tbuckley/cabot-search huggingface dataset:
Treatment efficacy implications of incorrect utilization of tumor marker levels and risk group assignment according to the International Germ Cell Consensus Classification (IGCCCG).
Authors: Tim Nestler, Pia Paffenholz, Christian Ruf, Yue Che, Christoph Alexander Seidel, Julia Heinzelbecker, Hans Schmelz, Cord Matthies, Peter Albers, Carsten Bokemeyer, Axel Heidenreich, Martin Pichler, Matthaeus Majewski
Journal: Journal of Clinical Oncology (2024)

505 Background: Patients withmetastatic germ cell tumors of the testis (GCTs) are risk-stratified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification system for further therapy decision. This risk classification is based on metastatic load as well as tumor marker levels of AFP, HCG and LDH assessed pre-chemotherapy after orchiectomy treatment. An incorrect classification is possible when pre-orchiectomy marker levels are used, possibly resulting in over- or undertreatment of patients. Therefore, the aim was to investigate the potential frequency and clinical relevance of incorrect risk stratification using pre-orchiectomy tumor marker levels. Methods: Patients with metastasized nonseminomatous GCT (NSGCT)were included in a multicenter registry analysis which was conducted by investigators of the German Testicular Cancer Study Group (GTCSG). Based on the marker levels at different timepoints, IGCCCG risk groups were calculated. The agreement was tested using Cohen’s kappa. Results: A total of698 of 1983 (35%) patients were diagnosed with metastatic NSGCTs, and 546 (78%) had sufficient data for 232 follow-up data points. By using pre-orchiectomy tumor marker levels, 111 patients (20%) would have been incorrectly classified. Seventy-five patients (14%) were classified into a higher risk category, and 36 patients (6%) were classified into a lower risk category. Cohen’s kappa was 0.69 (p &lt; 0.001), showing a strong agreement between the use of both marker timepoints. The treatment of misclassified patients would have resulted in an overtreatment of 75 patients or undertreatment of 36 patients. Conclusions: The use of pre-orchiectomy tumor marker levels may lead to an incorrect risk classification and might subsequently lead to under- or overtreatment of patients. Part of these data were published in: Majewski et al. Cancer Med. 2023.
Inconsistency in the assessment of retroperitoneal lymph node metastasis in patients with testicular cancer: Influence on clinical stage, therapy and relapse rate.
Authors: Tim Nestler, Angelina Strauch, Kai Nestler, Justine Schoch, Laura Kubitscheck, Stephan Waldeck, Hans Schmelz
Journal: Journal of Clinical Oncology (2024)

506 Background: In testicular germ cell tumor (GCT) staging, current guidelines lack consensus in the measurement of retroperitoneal lymph node metastasis, including the recommended plane and dimension. Therefore, our objective was to investigate current guideline recommendations for staging of retroperitoneal lymph nodes and their influence on clinical stage (cS), relapse rate and therapy. Methods: In this explorative study we retrospectively analyzed 154 cSI GCT patients who underwent orchiectomy without any adjuvant therapy and had a follow-up of ≥ 24 months. Here, cSI was defined as retroperitoneal lymph nodes &lt;10mm in axial short-axis diameter (SAD). In initial staging imaging the largest retroperitoneal lymph node was measured considering the different dimensions (SAD and long-axis diameter (LAD)) in the three different radiological planes: axial, sagittal and coronal. Results: In the studied cohort overall survival (OS) was 100% and relapse free survival was 82% with a mean follow-up of 95 months. By using axial SAD (RECIST 1.1) all patients were classified as cSI. Based on axial LAD (German S3 guideline) or LAD in any plane (EAU, ESMO, onkopedia and AJCC), significantly more patients would be classified as cSIIA (0% vs. 38% vs. 52%) or even cSIIB (0% vs. 1% vs. 25%; p&lt;0.001). Overtreatment would occur in 0%, 31%, and 61% ( p&lt;0.001) for axial SAD, axial LAD and LAD in any plane, while undertreatment would affect 18%, 10%, and 2% ( p&lt;0.001), respectively. A stage-appropriate therapy would hypothetically require the following number of chemotherapy cycles (BEP or Carboplatin): optionally 34 for axial SAD vs. up to 361 for LAD in any plane. Conclusions: We found a huge variety of clinical stages according to different lymph node staging recommendations in current guidelines. With a 100% OS rate in the entire cohort and considering the balance between the risks of overtreatment and undertreatment, with stage-adapted treatment at relapse, we strongly recommend adopting axial SAD in accordance with RECIST 1.1. Prospective validation is warranted to standardize guideline recommendations.
Occurrence of <i>NECTIN4</i> amplification in solid tumors and enfortumab vedotin response in metastatic urothelial cancer.
Authors: Niklas Klümper, Ngoc Khanh Tran, Stefanie Zschaebitz, Oliver Hahn, Friedemann Zengerling, Dora Nagy, Glen Kristiansen, Philipp Ivanyi, Camilla Marisa Grunewald, Christopher Darr, Katrin Schlack, Steffen Rausch, Manuel Ritter, Kerstin Junker, Arndt Hartmann, Viktor Grünwald, Michael Hölzel, Markus Eckstein
Journal: Journal of Clinical Oncology (2024)

