tbuckley/cabot-search huggingface dataset:
20-year trends in perioperative outcomes in patients with bladder cancer undergoing radical cystectomy with ileal conduit urinary diversion.
Authors: Kevin Lou Xu, Grace Ryu, Elizaveta Makarova, Katrina Bakhl, Suzanne Boltz, Seyma Demirsoy, Jay D. Raman, Hong Truong
Journal: Journal of Clinical Oncology (2024)

583 Background: Radical cystectomy is associated with considerable postoperative morbidities. Enhanced recovery after surgery protocol is a multimodal perioperative pathway implemented to improve post-surgical outcomes over the past decade. We sought to compare the 30- and 90-day postoperative morbidity and mortality rates following RC and ileal conduit urinary diversion between 2000-2010 and 2010-2020 to evaluate the trends in patient outcomes and areas that need improvement. Methods: This retrospective cohort study used data from TriNetX US Collaborative network which allowed access to de-identified patient health records from over 43 healthcare organizations. ICD-10 codes were used to identify patients with bladder cancer who underwent radical cystectomy and ileal conduit urinary diversion from 01/01/2000 to 01/01/2020. The rates of 30 and 90-day postoperative morbidities and mortalities were compared between 2000 – 2010 and 2010 – 2020 using the chi-squared test. Results: The 30 and 90-day complications by decade were summarized in Table. There were 738 cases reported from 22 HCOs from 2000 to 2010 and 10,052 cases reported from 43 HCOs from 2010 to 2020. The overall all-cause mortality at 30 and 90-days postop were 1.5% and 4.4%, respectively, and remain unchanged over the past 20 years. The most common complications within 90-days postop were urosepsis (19.1%), acute kidney injury (16.3%), and UTI (15.6%). While most complication rates remain stable, the rates of urosepsis, acute kidney injury, and UTI were higher between 2010 to 2020 compared to 2000 to 2010. Conclusions: Radical cystectomy and urinary diversion procedure is associated with high perioperative morbidities with up to 1 in 5 patients experiencing a complication within 90-days postop. Despite reported improvement in cancer-specific survivals from recent reports, the overall morbidity and mortality rates associated with the procedure have not improved over the past two decades. Further research is needed to improve surgical outcomes, especially in infectious complication and renal function, for patients with bladder cancer undergoing radical cystectomy. [Table: see text]
Identification of a novel prognostic gene signature in a clear cell renal cell carcinoma (ccRCC) population using an integrated multi-study single-cell RNAseq dataset.
Authors: Samuel García-Esteve, Natalia Jiménez, Caterina Aversa, Laura Ferrer-Mileo, Marta Garcia de Herreros, Laia Fernandez-Mañas, Laura González-Aguado, Carlota Rubio-Pérez, Inés Cobo-Diego, Manuel Mazariegos, Aleix Prat, Begoña Mellado-González, Òscar Reig-Torras
Journal: Journal of Clinical Oncology (2024)

465 Background: Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous disease with varying prognoses and treatment responses. Understanding the underlying molecular determinants of this diversity is key to tailoring effective treatment strategies for each patient (pt). Here, we leveraged single–cell RNA sequencing (scRNA–seq) data to assess intra–tumoral diversity and its impact on pt prognosis. Methods: scRNA–seq raw data from five published studies were processed with Seurat’s standard workflow and integrated to remove biases using Harmony. We then re–analyzed the malignant cell cluster, defined by CA9, NDUFA4L2, and IGFBP3 expression, at a higher resolution. The resulting tumor cell sub–clusters were subjected to differentially expressed gene (DEG) and gene ontology (GO) enrichment analyses. A signature based on all DEGs with a fold change &gt; 1.25 was applied on TCGA–KIRC cohort using single–sample gene set enrichment analysis and then correlated