tbuckley/cabot-search huggingface dataset:
Secondary primary malignancies among patients with GU cancer.
Authors: Nikita Tripathi, Ahsan Ayaz, Syed Arsalan Ahmed Naqvi, Muhammad Ali Khan, Akshat Saxena, Arifa Bibi, Aneeta Channar, Mark Tyson, Irbaz Bin Riaz, Ewan Kemar Cobran, Alan Haruo Bryce, Haidar Abdul-Muhsin, Parminder Singh
Journal: Journal of Clinical Oncology (2024)

98 Background: The risk of secondary primary malignancies (SPM) among the survivors of GU cancer is not well-established. In this study, we attempt to describe the patterns of SPMs in patients diagnosed with GU cancers. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat 8.4.2) was searched to obtain data on the incidence of SPM in adult patients (age &gt;18 years) diagnosed with GU cancers, including prostate, renal, and bladder cancer. Standardized incidence ratios (SIRs) with a 95% confidence interval (CI) were calculated. SIR was defined as the observed SPMS from each category divided by the expected number of SPMs in the age-matched US population for the same period. The data was further stratified by age (&lt;50y, 50-70y, &gt;70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy exposure. Results: A total of 1,041,217 patients were included in this analysis. In patients diagnosed with GU cancer, the incidence of overall SPM was 11%. Particularly, patients with GU cancers were observed to have a high incidence of Endocrine system SPM (1.52; 1.45-1.59), and urinary system SPM (1.51; 1.49-1.53) These results were consistent by different sociodemographic groups. In patients diagnosed with prostate cancer, the incidence of thyroid SPM was increased (1.31; 1.23-1.39). Particularly, prostate cancer patients treated with radiation therapy had increased incidence rates of SPM in the peritoneum, omentum and mesentery (1.57; 0.79-2.81) and urinary bladder (1.36;1.32-1.40) was higher as compared to those with no exposure to radiation therapy (1.11;1.08-1.13 and 1.03;1-1.06 respectively). Bladder cancer patients had an overall increased incidence of SPM in the esophagus (1.21; 1.08-1.35), lung, bronchus, trachea, and other respiratory organs (1.97;1.92-2.01), prostate (3.50;3.4-3.6) and kidney (1.86;1.76-1.97). A higher incidence of renal pelvis, ureter and other urinary organ SPM (11.08;10.48-11.07) was also notable in this population. Similarly, kidney cancer patients had a higher incidence of the endocrine system (3.00;2.74-3.27), prostate (1.24;1.2-1.29) and bladder 1.78;1.68-1.79 SPMs. Conclusions: This population-based study shows an increased risk of SPM development in GU cancer survivors compared to the general population. Clinicians should keep a high index of suspicion for SPMs and initiate appropriate workups at early warning signs.
Association of radiographic and pathologic outcomes in patients (pts) with advanced renal cell carcinoma (RCC) with and without thrombus receiving preoperative immune checkpoint inhibitor (ICI) regimens and circulating biomarkers.
Authors: Wadih Issa, Damla Gunenc, Song Zhang, Qinhan Zhou, Thomas Gerald, Isamu Tachibana, Raj Ramnik Bhanvadia, Payal Kapur, Solomon L. Woldu, Yair Lotan, Jeffrey A. Cadeddu, Kris Gaston, Qian Qin, James Brugarolas, Hans J. Hammers, Andrew Zhuang Wang, Vitaly Margulis, Tian Zhang
Journal: Journal of Clinical Oncology (2024)

415 Background: Primary RCC tumors and associated IVC thrombus have similar histology, however response to ICI is not always concordant. RCC with IVC thrombus is often difficult to manage, and perioperative ICI treatment responses remain largely unstudied. Methods: We conducted a retrospective analysis of pts with advanced RCC receiving preoperative ICI-based regimens at UTSW stratified by the presence of tumor thrombus. The primary objectives were pathologic change in both groups and radiographical response by RECIST 1.1 criteria for tumor and thrombus level change. The secondary objective was to evaluate biomarkers associated with thrombus. Comparisons were performed using a two-sample t-test or aChi-square test. Results: 65 pts were included (median age 64 years), 31 (48%) with baseline thrombus (9 (29%) renal vein thrombus; 6 (19%) level 1 IVC thrombus; 10 (32%) level 2; 2 (7%) level 3; and 4 (13%) level 4). 