tbuckley/cabot-search huggingface dataset:
A phase II study of tislelizumab (T) monotherapy as neoadjuvant treatment for cisplatin-ineligible high risk upper tract urothelial carcinoma (UTUC).
Authors: Jiwei Huang, Xinyun Cai, Wen Kong, Jin Zhang, Yonghui Chen, Haige Chen, Wei Xue
Journal: Journal of Clinical Oncology (2024)

591 Background: Platinum-based chemotherapy is standard of care after radical nephroureterectomy for patients with high risk UTUC. However, more than half of UTUC patients may suffer from severe renal function loss which limits the use of cisplatin. Here we report the efficacy and safety results of T in the neoadjuvant treatment of patients with high risk UTUC who are ineligible for cisplatin-based chemotherapy. Methods: Eligible patients had high risk UTUC defined as pathological high-grade UTUC (either by endoscopic biopsy or urinary cytology) and/or invasive aspect on radiological examination(cT2-T4a N0/X M0) and/or hydronephrosis, ECOG PS 0-2, no prior systemic therapy and ineligible for cisplatin. Patients with variant histology on biopsy were included. Patients were given T 200mg IV every 3 weeks for at most 4 cycles followed by surgery (radical nephroureterectomy or ureteral resection or endoscopic ablation). CTU or contrast enhanced MRI examination was performed before the third dose and another before the surgery. The primary endpoint was pCR(pT0N0). The secondary endpoint included PaR(＜pT2N0) and safety. Results: 16 patients were recruited between Mar 2021 and Sep 2022: median age was 65 years(46-71), 13(81.3%) male, 14(87.5%) cT3-cT4, 4(25%) cN+. All patients received at least 2 doses of T but 7 patients didn't accept all 4 doses as planned. 9 patients received radical nephroureterectomy, 1 patient received endoscopic ablation, 3 patients received segmental ureteral resection. 3 patients declined surgery due to disease progression or adverse events. Best radiological tumor response before surgery were 6(37.5%) cPR, 7(43.8%) cSD and 3(18.7%) cPD. Overall, 4 patients achieved pCR(25%) after surgery, among which 3 patients received radical nephroureterectomy. 1 patient received endoscopic ablation with no residual disease observed in specimens and was assessed as pCR after surgery with no recurrence observed 1 year after surgery. 7 patients were evaluated as ＜pT2N0. Grade 3/4 TRAE was 18.8%. No new safety signals were observed. Conclusions: The trial demonstrated a promising pCR rate of neoadjuvant tislelizumab in patients with high risk UTUC who were ineligible for cisplatin-based chemotherapy. Further exploratory analysis is ongoing to investigate underlying correlation between tumor immune microenvironment and treatment response. Clinical trial information: NCT04672330 .
Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with penile squamous cell carcinoma.
Authors: Mukti Patel, Alan Tan
Journal: Journal of Clinical Oncology (2024)

11 Background: Penile squamous cell carcinoma (SCC) is an extremely rare, aggressive disease, representing 0.4-0.6% of all malignancies in males in the U.S. and Europe. Early diagnosis is imperative, as lymphatic spread is associated with a dismal prognosis. The estimated 5-year survival rate in patients with pelvic lymph node involvement is 0%. Moreover, there are limited treatment options that carry significant toxicity risks. Accurate biomarkers to evaluate treatment response and guide treatment to improve outcomes are needed. Molecular residual disease monitoring with circulating tumor DNA (ctDNA) may be helpful in these scenarios. Methods: This is a retrospective analysis of a cohort of 7 patients with advanced HPV-unassociated penile SCC treated at Rush University Medical Center who monitored closely for molecular residual disease (MRD). Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at regular intervals. Progression of disease was based on radiographic imaging. Results: In our cohort, personalized, tumor-informed ctDNA assays were designed for 100% (7/7) of the patients. ctDNA was detectable in at least one time point in all of the patients. One patient underwent partial penectomy and lymph node (LN) dissection with 1/11 LN involved. He is being monitored without adjuvant treatment and has sustained ctDNA clearance. Another patient underwent surgery, and had positive post-operative ctDNA. He was treated with adjuvant TIP (paclitaxel, ifosfamide, and cisplatin) with subsequent ctDNA clearance. In 3 of the patients, ctDNA was checked at regular intervals and rising ctDNA prompted imaging studies that showed progression. These patients proceeded to second line treatment options. The remaining 2 patients are non-surgical candidate with LN positivity, who will begin treatment with TIP and monitoring of ctDNA after each cycle of chemotherapy. Twenty-eight percent (2/7) of patients remain alive with sustained ctDNA clearance. Twenty-eight percent (2/7) of patients remain alive with ctDNA positivity, planned to initiate treatment and monitoring of ctDNA at regular intervals. Forty-three percent (3/7) of patients who had persistent ctDNA positivity are now deceased. Conclusions: Our data suggests that a personalized, tumor-informed ctDNA assay is not only useful for MRD monitoring, but also highly predictive of treatment response and imaging-based progression in patients with penile SCC. In our sample, MRD status correlated with both radiographic progression and clinical outcomes. Prospective studies are needed to better understand how ctDNA can be used to guide neoadjuvant and adjuvant approaches, including treatment intensification or de-escalation, in patients with penile SCC.