with relapse–free survival (RFS) and overall survival (OS) by Kaplan–Meier and multivariate Cox analyses. Results: We integrated scRNA–seq data from 50 samples from 44 pt’s (40% T3–4, mean age 75, 10% females). A total of 288K cells were classified into 19 clusters. The tumor cluster was re–analyzed and three biologically distinct tumor cell sub–clusters (labeled MC 1 , MC 2 , and MC 3 ) were identified, each with unique molecular markers. GO analysis showed enrichment in genes associated with iron sequestration, oxidative phosphorylation, and apoptotic signaling, respectively. In the KIRC cohort, a 23–DEG signature from MC 2 strongly correlated with RFS (HR 0.49; 95% CI 0.35−0.67 p &lt; 0.001; 5-RFS: 74% vs. 54%) and OS (HR 0.44; 95% CI 0.33−0.60 p &lt; 0.001; 5-OS: 75% vs. 51%) and was independent of other clinical variables in the multivariate analysis (Table 1). Moreover, this signature identified a subset of T1–T2 tumors (47.8%) with low risk of relapse (HR 0.38; 95% CI 0.19−0.78, p = 0.008; 5-RFS: 92% vs. 80%) and longer OS (HR 0.35; 95% CI 0.20−0.62 p &lt; 0.001; 5-RFS: 90% vs. 68%). Conclusions: We have identified three distinct tumor cell sub–populations in an integrated scRNA–seq database, each characterized by unique transcriptomic profiles. A gene expression signature based on the MC 2 sub–cluster was prognostic in the TCGA dataset and may help in identifying patients with a higher risk of relapse and candidates to adjuvant therapy.[Table: see text]
The opposing effects of Class 1B and Class 2 FOXA1 mutations in prostate cancer.
Authors: Justin Hwang, Sachin Deshmukh, Sharon Wu, Andrew Elliott, Nishant Gandhi, Alex Patrick Farrell, Chadi Nabhan, Rana R. McKay, Elisabeth I. Heath, Sylvan Baca, Oliver Sartor, Scott Dehm, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2024)

216 Background: PCa harbors recurrent FOXA1 alterations, yet distinct alteration types may drive divergent consequences. Here, we established several classes of FOXA1 alterations and evaluated their clinical outcomes, molecular correlates, and immunologic landscape in a large cohort of primary and metastatic PCa samples from Caris Life Sciences. Methods: We interrogated the Caris DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. FOXA1 alterations were annotated based on amino acid (a.a.) location and prior functional studies (Table). Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates. Gene set enrichment analyses (GSEA) was used to estimate signaling pathway activity. Immune-cell fractions were inferred from bulk RNA-seq using quanTIseq. All comparisons are made relative to FOXA1 WT cases. Results: The overall prevalence of FOXA1 alterations was 16%, with no enrichment in metastatic PCa samples (15.5%). Class 2 mutations were enriched in histologic NEPC, were associated with a classical NEPC mRNA signature, and showed poor survival with ADT (HR 5.6, 95% CI: 2.5–12.5, p&lt;0.001). Conversely, metastatic PCa patients with Class 1B mutations had numerically improved survival with ADT (HR 0.76, 95% CI: 0.50–1.14, p=0.18). All FOXA1 alterations (except Class 2) resulted in increased FOXA1 transcripts, with 1B and 1C having the greatest effects (q&lt;0.0001). Class 0 and 3 alterations had 2–5 fold higher frequency of TMB-high and MSI-high status (q&lt;0.05). Conversely, Class 1B exhibited lower TMB and markedly fewer TP53 mutations (35.7% vs 20.3%, q&lt;0.001) and TMPRSS2-ERG fusions (34.5% vs 4.6%, q&lt;0.001). Class 1B was depleted of AR transcriptional signatures (q=0.01) but enriched of MYC signaling in GSEA analysis (FDR&lt;0.001), and showed reduced expression of B7-H3. On immune-cell deconvolution analysis, Class 1B showed reduced dendritic cells, but increased B cells and neutrophils (DC: 1.96% vs 0.01%, B cell: 4.27% vs 5.29%, neutrophils: 5.05% vs 8.00%, each q&lt;0.001). Conclusions: Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity. [Table: see text]
Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC).
