bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of cytoreductive nephrectomy (CN) and treatment (trt) sequence on overall survival (OS) in metastatic non-clear cell renal cell cancer (nccRCC).
Authors: Nelson Ariel Ann , Szabo Aniko , Kilari Deepak
Published: June 2024

e16543

Background: nccRCC accounts for 25% of kidney cancer diagnoses and encompasses a diverse group of kidney tumors with distinct biology for which trt in the metastatic setting is evolving. The role of CN for nccRCC population in the current trt landscape remains unclear. Methods: We retrospectively identified patients (pts) with nccRCC from The National Cancer Database (NCDB) participant user file (PUF) for Kidney and Renal Pelvis Tumors. Pts with de novo metastatic disease diagnosed between 2015 and 2020, received systemic trt with immunotherapy (IO) or non-immunotherapy (NIO) and underwent or could have undergone a CN were selected. Pts classified as having sarcomatoid histology were excluded. Demographic and disease characteristics were summarized using descriptive statistics. The cumulative incidence of CN was estimated using the Nelson-Aalen estimator. The association of demographic and disease characteristics on the cumulative incidence of CN was evaluated using univariate Fine-Gray regression. The effect of CN on survival was visualized via Simon-Makuch plot. P values were based on Mantel-Byar test. Cox regression with a time-dependent predictor was used to estimate the change in the hazard of death after CN. Results: We identified 982 pts, median age 60 (18 – 90) years, 61% male, 69% Caucasian and 28% African American. nccRCC histology included 66.5% papillary (n=653), 10.4% chromophobe (n=102), 9.9% medullary (n=97), 8.8% collecting duct (n=86), 4.4% unclassified (n= 43). 69% of pts received NIO (n= 676), 14% received IO + NIO (n= 134), 18% received IO only (n= 172). 40% had CN (n=390), the majority of CN (86%) occurred within 3 months of diagnosis. 89% had CN followed by systemic trt (n=348), 4.3% underwent initial systemic trt followed by CN (n=42). Median OS was 11 months for the entire group. For those who had CN, mOS was 13.9 vs 10 months for no CN (p=0.002). CN was associated with improved survival; HR 0.79 (95% CI 0.68,0.92; p=0.002). Median OS for pts who received systemic trt followed by CN was 32.6 vs 12.8 months for those who had CN followed by systemic trt vs 10 months for those who had no CN, (p=0.001). Upfront systemic trt followed by CN and CN followed by systemic trt were both associated with improved survival, HR 0.56 (95% CI 0.36, 0.87; p=0.009) and HR 0.83 (95% CI 0.69,0.99; p= 0.034) respectively. Choice of systemic trt was not associated with improved OS (p = 0.139). Unclassified and medullary histology were associated with worse OS, HR 1.60 (95% CI 1.09, 2.34; p=0.015) and HR 2.04 (95% CI 1.46,2.84; p=0.002) respectively. Conclusions: CN is associated with improved outcomes for pts with de novo metastatic nccRCC. Sequencing upfront systemic trt followed by CN may improve survival. Prospective randomized trials in the modern trt era are needed and ongoing (Ie. PROBE trial NCT04510597) to further assess the timing and sequencing of CN in pts with nccRCC.
Baseline geriatric 8 (G8) screening tool to predict overall survival in metastatic urothelial carcinoma treated with immune checkpoint inhibitors.
Authors: Rhee Christopher H , Goyal Subir , Liu Yuan , Martini Dylan J. , Nazha Bassel , Kucuk Omer , Carthon Bradley Curtis , Bilen Mehmet Asim , Brown Jacqueline T
Published: June 2024

e16575

Background: Checkpoint inhibitors (CPI) blocking PD-1 or PD-L1 are a mainstay in the treatment of metastatic urothelial cell carcinoma (mUC). Due to the high bar for clinical trial participation, older patients are underrepresented in trials resulting in FDA-approved therapies that are not always representative of real-world patients. The G8 questionnaire is an 8-question screening tool designed to assess frailty in older adults and alert to the need for geriatric assessment. We investigated the ability of the G8 score to predict clinical outcomes in patients with mUC treated with CPIs. Methods: We performed a retrospective analysis of patients with mUC treated with CPIs in any line of treatment at Winship Cancer Institute between 2016-2019. We collected demographic data, patient and disease characteristics, and immune-related adverse events (irAE). A baseline G8 score was evaluated using past clinic notes from providers, social workers, and dietitians. The G8 incorporates measures assessing food intake, weight loss, mobility, neuropsychological conditions, BMI, polypharmacy, self-assessed health, and age. A score of ≤ 14 suggests potential geriatric vulnerability. Progression-free survival (PFS) and overall survival (OS) were measured from the start of CPI until death or clinical or radiographic progression, respectively. The survival association with the G8 score was analyzed using univariate (UVA) and multivariable (MVA) analyses by the Cox proportional hazard model and Kaplan-Meier method. irAEs association was handled by logistic regression. Results: A total of 48 patients with a median age of 73.5 years were analyzed with 66.7% male 75% white. 70.8% of patients had a baseline G8 suggesting geriatric vulnerability despite 74.4% of patients being scored as having an ECOG score of 0-1. An impaired G8 score at CPI initiation was associated with an increased risk of death but not progression on both UVA and MVA. The association between lower rates of irAEs in patients with impaired G8 scores approached statistical significance (Table). The median OS in Kaplan-Meier analysis for patients with an impaired G8 score was significantly lower (6.8 vs 14 months, p=0.0110) but median PFS was comparable (2.5 vs 3.4 months, p=0.4237) to those with a normal G8. Conclusions: These results indicate that the G8 screening tool may be a useful prognostic tool in mUC patients when planning treatment with a CPI, however should be validated with larger cohort studies. [Table: see text]
Effect of body mass index (BMI) on efficacy of immune checkpoint inhibitors (ICIs) in patients with metastatic urothelial carcinoma (mUC) in real-world setting.
Authors: Lynn David , Dawsey Scott , Hobeika Charbel , Patgunarajah Ubenthira , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa
Published: June 2024

