tbuckley/cabot-search huggingface dataset:
Neutrophil extracellular traps in relation to efficacy of systemic therapy for metastatic renal cell carcinoma.
Authors: Rui-Yang Xie, Bing-Qing Shang, Hongzhe Shi, Xin-Gang Bi, Yan Song, Wang Qu, Hongsong Bai, Jie Wu, Honglei Cui, Gan Du, Lei Guo, Shan Zheng, Jianming Ying, Changling Li, Jianhui Ma, Ai-Ping Zhou, Shudong Zhang, Jianzhong Shou
Journal: Journal of Clinical Oncology (2024)

441 Background: The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. This study investigates the predictive value of neutrophil extracellular traps (NETs) in determining the efficacy of metastatic ccRCC. Methods: In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. The correlation between NETs and clinicopathological features was analyzed, and the predictive value of NETs for drug efficacy and prognosis was assessed using Cox proportional hazard analysis. Results: A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. H3Cit and MPO were predominantly expressed in the nucleus and cytoplasm, respectively. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p&lt;0.001). Increased levels of NETs in tumor tissue were associated with tumor N stage (p=0.02) and neutrophil-to-lymphocyte ratio (NLR) (p=0.02). In terms of predicting drug efficacy, a correlation between NETs levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p=0.037), while no correlation was observed in the targeted agent with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NETs levels were associated with poor OS (HR 1.87 [95% CI 1.24-2.81], log-rank p=0.003). Cox analysis revealed that IMDC score (HR 1.462 [95% CI 1.030-2.075], p=0.033) and tumor tissue NETs level (HR 1.733 [95% CI 1.165-2.579], p=0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC. Conclusions: The active NETs level in tumor tissue can serve as a predictor of drug efficacy in patients with metastatic ccRCC who received targeted agents with metachronous metastasis. However, no significant correlation was observed in the IO-TKI group, and further investigation is required. Elevated levels of NETs in tumor tissue were also associated with poor prognosis in OS prediction.
Evaluation of ctDNA in patients with mCRPC with liver metastases.
Authors: Minqi Huang, Georges Gebrael, Nicolas Sayegh, Crystal Casado, Nicholas Habibian, Opeoluwa Akerele, Kanika Gupta, Alexandra Lieberman, Jennifer Schwartz, Jodi Lyn Layton, Patrick L Sweeney, Brian E. Lewis, Neeraj Agarwal, A. Oliver Sartor, Elisa M. Ledet
Journal: Journal of Clinical Oncology (2024)