28 pts (43%) received ICI+ICI, while 20 pts (31%) received ICI+TKI and the rest received ICI monotherapy. 18/31 pts (58%) with thrombus and 20/34 without thrombus (59%) had metastasis at baseline. Pathological Tumor (pT) downstaging occurred in 13 pts with and 11 pts without thrombus; of these, 12 pts had received ICI+TKI and 12 pts ICI+ICI. Radiographic tumor (cT) downstaging occurred in 8/31 pts with thrombus and 7/34 pts without. 12/31 pts experienced thrombus downstaging. 5 pts with thrombus vs 2 pts without had complete tumor necrosis/pCR in the primary and radiographic PR, of whom 4/7 received ICI+TKI. In pts with IVC thrombus, preoperative ICI based regimens reduced median tumor size from 9.1 to 7.7 cm. Among responders in pts with IVC thrombus, ICI+TKI had a trend toward higher tumor shrinkage median (-3.3 vs -1.9 cm, p=0.3) and thrombus downstaging median ( -2 vs -1 levels , p=0.27) than ICI+ICI. Baseline anemia (Hemoglobin (Hgb), 11.1 vs 13.1 g/dL, p=0.002), lower Absolute Lymphocyte Count (ALC) (1.35x10^3 vs 1.55 x10^3 cells/uL, p=0.03), and higher Neutrophil-to-Lymphocyte ratio (NLR) (3.6 vs 3.2, p=0.03) were observed in pts with IVC thrombus. Conclusions: ICI+TKI regimens tend to have tumor downstaging, complete tumor necrosis/pCR in primary tumors, and some IVC thrombus control compared to ICI+ICI regimens. IVC thrombus is associated with lower Hgb and ALC and higher NLR levels. Prospective trials are ongoing to investigate perioperative treatment in pts with IVC thrombus. [Table: see text]
Comprehensive analysis of targetable alterations in urachal cancer by NGS.
Authors: David Joseph Benjamin, Tolulope Tosin Adeyelu, Andrew Elliott, Sourat Darabi, Thomas Lee, Rana R. McKay, Matthew James Oberley, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2024)

663 Background: Urachal cancer (UrC) is a rare genitourinary cancer with molecular drivers commonly found in colorectal cancer and harbors fewer actionable alterations. Although prior studies have identified genomic alterations associated with UrC, these lack comprehensive genomic profiling, often using targeted panels, and lack RNA interrogation. This study presents detailed characterization of molecular profiles and the tumor microenvironment of real-world UrC patient samples. Methods: UrC samples (n = 42) were profiled using next-generation sequencing (NGS) of DNA and RNA. Prevalence was calculated for pathogenic SNVs/Indels and copy number amplifications, dMMR/MSI status assessed by IHC and NGS, PD-L1 expression measured by IHC, and TMB-H defined as ≥ 10 mut/Mb. Immune cell fractions of TME were estimated using RNA deconvolution. Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Histological features were reviewed by a genitourinary pathologist. Results: UrC samples were collected from 19 males and 23 females with a median age at sample collection was 58.5 years (range: 24-86 years). Pathology review revealed the majority were adenocarcinomas (n=41/42, 97.6%), including mucinous (n=17/41, 41.5%) and enteric adenocarcinomas (n=10/41, 24.4%). Pathogenic variants were most commonly observed in TP53 (n = 35, 83.3%), KRAS (n=15, 36%), GNAS (n=5, 12%), SMAD4 (n=4, 10%), PIK3CA (n=4, 10%), STK11 (n=3, 7%), BRCA2 (n=3, 7%), ARID1A (n=2, 5%), PTEN (n=2, 5%), ERBB2 (n=2, 5%), BRAF (n=2, 5%), and APC (n=2, 5%). MAPK pathway alterations were present in 52.3% (n=22) overall, with increased MAPK pathway activation in MAPK-altered UrC (median MPAS: 0.77 vs -0.61, p = 0.066). Loss of heterozygosity was prevalent (n = 9, 29%). While no UrC tumors had dMMR/MSI, 5% (n=2) were TMB-H and 9% (n=3) were PD-L1+. The mean fraction of T cells – CD8 (0.4%) and monocytes (0.0%) represented a smaller fraction UrC TME composition compared to macrophages M1 (5.19%) and neutrophil (6.4%). The median NK cell fraction was significantly higher in MAPK-altered UrC patients (3.5 vs 2.7%, p = 0.022), yet a transcriptional signature of response to immunotherapy (IFN-g) was similar between MAPK-altered and MAPK-WT UrC patients (median IFN: -0.366 vs -0.384, p = 0.052). Conclusions: This study provides a comprehensive molecular characterization of UrC and the associated immune landscape. While MAPK and DNA repair gene alterations were common, UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials.
