tbuckley/cabot-search huggingface dataset:
Comparing the somatic, germline, and immune landscapes of upper tract urothelial carcinoma (UTUC) and UC of the bladder (UCB).
Authors: Kit L. Yuen, Margaret F. Meagher, Jacob Mercer, Binyam Yilma, Melissa Conrad Stoppler, Stamatina Fragkogianni, Nataliya Mar, Arash Rezazadeh, Shilpa Gupta, Petros Grivas, Aditya Bagrodia, Rana R. McKay, Tyler F. Stewart, Amirali Salmasi
Journal: Journal of Clinical Oncology (2024)

4520 Background: Molecular characterization of anatomically distinct UCs has been limited by the rarity of UTUC; however, recent advances in real-world data curation have enabled larger UTUC cohort generation. Here, we investigated the somatic, germline, and immunologic landscapes of UTUC compared to UCB. Methods: From the Tempus Database, we retrospectively analyzed de-identified next-generation sequencing data from 505 UTUC (224 ureter, 281 renal pelvis) and 2,416 UCB cases (2,379 bladder, 37 urethra). Tumors were sequenced with the Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration predicted from gene expression patterns, TMB, PD-L1 from IHC, MSI, and mismatch repair (MMR) were evaluated. Incidental germline alterations were assessed in 46 genes for patients with tumor/normal-matched (T/N) sequencing (UTUC n=285, UCB n=1,359). Chi-squared, Fisher's exact, and Wilcoxon rank-sum tests were used to assess statistical significance (p&lt;0.05, q&lt;0.05 for false discovery rate correction for multiple testing). Results: Median age of the UTUC and UCB cohort were 73 and 70 years, respectively (p=0.003). The UCB cohort had significantly more males (75% vs 56%, p&lt;0.001) and ever smokers (59% vs 46%, p&lt;0.001).Alterations in TERT, TP53, CDK12, RB1, ERBB2, and CDKN1A were more frequent in UCB, while KMT2D, FGFR3, BRIP1, CDKN2B, KRAS, and MYC more frequent in UTUC (Table). Additionally, FGFR3 fusions were more frequent in UTUC. Germline variants were found in 7.1% of UCB and 7.0% of UTUC cases, with trends towards higher prevalence of alterations in lynch-associated genes ( MLH1, MSH2, MSH6, PMS2) in UTUC (0.6% vs 1.8%, p=0.059). The prevalence of TMB ≥ 10 mut/Mb was higher in UCB vs UTUC (17% vs 11%, p&lt;0.001). UCB had increased PD-L1 positivity (p=0.013), whereas UTUC had more MSI-high (UTUC = 3.2% vs UCB = 1%, p=0.001) and deficient MMR (p=0.020) cases. There were similar proportions of total immune infiltrates in UCB and UTUC. However, UTUC harbored a higher percentage of CD4+ T cells (p&lt;0.001), while UCB had a higher proportion of regulatory T and NK cells (p&lt;0.001). Conclusions: Via comprehensive molecular characterization of UC, we observed distinct DNA alteration and tumor microenvironment patterns in UTUC and UCB. The germline results underline how T/N testing can identify patients with UTUC and/or UCB who can benefit from dedicated germline testing. Further research is warranted to elucidate the clinical implications of these findings. [Table: see text]
Lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in advanced renal cell carcinoma (aRCC): Patterns of progression and subsequent therapy in the CLEAR trial.
Authors: Viktor Grünwald, Robert J. Motzer, Daniel Keizman, Jens Bedke, Manuela Schmidinger, Michael D. Staehler, Vsevolod B. Matveev, Saby George, Thomas E. Hutson, Ulka N. Vaishampayan, Jaime R. Merchan, Masatoshi Eto, Sun Young Rha, Tom Waddell, Roberto Sabbatini, Philippe Barthelemy, Joseph E. Burgents, Min Ren, Ian Brown, Toni K. CHOUEIRI
Journal: Journal of Clinical Oncology (2024)

