tbuckley/cabot-search huggingface dataset:
Development of a novel RNA-based fibroblast growth factor receptor response signature (FGFR-PRS) for use in patients with urothelial cancer (UC).
Authors: Kirk L. Pappan, Gregory Mayhew, James M. Davison, Yoichiro Shibata, Joel Robert Eisner, Kirk Beebe, Michael Vance Milburn
Journal: Journal of Clinical Oncology (2024)

548 Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). However, ALT status may not fully capture all who may show clinical benefit as responses are observed in both ALT (+) and (-) patients. Improved test strategies are needed to identify patients most likely to respond to FGFRi. FGFR-PRS is an RNA-based signature developed to capture the biology of FGFR-active tumors independent ALT status and is intended to be used as a diagnostic (Dx) to identify a broader patient population likely to respond to FGFRi. Methods: Known oncogenic FGFR3 ALTs (S249C, R248C, FGFR3c-Y373C, FGFR3c-G370C, FGFR3:TACC3 and FGFR3:BAIAP2L1) were used as training labels for nearest centroid classifier development as described in Dabney et al, 2005 ( https://doi.org/10.1093/bioinformatics/bti681 ) using 2/3 of data from the TCGA BLCA dataset, predominantly comprised of muscle-invasive bladder cancer patients and a few mUC patients, for training. The resulting 80-gene signature was applied to the remaining 1/3 of TCGA and a separate BACI mUC dataset (Rose et al, 2021; https://doi.org/10.1038/s41416-021-01488-6) as test sets. In vitro drug sensitivity was evaluated using data from the Genomics of Drug Sensitivity in Cancer database (GDSC; https://www.cancerrxgene.org/ ). Differential gene expression (DGE) results were analyzed using WebGestalt 2019 (https://www.webgestalt.org/). Results: Thirteen and 18% of the TCGA and BACI UC cohorts were ALT (+), whereas 49% and 48% were FGFR-PRS (+) independent of ALT status. About half of the patients in either cohort were ALT (-)/ FGFR-PRS (-) and only 1% were ALT (+)/FGFR-PRS (-). FGFR 1-3 selective drugs had strong inverse correlations between FGFR-PRS score and IC50 across 18 GDSC bladder cancer cell lines. FGFR-PRS (+) samples had enhanced co-expression of FGFR3, FOXA1, and SHH and selected multiple differentiation ontologies. Conclusions: FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies. Analytical validation is ongoing to support FGFR-PRS for use as a clinical trial assay and eventual Dx.
MAPK pathway alterations as a targetable vulnerability in bladder cancer.
Authors: Vincent D'Andrea, Raie Bekele, Timothy Hanlon, Yuzhen Zhou, Rea Chroneos, Isabella Stelter, Kent William Mouw
Journal: Journal of Clinical Oncology (2024)

672 Background: Large-scale genomic studies of bladder cancer (BC) have identified MAPK as a recurrent pathway alteration. The MAPK pathway is a signaling cascade comprising of the proteins RAF, MEK, and ERK, which together control critical cellular processes. Currently, cisplatin-based chemotherapy and anti-PD1/PD-L1 agents are the backbone of systemic therapy in BC, yet only a subset of patients respond. As such, additional novel therapeutic strategies, such as targeting the MAPK pathway, are needed. Herein, we describe the impact of MAPK alterations on BC tumor properties sensitivity to novel MAPK-directed agents. Methods: The activity of the activity of RAF inhibitors (including RAF265 and the novel RAF dimerization inhibitor LXH254) was tested in BC cell lines with diverse MAPK pathway alterations including RAF1 amplification and NRAS mutations. Relative cell viability was measured by luminescence assay following treatment. RAF1-amplified UMUC9 cells were implanted as mouse flank xenografts which were randomized to treatment with vehicle or RAF inhibitor alone or in combination with a MEK inhibitor, trametinib. Mouse weights and tumor measurements were monitored during the treatment period and tumors were excised and weighed. C57BL/6 mice were orthotopically implanted with BBN cells with and without a RAF1 amplification using a surgical approach and tumor volumes were measured under ultrasound (US). Results: RAF1-amplified and NRAS-mutated cell lines demonstrated higher sensitivity to RAF inhibition than non-altered