tbuckley/cabot-search huggingface dataset:
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: Vittorio Fasulo, Massimo Lazzeri, Paolo Casale, Alberto Saita, Rodolfo Hurle, Marco Paciotti, Alessio Finocchiaro, Muhannad Aljoulani, Pietro Cavalli, Giulia Soldà, Ilaria De Simone, Piergiuseppe Colombo, Miriam Cieri, Federica Maura, Giovanni Lughezzani, Rosanna Asselta, Nicolò Maria Buffi
Journal: Journal of Clinical Oncology (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.
Patient reported outcomes (PROs) among patients with metastatic castration-resistant prostate cancer (mCRPC) by homologous recombination repair mutations (HRRm) gene clusters: Findings from the phase 3 TALAPRO-2 study cohort 2.
Authors: Karim Fizazi, Neal D. Shore, Peter C.C. Fong, Arun Azad, Nobuaki Matsubara, Fred Saad, Ugo De Giorgi, Jae Young Joung, Robert J. Jones, Stefanie Zschaebitz, Jan Oldenburg, Curtis Dunshee, Joan Carles, Andre P. Fay, Paul Cislo, Melissa Kirker, Cynthia G. Healy, Alexander Niyazov, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

109 Background: Cohort 2 of the TALAPRO-2 (NCT03395197) study demonstrated benefit in radiographic progression-free survival (rPFS) with talazoparib (TALA) plus enzalutamide (ENZA) (n=200) vs placebo (PBO) + ENZA (n=199) across gene subgroups in men with HRRm receiving first-line treatment for mCRPC. Post-hoc analyses aimed to understand PROs by HRR gene clusters. Methods: PROs were assessed at day 1 and scheduled visits (every 4 weeks until week 53, then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and PR25 and BPI-SF. Prespecified PRO endpoints included overall mean change from baseline (per longitudinal repeated measures mixed-effects model) and time to definitive deterioration (TTDD) with a clinically meaningful change of ≥10-points for the EORTC QLQ-C30. Stratified log-rank test and Cox proportional hazards model were used to make TTDD between-arm comparisons. Mutually exclusive gene clustering alteration dominance hierarchy was applied in the following order: any BRCA1/2 alteration (BRCAm cluster), PALB2 (PALB2 cluster), CDK12 (CDK12 cluster), ATM (ATM cluster), then any of all other HRR7genes (MLH1, CHEK2, NBN, FANCA, ATR, RAD51C, MRE11A). Results: A significantly longer TTDD in GHS/QoL was observed for TALA + ENZA vs PBO + ENZA in the BRCAm (HR=0.54, 95% CI (0.29, 0.99); p=0.043; median NE vs 19.0) and CDK12 clusters (HR=0.43 (0.19, 0.98); p=0.019, median 30.7 vs 16.6). Overall changes from baseline in GHS/QoL and worst pain are reported in the Table. Conclusions: PRO findings by HRR gene clusters are consistent with rPFS benefit analyses by gene clusters. This was an exploratory post-hoc analysis limited by missing PRO assessments and sample sizes especially in the PALB2 cluster. Clinical trial information: NCT03395197 . [Table: see text]
Homologous recombination repair gene mutation (HRRm) testing patterns and treatment selection from a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Neal D. Shore, Christopher Craver, Simon Blanc, Pratheesh Sathyan, Lindsay Aton, Prateesh Varughese, Marni Brisson Tierno
Journal: Journal of Clinical Oncology (2024)

210 Background: Routine germline and somatic testing is recommended by professional guidelines as standard of care for all mCRPC patients since the approvals of poly ADP ribose polymerase inhibitors (PARPi) for treatment in those with tumors harboring select HRRm. Yet, analyses suggest that many mCRPC patients are not offered testing and thus patients with HRRm+ tumors may not have the shared decision-making opportunity to consider PARPi therapy. We reviewed HRR testing and treatment patterns within a real-world cohort of mCRPC patients to identify potential clinical practice gaps. Methods: The IntegraConnect – Precision Q Database that includes electronic, practice management and payer data from 500 US sites of care was utilized to select a de-identified real-world cohort of newly diagnosed and actively treated mCRPC patients (excluding those with lymph node only metastasis) between 1/1/2020 – 12/31/2021. Patient charts were manually reviewed by medical curators to extract data including frequency and timing of germline and somatic testing for HRRm, testing modality (tissue or liquid biopsy), results of HRRm testing, and the use of PARPi in the HRRm+ patient cohort. Results: A total of 996 mCRPC patients met criteria with 93% managed by community oncologists, 6% community urologists, and 1% academic oncologists. 