212 Background: Patients with prostate cancer with liver metastases are known to have a worse prognosis. In this study, we evaluated ctDNA in mCRPC (metastatic castration-resistant prostate cancer) patients with and without liver metastases. Methods: A retrospective chart review identified mCRPC patients with liver metastases at Tulane Cancer Center and Huntsman Cancer Institute. Liver metastases were confirmed via molecular or conventional imaging. All patients had ctDNA assessed with a multi-gene cancer panel via the Guardant 360 assay. Alterations with &lt;0.1% allelic fraction, synonymous alterations, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Fisher’s Exact and Wilcoxon Rank Sum Tests. Correction for multiple testing was not performed, hence these alterations may be subject to a type 1 error. Results: 53 mCRPC patients with liver metastases and 144 mCRPC patients without liver metastases were included in the study. We found seven genes that are more likely to be pathologically altered in ctDNA in mCRPC patients with liver metastases (See Tables 1-3): AR (OR=2.38, 95% CI: [1.25, 4.52], p=0.01), BRAF (OR=2.74, 95% CI:[1.05, 7.18], p=0.05), BRCA2 (OR=5.33, 95% CI:[1.49, 19.02], p=0.01), CDK6 (OR=4.09, 95% CI:[1.35, 12.42], p=0.01), EGFR (OR=3.12, 95% CI:[1.22, 7.99], p=0.02), FGFR1 (OR=5.69, 95% CI:[1.81, 17.86], p-value=0.003), MYC (OR=4.55, 95% CI:[1.63, 12.68], p=0.004), and PIK3CA (OR=4.34, 95% CI:[1.87, 10.06], p=0.01). Additionally, mCRPC patients with liver metastases are more likely to have copy number alterations (CNA) (p= 0.01) compared to mCRPC patients without liver involvement. There were no other significant differences in the remaining 70 genes interrogated. Germline pathogenic alterations did not vary between the two groups. Conclusions: In mCRPC patients with liver metastases, these exploratory analyses suggest ctDNA testing is more likely to detect pathologic alterations in AR, BRAF, BRCA2, CDK6, EGFR, FGFR1, MYC, and PIK3CA. Additionally, mCRPC patients were more likely to have copy number alterations (CNA). Limitations of the Guardant 360 assays are notable in this setting given the incomplete ascertainment of gene deletions and the incomplete number of prostate-relevant genes assessed. [Table: see text]
Every-other-day or once-a-week: Long-term efficacy outcomes of the multicenter randomised PATRIOT prostate SBRT trial.
Authors: Wee Loon Ong, Harvey Charles Quon, Aldrich Ong, Patrick Cheung, William Chu, Hans T. Chung, Danny Vesprini, Amit Chowdhury, Dilip Panjwani, Yasir Alayed, Geordi Pang, Renee Korol, Melanie Davidson, Ananth Ravi, Boyd McCurdy, Liying Zhang, Meghan Kulasingham-Poon, Alexandre Mamedov, Andrea Deabreu, Andrew Loblaw
Journal: Journal of Clinical Oncology (2024)

325 Background: We aim to report the long-term efficacy outcomes of the PATRIOT trial, a multicenter phase 2 randomised trial of every-other-day (EOD) versus once-a-week (QW) schedule for stereotactic body radiotherapy (SBRT) for prostate cancer (NCT01423474). Methods: Between January 2012 and November 2013, 152 men with low to intermediate risk prostate cancer were randomised to prostate SBRT 40Gy in 5 fractions, delivered EOD (n=75) or QW (n=77). The oncological outcomes evaluated were biochemical failure (BF) (based on Phoenix criteria), metastases free survival (MFS), prostate cancer specific survival (PCSS) and overall survival (OS). Time-to-event was estimated from the start date of SBRT to event of interest or last follow-up. The cumulative incidence of BF was estimated using the Nelson Aalen estimates, while MFS, PCSS and OS were estimated using the Kaplan Meier method. Results: The median follow-up for the cohort was 91 months (IQR: 61-116 months). Five men in the EOD arm and eight men in the QW arm developed BF. The 8-year cumulative incidence of BF were 5.5% (SE=0.03) in the EOD arm and 9.6% (SE=0.04) in the QW arm (P=0.3). None of the men in the EOD arm developed metastases, while three men in the QW arm did. The 8-year MFS were 100% in the EOD arm and 95.9% (95%CI=91.4-100%) in the QW arm (P=0.08). Thirteen men had died at last follow-up, of which two were prostate cancer specific death. The 8-year PCSS were 100% in the EOD arm and 97.2% (95%CI=93.5-100%) in the QW arm (P=0.3), while the 8-year OS were 96.0% (95%CI=91.7-100%) in the EOD arm and 85.4% (95%CI=76.4-95.5%) in the QW arm (P=0.3). Conclusions: There are no statistically significant differences in long-term oncological outcomes between EOD and QW for five-fraction prostate SBRT in the PATRIOT trial. However, the trial was powered for acute toxicity differences, and not MFS or OS. Either prostate SBRT schedule could be safely delivered depending on patients’ preference, or for logistic reasons. We plan to combine these data with the Swiss EOD vs QW randomised trial (NCT01764646) to improve the power to detect these important outcomes. Clinical trial information: NCT01423474 .
Long-term outcomes of a multicenter prospective observational study of active surveillance for early-stage prostate cancer: The PRIAS-JAPAN study.
Authors: Takuma Kato, Ryuji Matsumoto, Akira Yokomizo, Yoichiro Tohi, Keiichiro Mori, Yoichi Fujii, Hiroshi Fukuhara, Takuma Sato, Junichi Inokuchi, Katsuyoshi Hashine, Shinichi Sakamoto, Mikio Sugimoto, Yoshiyuki Kakehi
Journal: Journal of Clinical Oncology (2024)

