tbuckley/cabot-search huggingface dataset:
Mutational signature and prognosis in adenocarcinoma of bladder.
Authors: Guoliang Yang
Journal: Journal of Clinical Oncology (2024)

655 Background: Adenocarcinoma of bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here we aim to reveal mutational and transcriptomic landscapes of adenocarcinoma of bladder and their relationship with prognosis. Methods: Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of bladder were included. These included 16 patients with primary bladder adenocarcinomas and 7 patients with urachal adenocarcinoma. Whole exome sequencing, whole genome sequencing, bulk RNA-Seq and single-cell RNA-Seq were conducted for the specimens. Correlation analysis, survival analysis and t tests were also performed. Results: Prevalent T&gt;A substitutions were observed among somatic mutations, and major tri-nucleotide contexts included 5′-CTC-3′and 5′-CTG-3′. This pattern was mainly contributed by COSMIC Signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes also enriched KEGG term “chemical carcinogenesis”. Transcriptomic analysis implied high immune infiltration and luminal-like feature in majority of samples. Interestingly, a small fraction of samples with APOBEC-derived mutational signature exhibited higher risk of disease progression compared with samples with only chemical carcinogen-related signature, confirming molecular and prognosis heterogeneity in bladder adenocarcinoma. Conclusions: This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and chemical carcinogen-related mutational signature indicates good prognosis in adenocarcinoma of bladder.
Baseline bone pain as a prognostic marker for survival for men with metastatic hormone-sensitive prostate cancer (mHSPC): Patient-level analysis of SWOG 1216 trial.
Authors: Georges Gebrael, Yeonjung Jo, Umang Swami, Melissa Plets, Chadi Hage Chehade, Arshit Narang, Shilpa Gupta, Zin Myint, Nicolas Sayegh, Catherine Tangen, Maha H. A. Hussain, Tanya B. Dorff, Primo N Lara, Seth P. Lerner, Ian M. Thompson, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

188 Background: Pain from bone metastasis significantly predicts overall survival (OS) in men with castration-resistant prostate cancer (PMID: 18487572). However, it has not been extensively evaluated in men with mHSPC. We hypothesized that baseline bone pain in men with mHSPC will be a significant prognostic marker for OS. Therefore, SWOG 1216 trial data which randomized men with mHSPC to androgen deprivation therapy (ADT) with orteronel vs bicalutamide was evaluated (PMID: 35446628,NCT01809691). Methods: Patient level data from SWOG 1216 were analyzed for those with documentation of baseline bone pain (yes or no). Patients were categorized into 2 cohorts: those with bone pain (BP 1 ) vs those without bone pain (BP 0 ). Progression-free survival (PFS) and OS were summarized by median with 95% confidence intervals (CI). Multivariable analyses on PFS and OS were done using Cox proportional hazard model, and were adjusted for treatment arm, disease burden, Gleason score, PSA (log base 2–transformed) and age (Table). All the analyses were done using R version 4.2.1. Results: Of the 1279 study participants: 301 men were in BP 1 (23.5%) vs 896 were in BP 0 (70.51%) cohort. Bone pain status was unavailable in 82 men (6.4%) men. Compared to BP 0, BP 1 cohort had lower median age (66 vs 68 years, p&lt;0.01) and higher disease burden (70.4% vs 41.6%, p&lt;0.001). Men in BP 0 cohort had significantly better median PFS (3.7 vs. 1.3 yrs; p&lt;0.001) and OS (NR vs 3.9 vs NR, p&lt;0.001) then men in BP 1 cohort. After adjustment for other prognostic variables including treatment, disease burden, Gleason score, log2PSA and age; bone pain was significantly associated with decreased PFS and OS (Table). Conclusions: Men with mHSPC with bone pain at baseline have worse survival outcomes despite treatment intensification and may be prioritized for enrollment in clinical trials. These data may aid patient counseling and warrant the inclusion of bone pain in the prognostic models of mHSPC. Clinical trial information: NCT01809691 . [Table: see text]
RC48-ADC versus BCG in adjuvant treatment of high-risk non-muscle-invasive bladder cancer with HER2 over-expression: A real-world retrospective study.