e16577

Background: There is emerging data on the role of BMI and outcomes of ICIs in various solid tumors, with underweight pts having worse outcomes to ICIs. The effect of BMI on efficacy of ICIs in pts with mUC is not clear. Methods: We identified 455 adult pts with mUC at the Cleveland Clinic treated who received >/= 2 cycles of ICI with pembrolizumab (P), atezolizumab (A), or avelumab (Av) between 2015 and 2023. Patient characteristics including age, sex, race, primary site (bladder vs upper tract UC (UTUC)), tumor histology and pre ICI treatment NLR values were collected. BMI was calculated and values were collected and compared to assess impact on overall (OS) and progression free survival (PFS) after ICI start date. BMI was broken down into four categories: underweight (BMI less than 18.5 kg/m2), normal weight (BMI between 18.5 and 24.9 kg/m2), overweight (BMI between 25 and 29.9 kg/m2) and obese (BMI 30 kg/m2 or greater). OS and PFS were estimated by Kaplan Meier method and compared using log rank test. Results: Median age of pts was 73 yrs (35-95) and 341 (75%) pts were males. 269 (59%) received P, 90 (20%) received A, and 96 (21%) received Av. We found that underweight pts had significantly worse OS compared to normal or higher BMI (p=0.001). BMI did not impact PFS (p=0.1) (Table). Conclusions: In our large real-world cohort of mUC pts receiving ICI, we report for the first time the effect of BMI on outcomes with ICI with underweight pts having better outcomes. Further prospective studies are warranted. [Table: see text]
Treatment patterns with intravesical bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder cancer (NMIBC): A real-world data analysis.
Authors: Sun Ran , Linghu Bolan , Somer Robert A. , Hampras Shalaka , Bhanvadia Sumeet Kaur , Scherer Emily , Greshock Joel , Sweiti Hussein
Published: June 2024

e16584

Background: Intravesical BCG is the recommended first-line treatment for high-risk NMIBC patients, with a recommended minimum 1-year duration consisting of 6 doses of induction followed by multiple doses of maintenance. However, up to approximately 50% of patients experience BCG failure, often within the first 6 months. Real world treatment patterns with BCG are not well understood. This study aims to characterize real-world BCG treatment patterns and treatment failure in NMIBC patients. Methods: This retrospective cohort study utilized comprehensive claims and electronic health record (EHR) from the US HealthVerity data between Oct 2015 and Dec 2022. This analysis included patients with NMIBC who received first BCG treatment within 90 days of their bladder cancer diagnosis, with a follow-up period of ≥ 3 years post BCG treatment. A descriptive analysis of the number of doses, treatment duration, and treatment discontinuation following the BCG initiation was conducted. Treatment discontinuation was defined as a gap of more than 1 year from the last BCG dose. Initiation of subsequent therapy post BCG was reported and used as a proxy for BCG failure. Results: A total of 13,525 patients met the study criteria and initiated BCG treatment between 2015 and 2022. Of all patients, 3193 (23.6%) received < 5 BCG doses, 3854 (28.5%) received 5-7 doses, and 6478 (47.9%) received > 7 BCG doses. The overall median was 7 doses (interquartile range [IQR]: 5,14). The median duration of BCG treatment was 156 days (IQR: 36, 489). BCG was discontinued in 66.9% patients within 1 year of initiation. A total of 6182 patients (45.7%) experienced treatment failure and received subsequent treatment, with 3550 patients (57.4%) initiating next treatment within 1 year of last BCG dose. Conclusions: In a large US real-world dataset, a majority of NMIBC patients treated with BCG received ≤7 doses and discontinued treatment within < 1 year of treatment initiation. Furthermore, nearly half of patients experienced BCG failure, thereby requiring subsequent therapies. This highlights a significant unmet need for treatments with improved tolerability and efficacy profile for patients with NMIBC.
Retrospective analysis of outcomes of patients with bladder cancer when neoadjuvant chemotherapy is delayed.
Authors: Kanyuka Zakhar , Kassir Sandy , Leong Nelson , Souied Osama
Published: June 2024