322 Background: Japan is participating in the Prostate cancer Research International: Active Surveillance (PRIAS) study as PRIAS-JAPAN since 2010. This study’s aim is to report the long-term outcomes of the PRIAS-JAPAN study initiated in 2010. Methods: Basic patient eligibility criteria were clinical stage ≤T2, PSA ≤10, PSA density (PSAD) &lt;0.2, number of positive cores ≤2, and Gleason score (GS) ≤6. Those have been revised progressively since then, and since January 2021, for patients who underwent MRI fusion biopsy at the time of initiation or follow-up biopsy, PSA ≤ 20, PSAD &lt; 0.25, and the number of positive cores ≤ 2 for GS3+3, and ≤ 6 for GS3+4. For the number of positive cores, the eligibility criteria were expanded to no limit for GS3+3 and no more than half of the total number of cores for GS3+4. PSA test every 3 months, rectal examination every 6 months, biopsy at 1, 4, 7, and 10 years, and every 5 years thereafter, and recommendation for secondary treatment after confirming pathological deterioration. Reevaluation of MRI within 3 months after diagnosis and targeted biopsy of the same site if there is a lesion suspicious for cancer, and recommends annual MRI when PSA-DT &lt; 10 years and annual systematic biopsy if MRI cannot be performed. Results: As of the end of February 2023, 1204 patients were enrolled. The eligibility criteria were met in 1173 patients. The median age, PSA, PSAD, and number of positive cores were 69 years, 5.3, 0.15, 1, 844, and 309, respectively, and the clinical stage was T1c in 1,019 and T2 in 154 patients. The acceptance rates of re-biopsy at 1, 4, 7, and 10 years were 83.0%, 63.5%, 39.0%, and 20.3%, respectively, and the pathological deterioration rate at each re-biopsy was 29.4%, 29.7%, and 35.6%, respectively. The pathological deterioration rate at the time of each biopsy was 29.4%, 29.7%, 35.6%, and 18.1%, respectively.467 patients selected subsequent therapy and prostatectomy was the most frequently chosen treatment option. Conclusions: Pathological deterioration was observed in about 30% of patients at the time of biopsy, but the rate of biopsy decreased over time. Adherence to biopsy was considered necessary for the safe implementation of active surveillance. Clinical trial information: 2021-211.[Table: see text]
Pathologic and survival outcomes following radical cystectomy for “progressive” and “de novo” muscle-invasive bladder cancer: A meta-analysis stratified by neoadjuvant chemotherapy status.
Authors: Leilei Xia, Anosh Dadabhoy, Erika L. Wood, Daniel Roberson, Thomas J. Guzzo, Trinity Bivalacqua, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2024)