673 Background: The anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains are frequent genomic events in mUC leading to NECTIN4 amplifications. Here, we aimed to evaluate the potential of NECTIN4 amplification as a genomic biomarker to predict EV response in patients with mUC. Methods: We established a NECTIN4-specific fluorescence in-situ hybridization (FISH) assay to assess NECTIN4 copy number variations (CNVs) in a multicenter EV-treated mUC patient cohort (UC-EV, N=77), and CNV data were correlated with membranous NECTIN4 protein expression (H-score) assessed via immunohistochemistry, EV treatment responses and outcomes. Next, we conducted a pan-cancer analysis of the The Cancer Genome Atlas (TCGA) datasets, comprising 10,712 patients across 32 cancer types, to investigate the relationship between NECTIN4 CNV, mRNA expression (RNAseq) and protein levels (RPPA) across entities. Results: In TCGA cohorts, NECTIN4 amplification occurs frequently across different solid cancer types, especially in 15-20% of bladder cancers (17% in TCGA-BLCA), as well as 5-10% in breast cancer (TCGA-BRCA) and lung adenocarcinoma (TCGA-LUAD). We confirmed the amplification frequency in our UC-EV cohort (18%). NECTIN4 amplification is significantly associated with both increased NECTIN4 mRNA expression (e.g., TCGA-BLCA, BRCA, LUAD) and membranous NECTIN4 protein expression (UC-EV), and represents a stable genomic alteration during metastatic progression. In the UC-EV cohort, all patients with NECTIN4 amplification (N=14) responded to EV. In multivariable Cox adjusted for age and sex, NECTIN4 amplifications led to a 93% risk reduction for death compared to a NECTIN4non-amplified status (HR=0.07, 95%-CI 0.01–0.53; P&lt;0.001). Conclusions: Our study highlights the value of NECTIN4 amplifications to predict EV responses in patients with mUC. NECTIN4 amplifications occur frequently in different cancer types and therefore have the potential to be a novel tumor-agnostic genomic biomarker that enables tailored NECTIN4-targeted therapies in various entities.
Pemetrexed (PEM) maintenance versus observation (OBS) in patients (pts) with advanced urothelial carcinoma (aUC) who completed first-line (1L) platinum-based chemotherapy (CTx) without disease progression (PREMIER, KCSG GU16-05).
Authors: Inkeun Park, Shinkyo Yoon, Il Hwan Kim, Kwonoh Park, Suee Lee, Bhumsuk Keam, Joo-Hwan Park, Jin Young Kim, Yoon Ji Choi, Byeong Seok Sohn, Jae-Lyun Lee
Journal: Journal of Clinical Oncology (2024)