Comparative health-related quality of life (QoL) in metastatic castration-sensitive prostate cancer (mCSPC): A living systematic review.
Authors: Rodolfo Garza Morales, Syed Arsalan Ahmed Naqvi, Ahsan Ayaz, Kaneez Zahra Rubab Khakwani, Zaryab Bin Riaz, Ammad Raina, Praful Ravi, Daniel S Childs, Jack R. Andrews, Jacob Orme, Ewan Kemar Cobran, Parminder Singh, Irbaz Bin Riaz, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2024)

111 Background: Comparative evidence of quality of life (QoL) outcomes regarding life-prolonging treatments for the management of first-line treatment of metastatic castration sensitive prostate cancer (mCSPC) is not known. Methods: This systematic review uses the living interactive evidence synthesis framework (PMID: 36862387). Phase III randomized controlled trials assessing contemporary systemic treatments in mCSPC were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global QoL at 3, 6, 12, and 24 mo. Positive SMD indicated better health-related QoL, with zero indicating a null effect. Mixed treatment comparisons were made using a network meta-analysis. P-scores were computed; a higher score indicated better QoL. Results: Of 10 clinical trials initially included, eight trials (15 references) reported QoL. At 3mo global QoL was improved with abiraterone (AAP)+ADT compared to D+ADT (SMD: 0.26; 95% CI: 0.13-0.39), enzalutamide (E)+ADT (0.18; 0.03-0.33), and ADT (0.14; 0.02-0.27). At 6mo, AAP+ADT significantly improved global QoL compared to D+ADT (0.74; 0.62-0.87), E+ADT (1.74; 1.56-1.92), and ADT (1.79; 1.65-1.93). D+ADT also improved global QoL at 6mo compared to ADT (1.05; 0.93-1.16) but not when compared to E+ADT. At 12mo, AAP+ADT improved global QoL compared to E+ADT (0.20; 0.05-0.34) and ADT (0.19; 0.07-0.31) but not compared to D+ADT (0.05; -0.07-0.17). D+ADT also improved global QoL at 12mo compared to ADT (0.14; 0.03-0.24) (Table). Global QoL has not been reported for ARASENS trial at this time. These results are available on the Living interactive website. Conclusions: The totality of evidence suggests improved global QoL with androgen-pathway inhibitors (API) doublet therapy. D+ADT may offer better QoL at longer 6 and 12 months of follow-up. QoL data for triplet therapy is still emerging and will be incorporated in the living review as soon as it becomes available. [Table: see text]
Adverse outcomes (AOs) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with intensified androgen deprivation therapy (ADT+).