Impact of intraoperative tranexamic acid use on overall survival and cancer specific survival in patients undergoing radical cystectomy.
Authors: Mohamed E. Ahmed, Jack R. Andrews, Ahmed M. Mahmoud, Prabin Thapa, Abhinav Khanna, Paras Shah, Vidit Sharma, R. Houston Thompson, Matthew K. Tollefson, Igor Frank, R. Jeffrey Karnes
Journal: Journal of Clinical Oncology (2024)

642 Background: Perioperative blood transfusion has been reported in up to 60% of patients undergoing RC. Unfortunately, perioperative blood transfusion in patient undergoing RC has been associated with poor oncological outcomes. Tranexamic acid (TXA) use has been proposed to decrease the need for perioperative blood transfusion. Here we seek to investigate the impact of intraoperative TXA on survival outcomes in patients undergoing radical cystectomy (RC) for bladder cancer. Methods: We queried the prospectively maintained Mayo Clinic Radical Cystectomy registry and identified all RC performed for bladder cancer between 1990-2021. Primary outcomes were patient’s overall survival and cancer specific survival among patients who received TXA versus patients who did not receive TXA. Results: Among 2929 patients who underwent RC in our institution between 1990-2021, 468 received TXA (IV) intraoperatively (Group A) and were propensity score matched 1:1 for age, neoadjuvant chemotherapy, adjuvant chemotherapy, pT stage, pN stage, and preoperative hemoglobin with a group who did not receive TXA (Group B, n= 468). At 8 years followup, 61% of patients who received TXA were alive versus 46% of patients who did not receive TXA. In univariable and multivariable analyses of factors associated with CSS (Table1), node positive disease, pT2-T4, peri-operative blood transfusion were associated with poor survival outcomes. While use of TXA was associated with improved CSS outcomes. Conclusions: In our study, TXA use in patients undergoing radical cystectomy was associated with decreased risk or peri-operative transfusion, improved patient’s overall survival, and cancer specific survival. We can’t explain the biological rational for improved survival however these findings warrant further prospective investigation. [Table: see text]
Association of body-mass index (BMI) with age, PSA, and survival in metastatic prostate cancer.
Authors: Martin W. Schoen, Robert Bruce Montgomery, Saira Khan, Daniel B. Eaton, Nicholas Fedele, Ashwin Sachdeva, Andrew Warren Hahn, Ruth Douglas Etzioni
Journal: Journal of Clinical Oncology (2024)

96 Background: Increased body-mass index (BMI) is associated with increased prostate cancer incidence and death. However, an ‘obesity paradox’ exists where patients with BMI have longer survival once diagnosed with cancer. We investigated the influence of BMI on overall survival of veterans with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: Two cohorts were identified in the US Veterans Health Affairs. The mHSPC cohort included patients diagnosed with de-novo mHSPC from 2011-2021. The mCRPC cohort was treated with abiraterone or enzalutamide from May 2011 to June 2017. We determined BMI at time of treatment and weight loss during the one year prior. BMI was categorized as ≤20, &gt;20-25, &gt;25-30 or &gt;30 kg/m2. We used Kruskal-Wallis testing for ordinal variables and Cox hazard models to assess the association between BMI, age, Charlson comorbidity index, PSA level at diagnosis, Black race, weight loss, and survival. Results: We identified 5019 veterans with mHSPC and 8159 with mCRPC. Mean BMI was 27.2 (SD 5.9) in mHSPC and 28.2 (SD 5.8) in mCRPC. Mean age was 75.7 years (SD 9.8) in mHSPC and mean age of 74.6 (SD 9.3) in mCRPC. Median overall survival was 25.6 months (95% CI 24.6-26.6) in mHSPC and 20.5 months (95% CI 19.9-21.1) in mCRPC. There were significant differences in age, Black race, and PSA at diagnosis across BMI strata with BMI&gt;30 having the youngest age, lowest percentage of Black race, lowest PSA, and longest survival in mHSPC and mCRPC (see Table). In unadjusted analyses, veterans with BMI&gt;30 had lowest risk of death with Hazard Ratio (HR) 0.66 (95% CI 0.60-0.71) in mHSPC and 0.60 (95% CI 0.56-0.64) in mCRPC compared to BMI&gt;20-25. In adjusted analyses, veterans with BMI&gt;30 had lowest risk of death with adjusted hazard ratio (HR) 0.89 (95% CI 0.81-0.97) in mHSPC and HR 0.77 (95% CI 0.72-0.83) in mCRPC compared to BMI&gt;20-25. Conclusions: Increased BMI is associated with younger age at diagnosis, lower PSA, and longer survival in both mHSPC and mCRPC. Further studies between BMI and prostate cancer are warranted to understand these complex interactions. [Table: see text]
Systemic and surgical treatment in renal cell carcinoma: Does timing matter?
