tbuckley/cabot-search huggingface dataset:
Initial screening efforts for the OPTIC RCC trial.
Authors: Scott Mattox Haake, Katy Beckermann, Yu-Wei Chen, Anupama Reddy, Nataliya Mar, Moshe Chaim Ornstein, Pedro C. Barata, Tian Zhang, Sumanta Kumar Pal, W. Kimryn Rathmell, Brian I. Rini
Journal: Journal of Clinical Oncology (2024)

478 Background: OPTIC RCC (NCT05361720) uses RNA sequencing (seq) of tumor tissue to assign therapy in front-line metastatic clear cell renal cell carcinoma (mccRCC) patients. The operational characteristics of tumor tissue procurement, sequencing, cluster assignment and start of therapy are presented. Methods: Patients diagnosed with mccRCC without prior systemic therapy are eligible for enrollment. RNAseq of primary and/or metastatic tumor tissue is performed by Tempus (Chicago, IL) and data analyzed via an automated cloud-based informatics tool. Results: Twenty-three patients have been screened. Twelve patients (52%) had both primary and metastatic tumors submitted for RNAseq, 4 (17%) had primary only, and 7 (30%) had only metastatic tumor available. Three patients (13%) failed screening because no tumors passed RNAseq quality control (QC). When possible, patients were assigned to clusters based on data from metastatic tumor (15/20, 75%). However, 5/20 (25%) of patients were assigned to clusters based on primary tumor sequencing data because the metastatic tumor was not available or failed QC. Eight patients (40%) were assigned to cluster 1/2, 7 (35%) were assigned to cluster 4/5, and 5 (25%) were assigned to cluster 3/6/7. Primary tumors were more likely to be assigned to cluster 1/2 (12/14, 86%) than metastatic tumors (5/10, 50%) (p&lt;0.01, Fisher’s exact test). Of the 9 pts with both primary and metastatic RNAseq, 5 patients had discordant tumor clusters (primary cluster 1/2 and metastatic cluster 4/5 or 3/6/7); 4 patients with concordant tumor clusters (both cluster 1/2). The mean time from consent to cluster assignment was 32 days (SD +/- 18), though this improved over time. Ten patients have started therapy. Conclusions: Patients with mccRCC can be enrolled on clinical trials that utilize tissue-based RNA sequencing biomarkers. Accrual and analysis correlating cluster assignment with treatment response are ongoing. This trial is funded by the DOD Kidney Cancer Research Program (W81XWH-22-1-1033). Clinical trial information: NCT05361720 .
Role of thromboprophylaxis during neoadjuvant chemotherapy before radical cystectomy in patients with bladder cancer: Results of a multicenter retrospective cohort study.
Authors: Luca Antonelli, Pedro David Wendel Garcia, Manja Deforth, Luca Afferi, Marco Borghesi, Alessandro Antonelli, Karl Tully, Andrea Mari, Renate Pichler, Francesco Claps, Jeremy Yuen-Chun Teoh, Gerald Bastian Schulz, Francesco Soria, Majed Alrumayyan, Michael Rink, Stefania Zamboni, Luke Lavallee, Marco Moschini, Ulrike Held, Christian Daniel Fankhauser
Journal: Journal of Clinical Oncology (2024)

598 Background: Patients undergoing radical cystectomy are at risk of developing venous thromboembolic events (VTE), with most VTEs occurring during neoadjuvant chemotherapy. The ASCO Clinical Practice Guideline Update recommends thromboprophylaxis in cancer patients with a high risk of VTE and a low risk of bleeding. However, the risks of VTE and bleeding with or without thromboprophylaxis in bladder cancer patients scheduled for radical cystectomy have not been well evaluated. Methods: We conducted a retrospective cohort study of patients with non-metastatic bladder cancer undergoing cystectomy across 28 centers in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis during neoadjuvant chemotherapy on VTE and bleeding. Results: Of 4886 patients, 4631 (95%) received neither thromboprophylaxis nor anticoagulation during chemotherapy. Thromboprophylaxis during neoadjuvant chemotherapy was prescribed in 151 (3%) patients mainly being enoxaparin (80%) with a median duration of 94 (range 38 to 104) days. In inverse probability weighting analyses, patients with thromboprophylaxis compared to patients without thromboprophylaxis during chemotherapy had not only a lower VTE (HR 0.32 [95% CI, 0.12 to 0.81], p-value = 0.016) but also a lower bleeding risk (HR 0.03 [95% CI, 0.09 to 0.12], p-value: &lt;0.0001). Conclusions: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomized trials in other malignancies. Our data suggests thromboprophylaxis seems protective against VTEs during neoadjuvant chemotherapy in bladder cancer patients planned for cystectomy. The ASCO guidelines recommending thromboprophylaxis during chemotherapy should therefore also be regarded as a standard of care in patients treated with neoadjuvant chemotherapy before cystectomy.
Evolving trends in prostate cancer: Disparities across income levels and global regions (1990-2019).
Authors: Chinmay Jani, Harshitha Dudipala, Eli Tran, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