Authors: Nabiel Ali Mir, Waqaas Akmal, Maaz Imam, Mihai Giurcanu, Russell Zelig Szmulewitz, Walter Michael Stadler
Journal: Journal of Clinical Oncology (2024)

113 Background: mCSPC pts experience adverse outcomes (AOs) with intensified androgen deprivation, resulting in treatment discontinuation; however, there is limited data to identify those at risk. The IRONMAN registry is a global initiative to enroll advanced prostate cancer patients worldwide, and survey data on AOs, patient-reported outcomes (PROs), and clinico-epidemiologic (demographic, cancer, and treatment) details. We report the prevalence and predictors of AOs from baseline demographic, clinical, and PRO information with the onset of AOs and present a risk prediction model for clinical use. Methods: We analyzed data from 553 mCSPC patients in the IRONMAN registry from inception to March 2023 who received ADT+ alone (Abiraterone 47.6%, Enzalutamide 26.9%, Apalutamide 22.6%, Darolutamide 2.9%) and had completed baseline PROs. We defined AOs, reported by 60 global sites, as non-progression-related clinically significant serious adverse events (csSAE), treatment discontinuation, and dose reductions (DR/DC), delineated as a composite outcome based on first event. We processed baseline variable groups: Demographics (race, ethnicity, marital status, study site), Clinical Factors (age, ECOG score, metastatic sites, ADT+, concurrent medications, labs [ALP, Hb, LDH, and PSA]), Concurrent therapies (steroid use within 30 days [d] &amp; steroid dose, radiation/surgery prior or planned in 6months) and PROs (EORTC QLQ-C30 and EPIC-23). We developed a multifactorial logistic regression model to predict adverse outcomes (AOs) within two years of initiating ADT+ therapy. All variables with less than 25-30% missing data were included. Variable selection was conducted in two layers: intra-group stepwise selection followed by an inter-group selection of variables retained from the first layer. The model's discriminatory ability was evaluated using the area under curve (AUC). Results: 553 pts met inclusion (51.6% North America, 72% White, mean age: 71 years [range, 40 to 96 years], and 62.9% confirmed bone-metastatic mCSPC). 119 pts (21.5%) developed AOs (61 csSAEs [18 dead; Median: 140 d; IQR 81-360 d], 58 DR/DC [Median: 122 d; IQR 43-262 d]). &lt;5% went off study. The multifactorial model (n=314 pts) performed well at predicting AOs (AUC 0.77 [0.70-0.84]), with significant factors being more self-reported pain, greater urinary frequency, prednisone&gt;5mg within 30d, more self-reported weakness and poor sexual function within 3 months of ADT+ initiation. Conclusions: 1 in 5 mCSPC patients on ADT+ experienced non-progression-related AOs at 2 years. Significant, easily assessed predictive factors are identified and may be utilized in their clinical management. A novel multifactorial model is presented to predict AOs at 2 years. Further validation, assessment of missingness bias, and imputation are planned.
Analysis of a national database to evaluate place-of-death preferences among patients with bladder cancer in the United States of America from 2003 to 2020.
Authors: Karan Jatwani, Mahnoor Sukaina, Atulya Aman Khosla, Riya Jayesh Patel, Vasanthan Muthusamy Kumarasamy, Rohit Singh, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2024)

580 Background: Bladder Cancer (BC) is associated with significant treatment related morbidity and mortality risk. End of life care (EOL) and advance care planning are crucial in oncology care of BC patients. Place of Death (PoD) is an important determinant of patient and caregiver preference, access to home-based supportive care, and cost of caregiving at EOL. We evaluate trends in PoD for patients and hospice utilization with BC in the U.S. from 2003 to 2020 based on the CDC WONDER (Centers for Disease Control and Prevention for Wide-ranging Online Data for Epidemiologic Research) database. Methods: We analyzed data using the CDC WONDER database from January 01, 2003, to December 31, 2020. The data for deaths due to bladder cancer was pooled using the International Classification of Diseases-10th (ICD-10) Revision code as C67, C67.1, C67.2, C67.3, C67.4, C67.5, C67.8, C67.9. The inclusion criteria included patients aged &gt;18. The demographic data was obtained to calculate descriptive statistics using age, gender, PoD, census region, and utilization of hospice mortality accordingly over the past two decades. Results: The analysis demonstrated that overall mortality due to BC were 319,229 from 2003-2020. Of these deaths, 27,990 (8.8%) were recorded in hospice facilities. The hospice mortality has steadily increased from 0.3% in 2003 to the highest of 9.10% in 2019, with a sharp decline to 7.3% in 2020. We noticed the PoD differed based on racial subgroups. More than half of African American (AA) population mortality was observed in a medical facility (57.01%) compared to Whites (50.27%). Hospice or death at home in AA were (42.99%) compared to whites (49.73%). Age stratified mortality analysis showed decreased hospice utilization in 25-44 yrs (9.61%) vs 65+ yrs (10.15%). Stratifying the results by the state census showed highest hospice utilization in Florida (25.23%) vs the lowest in Virginia (2.51%). Conclusions: To our knowledge this is the first study utilizing CDC WONDER database to demonstrate PoD preferences in BC related deaths. We observed a steady increase in hospice utilization from 2003-2020 throughout the US with a decline in 2020 possibly related to COVID pandemic. AA had higher mortality in medical facilities compared to whites, whereas the white population has utilized more hospice services or died at home. This study highlights the need for further efforts and policy changes needed to improve hospice utilization across the US with a focus on improved access to EOL care in BC patients.