e16588

Background: Bladder (urothelial) cancer is the sixth most common form of cancer in the United States of America and results in significant morbidity and mortality. American Urological Association (AUA) guidelines recommend that muscle-invasive bladder cancer (MIBC) is treated with a course of cisplatin-based multi-agent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). The optimal timing of NAC is not well studied. Therefore, we aimed to evaluate the impact of timing NAC treatment to compare clinical outcomes among patients at the Saskatchewan Cancer Agency (SCA). Methods: We conducted a retrospective cohort study of the SCA electronic registry, reviewing the clinical and pathological data of 42 patients diagnosed with MIBC and treated with platinum-based NAC from January 2000 to December 2018. Patients with non-MIBC, metastatic bladder cancer, non-urothelial carcinoma histology, and charts with insufficient data were excluded. Survival analysis using Kaplan-Meier methods and log rank tests were utilized to compare overall survival (OS), disease recurrence, and post-RC surgical pathological staging of patients with respect to pre-specified time intervals between diagnosis, NAC and RC. Results: Patients who received NAC later than 8 weeks after diagnosis were more likely to have reduced OS (HR 1.25, 95% Confidence Interval (CI): 1.09-1.35, p=0.02). They also were more likely to have lymph node involvement (HR 1.63, 95% CI: 1.03-1.77, p=0.006). Patients who received RC more than 6 weeks after NAC completion were more likely to have more advanced primary tumour staging on pathology (HR 1.95, 95% CI: 1.3-2.09, p=0.01), but did not have significantly decreased OS (HR 1.88, 95% CI: 0.48-1.95, p=0.08). Delayed NAC (HR 2.77, 95% CI: 1.44-4.57, p<0.001) and RC (HR 1.50, 95% CI: 1.08-3.10, p<0.001) were associated with increased recurrence. Age, sex, body mass index, NAC regimen, and prior intravesical treatment were not statistically associated with OS upon analysis with univariate cox proportional hazard regression analysis. Conclusions: This review suggests an OS benefit by reducing the time from diagnosis to NAC in MIBC patients. This finding contrasts other studies that do not demonstrate any impact of delayed NAC on OS. These findings align with other works that do not show a survival detriment of delaying RC beyond 6 weeks after NAC completion. However, delaying surgery is associated with more advanced pathologic tumour staging. This study identifies the possibility of an association between delays in treatment delivery and worse clinical outcomes in some cohorts. Accordingly, further investigation of interval timing can better inform treatment planning and resource allocation in the management of patients with MIBC.
The prognosis for patients with bladder cancer with recurrence after pathologic complete response or pathologic downstaging after radical cystectomy: EUMC RC cohort study.
Authors: Jo Jungmin , Lee Dong-Hyeon
Published: June 2024

e16613

Background: Pathologic complete response (pCR, pT0N0M0) or pathologic downstaging (pDS, <pT2N0M0) for bladder cancer is associated with increased overall survival (OS). However, some patients who achieved pCR or pDS experience recurrence, but these patients have not been targeted for adjuvant immunotherapy in studies to date, and the prognosis has not been well studied. We aim to examine the prognosis for bladder cancer patients with recurrence after pCR or pDS after radical cystectomy (RC). Methods: Of the 1562 patients who underwent a RC for bladder cancer between June 1996 and November 2023, 712 (45.6%), including 29 patients who did not undergo lymph node dissection, were identified as having pCR or pDS on final pathology. Of the 712 patients, 108 (15.2%) experienced recurrence. Results: Among 712 patients, 170 (23.9%) achieved pCR, 305 (42.8%) in pT1, 140 (19.7%) in Tis, and 97 (13.6%) in Ta. Out of the 170 patients with pCR, 12 (7.1%) experienced recurrence. Among the 305 patients with pT1, recurrence occurred in 63 (20.7%), and out of the 140 patients with Tis and 97 with Ta, 24 (17.1%) and 9 (9.3%) had recurrence, respectively. Only 150 (21.1%) patients received neoadjuvant chemotherapy (NAC), and 30 (27.8%) of the 108 patients who relapsed had received NAC. The median age of 108 patients with recurrence was 66.8 years old (range 31.3–86.2), and variant histology was observed in 10 (9.3%) surgical specimens. At a median follow-up of 36.7 months, the median time to recurrence was 15.5 months (10.4–20.6). Sixty-seven patients (62%) had local recurrence or lymph node-only metastasis. The distant metastasis was most common in the lung, liver, and bone (42, 38%). Conclusions: Patients with pCR or pDS at the time of radical cystectomy should prudently undergo surveillance, as recurrence and metastasis can still develop. Future studies are needed to reinforce these findings and decide whether to receive adjuvant treatment in the post-NAC setting.
Clinical and pathological characteristics of cancer of unknown primary with renal profile using gene expression profiling (GEP)–based cancer classification.
Authors: Allam Joelle , Ma Li , Zhao Jianping , Estrella Jeannelyn , Higbie Victoria , Willett Anneleis , Matamoros Aurelio , Lano Elizabeth A , Treuner Kai , Raghav Kanwal Pratap Singh , Huey Ryan W
Published: June 2024