Authors: Toni K. Choueiri, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Stefan N. Symeonides, Jaroslav Hajek, Yen-Hwa Chang, Jae-Lyun Lee, Naveed Sarwar, Howard Gurney, Marine Gross-Goupil, Mauricio Mahave, Naomi B. Haas, Piotr Sawrycki, Tian Zhang, Jerry Cornell, Aymen Elfiky, Joseph E. Burgents, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

LBA359 Background: The randomized, multicenter, double-blind, phase 3 KEYNOTE-564 study (NCT03142334) showed that adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo following nephrectomy in participants (pts) with ccRCC at an increased risk of recurrence. We report results from the third prespecified interim analysis with a median follow-up of ~57 months. Methods: Pts were aged ≥18 years and had histologically confirmed ccRCC with or without sarcomatoid features, increased risk of recurrence, ECOG PS of 0 or 1, nephrectomy and/or metastasectomy ≤12 weeks before randomization, and no prior systemic therapy for RCC. Pts were randomly allocated 1:1 to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≥17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. DFS by investigator assessment was the primary end point. Overall survival (OS) was a key secondary end point. Safety was a secondary end point. Results: 994 pts were randomized 1:1 to pembrolizumab (n=496) or placebo (n=498). The median time from randomization to data cut-off date of September 15, 2023, was 57.2 months (range, 47.9−74.5). Statistically significant improvement in OS was observed with pembrolizumab vs placebo (medians not reached, HR 0.62, 95% CI 0.44−0.87; P=.0024). A total of 55 OS events were observed in the pembrolizumab arm and 86 in the placebo arm. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86.0% with placebo. OS benefit was observed across key subgroups, including in pts with M0 disease (HR 0.63, 95% CI 0.44−0.90) or M1 NED (HR 0.51, 95% CI 0.15−1.75), with PD-L1 CPS &lt;1 (HR 0.65, 95% CI 0.31−1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42−0.91), and with presence (HR 0.69, 95% CI 0.28−1.70) or absence (HR 0.57, 95% CI 0.39−0.84) of sarcomatoid features. The observed DFS benefit with pembrolizumab vs placebo was consistent with prior interim analyses (HR 0.72; 95% CI 0.59−0.87). No new safety signals were observed. Conclusions: After a median of ~57 months of follow-up, adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival versus placebo in participants with RCC at increased risk of recurrence post surgery. KEYNOTE-564 is the first phase 3 study to show improved survival with any adjuvant therapy in RCC. These results continue to support adjuvant pembrolizumab as a standard of care. Clinical trial information: NCT03142334 .
A study of the association between enzalutamide blood concentrations and adverse events in patients with castration-resistant prostate cancer.
Authors: Taro Iguchi, MInoru Kato, Yukiyoshi Hirayama, Takeshi Yamasaki, Sayaka Yasuda, Nobuyo Morita, Ippei Chikazawa, Wakaba Fukushima, Satoshi Tamada, Katsuhito Miyazawa
Journal: Journal of Clinical Oncology (2024)

102 Background: Enzalutamide (ENZA) is effective in castration-resistant prostate cancer (CRPC), but subjective adverse events (AEs) such as fatigue and decreased appetite may make it difficult to continue ENZA due to AEs despite its effectiveness. Owing to AEs, half of the patients required a dose reduction to 120 mg, thereby eliminating the AEs and enabling patients to continue taking ENZA. We hypothesized that a dose reduction to 120 mg of ENZA would reduce AEs in patients while keeping serum concentrations in the therapeutic range. Methods: Patients with CRPC were treated with ENZA from 2015 to 2020 at Osaka City University Hospital and their serum was stored at least twice with written consent. All patients were treated with an initial dose of 160 mg of ENZA, and the dose was reduced to 120 mg if they complained of AEs. In the full dose group (no AEs with 160 mg of ENZA), serum concentrations of ENZA and its active metabolite (N-desmethyl enzalutamide: M2) were measured at 1, 3, and 6 months. In the reduced dose group, serum concentrations were measured before and after dose reduction. To clarify the relationship between AEs and the serum ENZA and M2 concentrations, the serum ENZA and M2 concentrations in patients with/without AEs and before/after dose reduction were compared. To examine whether dose reductions affect the efficacy of ENZA, PSA progression free survival, and the overall survival were compared between the full dose group and the reduced dose group. Results: Serum ENZA and M2 concentrations were measured in 246 samples from 84 patients and mean effective serum concentrations of ENZA + M2 were 28.0, 30.4, and 29.2 μg/mL in the full dose group at 1, 3, and 6 months, respectively; and 29.1 and 24.1 μg/mL at a dose of 160 mg and 120 mg, respectively, in the reduced dose group. Most of AEs were resolved by dose reduction and there was no statistically significant difference in PSA progression free survival (HR: 0.86, 95% CI: 0.44-1.68) or overall survival (HR: 0.60, 95% CI: 0.26-1.40) between the full dose group and the reduced dose group. Conclusions: A correlation between the ENZA dose and serum ENZA + M2 concentration was observed, but no association between AE and serum ENZA or M2 concentration was observed. Dose reduction to 120 mg reduced serum ENZA and M2 concentrations of the patients with AEs and resolved the AEs but did not affect the efficacy of ENZA. These results suggest that patients with AEs at 160 mg of ENZA can have their AEs resolved by reducing the dose to 120 mg without loss of efficacy.