59.2% (n=590) received testing for HRRm (19.8% germline (n=117); 59.8% somatic (n=353); 4.1% (n=24) germline + somatic; 16.3% (n=96) unknown) with testing rates increasing after PARPi approval: 15% between 1/1/2020 – 5/31/2020; 23% between 6/1/2020 – 9/30/2020; 62% between 10/1/2020 – 12/31/2021. The vast majority (64%) were tested after receiving mCRPC treatment, with 48% tested after failure on first line therapy. Somatic tissue testing was the predominant testing modality over liquid biopsy and germline testing. 31.7% (n=187) of tested patients were HRRm+ (11.2% germline (n=21); 73.8% somatic (n=138); 2.1% (n=4) germline + somatic; 12.8% (n=24) unknown), though not all tests utilized included the 14 HRR genes in the olaparib approval. BRCA2, ATM, CHEK2, and CDK12 HRRm were most commonly detected with a higher frequency of ATM and CHEK2 mutations seen in liquid biopsies. Of the mCRPC patients who were HRRm+, 66.8% (n=125) received PARPi. Conclusions: In this real-world analysis, 40.8% of mCRPC patients did not receive germline or somatic testing while 33.2% of HRRm+ patients did not receive PARPi. Optimizing germline and somatic testing for mCRPC is a significant unmet need, which negatively impacts therapeutic offerings.
Association between β3-adrenergic receptor agonist use and risk of kidney cancer among patients with overactive bladder.
Authors: Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Gwangmo Shin, Won Sik Ham
Journal: Journal of Clinical Oncology (2024)

456 Background: New aspects of β3-AR have been recently described with overexpression in cancers. Although post-authorization safety study of mirabegron, the first approved β3-AR agonist for overactive bladder (OAB), found no association between mirabegron use and risk of overall cancer, subgroup analysis revealed that some malignancies were significantly associated with β3-AR agonist use. This study aimed to examine whether cumulative β3-AR agonist use is associated with a higher risk of kidney cancer and demonstrate underlying mechanisms of β3-AR agonist through murine model. Methods: This nationwide population cohort study included newly diagnosed OAB patients who initiated their OAB medications between 2015 and 2020. In pulmonary metastatic orthotopic murine mRCC model, primary tumor weight and number of lung nodules were measured and evaluation of browning of perinephric fat (PF) and tumor immune microenvironment (TIME) was performed and compared between β3-AR agonist and vehicle treatment groups. Results: Among a total of 3,728,929 patients, 7,437 (0.2%) developed kidney cancer after starting OAB medications. There was an increased risk of kidney cancer among β3-AR agonist users (hazard ratio (HR)=1.514, 95% confidence interval (CI) 1.418–1.615) compared to anticholinergic users. The incidence of kidney cancer was also significantly increased with an increase in the cumulative dose of mirabegron (adjusted HR (aHR)=1.221 (1.104-1.351) for 30-180 cDDDs (cumulative defined daily doses), aHR=1.413 (1.281-1.558) for &gt;181 cDDDs) compared to low-dose cDDDs (&lt;30 cDDDs)). The β3-AR agonist treated mice demonstrated significantly higher primary tumor burden and lung metastasis with increased mitosis in cancer cells and browning of PF. Immunofluorescence analysis demonstrated that β3-AR agonist modulate TIME by increasing both myeloid-derived suppressor cells and regulatory T cells. Conclusions: This is the first study to demonstrate the association of kidney cancer and β3-AR agonist both in murine and human studies. By showing that the β3-AR agonist not only increases PF browning but also induces immune tolerance which eventually increases the initiation and progression of kidney cancer, we suggest β3-AR as the potential therapeutic target for novel anti-neoplastic approaches.