e16627

Background: Cancers of unknown primary (CUP) are rare and heterogeneous tumors with clinically unidentifiable origin at time of diagnosis, accounting for approximately 1-3% of all malignant neoplasms. CUP with Renal Profile (CUP-RP) appears to be a clinically distinct subset, based on immunophenotyping, specifically PAX8 staining. Precision in diagnosis is critical, as cytotoxic chemotherapy options for CUP do not overlap with tyrosine kinase inhibitors or checkpoint inhibitors used for renal cell carcinoma. Gene expression-based cancer classification in patients with CUP offers an objective molecular assessment in the search for CUP origin and further categorization. Methods: We retrospectively evaluated 300 patients with CUP composed of cases classified as renal profile (N=100, clear cell or papillary) or controls (N=200, non-renal cases) using the 92-gene assay (CancerTYPE ID), a validated classifier for predicting tissue of origin, between January 2018 and December 2022. Clinicopathologic data including immunohistochemistry (IHC) and molecular profiling (NeoTYPE) results were collected using pathology specimens and reports. Results: At baseline, median age at diagnosis was 69 years (range 31-89). Most patients were male (63%). For CUP-RP patients, pathology was reported as poorly differentiated in 47% of tumors. Tumors were described as adenocarcinoma in 27%, carcinoma in 63%, and malignant neoplasm in 10%. Median number of IHC stains performed was 11 (range 0-33). PAX8 staining was found to be strongly or focally positive in 88%. PAX8 was not tested in 36% of cases. Compared to non-renal profile CUP, CUP-RP patients were more likely to have bone biopsies (28% vs 16.5%, OR 1.97, p=0.02). CUP-RP were much less likely to have high-TMB (2% vs 28.2%, OR 0.07, p=.001). CUP-RP had a lower proportion of TP53 mutations (18.8% vs 81.2%, OR 0.028, p<0.0001) and KRAS mutations (13.3% vs 86.7%, OR 0.045, p<0.0001). Detailed IHC from 30 CUP-RP cases is shown in the table. CA IX was tested in 2/30 (6.7%) of cases. Conclusions: In this cohort of CUP with a molecular classification of renal cell carcinoma, we found a wide range in diagnostic work-up. The 92-gene assay can serve as an adjunct to IHC, to improve diagnostic accuracy for CUP. Critical immune stains necessary in diagnosis are performed infrequently. While PAX8 was often positive in CUP-RP, it was omitted in over 1/3 of cases. CUP-RP cases had lower TMB and less often mutations in TP53 and KRAS. Gene expression profiling presents an opportunity to complement standard pathology in the workup of this subset of CUP to guide treatment selection and improve clinical outcomes. [Table: see text]
Feasability of single-port gasless retroperitoneal laparoscopic adrenalectomy for patients with adrenal tumor: A prospective control study.
Authors: Liu Zhenhua , He Xiaobo , Long Yuhui , Ma Nan , Lai Renchun , Guo Shengjie
Published: June 2024

e16628

Background: The safety and efficacy of single-port-gasless retroperitoneal laparoscopic adrenalectomy (SPG-RLA) in the treatment of adrenal tumors have not been fully explored. We aimed to explore the safety and efficacy of SPG-RLA for adrenal tumors. Methods: Thirty patients with adrenal tumors <4 cm undergoing SPG-RLA were prospectively enrolled from July 2022 to February 2023. Operative time, blood loss, conversion and complication rates, and postoperative data were compared to another 30 patients with the same characteristics treated with traditional single-port retroperitoneal laparoscopic adrenalectomy (RP-LESS-A). Results: Both 30 SPG-RLA operations and 30 RP-LESS-A operations were completed without any mortality, reoperation, blood transfusion, or conversion. The mean operative time and blood loss were 62.3 min and 94.1 ml, respectively. Compared with the traditional surgery group, SPG-RLA patients had 15% lower hospitalization costs ( p < 0.001), lowerΔpCO2 (2.52 mmHg vs 6.86 mmHg, p = 0.001) and ΔpH (−0.05 vs −0.08, p = 0.004) values, and similar operative and postoperative complications, the average time to first oral intake (21.2 h vs 19.7 h, p = 0.106), ventilation time ( p = 0.058), duration of drainage ( p = 0.568), postoperative narcotic use ( p = 0.958), and postoperative hospitalization ( p = 0.116). However, the SPG-RLA group had longer operative time (62.3 min vs 45.7 min, p < 0.001), more blood loss ( p = 0.032), and longer incisional length ( p < 0.001). No local tumor recurrence or hormonal relapse was observed in the 6-month follow-up. Conclusions: SPG-RLA is a safe, minimally invasive, and economically viable surgery, which may especially be suitable for low-resource regions and in patients with cardiopulmonary insufficiency due to adrenal tumors. Clinical trial information: ChiCTR220005735 . [Table: see text]
Efficacy and toxicity of [177Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer in a real-world setting: Results from the U.S. Expanded Access Program and comparisons with phase 3 VISION data.
Authors: Calais Jeremie , Murthy Vishnu , Voter Andrew , Nguyen Kathleen , Allen-Auerbach Martin S. , Caputo Sydney , Ledet Elisa M. , Akerele Opeoluwa , Moradi Tuchayi Abuzar , Lawhn Heath Courtney , Carducci Michael Anthony , Pomper Martin , Paller Channing Judith , Czernin Johannes , Solnes Lilja , Hope Thomas A. , Sartor Oliver , Gafita Andrei
Published: June 2024

e17061

Background: ThePhase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged overall survival (OS) in metastatic-castration resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSi). The expanded access program (EAP) (NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. The VISION trial required strict inclusion and exclusion criteria, which may not represent the patient population encountered in clinical practice. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 in a real-world setting within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP between May 2021 and March 2022 at four institutions in the United States with available toxicity and outcome data were included. Outcome measures included overall survival (OS), ≥50% PSA decline rates (PSA-RR), and incidences of toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Differences in baseline characteristics, toxicity, and PSA-RR between the EAP and VISION were evaluated using a t-test of proportions. Results: 117 patients with mCRPC were eligible and included. Patients enrolled in the EAP were similarly pretreated with taxane-based chemotherapy regimens (>1 taxane: 47% vs 40%; p=0.16) and more heavily pretreated with ARSi (>1 ARSi: 70% vs 46%; p<0.001). EAP patients had similar levels of ≥3 grade anemia (18% vs 13%; p=0.15), thrombocytopenia (13% vs 8%; p=0.13), and neutropenia (3% vs 3%; p=0.85) and higher levels of ≥3 grade lymphopenia (34% vs 8%; p<0.001). Patients treated within the EAP experienced numerically shorter OS (median OS: 13.7 vs 15.3 months) and similar PSA-RR (40% vs 46%; p=0.29). Median follow-up was numerically shorter in the EAP compared with VISION (14.7 mo vs 20.3 mo). Conclusions: mCRPC patients treated with [177Lu]Lu-PSMA-617 in a real-world setting were more heavily pretreated with ARSi, had a similar safety profile, and experienced numerically shorter OS and similar PSA-RR compared with VISION trial patients. A major limitation of this study is that we did not have access to individual patient data from the VISION trial, so we were not able to assess whether differences in OS between VISION and the EAP were statistically significant.
Examining laboratory-based VISION eligibility and 177Lu-PSMA-617 outcomes in patients with metastatic castration-resistant prostate cancer.
Authors: Ghodsi Alireza , Demirci Ridvan Arda , Gulati Roman , Raychaudhuri Ruben , Cheng Heather H. , Hawley Jessica E. , Yezefski Todd , Haffner Michael C. , Montgomery Robert Bruce , Nelson Peter , Schweizer Michael Thomas , Yu Evan Y. , Chen Delphine L. , Iravani Amir
Published: June 2024

