tbuckley/cabot-search huggingface dataset:
The tumor immune profile of bladder cancer (BC) with HER2 over-expression and the investigation into RC48-ADC versus BCG in high-risk non-muscle invasive BC with HER2 over-expression.
Authors: Haoyang Liu, Junru Chen, Haolin Liu, Qiyu Zhu, Yige Bao, Banghua Liao, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

e16614 Background: Patients diagnosed with high-risk non-muscle invasive bladder cancer (HR-NMIBC) face a challenging prognosis, with a 5-year disease progression rate reaching up to 40%. The current standard treatment for HR-NMIBC involves transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy. BCG therapy is reported to exert anti-tumor therapeutic effects by inducing both innate and adaptive immunity. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression is strongly associated with poor tumor immunity and an unfavorable cancer prognosis. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. This study aims to evaluate the therapeutic potential of RC48-ADC in HR-NMIBC patients and explore the association between HER2 expression and immune profile of Bladder Cancer (BC). Methods: A retrospective analysis was conducted on patients diagnosed with NMIBC exhibiting HER2 overexpression (immunohistochemistry ≥2+) who underwent adjuvant therapy with either RC48-ADC or BCG at West China Hospital of Sichuan University between 2019 and 2023. The primary study endpoint was recurrence-free survival (RFS). Utilizing molecular data on bladder cancer (BC) from The Cancer Genome Atlas (TCGA), we included 100 cases each of HER2-low and HER2-high, determined by HER2 expression levels before and after a 25% threshold, to assess differences in tumor immunity between the two cohorts. Results: The study included 27 patients diagnosed with HR-NMIBC displaying HER2 over-expression. After TURBT, 10 patients received adjuvant therapy with RC48-ADC, while 17 received adjuvant therapy with BCG. Kaplan-Meier analysis revealed that patients receiving RC48-ADC exhibited better RFS compared to those receiving BCG (p=0.027). Additionally, in the RC48-ADC-treated group, the twelve-month RFS rate was 100%, while in the BCG-treated group, it was 58.8%. According to TCGA molecular data, our results showed that HER2-low BC demonstrated higher expression levels of various immune-related cytokine, including CXCL5, CXCL8, CXCL9, CXCL11 and so on. ESTIMATE analysis revealed that HER2 expression was negatively correlated with the interstitial score, immune score, and ESTIMATE score. Moreover, ssGSEA revealed stronger immune infiltration in the HER2-low BC group, including NK cells, B cells, CD8 T cells, Th1 cells, Th2 cells, and others. Conclusions: HER2 over-expression significantly influences the tumor immunity of BC and the HER2-directed ADC RC48 has demonstrated promising efficacy as adjuvant therapy in patients with HR-NMIBC according to RFS.
Renal cell carcinoma post-kidney transplant: An analysis of OPTN/UNOS database.