Authors: Haoyang Liu, Junru Chen, Haolin Liu, Qiyu Zhu, Banghua Liao, Zhenhua Liu, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

644 Background: Bladder cancer ranks as the tenth most prevalent malignancy globally, with non-muscle invasive bladder cancer (NMIBC) accounting for approximately 75% of cases. Patients diagnosed with high-risk NMIBC (HR-NMIBC) face a grim prognosis, characterized by a 5-year disease progression rate of up to 40%. Currently, the standard treatment for HR-NMIBC involves transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy. However, BCG infusion therapy is associated with prolonged duration, substantial costs, and a high frequency of toxic side effects. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown promising efficacy with a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma (mUC) in a Phase II clinical trial (NCT03507166). Therefore, investigating the therapeutic potential of RC48-ADC in HR-NMIBC patients holds significant clinical importance. Methods: We conducted a retrospective analysis on patients diagnosed with HR-NMIBC exhibiting HER2 overexpression (≥ HER2 2+) who underwent adjuvant therapy with either RC48-ADC, a HER2-targeting antibody-drug conjugate, or BCG, at West China Hospital of Sichuan University between 2019 and 2023. The primary study endpoint was the twelve-month recurrence-free survival (RFS) rate, with safety assessments as secondary endpoints. Results: A total of thirty patients diagnosed with HR-NMIBC displaying HER2 overexpression were included in the study. Following TURBT, eleven patients received adjuvant therapy with RC48-ADC, while nineteen received adjuvant therapy with BCG. The median follow-up duration for patients receiving RC48-ADC and BCG adjuvant therapy was 7.3 and 16.43 months, respectively. Among patients treated with RC48-ADC, the twelve-month RFS rate was 100%, with one out of the 11 patients experiencing relapse after 14.2 months of RC48-ADC adjuvant therapy. In the BCG-treated group, the twelve-month RFS rate was 57.6%. However, Kaplan-Meier analysis revealed no statistically significant difference between these two groups (P=0.22). In the RC48-treated group, the most commonly reported treatment-related adverse events (TRAEs) included alopecia (45.5%), arthralgia (18.2%), and nausea (18.2%). A total of 27.7% of patients experienced grade 3 TRAEs, including alopecia, rash, and hypoesthesia, with no observations of grade 4 or grade 5 TRAEs. Conclusions: RC48-ADC has demonstrated promising efficacy with a manageable safety profile as an adjuvant therapy in patients with HR-NMIBC. RC48 may be an alternative adjuvant therapy for BCG in terms of the 12-month recurrence-free survival rate.
Real world outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177-PSMA-vipivotide tetraxetan (Lu177-PVT).
Authors: Colin P Bergstrom, Hong Song, Shann Mika Ruiz, Joanne Chien, Kaidi Moore, Divya Ahuja Parikh, Sumit Shah, Alice C. Fan, Sandy Srinivas, Andrei Iagaru, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2024)

86 Background: Lu177-PVT is a novel radioligand, which was recently approved by the FDA to treat mCRPC. Real world data on its use and efficacy is limited. We aimed to build a new retrospective cohort of patients with mCRPC treated with 177 Lu PSMA-617 in order to investigate clinical and pathological variables associated with treatment responses. Methods: We identified patients with a confirmed diagnosis of prostate cancer and were treated at Stanford University Medical Center with at least one dose of Lu177-PVT including trial patients. Data collection included demographic, clinicopathological and outcome variables. Statistical analysis was performed using Chi-squared and log-rank Kaplan-Meier analysis. Results: We identified 85 patients who met study criteria and were treated between March 2021 and June 2023, the median age was 66, 33% were non-white, median PSA at treatment initiation was 60, and 94% had osseous metastasis. Patients were pretreated with a median of six lines (range: 1-10) of prior therapy including local therapies; prostatectomy (28%), radiation (61%), brachytherapy (11%), taxane (78%), immunotherapy including checkpoint inhibitor and Sipuleucel-T (24%), PARP inhibitor (6%), and Radium-223 (15%). A majority of patients also received prior germline or somatic genetic testing (79%), with homologous recombination germline and somatic deficiencies present in 13% of patients. Of the identified cohort, 19 patients were still undergoing active treatment with Lu177-PVT at the time of data collection. Of the 66 patients not currently undergoing active Lu177-PVT treatment, 29 patients discontinued treatment due to progressive disease (44%) and 14 (21%) to toxicity related to 177 Lu PSMA-617, completing a median of 4 cycles. 