lines. There was a significant reduction in tumor volumes of UMUC9-engrafted mice treated with RAF265 (n=10) or RAF265 plus trametinib (n=8) compared to vehicle controls (n=14). Mice treated with RAF265 alone or with RAF265 plus trametinib had significantly lower tumor weights than vehicle-treated mice. US monitoring showed that mice orthotopically implanted with RAF1-amplified BBN cells (RAF1, n=9) and empty vector cells (EV, n=9) showed take rates [RAF1=67%, EV=78%], mean tumor sizes [RAF1=23.0mm 2 , EV=12.5mm 2 , p=0.07], and tumor growth rates [RAF1=0.60mm 2 /day, EV=0.40mm 2 /day, p=0.19]. Conclusions: We sought to explore the vulnerabilities incurred by MAPK pathway alterations in BC. We tested the activity of a RAF inhibitors in BC cell lines with RAF1 amplifications and NRAS mutations and found that MAPK pathway-altered models displayed increased sensitivity to RAF inhibition compared to MAPK-unaltered models. We further showed this sensitivity in vivo with RAF1-amplified mouse xenografts and elucidated the synergistic effect of concurrent RAF and MEK inhibition. There was a trend towards larger tumors and more rapid growth rate in orthotopically-implanted RAF1-amplified BC cells compared to controls. Taken together, these data identify MAPK pathway alterations as a novel dependency in BC that may be clinically targeted with small molecule inhibitors.
Role of 18F-flotufolastat PET/CT imaging in men with high-risk prostate cancer following conventional imaging and associated changes in medical management: A phase 3b investigator-initiated trial.
Authors: Zachariah Taylor, Ilia Zeltser, Nachum Stollman, Laurence Belkoff
Journal: Journal of Clinical Oncology (2024)

TPS347 Background: 18F-Flotufolastat (18F-rhPSMA-7.3) is a prostate-specific membrane antigen (PSMA) ligand for the detection of prostate cancer (PCa). It targets the extracellular epitope of the PSMA molecule and is administered as a single intravenous (IV) bolus microdose. The molecular structure comprises a PSMA binding motif, a peptide spacer, an 18F-radiolabeled silicon fluoride acceptor moiety, and a gallium chelator complex. Recent studies have demonstrated the utilization of 18F-flotufolastat in newly diagnosed PCa is beneficial with high specificity for detecting N1 and M1 disease prior to surgery. While the evidence for utilizing PSMA imaging for staging of newly diagnosed PCa is growing, the impact on clinical management is yet to be examined. Here, we evaluate the sensitivity and specificity of 18F-flotufolastat for detection of N1 and M1 disease, with subsequent evaluation of management changes for patients with extraprostatic disease. Methods: This is a multicenter, prospective, randomized study comparing 18F-flotufolastat PET/CT to conventional imaging for staging men with high-risk PCa and the subsequent change in medical management of these men. High-risk patients are defined as grade group ≥3 (primary Gleason grade 4, or any Gleason grade 5), PSA ≥20, or clinical stage ≥T3. Inclusion criteria include males &gt;18y with untreated biopsy-proven PCa with high-risk features as detailed above, and informed consent. Exclusion criteria are as follows: any prior therapy for PCa, previous imaging for staging of PCa, history of other malignancy, and significant comorbidity. All men will undergo conventional imaging techniques to complete staging. Physicians will then record the patients’ treatment plan (surgery, radiation including planned radiation fields, hormonal therapy, or other). The patients will then undergo PET/CT with a single bolus of 296MBq 18F-flotufolastat IV. Results will be reported to the responsible physician who will provide a final management plan. If treatment is planned post-18F-flotufolastat, the patient will receive treatment as follows: Standard of care surgical treatment of PCa, including PLND; or if the 18F-flotufolastat PET detects M1 lesion(s), a biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required prior to treatment. The co-primary objectives of this study are the percentage of men with high-risk PCa upstaged to N1 or M1 disease, and the subsequent change in management. Clinical trial information: NCT05799248 .