Effects of perioperative chemotherapy on prognosis in muscle invasive bladder cancer treated with radical cystectomy.
Authors: Shingo Hatakeyama, Rikiya Taoka, Jun Miki, Ryoichi Saito, Wataru Fukuokaya, Yasuyuki Matsui, Takashi Kawahara, Ayumu Matsuda, Taketo Kawai, MInoru Kato, Tomokazu Sazuka, Takeshi Sano, Fumihiko Urabe, Soki Kashima, Hirohito Naito, Youji Murakami, Naotaka Nishiyama, Hiroyuki Nishiyama, Hiroshi Kitamura, Chikara Ohyama
Journal: Journal of Clinical Oncology (2024)

592 Background: We aimed to evaluate the effect of the number of neoadjuvant chemotherapy (NAC) cycles and the adding adjuvant chemotherapy (AC) after NAC in muscle-invasive bladder cancer (MIBC) on overall survival (OS). Methods: This multicenter retrospective study included 2674 patients with MIBC who underwent radical cystectomy (RC) from 36 institutions within the Japanese Urological Oncology Group. Among them, we selected 1687 patients with cT2-4NxM0 who were treated with RC alone or RC plus perioperative chemotherapy. We compared the effect of the number of NAC cycles (2 vs. ≥3 cycles) and the addition of AC on OS. Cox proportional-hazards regression was used to assess the association of treatment received with OS. Results: Of 1687 patients, 946 were treated with NAC with a median of 3 cycles. Use of NAC significantly prolonged OS compared to the RC alone. The pathological complete response rate was not significantly different between the 2 cycles (22.9%) and ≥3 cycles (27.5%, P = 0.112) groups. OS was not significantly different between the groups (P = 0.559). Multivariable Cox regression analysis showed that pathological high-risk (ypT2–4, pT3–4, or pN+) or cisplatin ineligibility were significantly associated with poor OS, but not the number of NAC cycles (P = 0.238). We identified 942 pathologically high-risk patients after RC who were eligible for AC. We observed no significant OS improvement with addition of AC after NAC as intensive perioperative chemotherapy. The primary limitation is selection bias from confounding by clinical indication. Conclusions: The impact of 3 or more NAC cycles and the addition of AC on OS in MIBC patients treated with RC may be limited.
Effect of variants in the <i>KLK3</i> gene on prostate cancer survival and time to metastases in a large biobank prostate cancer dataset.