25 Background: Prostate Cancer, the third most commonly diagnosed cancer in 2020 and the fifth leading cause of cancer mortality worldwide, has exhibited significant disparities in global prevalence and impact over recent decades. This study assesses the trends in incidence, mortality, and disability-adjusted life years from prostate cancer in the World Bank regions based on country income levels from 1990 to 2019. Methods: The Global Burden of Disease Study database was used to extract Age-standardized incidence rates (ASIR), age-standardized (ASDR), and life years (DALYs) for prostate cancer from different World Bank regions based on income levels from 1990 to 2019. Annual percentage change was also acquired. Mortality-to-incidence ratios (MIR) were then computed. Trends were assessed using Joinpoint regression. Results: Between 1990 and 2019, ASIRs increased across all income levels, with the greatest growth in the upper middle income (+64.7%). While ASDRs decreased in high income, upper middle income, and lower middle income levels, they notably increased in low income levels (+14.3%). DALYs decreased in high income and upper middle income levels, primarily in the high income (-25.7%), and increased in lower middle and low income levels, primarily in the low income (+13.8%). MIRs decreased in all countries, with the largest decrease in high income levels (-50%). In the last 30 years, high income countries have consistently observed the highest ASIR (2019: 77.5/100,000). However, in 1990 high income countries also had the highest ASDRs and DALYs. Interestingly, by 2019 this pattern shifted, with low income surpassing high income countries in both. Conclusions: Over the last 30 years, the incidence of prostate cancer has been rising regardless of income level. Despite the universal decrease of MIRs implying improved outcomes, screening, and therapeutical strategies, the contrasting trends in ASDRs and DALYs across income levels underscore the disparities in health outcomes. Higher income countries experienced highest cancer incidence but also the highest decrease in the mortality rates while lower income countries faced the opposite challenges with lower increase but higher mortality rates. [Table: see text]
ERBB3 expression in racially diverse patients with castration-sensitive prostate cancer and its association with a unique AR activity signature.
Authors: Jordan Vellky, Donald Vander Griend, Natalie Marie Reizine
Journal: Journal of Clinical Oncology (2024)

23 Background: Despite successful clinical management of castration sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. This number is even more striking in the context of racial disparities where prostate cancer mortality rates for Black/African American (AA) men are two to four times higher than those in every other racial and ethnic group in the US. Identification of molecular expression and activity patterns that vary by racial group may provide a key to addressing outcomes related to survival disparities, as current treatments have not been developed with attention to the inclusion of diverse patient populations. Developing a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide intelligent intensification of therapeutic strategies and improve survival, particularly in high-risk patient populations. Methods: Targeted deep sequencing was performed as routine care for treatment naïve patients in the UI cohort (n=30), and immunostaining was performed in racially diverse tissue microarray (n=149). Bioinformatics analyses were utilized to identify signaling pathways associated with biomarker overexpression in the UI cohort, consolidated publicly available RNA-seq datasets (n=664), and a racially diverse Gene Expression Omnibus dataset (n=68). Results: We identified ERBB3 overexpression (OE) in racially diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/AA men. Bioinformatics analyses showed a positive correlation between ERBB3 expression and the Androgen Response pathway despite low intraprostatic androgen and stable expression of androgen receptor (AR) transcript in Black/AA men. Clinically, ERBB3 OE is associated with high pre-treatment serum PSA in Black/AA men and is positively correlated with a clinically adaptable AR signature score. Preliminary outcomes data suggest Black/AA men with ERBB3 OE have a shorter time to disease progression. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling and serum PSA despite low intraprostatic androgen, suggesting ERBB3 OE as a prospective biomarker for ligand-independent AR activation. In this context, ERBB3 OE could stratify patients for intensification of therapy in castration-sensitive disease and emphasizes the importance of biomarker-directed clinical trials with diverse populations.
The distribution of mutations across tumor size in ccRCC and their prognostic importance in small masses.
Authors: Steven Monda, Shuchi Gulati, Allison May, Marc Dall'era
Journal: Journal of Clinical Oncology (2024)