Variant subtypes in bladder cancer and CA125-positive cancer cell state.
Authors: Heiko Yang, Hanbing Song, Paul Allegakoen, Kevin L. Lu, Janae Gayle, Bradley A. Stohr, Chien-Kuang Cornelia Ding, Jonathan Chou, Maxwell Meng, Sima P. Porten, Franklin W. Huang
Journal: Journal of Clinical Oncology (2024)

694 Background: Variant subtypes in bladder cancer are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made molecular characterization elusive. The aim of this study was to identify cell states unique to variant subtypes using single cell RNA sequencing. Methods: Fresh tissue was collected from bladder cancer patients undergoing surgery at our institution and sequenced using a bead-based single-cell RNA sequencing platform (SEQWELL). Tissue from histologic variants and high grade pure urothelial tumors were analyzed together for comparison. Pathologic diagnoses were independently confirmed. Analysis was performed using Seurat. Immunostaining validation was performed on a separately banked cohort. Bulk RNA sequencing data and clinical data were extracted and analyzed from The Cancer Genome Atlas (TCGA) database. Results: We generated a single cell RNA sequencing atlas of 9 variants (micropapillary, nested, squamous differentiation, pleomorphic giant-cell like, plasmacytoid, small cell) with 3 pure urothelial tumors for comparison. Our analyses reveal a tumor cell state shared among multiple variants that is characterized by highly specific expression of MUC16 (CA125) , KRT24, and WISP2 (Fig. 1). This cell state has transcriptional hallmarks of epithelial-mesenchymal transition and luminal-basal plasticity, and its signature is associated with poor survival and resistance to chemotherapy. Immunohistochemistry in a validation cohort demonstrates that CA125+ cells are found only in tumors with variant histology and not in conventional high-grade and low-grade urothelial carcinomas. Within variants tumors, CA125+ cells are more enriched in metastatic sites compared to the primary tumors, consistent with a more aggressive phenotype. Conclusions: A CA125+ cell state in variant subtypes in bladder cancer is associated with aggressive molecular features. Further investigation of this cell state is needed to define its role in the pathogenesis of variant tumors.
Effect of cytoreductive nephrectomy on the efficacy of immunotherapy in metastatic renal cell carcinoma by decreasing IL-6 to modulate tumor-associated macrophage and myeloid-derived suppressor cell.
Authors: Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Gwangmo Shin, Won Sik Ham
Journal: Journal of Clinical Oncology (2024)

457 Background: Although the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized, the role of CN in immuno-oncology era still remains. Since the efficacy of immune checkpoint inhibitor (ICI) is limited, the role of CN in combination with ICI from the perspective tumor immune microenvironment (TIME) was evaluated using murine models and hypothesized that interleukin 6 (IL-6) blockade would enhance the efficacy of ICI therapy. Methods: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Antibodies targeting PD-1, CTLA-4, and IL-6 were systemically injected through the peritoneum. Renca implanted kidney was removed in the CN performed group and the timing of CN was differentiated according to the upfront and deferred CN group. The remodeling of the TIME was analyzed by flow cytometry, immunofluorescence analysis, and measurement of cytokines. Results: Upfront CN group demonstrated significantly better survival outcomes compared to deferred CN group in low-tumor burden models, while significantly longer survival was reported in deferred CN group compared to upfront CN group in high-tumor burden models. CN modulate IL-6 levels which act as a negative regulator of myeloid-derived stem cells (MDSCs) and M2 tumor-associated macrophage (TAM). The blockade of IL-6 activated CD8+ T-cell accumulation and led to decreased expression of MDSCs and M2 TAM, which is similar to the effects on TIME by CN combined with ICI therapy. Conclusions: This study is the first animal study to demonstrate the role of CN in combination with ICI. CN decreases the production of the cytokine IL-6, increasing the anti-cancer immunity TIME through modulation of MDSC and M2 TAM. Our study provides a research basis for the significant role of IL-6 in tumor regression and highlights a novel target to improve the efficacy of immunotherapy.