e17062

Background: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) is an FDA-approved therapy for metastatic castration-resistant prostate cancer (mCRPC) and commonly used in late-line treatment for patients with extensive disease and diminished organ function. It is unclear whether patients with low bone marrow reserve derive benefit from the treatment. The study aimed to evaluate outcomes of treating mCRPC patients with 177Lu-PSMA-617, classifying them as either VISION-Eligible (VISION-E) or VISION-Ineligible (VISION-I) based on baseline laboratory test results. Methods: This retrospective cohort study evaluated patients who had received at least one cycle of 177Lu-PSMA-617 between June 2022 and July 2023. Eligible patients were then classified as VISION-E or VISION-I using VISION trial eligibility criteria: white blood cell (WBC) count ≥2.5 × 109/L or absolute neutrophil count ≥1.5 × 109/L, platelets (PLT) ≥100 × 109/L, hemoglobin (Hb) ≥9 g/dL, total bilirubin ≤1.5 × upper limit of normal (ULN), ALT or AST ≤3.0 × ULN, serum creatinine ≤1.5 × ULN, and albumin >3.0 g/dL. PSA decline of at least 50% relative to baseline (PSA50), PSA-progression-free survival (PSA-PFS), and overall survival (OS), were evaluated using tests of proportions or Cox regressions. Results: In our study of 123 patients (median age: 73 years, median cycles: 4), 85.4% had ECOG 0 or 1. 75.6% of the cohort were VISION-E, while 24.4% were VISION-I. No substantial differences were observed in baseline characteristics between the two groups, including age (p-value: 0.7) and ECOG (p-value: 0.5). Among VISION-I patients, 73.3% did not meet the threshold for hematologic lab results (16 patients with low Hb, 5 with low PLT, and 4 with low WBC), while 13.3% did not meet criteria for renal lab tests and an additional 13.3% did not meet criteria for liver lab tests. Overall, 52% of patients showed a PSA50, and the median PSA-PFS and OS of the total patient cohort were 9 (95% CI: 7.8-10.2) months and 11 (95% CI: 9.9-12.1) months, respectively. No statistically significant differences in PSA50 were observed between VISION-E (55.9%, 95% CI: 45%-66%) and VISION-I patients (40%, 95% CI: 23%-59%) (p: 0.13). The PSA-PFS and OS were not statistically significant different between VISION-E and VISION-I groups (median OS not reached vs. 13 months, p: 0.4, and median PSA-PFS of 4 months vs. 5 months, p: 0.5) (Table). Conclusions: In this study, the patients who did not meet VISION laboratory thresholds did not have statistically significant different PSA50, PSA-PFS and OS compared to those who met the criteria. A more lenient laboratory threshold appears to be acceptable for treatment with 177Lu-PSMA-617. [Table: see text]
Evaluation of tumor gene expression profile and Gleason score in patients with metastatic prostate cancer.
Authors: Freitas Carla Simone Moreira , Silva Thais Almeida Marques da , Silva Fabiana Rocha , Soares Aleida Nazareth
Published: June 2024

e17065

Background: The Gleason Score (GS) is a fundamental prognostic indicator in prostate adenocarcinoma. Despite this significant clinical relevance, the determinants underlying disease aggressiveness in relation to GS remain largely unknown. To explore gene expression profiles among patients diagnosed with metastatic prostate adenocarcinoma, considering GS variation. Methods: This study is prospective in nature and was approved by CONEP-SCBH-CAAE 42638620.3.0000.5138. The study included 30 patients with histologically confirmed metastatic prostate adenocarcinoma who had not undergone any treatment. Patients were stratified into two distinct cohorts based on GS: low GS (GS <8) and high GS (GS ≥ 8). This design allowed for a more in-depth analysis of the associations between gene expression profiles and GS variations in the context of metastatic prostate adenocarcinoma. Results: The data show that 26.7% of patients (n=8) had a GS lower than 8, while 73.3% (n=22) had a GS equal to or greater than 8. In patients with a GS lower than 8, genetic profile analysis revealed that the ATM gene was expressed in three patients and the BRCA2 and TP53 genes were detected in one patient (n=1 for each gene). In relation to patients with GS equal to or greater than 8, the TP53 gene was expressed in 7 patients; the BRCA2, CHECK2, FANCL, RAD51C and RAD54L genes were expressed in only one patient (n=1 for each gene). These results indicate a more prominent expression of TP53 in patients with high GS, suggesting a relationship between the expression of this gene and the aggressiveness of metastatic prostate cancer with GS ≥8. In the sample, no positivity was observed for the BRCA1, CDK12, CHECK1, PALB2, PPP2R2A, RAD51B and RAD51D genes. Conclusions: The results show that metastatic prostate cancer patients with GS ≥8 exhibit elevated TP53 gene expression. The current sample of 30 patients provides preliminary insight, but the statistical robustness of these associations could be improved with a larger cohort. Carrying out subsequent studies with a broader sample will allow for a more reliable validation of the observed trends, contributing to a more comprehensive understanding of the associations between the analyzed variables and gene expression in patients with metastatic prostate carcinoma. Therefore, the interpretation of the results presented must be carried out with caution, considering the need for a more substantial sample size to verify and consolidate possible associations identified. Clinical trial information: CAAE42638620.3.0000.5138.
Comparison of prostate-specific antigen (PSA) response in patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) vs abiraterone acetate (ABI): A real-world (RW) causal analysis.
Authors: Brown Gordon Andrew , Du Shawn , Khilfeh Ibrahim , Rossi Carmine , Diaz Lilian , Kinkead Frédéric , Lefebvre Patrick , Pilon Dominic , Ellis Lorie , Lowentritt Benjamin H
Published: June 2024