Authors: Saloni Savani, Het Patel, Arpita Pawa, Hemangini Dhaibar, Samip R. Master, Neeraj Singh
Journal: Journal of Clinical Oncology (2024)

e16528 Background: Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults, accounting for 90-95% of primary malignant kidney tumors and representing around 3% of all cancers worldwide.Kidney transplant recipients (KTRs) have a higher incidence of developing RCC compared to the general population but lower compared to ESRD population. In 2018, the incidence of RCC was 1.6/10,000 in the general population and 45-50/10,000 person years in ESRD patients, with an increased incidence in patients with risk factors like old age, African American descent, hypertension, and smoking. With this study, we sought to identify high-risk patients among KTRs who may benefit from surveillance imaging. Methods: The UNOS/OPTN database was used to select kidney transplant recipients between 1/1/2010 to 12/31/2022. Pediatric patients, patients with simultaneous multi-organ transplants, and those with other malignancies were excluded. The study computed the incidence of RCC during the first 5-year and between 5 to 10-year post-transplant periods. Additionally, univariate, and multivariable logistic regression analysis was conducted to identify predictors for the development of RCC. Results: A total of 202,837 patients were included in the study, of them 1042 developed RCC during the follow-up period. The mean time to diagnose RCC was 3.3 (SD:2.7) years. The incidence rate was 11.59 and 11.57 during the first 5 years of follow-up and during the next 5 years per 10,000 person-years respectively. The major risk factors associated with the development of RCC were age 35-49 (OR: 1.88, p&lt;0.001), age 50-64 (OR: 2.79, p&lt;0.001), age &gt;=65 (OR: 2.86, p&lt;0.001), BMI &gt;=30 (OR: 1.27, p=0.004) and race (African American (OR: 1.74, p&lt;0.001) or Caucasian (OR: 1.39, p=0.002)). In addition, underlying hypertension (OR: 1.23, p=0.01), pre-transplant RCC (OR:3.85, p&lt;0.001), and glomerulonephritis (OR: 1.28, p=0.009) causing ESRD were the significant risk factors for the occurrence of RCC during the 10-year follow-up period. The median graft survival and patient survival from the time of diagnosis to graft failure and patient mortality was 466 (109 – 1243) days &amp; 437 (109 – 1058) days respectively. Conclusions: The risk of developing RCC in the first 5 years of kidney transplant increases by 7-fold compared to the general population. Obese, middle-aged, African American, or Caucasian patients with a history of hypertensive nephrosclerosis, pre-transplant RCC, or glomerulonephritis are at a higher risk for developing RCC during the post-transplant period. RCC also increases the risk of early graft failure and death. RCC surveillance for post-kidney transplant patients is not currently recommended due to absence of the studies showing a cost benefit with this approach. Based on this study, further studies are warranted to assess the risks and benefits of initiating RCC surveillance in these select group of patients.
Clinical characteristics, oncologic outcome, and survival in patients with urothelial cancer with pure and partial squamous cell differentiation.
Authors: Maximilian Peter Johannes Karl Brandt, Nina Lache, Gregor Duwe, Nikita Fischer, Lisa Johanna Frey, Axel Haferkamp
Journal: Journal of Clinical Oncology (2024)

e16612 Background: In bladder cancer (BC) patients, pure (SCC) and partial (PSCC) squamous cell carcinomas belong to the most common histologic subtypes with approximately 5% of cases. They are highly aggressive and curative treatment in a local disease stage is typically radical cystectomy (RC). In case of tumor progression or metastatic disease, only limited data on the optimal treatment algorithm and its efficacy exists. In this study, we present clinical characteristics and oncologic outcome in a large patient cohort of SCC and PSCC. Methods: Between 2003 and 2021, we extracted data from patients with SCC and PSCC histology who received RC due to invasive bladder cancer. Clinical characteristics, treatment patterns, progression free- and overall survival were the primary outcome parameters. Kaplan-Meier curves were calculated for PFS and OS and a log rank test was applied to compare survival curves. Results: Overall, 770 patients were screened of which 26 men and 28 women with a mean age of 68.4 (SD 11.7) and 67.9 years (SD 14) years were identified. Twenty-three patients had SCC and 31 PSCC. No neo-adjuvant treatment was applied compared to 16 adjuvant chemotherapy regimens. Urinary diversion was ileal-conduit in 30 cases, Mainz-pouch in nine, ureterocutaneostomy in eleven, ileal neo-bladder in three and transverse conduit of the colon in one patient. The mean number of extirpated lymphnodes were 22.8 (SD 17.7) with a mean positivity of three (SD 8.3) lymphnodes. Mean follow-up was 11.5 months with a PFS of 5.9 and 8.7 mo. and OS of 13.3 mo. (SD 12.2) and 7.5 (SD 7.8) in men and women, respectively. There was no statistically significant survival difference for men and women as well as SCC and PSCC. Conclusions: This contemporary data demonstrated the aggressive nature of SCC of the bladder with IC being the most common urinary diversion. Compared to data from transitional cell carcinoma, PFS and OS was shorter and application of adjuvant Cx was overall low. Structured novel treatment modalities are urgently needed in this highly aggressive bladder cancer population.