Authors: Meghana Pagadala, Tyler J. Nelson, Julie Ann Lynch, Anthony Gao, Fatai Agiri, Kathryn Pridgen, Tyler Seibert, Kyung Min Lee, Brent S. Rose, Hannah Carter, Craig Teerlink, Richard Hauger
Journal: Journal of Clinical Oncology (2024)

219 Background: Prostate Specific Antigen (PSA), a serine protease, is the most widely used clinical biomarker to detect prostate cancer. It is a product of the KLK3 gene. Several SNPs in KLK3 gene have previously been implicated in prostate cancer aggressiveness and PSA levels, however, the effect of KLK3 SNPs on survival and metastatic disease is not clear. We surveyed common and rare variants within 10-Kb of the KLK3 gene to estimate their effect on prostate cancer survival and time to metastasis in a large biobank data set. Methods: We analyzed a cohort of 5,287 men who developed prostate cancer after enrollment in the Million Veterans Program (MVP), 619 of whom developed metastatic disease. We analyzed 1,583 imputed SNPs (Info-R 2 &gt; 0.3) that occurred within 10-Kb of the KLK3 gene, regardless of minor allele frequency. We conducted two separate analyses, the first concerned survival times of prostate cancer specific mortality and the second analysis concerned time to metastatic disease using the Survival R package. For each analysis, variants were collectively assessed for an effect on survival using SKAT-O (metaSeq R package). We also performed a logistic regression to test each SNP for association with Gleason score 8-10 at diagnosis. Results: We identified seven rare SNPs that significantly affected prostate cancer survival (Bonferroni corrected p&lt;3.16e -5 ) within 10-Kb of KLK3, 3 of which occurred within the gene boundaries (SKAT-O p=1e -4 ). We also identified 11 other SNPs that significantly affected time to metastasis (SKAT-O p=7e -3 ). The logistic regression of each SNP on Gleason score 8-10 at diagnosis identified 20 significant SNPs. The SNPs emerging from these analyses were all rare (minor allele frequency &lt; 1e -4 ), and no SNPs were in linkage disequilibrium with each other, indicating that they comprise independent signals. Conclusions: Understanding the mechanism and role of rare SNPs in the KLK3 gene in prostate cancer detection has important clinical implications, especially in an era when patients’ genetics is being used to inform PSA screening. These finding may identify patients who should undergo prostate biopsy at lower PSA thresholds and/or for whom PSA biochemical recurrence is a less reliable predictor of disease progression. Ongoing prospective and retrospective analyses of Veterans with these variants both prior to and absent any prostate cancer diagnoses and progression.
A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.
Authors: Karan Jatwani, Suresh Kalathil, Ronald Slomba, Bailey Farmer, Kristopher Attwood, Arya Mariam Roy, Prashant Singh, Eric Kauffman, Dharmesh Gopalakrishnan, Saby George, Ellis Glenn Levine, Khurshid Guru, Pawel Kalinski, Gurkamal S. Chatta
Journal: Journal of Clinical Oncology (2024)

340 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). A high intra-tumoral CD8 + T lymphocyte density is associated with improved survival post-RP, 1 suggesting possible clinical benefit from neoadjuvant chemokine modulation (CKM). 2,3 We present the interim results of a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP were randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (Arm A: rintatolimod + aspirin + IFN-α: “Complete CKM regimen”) vs CKM doublet (Arm B: rintatolimod + aspirin) vs no CKM (Arm C). Methods: Thirty patients (10 per arm) are to be enrolled to assess CD8 + T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations represent secondary endpoints. Correlative blood studies analyzed the pre- vs post-CKM changes in Granzyme B (GrB; marker of effector/cytotoxic function in CD8+ T cells and FoxP3 (Treg marker) in CD4+ T cells. Results: The trial has enrolled 11 patients thus far (N=5 Arm A, 3 Arm B, 3 Arm C). There were no clinicopathological differences between the groups. Eight patients (on Arms A and B) were analyzed for changes in cytotoxic T cell numbers (CTL-D: GrB+CD8+ T-cells) in the blood. In Arm A, the mean pre-CKM CTL-D was 35.5% (±23.2%) and post-CKM was 47.7% (± 32.5%), while in Arm B, respectively, 37.9% (±22.2%) vs 37.1% (± 21.6%). These changes were reflected in the increased CTL/Treg markers in the post-treatment samples of patients on Arm A. These data indicate the ability of the “complete CKM regimen” (Arm A) to selectively enhance the CTL effector function in circulating CD8+ T cells, without enhancing the Treg markers. CKM regimen was well tolerated with no Grade 3 or above adverse events (AEs). Conclusions: In this interim analysis, treatment in all arms was feasible and safe. CTL-D and CTL-D/Treg in Arm A (“complete CKM”) shows an increasing trend over the course of CKM treatment. The levels of CTL-D in the resected prostate tissues are being currently evaluated. The study continues recruiting patients. 1. Yang, Y et al (PMID 33085799). 2. Muthuswamy, R et al (PMID 27199259). 3. Theodoraki, MN et al (PMID 29853604). Clinical trial information: NCT03899987 .