Authors: Konstantin Egon Seitzer, Christopher Darr, Thomas Hilser, Andres Jan Schrader, Linda Huberth, Anne Mausbach, Martin Janssen, Laura-Maria Krabbe, Barbara Heitplatz, Boris A. Hadaschik, Martin Boegemann, Katrin Schlack, Viktor Grünwald
Journal: Journal of Clinical Oncology (2024)

417 Background: Today, targeted systemic therapy is standard 1st line treatment of advanced/metastatic renal cell carcinoma (aRCC). Upfront cytoreductive nephrectomy (CN) has been an important treatment option. Recently its role is under debate, especially in combination with the new 1st line treatments. Our study evaluated the current relevance of initial surgical intervention and the role of inductive systemic therapy in aRCC. Methods: We included 33 patients with aRCC from the University Hospitals in Essen and Münster initiating 1st line treatment from 03/18 to 01/23 pre or post surgery. We retrospectively formed two cohorts, either CN followed by systemic therapy (cohort 1; 13 patients) or vice versa (cohort 2; 20 patients). Patients received either Ipilimumab/Nivolumab (Ipi/Nivo) (42.4%) or a checkpoint inhibitor and tyrosine kinase inhibitor (CPI/TKI) combination (57.6%). Progression-free survival (PFS) was estimated with Kaplan-Meier-method from initiation of systemic therapy or CN to progression or death. In Cohort 2, we additionally analyzed the radiologic response of the primary measured by change of the longest diameter. The radiographic response was analysed according to RECIST1.1. Results: Patients’ age ranged from 44 to 80 years with a median of 63 years. Intermediate and poor prognosis occurred in 61.3% and 38.7% of cases. The two cohorts did not differ significantly regarding baseline characteristics. Median PFS was 8 vs. 23 months (p=0.03) in cohort 1 (95% CI 0.9-15.1) compared to cohort 2 (95% CI 18.8-27.2). In cohort 2 the time between start of systemic therapy and surgery was in median 8.5 months (95% CI 3.3-21.1), the primary had a median diameter of 10.7 cm (95% CI 4.5-13.3). Median reduction of the primary was in total 32.2%, 28.9% in the Ipi/Nivo and 34.7% in the CPI/TKI group (p=0.74). In seven patients (35%) response led to modification of the surgical approach, enabling partial instead of radical nephrectomy. Conclusions: The sequence of systemic therapy followed by surgery was associated with a significant PFS benefit. In addition, prior systemic therapy led to a primary reduction and better operability, in some cases even to kidney sparing surgery. Major limitation is the retrospective nature of our analysis and a potential selection bias. However, the sequence of prior systemic therapy followed by surgery in aRCC was associated with notably better outcomes.
HER2 and PD-L1 immunohistochemistry (IHC) expression, and HER2 genomic alterations: Associations and clinical outcomes for advanced bladder cancer.
Authors: David H Aggen, Neil J. Shah, Junting Zheng, Syed Muneeb Alam, Om Balar, Andrew Niederhausern, Ashley M. Regazzi, Neha Ratna, Samuel A Funt, Min Yuen Teo, Eugene J. Pietzak, David B. Solit, Dean F. Bajorin, Irina Ostrovnaya, Jonathan E. Rosenberg, Hikmat A. Al-Ahmadie, Gopa Iyer
Journal: Journal of Clinical Oncology (2024)

538 Background: Bladder cancer (BC) has a relatively high rate of human epidermal growth factor receptor 2 (HER2) alterations. The association between HER2 mutation/amplification, HER2, and PD-L1 immunohistochemistry (IHC) expression and associations with clinical outcomes for advanced bladder cancer (BC) has not been studied. Methods: We retrospectively analyzed BC samples for PD-L1 and HER2 IHC expression and compared HER2 alterations from genomic profiling with the MSK IMPACT platform. HER2 IHC expression was defined as 0, 1+, 2+, 3+, and PD-L1 IHC was the combined tumor and immune cell PD-L1 expression score (CPS). HER2 alteration was defined as either pathogenic mutation and/or amplification. We studied pairwise associations between HER2 alteration, PD-L1, and HER2 IHC expression in all patients and their associations with progression-free survival (PFS) and overall survival (OS) for muscle-invasive bladder cancer (MIBC) pts. Association analyses were performed using the Wilcoxon rank-sum test or Fisher’s exact test. Kaplan-Meier method and Cox proportional hazard models were used for time-to-event analyses. Results: Among 202 pts with HER2 IHC, 188 had MSK IMPACT, and 168 had PD-L1 