Randomized phase III clinical trial of neoadjuvant intravesical mitomycin C (MMC) treatment in patients with primary treatment-naïve vesical neoplasms: Interim analysis.
Authors: Alberto Saita, Rodolfo Hurle, Paola Arena, Chiara Pozzi, Miriam Cieri, Piergiuseppe Colombo, Massimo Lazzeri, Giovanni Lughezzani, Nicolò Maria Buffi, Vittorio Fasulo, Marco Paciotti, Stefano Mancon, Michela Lizier, Emanuela Morenghi, Maria Rescigno, Paolo Casale
Journal: Journal of Clinical Oncology (2024)

626 Background: The aim of the current study is to evaluate the safety, tolerability, and efficacy of neoadjuvant MMC in patients (pts) with non-muscle invasive bladder cancer (NMIBC). Methods: This is a prospective phase III randomized clinical trial in pts with primary clinical diagnosis of urinary bladder cancer or secondary recurrent untreated bladder cancer since May 2022 to September 2023 (EudraCT 2021-003751-42_studio ICH-013-). Pts are randomized 1:1 to neoadjuvant MMC arm (neoA) or standard arm (StA). In the 2 weeks before scheduled TUR (day 0) neoA pts receive intravesical instillations of MMC (40 mg/40 ml saline) at day -14 and -7 and cystoscopy with a cold cup biopsy at -14. After TUR, clinical choices both in the two groups, depend on histological evaluation of the tumour and EAU guidelines. Midstream and catheter urines are collected before instillations, at day 0 and after 3 months to respectively measure the level of specific biomarker (i.e., HMGB1) and to identify the microbiota. The expression of a mitomarker is evaluated on tissue samples. The primary endpoint is to assess safety, tolerability, and efficacy of neoadjuvant MMC in reducing the recurrence rate of BC calculated as the proportion of pts who achieve a complete response (no evidence of BC after 3, 6, 12 and 24 mo). The secondary endpoint will be the analysis of the rate of grade and stage progression to MIBC in case of recurrence and the correlation with biomarkers. Results: The interim analysis (median follow-up 6 months) included 54 pts: 26 in the StA and 28 in the neoA. Respectively in StA and neoA mean age at TUR was 66.5 (±9.9) and 65.8 (±9.9), males were 23 (88.46%) and 24 (85.71%). No statistically significant difference was observed between groups. 5 neoA pts [17.86% (95%CI 6.06-36.89)] after instillations reported 4 different adverse reactions, grade 1 of Clavien Dindo classification. NeoA pts showed higher level of HMGB1 at day 0 and after 3 months, suggesting an increased induction of immunogenic cell death (ICD). Shotgun metagenomics on microbial DNA from catheter urine is still ongoing. In field recurrence has been observed in 1 (3.85%) StA and 2 (7.14%) neoA pts. Conclusions: Preliminary data show neoadjuvant MMC to be safe and well tolerated and seem to correlate with increase of HMGB1. The short follow-up and the small sample size do not allow conclusion on the efficacy. Clinical trial information: EUCTR2021-003751-42 .
The impact and mechanisms of gut microbiota on the efficacy of neoadjuvant therapy in patients with MIBC.