47 patients (71%) had an overall decline in their PSA from baseline, with 32 patients (49%) experiencing a decrease greater than fifty percent. Median overall survival of patients not actively receiving 177 Lu PSMA-617 treatment was 366 days. Age, previous lines of therapy, and median time from diagnosis were not predictive of PSA treatment response (greater than fifty-percent reduction from baseline PSA). Conclusions: Lu177-PVT is a promising treatment for mCRPC in patients. Our results confirm ‘real-world’ activity of Lu177-PVT and align well with VISION study results, though real-world overall survival was comparatively shorter (12 months vs 15 months in VISION trial). Further investigation is warranted into predictors of response and toxicity.
Exploration of enfortumab vedotin (EV)–related cutaneous events by race in two real-world cohorts.
Authors: Evangelia Vlachou, Ronac Mamtani, Noah M. Hahn, Burles Avner Johnson, Jean H. Hoffman-Censits, Vivek Nimgaonkar
Journal: Journal of Clinical Oncology (2024)

544 Background: EV is an antibody drug conjugate, approved in advanced urothelial cancer (UC). The Nectin-4 target of EV is present in tumor and normal skin, and EV-related cutaneous events (EVCEs) are common. EVCEs often appear early with variable grade presentation. Continuation of EV is typically safe with supportive management, but rare life-threatening manifestations have occurred. Dermatologic conditions, including medication-related skin events are often underdiagnosed or under-staged in Black patients (pts). Black pts are also frequently under-represented in UC trials, and it is unknown whether EVCE incidence varies by skin tone. We explored whether EVCE frequency varies between Black and White pts in an urban cohort and a large community-based national dataset. Methods: This retrospective cohort analysis used data from Johns Hopkins Hospital (JH) and Flatiron Health (FH), a de-identified electronic health record (EHR)-derived database of community-based oncology clinics across the U.S. Pts treated with EV monotherapy at JH and in the FH database who self-identified as Black or White race were included. In the JH cohort, chart review was used to extract demographics, treatment details, and EVCEs. EVCEs were defined as any grade, new or exacerbated dermatologic event after EV initiation, not attributed to other cause. In the FH cohort, EVCEs were identified through pre-defined skin-related ICD-10 codes identified by the study authors. Odds ratios (OR) with 95% confidence intervals of EVCE incidence between Black and White pts were calculated separately for each cohort. Results: 78 toxicity-evaluable pts were identified in the JH cohort and 316 in the FH cohort. 12 were Black (15.4%) in the JH Cohort vs. 24 Black (7.6%) in the FH cohort. Median age was 71 years (IQR: 64-78), 20 (25.6%) were female, 50 (64.1%) pts had a primary site in the bladder, and 13 (16.7%) had EV as second-line and 49 (62.8%) as third - line treatment in the JH cohort, vs. 71 years (IQR: 65-77), 84 females (26.6%), 226 (71.5%) with bladder primary site, and 122 (38.6%) and 108 (34.2%) receiving EV as second-and-third-line treatment respectively in the FH Cohort. In the JH Cohort 8 of 12 Black pts (66.7%) as compared to 32 of 58 (55.2%) White pts experienced an EVCE (Table, OR 1.63, 95% CI [0.44, 6.0]). In the FH cohort, 6/24 Black pts (25%) compared to 46 /292 White pts (15.8%) experienced an EVCE (Table, OR 1.78, 95% CI [0.67, 4.73]). Conclusions: In this hypothesis-generating analysis of EV treated pts, the largest reported cohort of Black EV treated pts to date, we observed an increased EVCE frequency in Black pts relative to White, though statistical significance was not demonstrated. Future prospective EV studies should aim to recruit Black patients to better characterize this finding. [Table: see text]
Real-world utilization patterns of radium-223 in metastatic prostate cancer in the United States: An administrative claims database study.