4524 Background: In the primary analysis of the CLEAR trial of patients (pts) with aRCC, L+P significantly improved efficacy vs S (Motzer NEJM 2021). Results were further confirmed at the final prespecified OS analysis (Motzer JCO 2024). Here, we discuss patterns of progression and subsequent therapy in CLEAR. Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomly assigned (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were region and MSKCC prognostic risk group. To explore progression pattern within individual organs, time to progression was defined for each organ independently using lesions within each specific organ only, based on Independent Image Review per RECIST v1.1. Medians and quartiles were estimated with Kaplan-Meier (KM) method; 95% CIs were estimated with a generalized Brookmeyer and Crowley method. Hazard ratio (HR) reported is for L+P vs S based on Cox regression model with treatment as factor; HR was stratified by region and MSKCC prognostic groups. The Efron method was used for correction for ties. Results: The HRs (95% CI) of time to progression for L+P vs S across tumors in different organs were: bone, 0.40 (0.25-0.63); CNS, 0.47 (0.19-1.19); kidney, 0.65 (0.37-1.14); liver, 0.52 (0.32-0.84); lung, 0.48 (0.36-0.62); and lymph nodes, 0.63 (0.46-0.85). At overall disease progression, the median sums of diameters of target lesions were lower with L+P vs S (29.8mm vs 42.8mm; Table). In the L+P arm, 181 pts received subsequent anticancer regimens during survival follow-up (43 received axitinib and 101 received cabozantinib). In the S arm, 246 pts received subsequent anticancer regimens (47 received axitinib and 107 received cabozantinib). The median duration of axitinib as the first anticancer regimen (95% CI) after L+P was 23.7 months (5.3-not estimable [NE]), and after S was 12.6 months (6.8-NE). The median duration of cabozantinib as the first anticancer regimen (95% CI) after L+P was 13.2 months (8.2-NE), and after S was 7.1 months (4.1-20.0). Conclusions: Pts in the L+P arm trended to show later progression across tumors in different organs. At overall disease progression, the tumor burden of target lesions was lower with L+P vs S; and pts in the L+P arm stayed on 2L axitinib or cabozantinib longer than pts in the S arm. Together, these results continue to support L+P as a standard-of-care 1L therapy in pts with aRCC. Clinical trial information: NCT02811861 . [Table: see text]
Irinotecan plus anlotinib or further in combination with penpulimab as second-line treatment of metastatic colorectal cancer (ZL-IRIAN).
Authors: Chenchen Wang, Wenhua Li, Xiaodong Zhu, Qirong Geng, Xiaoying Zhao, Weijian Guo
Journal: Journal of Clinical Oncology (2024)

3570 Background: The irinotecan based chemotherapy in combination with bevacizumab had become the standard second-line treatment for metastatic colorectal cancer (mCRC), but the efficacy was limited. Anlotinib, an oral anti-angiogenic tyrosine kinase inhibitor, had initially shown promising clinical effects when combined with chemotherapy in the first-line treatment of mCRC. Whether anlotinib could bring clinical benefit in the second line treatment warrants further exploration. The PD-1 antibody might have partial effects when combined with anti-angiogenic agents with or without chemotherapy in first- and third-line treatment for proficient mismatch repair (pMMR)/ microsatellite stable (MSS) mCRC. Our study was to explore the rationality of anlotinib plus chemotherapy or further combined with a novel anti-PD-1 IgG1 antibody—penpulimab in the second line treatment of mCRC. Methods: This study was an open label, non-randomized, multi-cohorts, phase II prospective clinical trial that included pts with pMMR/MSS mCRC who were eligible for the second-line systemic treatment. Two cohorts were established as follows: Cohort A consisted of anlotinib(10mg daily, d1-10, q2w) + irinotecan (180mg/m 2 d6, q2w) (n=23); Cohort B consisted of anlotinib (8mg daily, d1-10, q2w)+irinotecan (180mg/m 2 d6, q2w) + penpulimab (200mg, d6, q2w) (n=23). Pts were initially enrolled in Cohort A. If the ORR in Cohort A was ≥15% (at least four patients in Cohort A reached CR/PR), the enrollment of Cohort B started. The primary endpoint was ORR. Secondary endpoints included progress free survival (PFS), overall survival (OS), duration of response (DoR), disease control rate (DCR) and safety. Results: A total of 23 Pts were enrolled in A cohort from March 9 2022 to December 3 2023. With an ORR of 39.1% (9/23) and DCR of 87.0% (20/22), the median PFS was 9.57 months (95% CI 5.24-13.90 months), and the 6-month and 12-month PFS rates were 70.9% and 38.2%, respectively. Pts in B cohort were enrolled from October 25 2022 to November 22 2023, a total of 23 pts were enrolled, 2 pts withdrew their informed consent before treatment and 21 pts received at least one dose of treatment. ORR of 21 pts was 42.9% (9/21), and the DCR was 90.5% (19/21). The median PFS had not reached, with the 6-month and 12-month PFS rates as 70.7% and 55%, respectively. Safety profile indicated that 65.2% (15/23) and 57.1% (12/21) experienced grade≥3 adverse events in A cohort and B cohort, respectively. Conclusions: The combination of anlotinib with irinotecan +/- PD-1 blockade in second-line treatment for mCRC had shown promising efficacy and good safety. Whether PD-1 blockade could bring extra survival benefits required longer follow-up. Clinical trial information: NCT05229003 .
Changes in treatment (Rx) patterns and attrition rates in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Gliceida Galarza Fortuna, Yeonjung Jo, Chadi Hage Chehade, Arshit Narang, Georges Gebrael, Vinay Mathew Thomas, Beverly Chigarira, Ethan Anderson, Archisman Mazumder, Zeynep Irem Ozay, Neeraj Agarwal, Benjamin L. Maughan, Umang Swami
Journal: Journal of Clinical Oncology (2024)