Authors: Tao Li, Tianyu Qi, Kaijie Wu
Journal: Journal of Clinical Oncology (2024)

669 Background: Platinum-based neoadjuvant chemotherapy, such as gemcitabine/cisplatin (GC) or dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (ddMVAC), followed by radical cystectomy (RC), represents the current standard of care for T2-T4aN0M0 muscle-invasive bladder cancer (MIBC). Regrettably, only 40% of patients who received neoadjuvant chemotherapy achieved a pathological complete response (pCR). Recently, several trials showed a promising efficacy of immune checkpoint inhibitors (ICIs) plus neoadjuvant chemotherapy. BGB-A317-2002 study indicated that the addition of tislelizumab to GC can increase the pCR rate to 54.5%, with a pathological downstaging rate of 77.3%. Nevertheless, a subset of patients failed to derive benefits from ICIs plus neoadjuvant chemotherapy. Methods: This study aimed to explore the impact and mechanisms of gut microbiota on the efficacy of neoadjuvant therapy through the analysis of fecal samples obtained from MIBC patients who received GC or GC plus ICIs. Here, we reported the impact of gut microbiota on treatment outcomes in patients who received GC. Results: A total of 54 patients who received neoadjuvant GC chemotherapy were enrolled. Among them, 23 (42.59%) exhibited a pathological response (responsive group), and 31 (57.41%) showed no response (non-responsive group; no imaging changes or disease progression). Metagenomic sequencing on fecal samples from patients before and after therapy showed that the Shannon index in species level (1.182 vs. 0.954, p=0.016) and abundance of Ruminococcus gnavus were significantly greater in the responsive group than non-responsive group. It suggested that responsive patients displayed higher species richness of gut microbiota. Conclusions: The efficacy of neoadjuvant GC chemotherapy in MIBC patients may be potentially influenced by the number of gut microbiota populations. Additionally, the potential application value of Ruminococcus gnavus in improving the efficacy of non-responsive patients is noteworthy. A larger-scale study is needed to determine the above findings.
Transperineal prostate biopsies without routine administration of perioperative antibiotics: A single-institution retrospective analysis.
Authors: Benjamin Lichtbroun, Mann Patel, Labeeqa Khizir, Munisa Said, Alexis Consalvo, Austin Chien, Kevin J. Chua, Arnav Srivastava, John Pfail, Sammy Elsamra, Thomas L. Jang, Saum Ghodoussipour
Journal: Journal of Clinical Oncology (2024)

310 Background: Infections are the most feared complication of transrectal prostate biopsy. Unfortunately, these complications are not infrequent. With antibiotic resistance becoming increasingly common, our institution has transitioned to a transperineal approach without use of perioperative antibiotics or bowel preparation. Given this significant change in practice pattern, we retrospectively analyzed these patients for rates of post-operative complications, 30-day hospital readmissions, and detection of prostate cancer. Methods: We retrospectively analyzed 146 patients who underwent a transperineal prostate biopsy at our institution in 2022. We recorded rates of complications including UTIs, sepsis, hematuria, and 30-day hospital readmissions. We also analyzed the percentage of patients found to have prostate cancer. Results: Of the 146 patients analyzed, 8 patients received peri-operative antibiotics (5.47%) - this was at the discretion of the surgeon performing the procedure. The reason 8 patients received peri-operative antibiotics was due to a prior infectious complication following a previous transrectal prostate biopsy. No patient received bowel preparation. Pre-procedure MRI was performed in 134 patients who had a MRI-ultrasound fusion biopsy. Hematuria was reported in 12 patients (8.21%) and there were zero infectious complications (UTI or sepsis). There were no 30-day readmissions amongst this cohort. Median procedure time was 24 minutes (Table). 86 patients were found to have adenocarcinoma (58.90) while 48 patients had benign pathology (32.87%). Conclusions: Despite a small percentage of patients receiving perioperative antibiotics, we had zero patients develop sepsis or an UTI. Our 30-day readmission rate was also 0%. With the high reported rates of infectious complications after transrectal prostate biopsy and antibiotic resistance becoming increasingly common, our data supports the notion that transperineal prostate biopsies are safe and can largely be done without the use of perioperative antibiotics.[Table: see text]
A novel radiomics-miRNAs integrated model to predict the histopathology of residual retroperitoneal masses in metastatic nonseminomatous germ cell tumors.