Authors: Amit D Raval, Yiqiao Zhang, Matthew J. Korn, Niculae Constantinovici
Journal: Journal of Clinical Oncology (2024)

79 Background: Radium (Ra)-223 is approved for use in men with symptomatic castration resistant prostate cancer (CRPC) with bone metastases, demonstrating benefits in terms of overall survival and quality of life with a reliable safety profile. In the rapidly evolving treatment landscape for prostate cancer, real-world (RW) data on Ra-223 utilization are limited. We aimed to examine the RW utilization patterns of Ra-223 in patients with metastatic prostate cancer using a large administrative claims database in the US. Methods: A retrospective cohort of men treated with Ra-223 was identified using the closed claims private payor database of the Komodo Research Dataset covering the period from 01/01/2017 to 06/30/2022. The earliest administration of Ra-223 in men with bone metastatic prostate cancer was considered as index date. Individuals were required to have continuous insurance coverage at least 12-month pre-index (baseline) and least 6-month post index or until death if patients survived &lt; 6 months (follow-up). Logistic regression was used to identify baseline demographic, clinical, medications, or healthcare resource use-related factors associated with receiving 5+ cycles of Ra-223. Results: The study cohort comprised of 1,376 men with a median age of 68 years at the time of Ra-223 initiation. Most men were treated by oncologists (52.2%), having bone only metastases (51.5%), having Charlson comorbidity index (CCI) ≥ 1 (76.2%). Diabetes (34.1%), peripheral vascular disease (29.9%), pulmonary disease (25.9%) and mild liver disease (25.1%) were the most common pre-existing comorbidities. Therapies received prior to Ra-223 were androgen receptor pathway inhibitors (75.4%), chemotherapy (32.1%), sipuleucel-T (13.7%) and bone health agents (73.7%). Ra-223 was utilized as a combination therapy by 26.0% of the overall population, predominately with enzalutamide. Nearly 15%, 38%, and 31% received Ra-223 (mono or combination therapy) as 1 st , 2 nd , and 3 rd line therapy, respectively. Approximately 46% of the overall cohort and 54% of those who survived ≥ 6 months had received 5+ cycles, respectively. In regression analysis, men with short survival (&lt;6 month) [Odds ratio, OR: 0.05, 95% confidence interval (CI): 0.03, 0.10], low CCI (0 vs. 4+) (OR: 0.38, 95% CI:0.19, 0.76), and pulmonary disease (OR: 0.71, 95% CI: 0.52, 0.97) had lower likelihood of completion of 5+ cycles. Conclusions: Nearly half of men completed 5+ cycles of Ra-223 therapy in a large US cohort of relatively young mCRPC men with private health insurance. Advanced disease state with short survival and low comorbidity were key factors associated with lower completion of 5+ cycles. The findings highlight the importance of utilizing Ra-223 early after mCRPC diagnosis, when the probability of &gt;6-month survival is higher, to enhance treatment completion that has been shown to result in better outcomes.
Impact of <i>TP53</i>, <i>RB1</i>, and <i>PTEN</i> mutations on overall survival in metastatic prostate cancer: A multi-center study via the Guardian Research Network.