EIF2S1 as a novel diagnostic marker for bladder cancer in urinary extracellular vesicles.
Authors: Eisuke Tomiyama, Kazutoshi Fujita, Taigo Kato, Koji Hatano, Atsunari Kawashima, Norio Nonomura
Journal: Journal of Clinical Oncology (2024)

692 Background: Urinary extracellular vesicles (uEVs) secreted directly from BCa are considered a promising tool for diagnosing BCa, as they contain cancer-specific molecules. Among them, proteins in uEVs have attracted considerable attention, and several membrane EV proteins have been reported as urinary markers for BCa. However, few studies have focused on non-membranous (cytoplasmic) EV proteins. This study aimed to explore and validate a uEV-based diagnostic marker for BCa, focusing on cytoplasmic EV proteins. In addition, the functions of the identified protein were assessed. Methods: uEVs were isolated by ultracentrifugation with a sucrose cushion. Shotgun proteomics (TMT-labeled LC-MS/MS) was performed on uEVs from seven patients with BCa and four healthy individuals. Diagnostic marker candidates were selected from the identified cytoplasmic EV proteins and validated with targeted proteomics (SRM/MRM) of uEVs from 49 patients with BCa and 48 individuals without BCa, including patients with hematuria. The functional analysis of the identified EV protein was conducted in vitro. Results: Shotgun proteomics identified 1960 proteins, of which 17 cytoplasmic EV proteins were significantly elevated in the uEVs from patients with BCa (Fold change &gt;1.5, p-value &lt; 0.05). Of these, all ten measurable EV proteins were confirmed to be significantly elevated in urine from patients with BCa, of which EV-EIF2S1 showed the best diagnostic performance (ROCAUC: 0.83, sensitivity: 80%, specificity: 77%) in the validation cohort. Additionally, EV-EIF2S1 distinguished patients with BCa from non-BCa hematuria patients in a suitable manner (ROCAUC: 0.92, sensitivity: 82%, specificity: 83%). In the functional analysis of EIF2S1 in BCa cell lines T24 and 5637, the knockdown of EIF2S1 markedly inhibited cell proliferation. Cell cycle studies showed that the knockdown of EIF2S1 resulted in cell cycle arrest and induction of apoptosis. Therefore, EIF2S1 was considered an essential protein for the growth and survival of BCa cells. Conclusions: We identified EIF2S1 in uEVs as a novel diagnostic marker for BCa, enabling accurate and non-invasive diagnosis for BCa in a hematuria setting.
Estimating Bayesian priors for a non-inferiority randomized trial of gemcitabine-based chemoradiation for muscle invasive bladder cancer.
Authors: Abigail Pepin, Priyamvada Maitre, Xingmei Wang, Vedang Murthy, Ronac Mamtani, John Paul Christodouleas
Journal: Journal of Clinical Oncology (2024)

575 Background: Gemcitabine (gem) is a convenient radiosensitizer for muscle invasive bladder cancer (MIBC). However, the effectiveness and toxicity of gem have not been studied in a randomized control trial (RCT) against non-gem radiosensitization. This analysis aims to generate informative Bayesian prior distributions for effectiveness and toxicity outcomes to be used in a non-inferiority RCT of gem versus non-gem radio-sensitizers. Methods: We extracted all patients (pts) treated with curative intent concurrent chemoradiotherapy for node negative MIBC at a single institution between 2010-2022 and divided into gem vs non-gem cohorts. To minimize impact of confounding, we used freedom from distant metastases (FFDM) as our primary measure of effectiveness, censoring for both loss to follow up and death. We used a non-informative uniform prior to estimate the posterior distribution of hazard ratios (HR) for FFDM. We used a non-informative Jeffrey’s prior to estimate the posterior distribution of odds ratios (OR) for dichotomized acute grade 2 or higher gastrointestinal (G2+ GI) and genitourinary (G2+ GU) toxicities. We adjusted for age, T-stage, prior