Treatment patterns of metastatic urothelial cancer in the United States.
Authors: Xue Wang, Andi Chin, Lyuba Popadic, Francesca Devine, Tayla Poretta, Kerstin Schmidt, Mitch Sierecki, Jean H. Hoffman-Censits
Journal: Journal of Clinical Oncology (2024)

e16500 Background: Bladder cancer is the sixth most prevalent malignancy in the United States, of which urothelial carcinoma (UC) is the predominant histologic type. The prognosis of metastatic UC (mUC) is generally poor with standard platinum-based chemotherapy (PBC) regimens. With approvals of immunotherapy (IO) and antibody drug conjugates (ADCs) in recent years, the treatment landscape has been evolving substantially. This study aimed to describe current, real-world treatment patterns of mUC. Methods: This retrospective study used de-identified, open and closed administrative claims data from Komodo’s Healthcare Map between 1/1/2016 and 5/31/2023. Adult patients were required to have ≥2 claims for UC diagnosis and ≥2 secondary neoplasm claims (within 30 days before or any time after the first UC claim). In closed claims, patients were required to have continuous enrollment during the 6-month baseline period, whereas patients in open claims were required to have at least the median number of claims among all patients in open claims. Index date was defined as the earliest date of a secondary neoplasm claim following UC diagnosis. Patients were observed until death or end of study, whichever occurred first. Treatment patterns, including duration of treatment (DOT), were evaluated in patients who initiated first line (1L) treatment on or after 1/1/2020. A sensitivity analysis was conducted in closed claims alone. Results: Among 38,557 patients who were diagnosed with mUC, 44% received at least one line of treatment at any time. After removing patients who started 1L before 1/1/2020, 28,576 patients meeting eligibility criteria were included at baseline. Median age was 74 years; 77% patients were male; 38% had diabetes or hyperglycemia at baseline; 67% had de novo mUC. PBC with or without IO maintenance, were the most common 1L treatment regimens (47%). IO (39%) and enfortumab vedotin (EV, 21%) were the dominant regimens in 2L. Sacituzumab govitecan (SG) was predominantly administered in 3L (17%). Median DOT was generally longer in earlier versus later lines for most therapies, including PBC followed by IO maintenance, ADCs, FGFR targeted therapy and EV+Pembrolizumab (P), and were similar for other therapies (Table). Findings were similar in the sensitivity analyses. Conclusions: Novel therapies, such as IO and ADCs, have provided additional treatment options for patients diagnosed with mUC. Future studies with longer follow-up are needed to characterize the shifting treatment paradigm, as EV+P becomes a standard of care in 1L mUC. [Table: see text]
Integrative genomic analysis examines molecular and clinical disparities between bladder urothelial carcinoma and upper tract urothelial carcinoma.
Authors: Yoon Ji Choi, Jwa Hoon Kim, Jae-Lyun Lee, Woo Kyun Bae, Miso Kim, Ji Hyun Park, Jonggwon Choi, Inkeun Park, Sang Joon Shin, Jungmin Jo, Se Hoon Park, Kwonoh Park, Jiwon Kim, Jason Sa
Journal: Journal of Clinical Oncology (2024)

e16553 Background: The clinical outcome of urothelial carcinoma presents significant variability, reflecting its intricate molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns. Methods: To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 Korean BLCA and UTUC patients from the K-MASTER cohort. Results: Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study identified increased treatment resistance to both platinum-based chemotherapy and immunotherapy in UTUC patients. Notably, tumor mutational burden (TMB) and microsatellite instability score independently demonstrated robust predictive capabilities for immunotherapy response in BLCA and UTUC, respectively. Lastly, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, contrasting with mutations in FGFR2 linked to increased resistance to chemotherapy. Conclusions: Collectively, our findings provide important insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.