566 Background: Muscle-invasive bladder cancer (MIBC) can present as de novo MIBC (dnMIBC) or progressive MIBC (pgMIBC), the latter occurring in patients with a history of non-muscle-invasive bladder cancer (NMIBC). Retrospective cohort studies have reported varied survival outcomes following RC for pgMIBC versus dnMIBC.Here we aim to pool previous studies and compare survival and pathologic outcomes in patients with pgMIBC and dnMIBC following radical cystectomy (RC), with an investigation of the impact of neoadjuvant chemotherapy (NAC). Methods: A comprehensive literature search was conducted on PubMed and EMBASE databases to identify studies comparing pgMIBC to dnMIBC. Survival outcomes, including cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS), as well as pathologic outcomes following surgery (rates of ≤pT1, pT0, pT3/T4, and pN+ disease) were compared between pgMIBC and dnMIBC. Results: The analysis included 19 cohorts from 16 studies, categorized into three groups based on NAC status: 1. patients who underwent RC following completion of NAC (RC + NAC only group); 2. patients who underwent RC, with or without NAC (RC +/- NAC group); 3. patients who only underwent RC without NAC (RC only group). Compared to dnMIBC, pgMIBC demonstrated worse outcomes for CSS, OS, and RFS. In the RC + NAC only group (3 cohorts), the hazard ratio (HR) for CSS was 1.52 (95% confidence interval [CI] = 1.05-2.2), the HR for OS was 1.46 (95%CI = 1.05-2.02). Similarly, in the RC +/- NAC group (6 cohorts for CSS and 3 cohorts for OS), the HR for CSS was 1.27 (95%CI = 1.05-1.55), and the HR for OS was 1.27 (95%CI = 1.08-1.51). There were no significant differences observed in pathologic outcomes, including rates of ≤pT1, pT0, and pT3/T4 disease, across all subgroups. However, pgMIBC was associated with a higher risk of nodal metastatic (pN+) disease in the RC + NAC only group (4 cohorts, relative risk [RR] = 1.43, 95%CI = 1.12-1.84). Conclusions: The findings highlight the potentially worse prognosis in patients with pgMIBC compared to dnMIBC, even with the modern use of NAC. The study emphasizes the importance of careful patient counseling, further classification of patients for treatment selection, and the consideration of additional or innovative systemic therapies for pgMIBC.
The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): A study protocol for a multi-center, prospective, randomized trial.
Authors: Jee Soo Park, Jongchan Kim, Jinhyung Jeon, Jongsoo Lee, Won Sik Jang, Seung Hwan Lee, Woong Kyu Han, Young Deuk Choi, Kyo Chul Koo, Kang Su Cho, Byung Ha Chung, Won Sik Ham
Journal: Journal of Clinical Oncology (2024)

TPS490 Background: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN. Methods: This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy (ST) only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2023 and will enroll 40 patients. Clinical trial information: NCT05753839 .
Topological heterogeneity of genomic and immunologic effects from combination immunotherapy treatment in the neoadjuvant setting for renal cell carcinoma (RCC).
Authors: Tyler Alban, Salendra Singh, Paul G. Pavicic, Patricia A. Rayman, Prerana Parthasarathy Bangalore, Amit Rupani, Vladimir Makarov, Christopher Przybycin, Jennifer S. Ko, Venkatesh Krishnamurthi, Steven Campbell, Timothy An-thy Chan, Brian I. Rini, C. Marcela Diaz-Montero, Moshe Chaim Ornstein
Journal: Journal of Clinical Oncology (2024)

454 Background: We present a multi-regional genomic analysis of tumor from a phase 1b clinical trial of perioperative durvalumab (D) and tremelimumab (T) in patients (pts) with high-risk RCC. Genomic &amp; transcriptomic analyses were performed on nephrectomy samples post neoadjuvant therapy to assess genomic/immunologic impact of combinatorial D+T therapy compared to D alone. Methods: Post-treatment nephrectomy samples were regionally sampled at 4 locations: non-tumor, tumor distant, tumor near, and tumor center. RNA-sequencing was performed on all 4 regions and utilized on a per patient basis to identify regional tumor microenvironment alterations compared to normal kidney. Whole exome sequencing was performed on tumor center. Results: 29 pts enrolled in the trial. 15 were included in the analysis; 5 received neoadjuvant D and 10 received D+T. 60 multi-regional specimens were analyzed; each patient's own normal kidney tissue served as their baseline. There were significant transcriptional differences in D+T compared to D alone (Table). While many of these genes overlapped between treatment arms, the amplitude of differentially expressed genes (i.e., differences between normal and tumor tissue) were greater in the D+T arm, particularly among immune related genes, such as CD8A, CXCL9, CXCL13 and PRAME. Enhanced immune activity was confirmed by immune deconvolution analyses showing broad regional immune infiltration of lymphocytes, including CD8 + T cells, in D+T, which was not detected in D alone. Further comparison of mutational profiles within this cohort showed that D+T treatment resulted in increased clonality compared to D. Conclusions: These data highlight the potential differential genomic/immunologic impact of combination immunotherapy vs single agent across tumor topology. It also demonstrates the utility of pt specific comparisons and a multiregional sampling approach. D+T treatment resulted in enhanced immune activity in RCC tumors and activation of anti-tumor processes above and beyond D alone. This design increases power &amp; biological interpretation of small pt cohorts and allows additional insight into enhanced activation of the immune system with D+T. Summary of transcriptomic comparisons within D &amp; D+T cohorts per region where p &lt;0.05 was used as selection criteria along with positive &amp; negative log fold change. Pathway analysis performed using Hallmarked pathways based on differentially expressed genes, and Celltype deconvolution via ssGSEA (p&lt;0.05). [Table: see text]
Upfront (uCN) vs. deferred (dCN) cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 3323 patients.
Authors: Stepan M. Esagian, Jose A. Karam, Pavlos Msaouel, Dimitrios Makrakis
Journal: Journal of Clinical Oncology (2024)