479 Background: Substantial efforts have been made to delineate mutational pathways to progression in ccRCC and the prognostic importance of key mutations, yet the distribution of these mutations across tumor size remains unknown. We hypothesized that VHL and PBRM, as more truncal mutations, would be roughly equally prevalent across tumor sizes, while mutations associated with aggressive disease - SETD2, BAP1, and CDKN2a copy-number loss - would be predominantly observed in larger tumors. We further hypothesized that SETD2, BAP1, and CDKN2a copy-number loss mutations, when present in smaller (≤7 cm) ccRCC tumors, would portend worse prognosis. Methods: We assessed a combined cohort of 333 ccRCC tumors from TCGA-KIRC and TRACERx Renal for the distribution of mutations across tumor size. Logistic regression was used to model the presence of each mutation against tumor size. We assessed a subset of 194 tumors ≤7cm for associations of key mutations with clinical outcomes while controlling for size. In small masses, logistic regression was used to model the presence of metastatic disease and invasive disease, and Cox proportional hazards was used to model overall survival, against SETD2, BAP1, CDKN2a copy-number loss, and tumor size. Results: On logistic regression an increase in one centimeter of tumor size was associated with SETD2, BAP1, and CDKN2a loss at odds ratios of 1.16, 1.11, 1.19 (p&lt;0.05); whereas no significant association was observed between tumor size and both VHL and PBRM1 (p=0.18, p=0.65). Among 194 tumors ≤7 cm, SETD2 and CDKN2a loss were associated with metastatic disease at odds ratios of 3.86 and 3.84 (p&lt;0.05); CDKN2a loss was associated with worse overall survival at hazard ratio 2.19 (p&lt;0.05), all while controlling for tumor size. Conclusions: SETD2 mutations, BAP1 mutations, and CDKN2a copy-number loss are rare in small ccRCC and are increasingly common in larger tumors, whereas VHL and PBRM1 are fairly evenly distributed across tumor sizes. In tumors≤7 cm, SETD2 mutation and CDKN2a loss were associated with metastatic disease and CDKN2a loss was associated with worse overall survival. SETD2 mutations and CDKN2a loss may help risk stratify ccRCC in biopsied and resected tumors. [Table: see text]
Maintenance of patient-reported quality of life (EQ-5D-3L) post neoadjuvant relugolix prior to the initiation of prostate radiation therapy.
Authors: Min Ji Koh, Min Jung Koh, Jessica Hsueh, Lindsey Gallagher, Malika Danner, Alan Zwart, Marilyn Ayoob, Thomas M. Yung, Deepak Kumar, Michael Carrasquilla, Paul Denis Leger, Nancy Ann Dawson, Simeng Suy, Sean P. Collins
Journal: Journal of Clinical Oncology (2024)