Blue light cystoscopy versus white light cystoscopy for the detection of bladder cancer in China: An analysis of unpublished clinical trial and real-world data.
Authors: Hanzhong Li, Hailong Hu, Lulin Ma, Jianming Guo, Xiuheng Liu, Jian Huang, Yonglian Guo, Jin Wen, Shudong Zhang, Hongxian Zhang, Shuai Jiang, Cheng Liu, Wang He, Xinli Kang, Fei Wang
Journal: Journal of Clinical Oncology (2024)

593 Background: Blue light cystoscopy (BLC) is superior to white light cystoscopy (WLC) in detection of bladder cancer, but no multi-center studies have been conducted in China with modern 4K LED equipment. The objective of this post hoc analysis of a randomized controlled trial (RCT) and a real-world study (RWS) was to compare BLC with WLC in the detection of bladder cancer and to determine the similarity between the RCT and RWS. Methods: In RCT (NCT05600322), patients with known or suspected bladder cancer were enrolled at seven hospitals in China from November 2022 to June 2023. In the prospective RWS, patients with known or suspected bladder cancer were enrolled at Hainan General Hospital from December 2022 to July 2023. Patients received intravesical HAL (Hexvix, Photocure ASA) and underwent WLC before BLC (System blue, Richard Wolf GmbH). Some patients were randomized to WLC to avoid observational bias. The primary endpoint was the proportion of patients with histologically confirmed tumors (Ta, T1, or CIS) who have at least one such lesion found by BLC but not by WLC. Secondary endpoints included, detection of CIS, lesion specific detection rate, false positive rates, and adverse events (AE). Results: 158 patients were enrolled in RCT, in which 37 patients were training patients, six patients were randomized to not undergo BLC, one patient withdrew. 114 patients remained in the full analysis set. 19 patients were enrolled in RWS. In patients confirmed with Ta, T1, or CIS, 42/97 patients (43.3%) in RCT and 4/12 patients (33.3%) in RWS had at least one confirmed lesion found by BLC but not by WLC (all p&lt;0.0001). 11/114 patients (9.6%) with CIS in RCT and 1/14 patients (7.1%) with CIS in RWS showed at least 1 additional confirmed CIS lesion found by BLC but not by WLC. In RCT, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 94.7%, 100%, 98.2% and 100% for BLC and NA, 42.1%, 76.1%, 91.2% and 100% for WLC, respectively. In RWS, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 100%, 100%, 100% and 100% for BLC and NA, 50%, 81%, 100% and 100% for WLC, respectively. The false-positive rate was 23.2% and 16.0% for BLC and WLC in RCT and was 25.0% and 15.4% in RWS, respectively. In RCT, 200 AEs were observed in 95 patients, all mild to moderate, of which 191 were classified as unrelated to HAL. In RWS, 16 AEs were observed in 15 patients, all mild and were all unrelated to HAL. Conclusions: Both RCT and RWS confirm the superiority of BLC based on innovative LED technology with HAL over WLC in detection of bladder cancer in Chinese populations, especially CIS, and HAL is well tolerated. Clinical trial information: NCT05600322 .
Avelumab first-line maintenance (1LM) for advanced urothelial carcinoma (aUC): Long-term patient-reported outcomes (PROs) in the phase 3 JAVELIN Bladder 100 trial.
