tbuckley/cabot-search huggingface dataset:
A double-blinded, placebo-controlled, cross-over pilot trial in healthy men to study the effects of <i>Angelica gigas</i> herbal supplement on prostate cancer–relevant inflammatory cytokines.
Authors: Anne-Laure Strong, Deepkamal N. Karelia, Todd D. Schell, Diane Hershock, Tongyao Fan, Dongxiao Sun, Junjia Zhu, Elizabeth Proctor, Cheng Jiang, Monika Joshi, Junxuan Lu
Journal: Journal of Clinical Oncology (2024)

170 Background: The ethanol extract of the root of Angelica gigas Nakai (AGN) dose-dependently inhibits animal models of prostate cancer. Multi-omic analyses have implicated immune and anti-inflammatory responses in the anti-cancer action. In our single dose-PK study (NCT02114957) in healthy volunteers with AGN dietary supplement CognI.Q, we observed a near doubling of the natural killer (NK) mRNA signature in peripheral blood mononuclear cells (PBMC) at 24 h after dosing while the inflammatory cytokine IL-8 mRNA was decreased by one half over the pre-dose baseline. Given NK incapacitation and inflammation have been linked to prostate cancer, the current trial (NCT03630328) was designed to assess safety and to delineate CognI.Q-specific immune and anti-inflammation functions. Methods: We used a double-blinded, placebo-controlled and crossover trial design to monitor hepatic and renal safety metrics based on Comprehensive Metabolic Panel (CMP) and compare the immune cell and cytokine responses to CognI.Q and placebo. Supplement period of 3 weeks was followed with a 2-week washout period. We employed the Ella microfluidic multiplex immunoassay to evaluate select plasma cytokines. Results: Fourteen healthy men completed the trial protocol. Physical examination on study visit days did not reveal any adverse events. Blood CMP monitoring detected abnormal hepatic integrity values in three subjects, all in the second washout period and were attributed to use of anti-allergy medication, an herbal tea for tooth ache, and excessive alcohol, respectively. Analysis of plasma cytokines detected corresponding elevation of MIG, CCL4, CXCL10 and IL-8 with these hepatic damage events. With the exclusion of these subjects or time point, the plasma cytokine measurement did not reveal a significant response to CognI.Q supplement vs. placebo. Conclusions: CognI.Q supplement at the current recommended dose (400 mg, twice per day) did not impair hepatic integrity or renal function, nor did it modulate select plasma cytokines in healthy men. Phase I dose-escalation trials should be implemented to establish safety profile and assess immune and inflammation modulatory effects of AGN supplement beyond the current dose. Clinical trial information: NCT03630328 .
Association of aggressive prostate cancer features on whole-mount histopathology and quantitative measures on PSMA PET.
Authors: Ida Sonni, Daniel Hyeong Seok Kim, Arthur Ter-Pogosyan, Tristan Grogan, Nashla Barroso, Preeti Ahuja, Priti Soin, Jeremie Calais, Robert Evan Reiter, William Hsu, Johannes Czernin, Anthony E Sisk, Steven Raman
Journal: Journal of Clinical Oncology (2024)

289 Background: The intraductal carcinoma (IDC) and the large cribriform growth pattern (LCP) are two architectural patterns of prostate cancer (PC) associated to more aggressive disease, high Gleason scores, advanced tumor stage, biochemical relapse, and distant metastasis. Predicting the presence of these pathology features could be of significant help in case whole-mount pathology (WMHP) is not available. The goal of this analysis was to assess the distribution of quantitative parameters from 68Ga-PSMA-11 PET/CT (PSMA PET) in lesions with and without LCP/IDC patterns on WMHP. We assessed the ability of pre-surgical PSMA PET imaging to predict the presence of aggressive pathology features. Methods: With IRB approval and HIPAA compliance, we derived a study cohort of PC patients who underwent PSMA PET prior to robotic radical prostatectomy (RALP). WMHP analysis described presence/absence of LCP and IDC patterns in each identified PC lesion. Board-certified physicians contoured all PC lesions on PSMA PET. Only lesions matching with WMHP were included in the analysis. PSMA PET metrics (SUVmax, SUVmean and PSMA-volume) were extracted. All lesions were categorized in sub-cohorts as LCP+/IDC+, LCP+/IDC-, LCP-/IDC-, and LCP-/IDC+. One way-ANOVA assessed significant differences among the imaging parameters in the sub-cohorts. The area under the curve (AUC) from ROC analysis was used to assess the ability of imaging metrics to predict the presence of aggressive PC features on WMHP. Results: The final cohort comprised 155 patients and 177 lesions. The median (IQR) PSA at time of RALP was 9.2 (5.55-15.05). 73/177 lesions (41.2%) were categorized as LCP+/IDC+, 63/177 (35.6%) as LCP-/IDC-, 37/177 (20.9%) as LCP+/IDC-, and 4 (2.3%) as LCP-/IDC-. SUVmax (p=0.007), SUVmean (p=0.048) and lesion size on PSMA PET (p=0.003) were significantly higher in lesions showing LCP, whereas only lesion size was significantly higher in lesions showing IDC (p=0.003). Lesions showing LCP+/IDC- had significantly higher SUVmax (p=0.002) and SUVmean (p=0.001) than lesions showing LCP-/IDC-. SUVmean was significantly higher in LCP+/IDC- than in LCP+/IDC+ (0.043). SUVmax and SUVmean were not significantly different among other sub-cohorts. Lesion size on PSMA PET was significantly higher in LCP+/IDC+ than in LCP-/IDC- (0.009). A logistic regression model analysis showed that PSMA PET quantitative measures predict the presence of LCP and/or IDC with moderate accuracy (AUC= 0.69; p=0.001). Conclusions: Higher SUVmax and SUVmean are found in lesions showing LCP, but not in those showing IDC. A linear regression model including SUVmax, SUVmean and PSMA PET lesion volume was able to predict with moderate accuracy the presence of pathology features of aggressive prostate cancer (AUC: 0.69).
Real-world outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and tumors harboring androgen receptor (<i>AR</i>) ligand-binding domain (LBD) mutations.
Authors: Tyler F. Stewart, David Chandiwana, Ashley Doyle, Nana Boame, Jayati Saha, Nicole Zhang, Darrin Benjumea, Andrew Rava, Janaki Parameswaran, Michelle L. Edwards, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2024)