117 Background: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy (RT) for unfavorable intermediate- to high-risk prostate cancer. Relugolix is a new oral GnRH receptor antagonist that achieves high rates of rapid profound castration (total testosterone &lt; 20 ng/dL), which may impact health-related quality of life. This prospective study sought to evaluate the impact of neoadjuvant relugolix on health-related quality of life in prostate cancer patients prior to the start of prostate RT. Methods: Patients treated at Georgetown between May 2021 and August 2023 with neoadjuvant relugolix (at least 2 months prior to RT) per an institutional protocol were included in the study (IRB 12-1775). The 5-item EQ-5D-3L, a validated questionnaire that assesses the patient-reported health status outcome, was collected for each patient at baseline (before relugolix initiation) and one hour prior to RT initiation. EQ VAS Score Overall ranges from 0-100 with a higher score indicating better quality of life. Individual items including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were scored on a three-point scale from 1 (No problems) to 3 (Extreme). To examine changes before and after relugolix treatment, McNemar’s test and paired samples t-test were used. Minimally important difference (MID) calculated by 0.5 of standard deviation at baseline was used to examine clinical significance. Results: Of 79 patients, the median age was 73 years, and 42% were non-white. Patients initiated relugolix at a median of 4 months prior to questionnaire administration (IQR: 3.9-5.4), at which most (95%) patients achieved castration (≤ 50 ng/dL). The VAS Score Overall was significantly higher at baseline (Mean ± SD: 83 ± 10) than the paired score at the start of RT (80 ± 14, p = 0.01). This change was not clinically significant. There were no statistically or clinically significant differences in any of the 5 individual items. Conclusions: Neoadjuvant relugolix prior to prostate radiation therapy did not clinically significantly affect patient-reported quality of life. Also, there was no statistically significant decrease in each of the 5 individualized items evaluating health-related quality of life. Future studies should focus on comparing it to GnRH agonist-induced change in quality of life. [Table: see text]
Survival outcomes for rural patients with advanced prostate cancer: A SEER investigation.
Authors: Liang G Qu, J. Bailey Vaselkiv, Marlon Perera, Lorelei A Mucci
Journal: Journal of Clinical Oncology (2024)

22 Background: It is unknown if the impact of rural versus urban settings may impact outcomes in men with metastatic prostate cancer, and in particular survival. This study aimed to examine differences in survival for patients in the United States with de novo metastatic prostate cancer, according to urban-rural status. Methods: This retrospective cohort study utilised data from the publicly available Surveillance, Epidemiology, and End Results database. Data on demographics, urban-rural status, histopathology, and survival were extracted for men aged 18-75 diagnosed with metastatic prostate cancer between 2009-2018. Rurality was re-classified from the rural-urban continuum code which ranged from 1 (most urban) to 9 (most rural). Individuals missing rurality status or survival-related data were excluded. Overall and cancer-specific survival between individuals living in urban and rural settings were analysed using multivariable Cox regression and adjusted restricted mean survival time modelling. Subgroup analyses were performed for histological subtypes of prostate cancer. Sensitivity analyses were performed using varying definitions of rurality. Results: Altogether, 21,291 individuals were included, with 2,510 living in rural settings, defined as rural-urban continuum code ≥ 4. The rural and urban participants differed in age, race, U.S. region, and marital status. There was no association between urban-rural status and overall survival (adjusted hazard ratio [HR] = 1.03, 95% confidence interval [CI]: 0.97-1.09, 11,333 events) or cancer-specific survival (1.03, 0.97-1.10, 9,380 events) using Cox regression models. Adjusted restricted mean survival time modelling demonstrated that urban patients lived 2.29 months longer than rural patients (95% CI: 0.61-3.97). Sub-analyses of neuroendocrine, intraductal, and other histological subtypes did not show an association between urban-rural status and overall survival. A more selective definition of rurality (rural-urban continuum code ≥ 5) resulted in a persisting difference in overall mean survival time (2.12 months, 0.24-4.01) using restricted mean survival time modelling. Similarly, a broader definition of rurality (rural-urban continuum code ≥ 3) also resulted in a difference in overall mean survival time (1.98 months, 0.59-3.36). Conclusions: This retrospective analysis demonstrated that a U.S. individual with metastatic prostate cancer who resided rurally died sooner compared to those from urban areas, suggesting greater disease impact in rural settings.
Therapeutic targeting of metabolic dysfunction by amino acid restriction and alternate day fasting in renal cell carcinoma models.
Authors: Sabrina Orsi, Chris Rupert, Musea Chang, Sean Colligan, Abbas Jawadwala, Ilaria Delle Fontane, Filomena De Nigris, Roberto Pili
Journal: Journal of Clinical Oncology (2024)