621 Background: Four-to-six cycles ofplatinum-based CTx have been a standard treatment for aUC. However, disease progresses within several months after completion of 1L CTx. Switch maintenance after 1L with effective and safe regimen is an attractive approach to delay disease progression. PEM showed modest response as a salvage CTx in aUC with mild toxicities, which are good candidate for maintenance therapy. We evaluated PEM as switch maintenance therapy versus OBS in pts with aUC whose disease had not progressed. Methods: Eligible pts with aUC without disease progression after 4-6 cycles of either cisplatin or carboplatin-based regimen were randomized 1:1 to receive maintenance PEM (500 mg/m 2 IV q3 weeks, up to 16 cycles) or OBS until disease progression, stratified by Galsky et al.’s post-treatment prognostic nomogram for pts with mUC completing 1L cisplatin-based CTx. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), response rate, and safety. Results: This trial was closed early due to poor accrual after avelumab maintenance approval. From Oct 2016 to Dec 2022, a total of 97 pts was randomly assigned to maintenance PEM (n=49) or OBS (n=48). Median age (range) was 69 years (43-90) and 66 (33-82), and male was 63% and 73%, respectively. 1L regimen included gemcitabine plus cisplatin (84% and 83%, respectively), gemcitabine plus carboplatin (12% and 6%, respectively), and MVAC (4% and 10%, respectively). Response to 1L were CR (8% vs. 19%), PR (69% vs. 67%), and SD (22% vs. 15%). Most common metastatic site was abdominopelvic lymph nodes (61% and 65%) and lung (37% and 29%). For PEM group, median administered cycle was 6 (range 1-16), and most common reason for discontinuation was disease progression (53%), followed by completion of planned cycles (20%). With a median follow-up of 19.1 months, median PFS was 6.0 months (mo) [95% confidence interval (CI) 3.4-8.5] for PEM vs. 2.3 mo (1.8-2.7) with a log rank p=0.027, with a hazard ratio (HR) of 0.61 (95% CI 0.40-0.95). Median OS was 25.5 mo (95% CI 11.9-30.1) vs. 26.8 (11.9-41.7) (p=0.607, HR 1.18, 95% CI 0.62-2.26). Anemia (29%), fatigue (18%), and neutropenia (12%) were the most frequent adverse events, and these adverse events were mostly grade 1 or 2, and manageable. Conclusions: PREMIER trial showed that switch maintenance PEM prolonged PFS with statistical significance in aUC after 1L platinum-based CTx and had very favorable safety profile. Combination maintenance therapy including PEM needs further investigation. Clinical trial information: NCT03193788 .
Performance of the OncoUrine test on predicting patients who can avoid Re-TURBT and prognosis: A prospective, multicenter clinical study.
Authors: Xiao Yang, Lingkai Cai, Bing Zhen, Lin Yuan, Zhenqian Qin, Xinfeng Chen, Jie Han, Xuping Jiang, Yaqun Xin, Hongling Yuan, Dandan Cao, Qiang Lu
Journal: Journal of Clinical Oncology (2024)

623 Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. However, no reliable predictors have been developed to help select patient candidates who could avoid Re-TURBT in NMIBC. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). A total of 162 patients who underwent initial TURBT and were scheduled for Re-TURBT were enrolled in this study between June 2021 and August 2023 from four centers. Urine sample of each patient was collected prior to Re-TURBT. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. The OncoUrine test results were compared to pathological results at Re-TURBT to assess the performance in predicting residual tumor and predictive value of risk stratification. Patients who received intravesical infusion chemotherapy or BCG were followed up for recurrence analysis. Results: 151 patients were finally included for performance analysis. At Re-TURBT, 48 (31.8%) samples had residual tumor and 103 (68.2%) had no residual tumor. 1 Ta and 2 T1 patients were up staged to T2 at Re-TURBT. Overall, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of OncoUrine test were 77.1%, 77.7%, 61.7%, and 87.9%. Compared to OncoUrine, Cytology prior to Re-TURBT yielded a high specificity of 95.8% but lower sensitivity of 20% and combined with OncoUrine improved the sensitivity to 75.6%. In the overall OncoUrine test results, variants from 12 genes showed positive mutations. TERT, TP53, ERBB2, FGFR3, and PIK3CA were on the top 5 of the lists with other mutations from ERBB3, ERCC2, U2AF1, HRAS, KDM6A, KRAS, and ROHA. 132 were followed up with a median of 362 days (range 21 to 953). 19 patients were found recurred. The pathological results at Re-TURBT, OncoUrine, methylation and TERT results were risk stratification approaches for the recurrence analysis (positive vs. negative, p＜0.05). Conclusions: OncoUrine test after initial TURBT for NMIBC showed promise as to guide patient selection for Re-TURBT and risk stratification in the management of NMIBC. Clinical trial information: NCT05112523 .
Sequential endoluminal gemcitabine and docetaxel versus bacillus Calmette–Guérin for the treatment of high-grade upper tract urothelial carcinoma.
Authors: Ian M. McElree, Sarah L. Mott, Vignesh T. Packiam, Michael A. O'Donnell, Ryan L. Steinberg
Journal: Journal of Clinical Oncology (2024)