4527 Background: Rx landscape of mccRCC has evolved rapidly with the approval of antibodies directed against programmed cell death protein-1 (PD-1) in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor receptor tyrosine kinase (TKI) inhibitors. However, real-world data on Rx trends and attrition before and after PD-1 inhibitor approval are lacking. Herein, we analyze them in a large real-world cohort in the United States. Methods: This IRB-approved retrospective study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Inclusion: Metastatic RCC with clear cell histology diagnosed between 1/1/2011 to 1/31/2022 receiving Rx with opportunity of at least 1 year follow up. Exclusion: Pts needing Rx for ≥2 malignancies. Based on the approval date of PD-1+CTLA4 of 4/16/18, pts were separated into 2 groups: b2018 (1L Rx before 4/16/2018) and a2018 (1L Rx after 4/16/18). Landmark analysis was performed at 1 year after Rx discontinuation to identify pts who died, were alive but did not need Rx, or starting next-line Rx. All analysis was done using R version 4.2.3. Results: Of 12707 pts, 7923 met the eligibility criteria (b2018: 4561 pts and a2018: 3362 pts). Rx trends are summarized in the table. 1L Rx for the majority of pts changed from TKI monotherapy (mono; 79%) b2018 to PD-1 combination therapies a2018 (58%). TKI mono remained the most common Rx in both groups after 1L (Table). In the b2018 cohort, 58% of patients received 2L Rx, and 32% received 3L. In the a2018 cohort, 42% and 16% received 2L and 3L, respectively. At 1-year landmark analysis after 1L discontinuation: in the b2018 group, 58% pts received next Rx, 30% died without further Rx, and 12% were alive without Rx while in the a2018 group, 42% pts received next Rx, 26% died without further Rx and 32% were alive without Rx. Conclusions: Despite the increase in the utilization of PD-1+CTLA-4 and PD-1+TKI regimens since 2018, a significant number of patients still did not receive novel combination regimens in the 1L mccRCC setting in this real-world population in the United States. Furthermore, with the uptake of PD-1 based combinations in 1L, a higher proportion of pts experience treatment free interval or were alive without further therapy at 1 year landmark analysis after 1L Rx discontinuation. These findings need validation in other datasets and can help patient counseling in clinics.[Table: see text]
Impact of Latino ethnicity on the gut microbiome composition of patients with metastatic renal cell cancer (mRCC).
Authors: Regina Barragán Carrillo, Nazli Dizman, Hedyeh Ebrahimi, Luis A Meza, Paulo Gustavo Bergerot, Tanya B. Dorff, Joann Hsu, Zeynep Busra Zengin, Nicholas Salgia, Alex Chehrazi-Raffle, Abhishek Tripathi, Daniela V. Castro, Benjamin Mercier, Gregory Caporaso, Keehoon Lee, Sumanta Kumar Pal
Journal: Journal of Clinical Oncology (2024)

4521 Background: Latinos with mRCC may have poorer outcomes with frontline immune checkpoint inhibition (ICI) compared to their non-Latino counterparts (Chehrazi-Raffle et alOncologist 2023). Recent studies have shown that the composition of the gut microbiome can impact outcomes with ICI (Routy et alScience 2018). Therefore, we aimed to investigate the differences in gut microbiome composition between Latino and non-Latino patients (pts) with mRCC. Methods: Stool specimens were prospectively collected in treatment-naïve pts with mRCC. We dichotomized pts into Latino vs non-Latino groups. Pts provided a stool sample (OMNIgene Gut) at baseline. Whole metagenome sequencing was performed on stool specimens collected. Taxonomic profiling was conducted using MetaPhlAn 4. ANCOM-BC analysis was used to identify differences in the relative abundance of bacterial species between groups. Alpha-diversity was evaluated using the Shannon diversity index and Evenness analysis, employing the Kruskal-Wallis test. Beta-diversity was assessed using the Bray-Curtis and Jaccard dissimilarity measures. The ratio of Firmicutes/Bacteroidetes (F/B), a measure of gut dysbiosis, was computed at baseline in the two cohorts. Results: Among 59 pts assessed, 27 and 32 were Latino and non-Latino, respectively. Median age of the cohort was 60 (range, 36-90). Most were male (71%), had clear cell RCC (88%) and had intermediate/poor risk disease (79%). ANCOM-BC analysis showed an enrichment of 14 bacterial species and a depletion in 3 species at baseline in the Latino group (p ≤ 0.05). Three Roseburiaspp. were enriched in the Latino pts, namely R. faecis (log-fold change [LFC]: 2.6), R. hominis (LFC: 2.0) and R. inulinivorans (LFC: 1.8). Additionally, Eubacterium rectalewas also enriched in the Latino group (LFC: 2.0). In contrast, in non-Latino pts Methylobacterium spp. was enriched (LFC: 1.3). The F/B ratio was higher in the Latino group as compared to the non-Latino group (1.00 vs 0.92). We did not observe any differences in alpha and beta diversity. A detailed analysis of simultaneously collected dietary logs is ongoing. Conclusions: Our examination of the gut microbiota of pts with mRCC revealed significant differences based on ethnicity at baseline. Specifically, the Latino group exhibited an enhancement of Roseburia spp. and E. rectale, species previously linked to favorable outcomes with ICIs, despite a higher F/B ratio (suggesting a greater degree of dysbiosis). Our findings advocate that clinical trials related to the microbiome should potentially account for baseline differences in ethnicity.
The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance
Authors: Haiyang Yun, Julian Zoller, Fengbiao Zhou, Christian Rohde, Yi Liu, Maximilian Felix Blank, Stefanie Göllner, Carsten Müller-Tidow
Journal: Leukemia (2024)

RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.
Multi-omics analyses and molecular subtypes to provide potential therapeutic implications in fumarate hydratase-deficient renal cell carcinoma.
Authors: Xingming Zhang, Junjie Zhao, Xiaoxue Yin, Jiayu Liang, Yongquan Wang, Linmao Zheng, Ping Tan, Sha Zhu, Junru Chen, Jinge Zhao, Niels J Rupp, Xinan Sheng, Qiang Wei, Xiang Li, Jin Yao, Zhenhua Liu, Pengfei Shen, Ni Chen, Hao Zeng, Guangxi Sun
Journal: Journal of Clinical Oncology (2024)

4522 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conducted a comprehensive integrated genomic study. Methods: A total of 126 treatment naïve FH-deficient RCC tissue samples were extracted from our multi-center database. Whole-exome, RNA-seq, and DNA-methylation sequencing were performed. All cases were confirmed with both FH/2SC immunohistochemical staining and FH alterations analysis. Results: Through whole-exome sequencing, we found FH alteration patterns were associated with both tumor behavior and patient survival outcomes. Tumors harboring FH truncating alteration (including nonsense, frameshift and splice site mutations) and mutations near hinge regions (such as p.S419L), were predominantly associated with more aggressive tumor behavior and poorer prognosis. We further developed a CpG sites-specific methylation signature for precise identification of FH-deficient RCC. More importantly, transcriptomic analysis unveiled three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derived the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 displayed moderate response to this therapeutic approach. In contrast, tumors in C3 exhibited an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. Conclusions: These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.
Evaluating the potential of micronuclei DNA from erythrocytes for early detection or recurrence risk prediction of colorectal cancer.
Authors: Xingyun Yao, Haobo Sun, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Jie Pan, Fangchao Zhu, Fei Meng, Honghao Liang, Yanfei Cao, Jun Li, Kefeng Ding, Xiaofei Gao
Journal: Journal of Clinical Oncology (2024)

3577 Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Also, better predicting the recurrence risk following initial treatment serves as an important factor influencing survival of CRC patients. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and CRC patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we explored the potential of MN-DNA for early detection or recurrence risk prediction of CRC patients. Methods: Peripheral blood (1-2ml) was obtained from a training cohort of 1165 individuals, a validation cohort of 290 individuals, and a test cohort of 363 individuals. MN-DNA was isolated and sequenced from erythrocytes. Predictive models were developed using distinctive taMN-DNA features identified by genome-wide analysis to differentiate between HD and AA or CRC. A clinical trial comparing MN-DNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). In addition, we conducted a retrospective study on CRC patients after postoperative treatment for evaluating the potential of MN-DNA in predicting CRC recurrence risk, with 28 non-recurrent after initial surgery and treatment and 6 relapsed patients enrolled. Results: The predictive CRC model built on taMN-DNA features achieved an AUC of 97.93%, with 88.61% sensitivity at 95.05% specificity, especially 89.58% sensitivity for early-stage (stage I-II) CRC in the test cohort. The detection of AA achieved an AUC of 93.01%, with 68.29% sensitivity at 92.48% specificity in the test cohort. Comparing MN-DNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Finally, 92.86% patients who had no recurrence were detected with negative prediction results, whereas 83.33% patients who had relapsed were detected positive prediction result. Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enable accurate detection of AA and early-stage CRC as well as recurrence risk prediction. A larger clinical study (NCT05875584) is ongoing and will further validate the application of MN-DNA in CRC detection.