e17070

Background: Patients with de novo mCSPC experience poor clinical outcomes which can be improved by treatment with androgen receptor signaling inhibitors (ARSIs). A prior RW study of patients with mCSPC initiated on APA or ABI found that APA initiators had significantly higher rates of PSA decline ≥90% (PSA90). This study compared PSA90 response by 6-months for patients with de novo mCSPC initiated on APA or ABI. Methods: Claims from the Komodo Health Solutions Research Database were linked with electronic medical records in US community urology practices from PPS Analytics. Exclusive APA and ABI cohorts were defined based on an initial pharmacy claim or dispensation for APA or ABI on or after 9/17/2019 (index date). Castration-sensitive patients were defined as de novo mCSPC if metastasis was observed ≤180 days after the initial prostate cancer (PC) diagnosis. Patients were also included if they had ≥12 months of pre-index clinical activity and had ≥1 PSA test within 13 weeks pre-index. Patients were followed until the earliest of index ARSI discontinuation (i.e., gap ≥90 days supply) or switch, radiopharmaceutical use, or end of clinical activity or data availability (9/30/2022). Inverse probability treatment weighting (IPTW) was used to balance pre-index covariates between cohorts (i.e., age, race, region, payer type, index year, time from metastasis to index date, time from first PC diagnosis to index date, metastasis location, use of androgen deprivation therapy, first-generation antiandrogens or chemotherapy, most recent PSA and testosterone levels, and earliest Gleason score). PSA90 was defined as the earliest ≥90% decline in PSA relative to the most recent value within 13 weeks pre-index. The proportion of patients achieving PSA90 by 6-months was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: A total of 356 APA and 324 ABI patients with de novo mCSPC were identified. Patient characteristics were balanced with IPTW (Table). By 6 months post-index, 82.0% of APA patients and 73.5% of ABI patients had a PSA measurement. By 6 months, significantly more APA patients attained PSA90 response relative to ABI patients (62.2% vs 41.6%; p<0.001; Table). Median time-to-PSA90 was 3.6 months for APA, and 10.3 months for ABI. Conclusions: This US-based RW study showed that a higher proportion of patients with de novo mCSPC initiated on APA achieved a deep, early PSA response relative to those on ABI. [Table: see text]
Can PSMA-PET be a better way to select patients for an intermittent treatment? Results from a prospective cohort.
Authors: Lages Dr. Paulo Sergio , Zulli Guilherme Augusto , Carcano Flavio Mavignier , Barbosa Michelle , Lages Luciana , Bergerot Paulo Gustavo , Rosa Diogo Augusto Rodrigues , Jardim Denis L. , Dias Mariane Fontes , Penna Coutinho Luiz Flavio , Vargas Pivato de Almeida Daniel
Published: June 2024