613 Background: BCG is currently the only endoluminal treatment option for high-grade (HG) upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown promising efficacy as a treatment for HG UTUC, though a comparison to BCG is lacking. We report the outcomes of patients treated with endoluminal Gem/Doce versus BCG for non-invasive HG UTUC. Methods: A retrospective review of patients treated with Gem/Doce versus BCG for clinically non-invasive HG UTUC was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks. If disease free, maintenance therapy for Gem/Doce was monthly for 6 months and a single 3 week mini-cycle for BCG. Recurrence was defined as biopsy-proven disease or HG cytology. Progression was defined as development of muscle invasion, metastases, or death due to cancer. Results: The final cohort included 59 patients with 71 treated upper tract units; 36 received BCG and 35 received Gem/Doce. Median follow-up was 62 months in the BCG group and 29 months in the Gem/Doce group. Indication for treatment included a positive HG cytology in 78% and 89% of the BCG and Gem/Doce groups, respectively; the remaining patients in each group presented with pathologically-confirmed HG disease. The 2-year estimates for recurrence-free and nephroureterectomy-free survival were 57% and 87% for the BCG group and 56% and 100% for the Gem/Doce group, respectively (Table). Upon multivariable analysis, treatment with Gem/Doce was not associated with an increased risk of recurrence versus BCG (HR 0.78, 95%CI 0.33-1.85; p=0.57). In total, 19% of patients receiving BCG and 15% of patients receiving Gem/Doce experienced a grade 3+ adverse event. The development of any symptoms was not statistically different between treatment groups (p=0.28). There were two deaths recorded during the study period, one in each treatment group. Conclusions: Endoluminal Gem/Doce and BCG have similar oncological outcomes and major AE rates in the treatment of HG UTUC. Further prospective evaluation is warranted. [Table: see text]
Applying fragmentomics profiles of urinary cell-free DNA for bladder cancer detection.
Authors: Ruiyun Zhang, Hang Dong, Shuang Gan, Haoran Tang, Jingyu Zang, Pan Du, Shidong Jia, Guanglei Zhuang, Haige Chen
Journal: Journal of Clinical Oncology (2024)

671 Background: The liquid biopsy approach focusing on DNA molecules supports non-invasive diagnosis of bladder cancer. While utilizing cell-free DNA fragmentation characteristics for the cancer detection has shown potential in plasma, its applications in urine remained unexplored. Methods: We enrolled 70 patients with bladder cancer and 49 healthy individuals in this study. The urinary cell-free DNA (ucfDNA) was extracted and tested by PredicineSCORE, a low pass whole genome sequencing (LP-WGS) assay to identify tumor-specific features. The ucfDNA fragmentomics profiles including the coverage at specific region, length and end-motif of fragment was implemented. We also investigated the copy number variation and the inferred tumor fraction which was adjust by the Expectation-Maximum (EM) algorithm. Subsequently, an ensembled machine learning model were constructed for classification of bladder cancer and normal control. Results: We observed strong correlation between tumor fraction and specific features. The absolute correlation coefficient between tumor fraction with the LYL1 bonding sites relative depth, the insert size ratio of short reads, and the CCCA end motif were above 0.9, 0.75 and 0.7, respectively. To further assess the robustness of PredicineSCORE assay, we then diluted the tumor samples with tumor fraction ranging from 0.1% to 50% by manually mix reads from tumor samples into normal samples. By applied XGBoost algorithm, the performance (F1 score &gt; 0.95) showed promising ability to distinguish tumor from normal samples. The limit of detection (LOD) was less than 1%, indicating heightened sensitivity compared to previously proposed models. Conclusions: The study suggests that urinary cell-free DNA fragmentomic profiling may enhance the precision of non-invasive bladder cancer detection.
Excess intermediate risk nonseminoma and regional lymph node metastases at presentation in patients with Hispanic germ cell tumor.
Authors: Adam Kolawa, Siddharth Iyengar, Justin Wayne Wong Tiu-lim, Angel Arizpe, Elizabeth Pan, Irene Chen, Stefani Frost, Siamak Daneshmand, Anne K. Schuckman, Hooman Djaladat, David I. Quinn, Varsha Tulpule, James S. Hu, Victoria K. Cortessis, Anishka D'souza
Journal: Journal of Clinical Oncology (2024)