Authors: Xiangdong Li, Renjie Ding, Zhuowei Liu
Journal: Journal of Clinical Oncology (2024)

507 Background: Patients with metastatic nonseminomatous germ cell tumours (NSGCTs) are treated with cisplatin-based chemotherapy, followed by postchemotherapy retroperitoneal lymph node dissection (pcRPLND) for patients with residual nodal masses &gt;1 cm. However, 40–50% of patients who undergo pcRPLND are found to have fibrosis/necrotic tissue alone, which may result in overtreatment. Previous prediction models were based on a single method. We hypothesized that a radiomics-based model combined with serum micro-RNAs (miRNAs) including miR371 and miR375 could exhibit better prediction performance in histopathological presence of visible germ cell tumor, teratoma, and fibrosis/necrotic residual retroperitoneal masses. Methods: A retrospective review of 105 patients with 145 residual retroperitoneal masses undergoing pcRPLND for metastatic NSGCTs was performed to develop a prediction model. The dataset was split into separate training cohorts for model construction and validation cohorts for internal validation. On contrast-enhanced axial computed tomography images, 145 corresponding regions-of-interest (ROIs) of residual masses were segmented and 1130 radiomic features per ROI were extracted. After stepwise feature reduction based on reproducibility, variable importance, and correlation analyses, a logistic regression model was established on the selected most important features. Serum miRNA were used to optimize the classifier. The area under receiver operating characteristics curve (AUC), calibration curve, and decision-curve analyses (DCAs) were used to evaluated the prediction model. Results: The trained machine learning model achieved an AUC of 0.772 (95% CI: 0.670-0.875) in the training cohort and 0.764 (95% CI: 0.589-0.938) in the validation cohort. When serum miR371 and miR375 were added to the radiomics signature, the AUC of training cohort was improved to 0.900 (95% CI: 0.826-0.973), and the AUC of validation cohort was improved to 0.939 (95% CI: 0.847-1.000). Nomogram including radiomics score (Radscore) and miRNA was also performed, and the calibration curve analysis and the DCAs confirmed the agreement between prediction and observation and the clinical utility of the radiomics-miRNA prediction model respectively. Conclusions: Radiomics-miRNAs integrated model represents a novel tools for improved prediction of the histopathology of residual retroperitoneal masses in metastatic NSGCTs, aiming at reducing overtreatment. External validation and prospective datasets are needed to further validate this model.
Impact of renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with metastatic renal cell carcinoma (mRCC).
Authors: Kathryn Fortune, Soham Ali, Jack Masur, Paul Vincent Viscuse, Michael Edward Devitt, Robert Dreicer, William Paul Skelton
Journal: Journal of Clinical Oncology (2024)

424 Background: The renin-angiotensin system (RAS), traditionally associated with blood pressure regulation and fluid balance, also plays a role in tumor development and growth among several cancer types. Renin-angiotensin system inhibitors (RASI), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown in studies of various malignant neoplasms to be associated with improved outcomes. In metastatic urothelial cancer, the use of ACEI and ARBs has been associated with higher rates of tumor regression among patients (pts) receiving immunotherapy (IO) with PD1/L1 inhibitors. One potential mechanistic explanation is RASI-induced downregulation of TGF-beta, for which high expression is a known mechanism of PD1/L1 inhibitor resistance. While the development of novel IO therapies has changed the treatment landscape for mRCC, only one study to date has examined the impact of RAS inhibition in pts with mRCC receiving IO. We hypothesized that concurrent RASI in pts with mRCC receiving IO is associated with increased tumor regression. Methods: We conducted a retrospective analysis of pts with mRCC receiving immunotherapy as a first or second line of treatment from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RASI on tumor regression. The primary endpoint in this study was any regression of tumor on imaging. Results: Data were available for 147 pts with mRCC who received IO as a first- (n=104, 70.7%) or second- (n=43, 29.3%) line treatment. 52 pts (35.4%) received ACEI/ARBs during IO; 42 pts (40.4%) who received IO as first-line treatment were on ACEI/ARBs and 10 patients (23.2%) who received IO as a second-line treatment were on ACEI/ARBs. Analysis showed that pts who received ACEI or ARBs during IO were more likely to have tumor regression compared to pts who were not on concurrent RASI (OR 7.43 [95% CI 2.70-23.53], p=0.0002). This held true regardless if pts received IO as a first-line (OR 6.02 [95% CI 1.84-23.38], p=0.005) or second-line (OR 9.71 [95% CI 1.51-122], p=0.032) treatment. Conclusions: Our hypothesis generating study suggests that in our RCC population the concurrent use of RASI in pts with mRCC receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RASI in combination with IO for mRCC pts. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population.[Table: see text]