Authors: Mohammad Arfat Ganiyani, Pushan Prabhakar, Atulya Aman Khosla, Shreyas S Bellur, Arjun Pon Avudaiappan, Liz Bond, Suresh Marada, Andrea McCracken, Charlie Hurmiz, Bruno R. Bastos, Rohan Garje
Journal: Journal of Clinical Oncology (2024)

82 Background: The treatment paradigm for metastatic prostate cancer has significantly improved in the past decade. Nevertheless, there remains an unmet need for novel biomarker-driven risk stratification. Studies have shown that genetic alterations in any of the PTEN, RB1, and TP53 genes influence the prognosis, potential for androgen independence and overall survival of individuals diagnosed with advanced prostate cancer. Based on these findings, we compared survival rates by contrasting patients with any of these mutations to those lacking them, using an extensive real-world sample from community oncology centers across the Guardian Research network (GRN). Methods: All patients diagnosed with metastatic prostate cancer who had undergone Next-Generation Sequencing (NGS) were included across an oncology-focused hospital consortium network database (GRN). Study participants were classified into two cohorts based on the presence or absence of biomarkers. Patients harboring at least one of the following genomic alterations— TP53, Rb, or PTEN—were categorized as "biomarker-positive." Those without these mutations were designated as "biomarker negative." Overall survival (OS) was compared between the two cohorts by Kaplan-Meier Curve analysis. Results: We identified 350 patients with metastatic prostate cancer, of which 140 were biomarker positive and 210 were biomarker negative. The biomarker-positive cohort had a lower overall survival (p=0.002) when compared to the biomarker-negative cohort. For the sub-group with a minimum follow up of four years, median survival was 35.8 months vs 67.2 months for biomarker marker positive and negative cohorts, respectively. Furthermore, the biomarker-positive cohort was associated with significantly higher number of patients with bone and liver metastases. Conclusions: Our study indicates poor overall survival in patients with TP53, RB1, and PTEN mutated prostate cancer, underscoring the need for novel treatment strategies for this aggressive disease genotype. Future studies based on genomic risk stratification are needed to customize therapies through appropriate intensification or de-intensification based on individual genomic profiles. [Table: see text]
Survival outcomes in patients (pts) with prostatic cancer (PCa) based on pathologically confirmed sites of metastasis.
Authors: Gliceida Galarza Fortuna, Shayan Nazari, Umang Swami, Andrew Elliott, Georges Gebrael, Aditya Bagrodia, Dhruv Puri, Chadi Nabhan, Rana R. McKay, Emmanuel S. Antonarakis, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

72 Background: In a meta-analysis of 9 phase III trials involving 8,820 pts with metastatic castration-resistant prostate cancer, overall survival progressively decreased from those with lymph node only disease to those with bone, lung, and liver metastases. Herein, we aimed to validate these results in a large real-world dataset based on pathologically confirmed site of metastasis. Methods: PCa tissue specimens derived from the primary Pca (PPCa) and metastatic sites were molecularly profiled by Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was assessed using insurance claims data, with OS calculated from date of initial tumor diagnosis to death or lost to follow-up using Kaplan Meier estimates and log-rank test. Molecular and immunologic differences by specific metastatic site are presented in a companion abstract. All the analyses were done using CODEai. Results: 6,069 PCa specimens were included in the analysis [n= 3,411 prostate, n=1,634 non-visceral (bone and lymph node), n=1,029 visceral disease (lung, liver, peritoneum, brain, other.)]. PCa specimens (n=6,069) were stratified based on tumor biopsy site, including prostate (n= 3411), NV (bone and lymph node; n=1,631), and visceral (lung, liver, peritoneum, brain, other; n=1027) subgroups. The median OS from initial diagnosis was significantly longer for pts with PPCa compared to those with visceral metastatic PCa (median OS 70.2 vs 55.5 months; HR 1.42, 95% CI: 1.28-1.58, p&lt;0.001) as well as non-visceral PCa (median OS 70.2 vs 63.9 months; HR 1.15, 95% CI: 1.05 – 1.27, p=0.004). The comparison of median OS by site of metastatic disease compared to bone metastasis is presented in the Table. Conclusions: We validate the results of prior studies in a real-world PCa population and show differential OS based on the site of metastases, with liver metastases associated with the shortest OS and lung metastases showing the longest OS. These data argue against combining liver and lung metastases into a single category of visceral metastases when visceral metastasis is used as stratification factor for randomized trials. [Table: see text]