e17073

Background: The current strategy for advanced disease is continuous androgen suppression, but new technologies such as PSMA-PET may set a rule for identifying some patients for new strategies. The addition of novel hormone agent (NHA) to systemic treatment of metastatic hormone sensitive prostate cancer (HSPC) has been associated with overall survival benefit and metastasis directed therapy (MDT) has been demonstrated benefit postponing ADT. There is an increasing volume of data on the use of fixed-duration NHA for patients with recurrent HSPC, most of whom are expected to present oligometastatic disease if PSMA PET/CT scans are used. We evaluate clinical outcomes of intermittent androgen deprivation therapy in patients with oligorecurrent or oligometastatic HSPC (or/omHSPC)treated with ADT + NHA + MDT, based on PSMA-PET imaging. Methods: This is a prospective cohort of patients with or/omHSPC treated with fixed-duration ADT + NHA in association with PSMA PET/CT-guided MDT (+ primary tumor irradiation if de novo metastatic) from a single institution in Brazil. Descriptive statistics was used in order to characterize the study population and relapse-free survival (RFS) after systemic therapy discontinuation (defined as PSA > 0.2 ng/mL for previous prostatectomy or > 2+nadir if presence of primary tumor in place) was assessed. Analysis of testosterone recovery and other clinic laboratorial factors were also performed. All patients had an undetectable level of PSA and a PSMA-PET with a complete response to be elegible to the intermittent treatment. Results: Between 2019 and 2023, 20 patients with or/omHSPC were treated with fixed-duration ADT + NHA and PSMA PET/CT-guided MDT. The median age was 64 years-old (range: 47-85), 11 patients presented with de novo omHSPC, and distribution across Gleason grades was: grade 1: 2, grade 2: 3, grade 3: 9, grade 4: 3, and grade 5: 2 patients. Metastasis were diagnosed on bone (7) and/or lymph nodes (19). Median PSA at treatment start for orHSPC population was 3.01 ng/mL (range: 0.15-14.74). The median total testosterone level prior to ADT start was 327 ng/dL (range: 22-494). Distribution across NHA was: abiraterone/prednisone: 13, enzalutamide: 4, apalutamide: 2, abiraterone>enzalutamide: 1 patient. With a median follow-up of 13 months after ADT + NHA discontinuation, no patient has progressed, with 54.5% of patients already presenting testosterone recovery. Conclusions: The results of this single-center prospective cohort incorporating PET-PSMA for inclusion and monitoring patients with oligometastatic and oligorecurrent disease suggests that intermittent androgen blockage is promising in the era of NHA.
Identification of potential biomarkers with alternative splicing landscape of HIPEC-treated ovarian cancer: An RNAseq sub-analysis of a HIPEC clinical trial.
Authors: Dellinger Thanh Hue , Hansen Nathaniel P. , Ruel Nora H. , Frankel Paul Henry , Yost Susan Elaine , Invernizzi Marta , Eng Melissa , Han Ernest Soyoung , Raoof Mustafa , Wu Xiwei , Cho Hyejin , Lee Stephen , Kebria Mehdi , Hakim Amy , Wang Edward Wenge , Paz Isaac Benjamin , Rodriguez-Rodriguez Lorna , Pirrotte Patrick
Published: June 2024

e17577

Background: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy improves survival in ovarian cancer patients. Currently, no biomarkers exist to select for patients who best benefit from HIPEC. We compared the slicing landscape of ovarian cancer tumors of good and poor HIPEC responders in a Phase I clinical trial, to identify potential predictive biomarkers. Methods: A total of 35 ovarian cancer patients enrolled in a Phase I HIPEC trial (NCT01970722), in which nine patients had paired pre-and post treatment tissue samples collected. Pre-HIPEC tumor samples had RNA isolated, and whole-transcriptome library construction performed. FASTQ files from tumor samples were aligned to GRCH38 and ran through SplAdder (PMID:26873928) to identify alternative splicing events. Outlier splice events were ranked by mean log-likelihood score and converted to amino acid sequences using Bisbee (PMID:34031440). The top 15 outlier events were run through NetMHCpan (PMID:32406916) and DeepHLApan (PMID:31736974) to predict putative neoantigens. Results: Among nine HIPEC-treated ovarian cancer patients with available RNAseq data, five were considered good responders (≥12months PFS), and four as poor responders (<12 months PFS). Alternative splicing analysis identified 519splice events as outliers between good and poor responders, with 250reported to be novel. Of the 250 novel splicing events, we identified a novel protein coding 3’ end splice event in CPNE1 which was alternatively spliced in at a Percent-Spliced-In (PSI) of 99% in three out four poor responders. The same splice event was alternatively spliced at a PSI of 30.3% in four out of five good responders. CPNE1 plays a role in calcium mediated intracellular processes, and is involved in the TNF-alpha receptor signaling pathway, thus playing an important role in cell proliferation, differentiation, apoptosis, and modulation of immune responses and induction of inflammation. The encoded novel peptide from the CPNE1 splice event produced six predicted strong binding sites based on a binding score>0.80 and an immunogenic score>0.80. Conclusions: CPNE1 was identified as a differentially spliced event in poor HIPEC responders with ovarian cancer. Poor HIPEC responders had higher immunogenic score. Alternative splicing analysis may be a promising method to determine potential biomarkers for HIPEC treatment in ovarian cancer patients. Clinical trial information: NCT01970722 .
Early detection, clinicopathological subtyping and prognosis prediction for patients with endometrial cancer using fragmentoimcs-based liquid-biopsy assay.
Authors: Rao Qunxian , Zhou Hui , Weng Wanying , He Yiru , Tang Wanxiangfu , Chen Xiaoxi , Wu Xuxiaochen , Bao Hua , Lin Zhongqiu , Zhang Bingzhong
Published: June 2024