502 Background: Testicular germ cell tumors (TGCTs) is the leading solid-organ malignancy of adolescent/young adult males. Incidence is rising in all racial/ethnic groups, and most rapidly in Hispanics, who tend to be younger than non-Hispanic white (NHW) patients at diagnosis yet have poorer survival. Understanding these disparities is an urgent research priority, but granular prognostic information is inadequate in large population-based registries. We therefore initiated an investigation of a largely Hispanic clinical cohort. Methods: We identified consecutive patients with pathologically confirmed TGCT treated from 2015 to 2020 at two major referral centers in the US, with a large Hispanic population (the Los Angeles General Medical and USC/Norris Comprehensive Cancer Centers) and collected detailed features of demography, clinical presentation, treatment, and outcome into a structured RedCAP database. We used chi-square, Fisher exact, and Mann-Whitney U tests to compare established prognostic features between Hispanic and NHW patients. Results: Among 27 NHW and 75 Hispanic patients, Hispanics were younger at diagnosis (median 27 vs 30 years, p=0.5), diagnosed less frequently with pure seminoma (12% vs 23%, p=0.19), and experienced shorter time to first progression (median 8.5 vs 19 months, p=0.6). Among non-seminoma patients, Hispanics had higher probability of IGCCCG intermediate risk (26% vs 0%, p=0.03) but similar frequency of poor risk disease (Table). Accordingly, Hispanics had more regional lymph node involvement at presentation (48% vs 19%, p=0.03) but comparable frequency of visceral metastasis. Conclusions: Hispanic patients had adverse features already evident in population-based data, and novel findings of higher risk stratification and greater lymph node involvement than NHWs. Expansion of clinical series will be vital to identifying factors and processes that underlie adverse presentation and outcomes of Hispanics with TGCT, and to refining guidelines for care of the growing population of Hispanic patients with TGCT. [Table: see text]
Promises and Perils of Consumer Mobile Technologies in Cardiovascular Care
Authors: Niraj Varma, Janet K. Han, Rod Passman, Lindsey Anne Rosman, Hamid Ghanbari, Peter Noseworthy, Jennifer N. Avari Silva, Abhishek Deshmukh, Prashanthan Sanders, Gerhard Hindricks, Gregory Lip, Arun R. Sridhar
Journal: Journal of the American College of Cardiology (2024)
Safety and efficacy of enfortumab vedotin in patients with metastatic/locally advanced urothelial cancer: Real-world evidence from a European database.
Authors: Stefanie Zschaebitz, Niklas Klümper, Thomas Büttner, Nina Holzwarth, Nadine Biernath, Alexander Höllein, Guenter Niegisch, Daniel Seidl, Can Aydogdu, Analena Handke, Pia Paffenholz, Katrin Schlack, Richard Cathomas, Eva Erne, Severine Banek, Robert Tauber, Jozefina Casuscelli, Anna Katharina Seitz, Viktor Grünwald, Christopher Darr
Journal: Journal of Clinical Oncology (2024)

553 Background: Enfortumab vedotin (EV) is an antibody drug conjugate targeting Nectin-4. It was approved by EMA/FDA in patients (pts) with metastatic/ locally advanced urothelial cancer post platinum and immune check point inhibitors following the results of the EV-301 trial. We report updated efficacy and safety data of EV in a large European cohort of real-world pts (GUARDIANS consortium) treated in hospitals and private practices. Methods: Retrospective data were collected from 25 German and Swiss hospitals and private practices for pts who received EV. Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated by local investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Weidentified 188 pts (32.4% female) with a median age of 66 yrs (range 31-89; 22.3% &gt;/= 75 yrs). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2/3-4/unknown in 36/39/11/3/11%. EV was administered in the fourth or later line in 43% of pts. Overall response rate (ORR) was 46.3% (partial remission: 42.0%, complete response 4.3%), disease control rate was 58.0%. Median OS (mOS) was 12.0 months (mo) (95% confidence interval 9.65-14.35) and median PFS (mPFS) was 7.0 mo (95% confidence interval 5.43-8.57). Any-grade AEs were observed in 71% and CTCAE grade ≥3 AEs in 32% of pts. Most common AEs were peripheral sensory neuropathy (33.5% any grade), skin toxicity (24.5%) and fatigue (22.9%). In pts &gt;/= 75 yrs, females, and pts treated in &gt;/=4 th line mOS, mPFS, ORR, and toxicities were comparable to younger and male counterparts and pts treated in &lt;4th line, respectively. Limitations are retrospective design and short follow-up. Conclusions: Anti-tumor activity of EV in real-world pts including difficult-to-treat subgroups is comparable to the results of the pivotal EV-301 trial. No new safety signals were observed.