469 Background: The use of immunotherapies and targeted drugs has significantly improved the clinical outcome of kidney cancer patients. However, the inevitable long-term toxicities and development of drug resistance remain a critical challenge for advanced clear cell and non-clear cell renal cell carcinoma (RCC) patients thus highlighting the need for novel therapeutic strategies. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of RCC. As diet has been reported to potentially modulate tumor metabolism, dietary interventions represent an innovative strategy to treat metabolically dysregulated tumors. However, the biological basis of the success of dietary interventions is unknown, representing a critical roadblock in the use of dietary restrictions in patients. In this study, we investigated the role of amino acid (AA) restriction and alternate day fasting in metabolic and energy dynamics in preclinical models of clear cell and translocation RCC with the overall goal of expanding the understanding of metabolism’s role in tumor progression and response to therapies. Methods: Seahorse, immunofluorescence, metabolomics, transcriptomics, genetic silencing, and pharmacological inhibition were utilized to assess the mechanisms underlying nutrient utilization and metabolic dysfunction in RCC. Patient-derived organoids and murine xenograft models were used to demonstrate the impact of dietary interventions and targeted therapies Results: Our data suggests that oxidative-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells but in all the tRCC cells assessed. AA restriction was associated with decreased oxidative phosphorylation in RCC models with baseline elevated mitochondrial function. Similarly, RCC models with a more glycolytic phenotype had decreased glycolytic function and reduced tumor burden in response to fasting conditions. The results from combining dietary interventions and targeted therapies are ongoing and will be presented. Conclusions: Our data suggests that oxidative-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells but in all the tRCC cells assessed. AA restriction was associated with decreased oxidative phosphorylation in RCC models with baseline elevated mitochondrial function. Similarly, RCC models with a more glycolytic phenotype had decreased glycolytic function and reduced tumor burden in response to fasting conditions. The results from combining dietary interventions and targeted therapies are ongoing and will be presented.
De novo financial toxicity following radical cystectomy for bladder cancer and its impact on health-related quality of life.
Authors: Thilo Westhofen, Alexander Buchner, Lennert Eismann, Severin Rodler, Armin Becker, Christian G. Stief, Alexander Kretschmer
Journal: Journal of Clinical Oncology (2024)

587 Background: Financial toxicity (FT) is a patient-reported outcome measure (PROM), defined as the detrimental effect of financial burden caused by a cancer diagnosis on a patient’s well-being. Although FT is common among cancer patients, little is known about FT following radical cystectomy for bladder cancer in countries with universal health coverage. We aimed to assess de novo FT and its impact on health-related quality of life (HRQOL) in a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: 1606 consecutive patients who underwent RC at a large tertiary care center were included. PROMs were prospectively assessed preoperatively, postoperatively at 3mo, then annually until a maximum follow-up of 120mo, applying the validated EORTC QLQ-C30 questionnaire, and the bladder cancer-specific QLQ-BLM30 and FACT-BL-questionnaires. FT was assessed by the “financial toxicity subscale” (FTS) of the EORTC QLQ-C30. Based on previous reports, meaningful FT was defined as FTS ≥ 17. Multivariable regression analysis was used to identify predictors for the development of de novo FT. Separate modeling of longitudinal HRQOL was performed for patients with de novo FT (FT-cohort) and without FT (no-FT-cohort). Results: 93 Patients reporting FT prior RC were excluded from further analysis. 37.6% of the included patients reported de novo FT within 12 months after RC with a mean FTS-score of 55.2 (SD 26.3). Baseline clinicopathological characteristics did not differ between the FT-cohort and the no-FT-cohort (p-range .072-.370). Multivariable logistic regression analysis revealed male gender (OR 3.448, 95%CI 1.10-11.49, p=.045), urban neighborhood (OR 1.532, 95%CI 1.01-2.53, p=.049), a positive smoking history (OR 2.491, 95%CI 1.18-5.26, p=.017) and ileal conduit urinary diversion (OR 2.179, 95%CI 1.03-4.61, p=.042), to independently predict de novo FT following RC. Longitudinal analysis of HRQOL revealed no significant difference in baseline general HRQOL assessed by the global health status domain (GHS) between both cohorts (p=.934). Postoperatively, patients with de novo FT reported significantly worse general HRQOL compared to patients without FT (p= .001). In the longer term, the FT-cohort reported significantly worse GHS scorer up to 84mo after RC. Conclusions: The current study provides prospective data from a unique contemporary patient cohort, which reveals independent predictors for de novo FT following RC. Furthermore, it displays the natural course of general HRQOL for patients who develop de novo FT.