CPS. The overall incidence of HER2 alteration was 22.3%; 48.2% had CPS ³10, and HER2 IHC distribution was 0:18.8%, 1+:29.7%, 2+:33.7%, and 3+:17.8%. The CPS score was inversely associated with HER2 IHC expression (p&lt;0.001). No association was noted between CPS score and HER2 alteration (p=0.735). HER2 altered tumors were strongly correlated with high-level HER2 IHC expression (p&lt;0.001). However, 41% (n=14/34) of HER2 IHC 3+ samples did not have HER2 alterations, and 17% (n=7/36) of HER2 altered samples had HER2 IHC expression of 0. In patients with MIBC, HER2 alteration and HER2 IHC expression (0/1+ vs. 2+/3+) were not associated with PFS (p=0.5 and p=0.4, respectively) or OS for MIBC pts (p=0.84 and p=0.94, respectively). A higher PD-L1 CPS score (&gt;=10 vs &lt;10) was associated with improved PFS for MIBC pts (p=0.03). Conclusions: Our study is the first to describe an inverse correlation between HER2 IHC expression and PD-L1 CPS score. Furthermore, HER2 IHC overexpression is strongly associated with HER2 amplification, but a subset of patients with high HER2 protein expression are potentially missed by genomic profiling alone. HER2 expression by IHC or HER2 genomic alteration is not a prognostic marker for MIBC pts in this cohort. This data provides the foundation for further HER2-directed advanced BC studies. [Table: see text]
Fragmentomics of cell-free DNA from targeted panels in genitourinary malignancies.
Authors: Amy K Taylor, Kyle Helzer, Marina Nasrin Sharifi, Jamie M Sperger, Yue Shi, Matti Annala, Shannon Reese, Katherine Kaufmann, Jennifer L. Schehr, Nan Sethakorn, David Kosoff, Christos Kyriakopoulos, Andrew J. Armstrong, Rana R. McKay, Felix Y Feng, Kari Braun Wisinski, Hamid Emamekhoo, Alexander William Wyatt, Joshua Michael Lang, Shuang Zhao
Journal: Journal of Clinical Oncology (2024)

199 Background: The detection of genomic alterations in cancer is critical for identifying clinically actionable alterations for treatment decisions. Tumor samples historically have been required, but obtaining tissue for molecular profiling is not always feasible, especially in the metastatic setting. The isolation and analysis of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) via blood-based “liquid” biopsies offers non-invasive sampling of the tumor. Recently, fragmentation patterns of cfDNA (i.e. “fragmentomics”) have emerged as a method for inferring epigenomic and transcriptomic information. However, these analyses use whole-genome sequencing, which lacks the necessary depth to cost-effectively assess genomic alterations, limiting the application of these techniques clinically. Methods: We developed a novel cfDNA fragmentomics machine learning approach for standard targeted cancer gene panels in order to identify genitourinary (GU) and non-GU cancers from two independent metastatic cancer cohorts: a published cohort from GRAIL (prostate cancer, non-GU cancers, normal samples, N=198) and an expanded institutional cohort from the University of Wisconsin (prostate adenocarcinoma, neuroendocrine prostate cancer (NEPC), renal cell carcinoma (RCC), bladder cancer, non-GU cancers, normal samples, n = 431). Results: In the GRAIL cohort, 10-fold cross-validation AUCs were 0.987 for identifying prostate cancer, 1.00 for normal samples, and ranged from 0.922-0.958 for the non-GU cancers. In the UW cohort, 10-fold cross-validation AUCs were 0.950 for bladder cancer, 0.982 for prostate cancer, 0.993 for NEPC, 0.925 for RCC, and 0.980 for normal samples, and ranged from 0.874-0.954 for non-GU cancers. Our assay can sensitively detect and accurately distinguish GU and non-GU malignancies despite a median ctDNA fraction of only 0.076 in the GRAIL cohort, and a median ctDNA fraction of only 0.022 in the UW cohort. Conclusions: Our enhanced machine learning approach for examining fragmentomics in standard cancer gene cfDNA panels unlocks the potential for these established assays to be utilized to answer critical clinical questions beyond somatic variant identification. The excellent performance of our innovative approach even in samples with low ctDNA fractions suggest potential applications such as multi-cancer early detection and minimal residual disease monitoring. This framework could dramatically expand the potential of already existing clinically used assays and minimizes barriers for continued biomarker development.