Comparison of clinical outcomes of bladder preservation and surgery in a real-world study of patients with muscle invasive urothelial carcinoma using urine and plasma based MRD (minimal residual disease) assays.
Authors: Cherry Au, Alan Tan
Journal: Journal of Clinical Oncology (2024)

e16580 Background: Recently, non-invasive urine/plasma-based minimal residual disease (MRD) assays have demonstrated the ability to reliably detect deep molecular alterations in bladder cancer patients. Similar to circulating tumor DNA, urinary tumor DNA (utDNA) is a noninvasive method of measuring MRD by evaluating the molecular landscape of tumor DNA shed in urine with next generation sequencing techniques. UtDNA can reflect the tumor landscape in real-time in patients with urothelial carcinoma via direct shed into the urine and can be utilized in monitoring for disease progression and also treatment response. This study investigates tissue-informed blood MRD and urine-informed urine MRD tests in the real world setting. Methods: A cohort of 40 real-world bladder and UTUC patients were included in this study. Treatment modalities such as neoadjuvant chemotherapy, trimodality therapy (TMT) for bladder preservation, and systemic chemotherapy/immunotherapy were utilized. Matching time point blood samples and urine samples were collected at variable intervals depending on the treatment regimens the patients received. Urine samples were tested using the PredicineBEACON urine MRD assay, which used the urine PredicineWES+ whole exome sequencing results from baseline urine samples for the design of a personalized MRD panel. Patients were followed up with MRD tests until otherwise censored. Results: There were a total of 94 urine and 253 plasma-based MRD tests with a success rates of over 90%, indicating the maturation of liquid biopsy lab technologies. Patients were followed for a median of 6.5 months between the first MRD assay and most recent follow up. MRD status and tumor fraction (TF) were monitored. The TF and kinetics from the urine MRD assay were in high concordance with the blood MRD assay results at matching time points. The mutation allele frequency time course changes matched with patient treatment responses and progression events in most cases. Clear increase in mutations and TF were observed in patients with progressive disease. Patients receiving definitive therapy had good disease-free survival time (longest &gt;2 years), and there is no significant difference between bladder preservation or surgery-based intervention. Conclusions: In this study, we observed no significant difference in clinical outcomes between bladder cancer patients receiving bladder preservation or surgery-based intervention. Urine and blood-based MRD tests closely correlated with clinical outcomes. Our study emphasizes the value of serial monitoring of urine/plasma-based MRD assays in informing MRD status or treatment response for patients who undergo bladder preservation or cystectomy. The number of cases was limited in this study and further follow up will be needed to confirm the findings in this study.
Association between body mass index and physical activity among prostate cancer survivors.
Authors: Shabbir Haiderbhai, Abe Eric Sahmoun
Journal: Journal of Clinical Oncology (2024)

5029 Background: Prostate cancer (PCa) has become a chronic disease due to advances in treatment and earlier detection. Therefore, factors that modify survival post‐diagnosis are important. Obesity is associated with increased PCa recurrence and mortality. Thus, interventions that reduce obesity, e.g., physical activity (PA) may prolong survival. We assessed the association between body mass index (BMI) and PA among prostate cancer survivors as well as other modifiable predictors of PA. Methods: We conducted a cross-sectional analysis of data from the 2018-22 Behavioral Risk Factor Surveillance System, an ongoing national population-based telephone survey conducted in the U.S. The outcome variable is PA after PCa diagnosis. We classified BMI (exposure) using standard cut points defined by the WHO. Multivariable weighted logistic regression was used to examine the association between BMI and PA adjusting for confounders. All significance tests were two-sided and p-value &lt; 0.05 was significant. The data were analyzed accounting for the complex sample survey design. Results: Of the 4,944 prostate cancer respondents, 78% were 65 years or older and 69% were White. 23% were obese class I and 11% were obese class II &amp; III. Obese class I and obese class II &amp; III respondents were significantly less likely to report PA (OR=0.48; 95% CI: 0.28-0.84 and OR=0.37; 95% CI: 0.20-0.67; respectively). Men who received a summary of their cancer treatment were significantly more likely to report PA (OR=1.53; 95% CI: 1.03-2.28). Current smokers were less likely to report PA (OR=0.50; 95% CI: 0.26-0.96). Conclusions: Obese men and current smokers were less likely to report PA. Men who received a summary of their cancer treatment were more likely to report PA. Healthcare providers should talk to their patients about the benefit of exercising and refer patients to available exercise programs. Key words: Prostate Cancer Survivorship; Body Mass Index; BRFSS; Quality of Care, Healthy Behaviors.
