have shown promise in identifying TGCTs. Research has particularly highlighted the overexpression of miR-371a-3p and miR-375-3p in TGCTs. Nevertheless, these miRNAs are not effective in distinguishing between teratomas and other TGCT types. The Cancer Genome Atlas (TCGA), a publicly accessible database, offers clinical and miRNA data on various tumors, including TGCTs. Our objective is to leverage TCGA to identify miRNAs that can be used to classify TGCTs containing teratomas from those that do not. Methods: Between 2001 and 2013, TCGA gathered a total of 135 primary TGCT samples. We group these tumors into those without teratomas and those with any teratomatous components. We used EdgeR, a Bioconductor package designed for differential expression analysis of RNA that accounts for both biological and technical variation. A false discovery rate of less than 1e-8 was applied. A heatmap was generated to display the hierarchical clustering of differentially expressed miRNAs. Results: Based on the above cut-off, a panel of 50 miRNAs of differentially expressed miRNA were used to generate a hierarchical clustering that showed clear clustering between the two groups. Notably, tumor suppressor miRNAs such as hsa-mir-203a, hsa-mir-199, and hsa-mir-152, which are usually downregulated in non-teratoma TCGT, are overexpressed in teratomas. Other miRNA including hsa-mir-146a and hsa-mir-3607, which are downregulated tumor suppressors for non-TCGT are also downregulated in teratomas but not in teratoma-free TGCT. Conclusions: Despite the high cure rate for TGCTs, tumors containing chemotherapy-resistant teratomas still contribute to elevated mortality rates. Utilizing TCGA data, we identified a set of miRNAs that are effective in distinguishing between teratoma-containing and teratoma-free TGCTs. This miRNA panel has the potential to inform decisions related to surgical treatment plans and provide further insight into the biology of the disease.