e17584

Background: Endometrial cancer (EC) is among the most common types of gynecologic malignancies worldwide. Currently, it is estimated that there are approximately 66,200 incidences and 13,030 cancer-related mortalities each year in the USA. If detected early, the five-year survival rate for localized endometrial cancer patients is at an optimistic 95%. However, the survival rates plunge dramatically to only 17.8% for patients with distant malignancies. Thus, timely diagnosis for endometrial cancer patients at an early stage can significantly enhance the chances of successful treatment, which is essential for reducing EC-related deaths. Methods: A cohort enrolled 120 patients with endometrial cancer and 120 female healthy volunteers from December 2018 to October 2019, was used to develop a predictive model for early detection of endometrial cancer. Five different fragmentomic features were profiled from low-pass WGS data and were used by four different algorithms for constructing base models before assembling to a final predictive model. An independent perspective test cohort, consisting of 62 endometrial cancer patients and 62 healthy controls enrolled from February to December 2020, was used for performance assessment of the final early detection model. Additional models were also developed for predicting clinicopathological features such as stage, grade, histological subtype, MSI and recurrence-free survival. Results: Our early detection model showed an excellent AUC of 0.96 in the independent test cohort, reaching a sensitivity of 75.8% at 96.8% specificity. Our model maintained its predictive power across different stages, yielding sensitivities of 74.4%, 85.7%, 75% and 75% for stage I to IV, respectively. Additionally, our models showed moderate predicting power for various clinicopathological features including stage (AUC: 0.72), histological subtypes (AUC: 0.73), grade (AUC: 0.59) and MSI (AUC: 0.77), respectively. Furthermore, a LASSO Cox regression model was capable of predicting patients’ recurrence-free survival. The model predicted risk score could identify high-risk patients who were 8.6 times more likely to develop recurrence, independent from other clinical factors (Hazard Ratio = 8.6, p < 0.001). Finally, an unsupervised similarity network fusion divided the endometrial cancer patients into a high-risk cluster and a low-risk cluster, while patients in the high-risk cluster had a 6.2 times higher risk for recurrence (HR = 6.2, p = 0.049). Notably, high-risk patients predicted by both methods had an even higher risk (HR = 10.1, p < 0.0001). Conclusions: By utilizing a fragmentomic-based liquid biopsy assay and machine learning algorithms, our model showed great clinical potential for the early detection, clinicopathological subtyping and prognosis prediction in patients with endometrial cancer.
Enfortumab vedotin plus pembrolizumab in the treatment of locally advanced or metastatic bladder cancer of variant histology: A phase II study.
Authors: Nazha Bassel , Brown Jacqueline T , Liu Yuan , Kissick Haydn , Carthon Bradley Curtis , Kucuk Omer , Harik Lara R , Narayan Vikram M , Joshi Shreyas S , Bilen Mehmet Asim
Published: June 2024

TPS4615

Background: Bladder cancers of variant histology (BCVH) account for up to 25% of bladder cancer incidence and affected patients (pts) usually have poor outcomes. The treatment options are limited due to the underrepresentation or exclusion of BCVH pts from trials for locally advanced or metastatic urothelial cancer (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate specific for Nectin-4. In the EV 302 Phase III trial, EV+pembrolizumab (pembro) significantly prolonged overall survival (OS) compared to platinum-based chemotherapy in mUC (HR 0.47, 95% CI 0.38-0.58) and was recently FDA-approved as standard of care in 1L mUC. Translational studies from our center show Nectin-4 expression in many BCVH pts and data support immune-checkpoint inhibitor (ICI) activity in subsets of these pts. We hypothesize the presence of clinical activity of this combination in BCVH. Therefore, we designed this trial to assess the efficacy and safety of EV+pembro in locally advanced or metastatic BCVH (mBCVH). Methods: This is a Phase II, open-label, single-center trial at the Winship Cancer Institute of Emory University (NCT05756569) for pts with mBCVH. Pts will receive pembro 200mg IV on Day 1 and EV 1.25mg/Kg IV on Days 1 and 8 of a 21-day cycle for up to two years. The eligibility criteria include histologically confirmed variant histology or non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (according to the WHO 2016 Classification), ECOG 0-1, and any line of therapy. Pts with neuroendocrine bladder cancer, non-epithelial cancers (e.g. sarcoma, lymphoma), prior ICI and/or EV treatment are excluded. Overall response rate (ORR) per RECIST 1.1 is the primary outcome and will be tested using Simon's two-stage design (n=25). The first interim analysis is planned after 15 patients. The desirable target is ORR≥30% relative to a null hypothesis of ORR ≤10%. This statistical design yields a type I error rate of 0.05 and a power of 80% for a true ORR≥30%. Key secondary outcomes include OS, progression-free survival, duration of response, and incidence of adverse events per CTCAE v5.0. Correlative biomarker analyses using blood- and tissue-based assays will be conducted during screening and at disease progression. The trial is currently open for enrollment. Clinical trial information: NCT05756569 .
A phase III randomized trial of eribulin (E) with gemcitabine (G) vs standard of care (SOC) for patients (pts) with metastatic urothelial carcinoma (mUC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937 updated design.
Authors: Sadeghi Sarmad , Plets Melissa , Lara Primo N , Tangen Catherine , Berg Stephanie A. , Brown Jason R , Bangs Rick , Nakagawa Darrell , Daneshmand Siamak , Ian M. Jr.  , Flaig Thomas W. , Petrylak Daniel P. , Lerner Seth P.
Published: June 2024

TPS4617

Background: UC is 2nd most common genitourinary cancer. Enfortumab vedotin (EV) + pembrolizumab became a SOC in 2023 in frontline mUC setting. In previously treated mUC setting, erdafitinib is approved for pts with FGFR alterations, while all pts have the option of sacituzumab govitecan (SG) with objective response rate (ORR) of 27% (N=113). A phase I/II CTEP study of eribulin (E) for mUC established the activity of E with ORR of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 71% ORR (n=7) for GE vs 24% for E (n=49). This trial has now been amended to account for first-line treatment changes and to include SG as a control arm option. Methods: This is an updated phase III, randomized trial comparing GE vs. SOC (SG, docetaxel, paclitaxel, or G monotherapy). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle and G is given at 1000 mg/m2 on D1 and D8. SOC follows approved dosing. There is no limit to the number/sequence of prior regimens. In brief, all pts must have: received systemic therapy with EV; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. The study seeks to find at least a 50% increase in the primary endpoint of OS (Hazard Ratio (HR) = 0.667). The secondary endpoints include ORR, and progression free survival (PFS). One-sided 0.05 type I error to account and 80% power to detect a 50% improvement in OS. We require 92 eligible pts in each arm for a total of 184. The amended and restructured study was approved in January of 2024. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Eribulin is provided by Eisai. Clinical trial information: NCT04579224 .