Prediction of immune checkpoint inhibitor (ICI) response in patients with urothelial cancer (UC) by a novel RNA-based ICI response signature (ICI-PRS).
Authors: Jonathan Shepherd, Gregory Mayhew, John Guo, Kirk Beebe, Joel Robert Eisner, Michael Vance Milburn
Journal: Journal of Clinical Oncology (2024)

e16502 Background: Immune checkpoint inhibition (ICI) shows great promise, including approval of pembrolizumab, nivolumab and avelumab in urothelial cancer (UC). However, the overall percentage of UC patients with clinical benefit is relatively small, despite biomarker use to select patients (e.g., PD-1 expression and TMB). Recently, several accelerated approvals (atezolizumab and durvalumab) were subsequently withdrawn following failure to show improved survival compared to standard of care (SOC) treatment in Phase 3 +/- biomarker use. To address the need for better ICI biomarkers, we developed an RNA-based predictive response signature (ICI-PRS) with the primary objective of being prognostic for ICI-treated patients, but not for SOC treatment (Shepherd et al, 2024 ASCO GU). ICI-PRS uses a novel ICI-specific survival signature with tumor-derived and immune associated features to evaluate the likelihood of responding and having longer survival with ICI therapy independent of non-ICI therapy. Herein we report the initial clinical validation of the ICI-PRS using independent datasets of patients with UC treated with ICI. Methods: RNA expression and clinical data were retrospectively evaluated in two independent cohorts of patients with UC treated with ICI: Bladder Cancer Advocacy Network (BCAN) UC-GENOME cohort (dbGaP phs003066.v1.p1 and cBioPortal (n=105) [PMID36333289]) and BACI cohort (Gene Expression Omnibus (GEO;GSE176307 (n=84 for patients treated with &gt;1 cycle) [PMID: 34294892])). ICI-PRS was applied and an optimal cutoff value to designate binary response prediction (complete response + partial response (PR/CR) vs. stable disease + progressive disease (SD/PD)) was derived with Youdin’s method using the receiver operator characteristic (ROC) curve of the original IMVigor210 training set. Results: Samples predicted to be ICI-PRS positive show consistent associations with overall survival (OS) when receiving ICI treatment. A lower hazard ratio (HR) was found for both BACI [HR (95% CI): 0.455 (0.24-0.86); and BCAN 0.540 (0.30-0.98)]. Response to ICI therapy was also associated with ICI-PRS scores, as patients achieving either CR or PR had significantly lower ICI-scores than those with SD or PD in both BACI (p=0.001) and BCAN (p=0.012). Conclusions: Herein we describe initial clinical validation of ICI-PRS in two independent cohorts of UC patients treated with ICI. It provides ICI-treatment specific prognostic and predictive value for patients with UC and may have application alone or in combination with other signatures when determining treatment sequencing or rational combination strategies. These results support further evaluation of the ICI-PRS and potential development as a diagnostic test for selecting UC patients most likely to benefit from ICI therapy either alone or in combination with non-ICI therapy.