440 Background: Despite the well-established role of CN in the management of mRCC, the optimal timing of CN in regard to systemic therapy remains unclear. Methods: We systematically searched the MEDLINE, EMBASE, and Web of Science databases until August 26 th , 2023, for studies comparing uCN and dCN and reconstructed overall survival (OS) IPD from their published Kaplan-Meier survival curves. We then performed one-stage and two-stage meta-analyses of OS, using parametric and non-parametric effect estimates. Landmark analyses using 6-month and 12-month cutoffs were used to account for immortal time bias. We also performed subgroup analyses according to MSKCC/IMDC risk and systemic therapy type. The risk of bias was assessed using the ROBINS-I and RoB2 tools. Results: We identified twelve studies (ten retrospective cohort and two randomized controlled trials) eligible for inclusion. Only two out of ten retrospective studies adjusted for immortal time bias and none of them appropriately adjusted for all predetermined confounding factors. A total of 3323 (2610 uCN and 713 dCN) patients were included in our analysis. Baseline characteristics, including age, gender, histology, IMDC/MSKCC risk score, and location of metastases were comparable between the two groups; the dCN group had more patients with ≥2 metastases (65.4% vs. 47.6%). Deferred CN was associated with superior OS in the one stage (HR: 0.75, 95% CI 0.67–0.84), 6-month landmark (HR: 0.74, 95% CI 0.65–0.84), 12-month landmark (HR: 0.78, 95% CI 0.68–0.91) and two-stage (HR: 0.69, 95% CI 0.58–0.84) meta-analyses. Similarly, dCN was associated with superior OS in the TKI-treated (HR: 0.61, 95% CI 0.51–0.74), ICI-treated (HR: 0.67, 95% CI 0.46–0.97), and intermediate IMDC/MSKCC risk (HR: 0.73, 95% CI: 0.55–0.97) subgroups. Conclusions: Deferred CN for the treatment of mRCC is associated with superior overall survival compared to uCN. Randomized studies are warranted to validate or refute these findings. Further studies to establish predictive models are needed to optimize selection of mRCC patients most likely to benefit from dCN. [Table: see text]
SECuRE: A dose escalation/expansion study to assess the anti-tumor efficacy of <sup>67</sup>Cu-SAR-bisPSMA in patients with metastatic castrate-resistant prostate cancer.
Authors: Geoffrey Johnson, Eva Lengyelova, Luke T. Nordquist, Vikas Prasad, Monique Anderson, Othon Gervasio, Michelle Parker, Robert M. Miller, A. Oliver Sartor, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2024)

TPS246 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64 Cu-SAR-bisPSMA (imaging) and 67 Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64 Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68 Ga-PSMA-11. Pre-clinical efficacy data of 67 Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67 Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64 Cu-SAR-bisPSMA and 67 Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64 Cu-SAR-bisPSMA PET may be treated with 67 Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64 Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67 Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67 Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64 Cu- and 67 Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67 Cu-SAR-bisPSMA. The 67 Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67 Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604 .