non-MIBC, neoadjuvant chemotherapy in all analyses. Results: A total of 106 pts were included (50 = gem, 56 = non-gem, of which 27 [48%] received mitomycin/5FU); 81% had cT2 disease and median radiation dose was 6480 cGy (range 4500-6480 cGy). Compared to pts in non-gem cohort, pts in gem cohort were older (mean age: 80 vs 76), had less advanced primaries (T3-T4: 14% vs 23%), were less likely to get neoadjuvant chemotherapy (12% vs 29%), were less likely to have prior non-MIBC (10% vs 13%), were less likely to complete full course radiotherapy (88% vs 94.6%), and had shorter follow-up (median 1.3 versus 2.3 years). The 2-year FFDM for the gem and non-gem were 62% and 66%. Table 1 shows rates of acute GI/GU toxicity. The median posterior HR (high probability density (HPD)) for FFDM was 1.54 (0.63-2.86). The OR (HPD) for grade 2+ GI toxicity was 2.4 (HPD 0.78-5.44) and grade 2+ GU toxicity was 0.91 (HPD 0.29-1.82) in gem vs non-gem cohorts. Conclusions: Our analysis suggests skeptical priors for FFDM (50% chance of at least 54% worse HR) and acute G2+ GI toxicity (50% chance of at least 140% worse OR) toxicity and a neutral prior for acute G2+ GU toxicity for a non-inferiority RCT of gem vs non-gem radiosensitization. Validation in a second institutional cohort will be available for our presentation. [Table: see text]
Post radical prostatectomy (RP) PSA outcomes following 6 versus 18 months of perioperative androgen receptor signaling inhibitors (ARSI) in men with localized high-risk prostate cancer: Results of Part 2 of a randomized phase 2 trial.
Authors: Rana R. McKay, Wanling Xie, Xiaoyu Yang, Andres Acosta, Dana E. Rathkopf, Vincent Paul Laudone, Glenn Bubley, David Johnson Einstein, Peter Chang, Andrew Wagner, Christopher J. Kane, Mark A. Preston, Kerry L. Kilbridge, Steven Lee Chang, Atish Dipankar Choudhury, Mark Pomerantz, Quoc-Dien Trinh, Adam S. Kibel, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2024)

326 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, abiraterone acetate, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. We demonstrated favorable pathologic responses (tumor ≤5 mm) in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant AAPL. Methods: At Part 2, patients were randomized 1:1 to AAPL for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (&lt;ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. Secondary endpoints included safety and time to testosterone recovery (&gt;200 ng/dL). Results: Overall, 69% (n=82/118) of patients enrolled to Part 1 were randomized to Part 2, of whom 58.5% (n=48) had ≥ ypT3 disease at RP. Patient preference was the main reason for non-randomization in Part 2. Of patients not randomized to Part 2, 32.3% (n=10) had a pathologic complete response or minimum residual disease (tumor ≤5 mm) at RP. In the intent-to-treat analysis, 3-year bPFS was 81% for Arm 2A and 72% for Arm 2B; the difference was not statistically significant (HR 0.81 90% CI 0.43-1.49). In a post-hoc per-protocol analysis, the 3-year bPFS was 83% for AAPL treated patients and 69% for patients on observation (HR 0.50 90% CI 0.26-0.97). Of patients randomized to Part 2, 81% of patients had testosterone recovery in the AAPL treated group compared to 95% in the observation group with median to recovery of 8.7 months compared to 4.0 months, respectively. Of the 37 patients receiving AAPL on Arm 2A, 28 (75.7%) experienced any grade treatment-related adverse event (TRAE) and 4 (10.8%) had grade 3-4 TRAE. The most common any grade TRAE were fatigue (27%) and hypertension (16%). Conclusions: Neoadjuvant ADT in localized high-risk prostate cancer resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, Part B of the study was underpowered to detect a difference between treatment arms. Subsequent studies will evaluate clinical and molecular predictors of bPFS. Clinical trial information: NCT02903368 .