Authors: Petros Grivas, Jeanny B. Aragon-Ching, Joaquim Bellmunt, Yohann Loriot, Srikala S. Sridhar, Po-Jung SU, Se Hoon Park, Yoshiaki Yamamoto, Natalia Jacob, Jason Hoffman, Mairead Kearney, Michael Schlichting, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

581 Background: In the JAVELIN Bladder 100 trial, avelumab 1LM + best supportive care (BSC) significantly prolonged overall survival vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based induction chemotherapy, and health-related quality of life was maintained. We report long-term and exploratory PRO analyses in the overall avelumab + BSC arm (any treatment duration) and in the subgroup with ≥12 months of avelumab treatment. Methods: In JAVELIN Bladder 100 (NCT02603432), PROs were a secondary endpoint assessed at baseline, on day 1 of each 4-week cycle, at end of treatment/withdrawal, and up to 90 days post treatment. PRO instruments used were National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol 5 Dimensions 5 Levels (EQ-5D-5L). Descriptive and mixed-effect model analyses were conducted. Data were not evaluated in the BSC alone arm because few pts remained on study treatment at later time points. Results: At data cutoff (Jun 4, 2021), median follow-up in the avelumab arm (n=350) was 38.0 months (≥2 years in all pts), and median duration of treatment was 5.8 months. In pts treated for ≥12 months (n=118 [33.7%]), baseline characteristics were similar to those in the overall avelumab + BSC arm, except for a higher proportion with ECOG performance status of 0 (70.3% vs 60.9%) and lower proportion with visceral metastases (47.5% vs 54.6%). In both populations, completion rates for both PRO instruments among evaluable pts were &gt;80% at all time points during treatment. On average, PRO scores remained stable throughout treatment, and no clinically relevant changes from baseline were reported (Table). Among pts treated for ≥12 months, ≈75% of evaluable pts reported no change or a decrease in being bothered by treatment side effects throughout 24 months of treatment. Conclusions: Prolonged avelumab 1LM treatment (≥12 months) was associated with stable PROs, indicating preservation in quality of life. The results further support the use of avelumab 1LM until progression or unacceptable toxicity as standard of care with level 1 evidence in pts with aUC who are progression-free after platinum-based chemotherapy. Clinical trial information: NCT02603432 . [Table: see text]
Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Authors: Eddy Saad, Chris Labaki, Benjamin Miron, Jihye Park, Ziad Bakouny, Amin Nassar, Renee Maria Saliby, Karl Semaan, Marc Eid, Kevin Meli, Yasmin Nabil Laimon, Daniel M. Geynisman, Rutika Kokate, David A. Braun, Sabina Signoretti, Bradley Alexander McGregor, Elizabeth R. Plimack, Toni K. Choueiri, Eliezer Mendel Van Allen, Matthew R. Zibelman
Journal: Journal of Clinical Oncology (2024)

459 Background: While immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC), acquired resistance (ARX) is commonly encountered. We aimed to characterize the genomic and transcriptomic correlates underlying ARX in ICI-treated mRCC patients. Methods: We identified pts with mRCC at Dana-Farber Cancer Institute and Fox Chase Cancer Center, treated with ICI-based regimens who had an initial response to therapy followed by disease progression. Tissue samples from the primary tumors or metastases were collected before ICI treatment and after ARX from a treatment-emergent escape lesion. Whole exome sequencing (WES) and bulk RNA-sequencing (RNA-seq) were performed. Somatic mutations were called using the Cancer Genome Analysis pipeline. Differential gene expression analysis (DGE) was run using DESeq2, followed by gene set enrichment analysis (GSEA). Immune cell fractions were estimated using CIBERSORTx. Cell fraction and tertiary lymphoid structures (TLS) scores were compared between post and pre-ARX samples using the Wilcoxon test. Results: A total of 41 samples (n=23 pre-ARX and n=18 post-ARX) were collected from 14 unique patients. After quality control, WES and RNA-seq data were available for 27 samples (14 pre-ARX and 13 post-ARX) and 9 samples (3 pre-ARX and 6 post-ARX), respectively. No discernable enrichment of gene mutations was detected in the post-ARX setting compared to the pre-ARX. DGE identified 61 downregulated immunoglobulin genes in the post-ARX setting. GSEA revealed significant depletion of pathways associated with B-cell and T-cell function in post-ARX samples (all adjusted p&lt;0.05). Similarly, a trend towards decreased naïve B cell and CD8+ T cell fractions was observed in the post-ARX setting (p=0.17 for both). Three previously reported TLS-associated expression signatures were depleted in the post-ARX samples compared to pre-ARX (p=0.015, p=0.065 and p=0.065, respectively). Immunohistochemistry assessment of 3 samples from one pt using ant-CD3 and CD20 antibodies confirmed the presence of TLS in the pre-ARX sample and their absence in two different post-ARX samples. Conclusions: In our cohort of pts with mRCC, no gene mutations were implicated as drivers of ARX. However, ARX was associated with downregulation of B-cell signaling and humoral mediated immunity, as well as absence of TLS. Ongoing efforts are in progress to include more samples.