77 Background: In mCRPC, AR T878 and/or H875 and L702H mutations have been associated with disease progression and poor prognosis. This study characterized real-world overall survival (rwOS), testing practices, mutation prevalence, and treatment patterns in patients with mCRPC with and without tumors with missense mutations in the AR LBD (amino acids 671–920). Methods: In this retrospective analysis of the Guardant Inform Database (Mar 11, 2014–Jun 30, 2022), men (aged ≥18 y) with mCRPC who were tested with Guardant360 (G360) next-generation sequencing and diagnosed/treated at a clinical site in the US with a first-line (1L) treatment were included. Matched rwOS was assessed in 2 subpopulations: patients with any missense mutation in AR LBD, excluding those with AR L702H alone ( AR LBD group), and patients with AR T878 and/or H875 without L702H ( AR 878/875 group) and compared with patients without any AR LBD missense mutations (control group). Patients were matched (1:5) on key prognostic variables, including age, Elixhauser Comorbidity Index weighted score, smoking status, prior novel hormonal agent (NHA) use, and 1L treatment year. Mutation prevalence, patient demographics, frequency and timing of G360 tests, and treatment patterns were assessed in patients treated from 2018 to 2022 to reflect more recent trends. Results: In the matched rwOS analysis, patients in the AR LBD group (n=275) had statistically significantly shorter 1L median rwOS compared with the control group (n=1375): 27.3 vs 47.8 months; P&lt;0.0001. Similarly, patients in the AR 878/875 group (n=154) had shortened median rwOS compared with the control group (n=770): 28.9 vs 44.4 months; P=0.0004. Of 4833 patients treated for mCRPC from 2018 to 2022, 20% had AR LBD mutations, 4% had AR 878/875 with L702H, and 6% had AR 878/875 without L702H. Most patients (59%) were first tested at some point after 1L therapy, with only 15% of patients receiving &gt;1 G360 test. Mutation prevalence was higher in patients tested in fourth-line (4L) compared with 1L, particularly for AR L702H mutations (17% vs 10%) and all AR LBD mutations (27% vs 20%). Use of NHAs was lower in 4L compared with 1L (20% vs 33%), whereas use of taxanes was higher (31% vs 22%). Conclusions: Patients with AR LBD–mutated mCRPC had notably shorter rwOS than those whose tumors did not harbor AR LBD mutations, indicating an unmet need for this population. The prevalence of AR LBD mutations was higher in later lines of therapy, but repeat testing rates were low, suggesting that AR LBD mutations may go undetected.
A meta-analysis of overall survival and response in metastatic adrenocortical carcinoma: A review of 23 prospective trials of 880 patients.
Authors: Angus Hall, Megan Crumbaker, James Pham, Jia (Jenny) Liu, Hao-Wen Sim, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2024)

4 Background: Metastatic adrenocortical carcinoma (mACC) is a rare, aggressive tumour of the adrenal gland, with historically poor survival and limited established treatment modalities. The aim of this study was to systematically search for and analyse all prospective trials for mACC to establish benchmark response and survival outcomes. The study was registered on PROSPERO CRD42023430557. Methods: A systematic review and meta-analysis of five databases was performed between June 2023- July 2023. Key outcomes extracted included patient demographics, overall survival (OS), progression-free survival (PFS) and objective response rates (ORR). ORR was calculated using a random effects model and inverse variance methods. Time-to-event outcomes including PFS and OS, were extracted digitally from available Kaplan- Meier curves using the IPDfromKM tool and individual patient data (IPD) was generated as per Guyot et al. The PFS and OS data from individual studies were then pooled using a multivariate extension of the DerSimonian–Laird method to generate summary survival curves. Results: The final 23 trials (5 Phase 1b, 16 Phase II and 3 Phase 3) encompassed 880 patients were retrieved. Pooled ORR was 9.0% overall (2.9% for targeted therapy, 12.3% for chemotherapy and 15.3% for immunotherapy). Median OS was 9.9 months (7.4 months for targeted therapy, 11.2 months for chemotherapy and 10.6 months for immunotherapy). Median PFS was 2.6 months (2.7 months for targeted therapy, 3.0 months for chemotherapy and 2.1 months for immunotherapy). Kaplan-Meier curves for OS were available for 10 treatment lines (n = 605), with a pooled median OS of 9.9 months (95% CI 7.7-11.9) and 12-month OS of 41.6% (95CI 33.1-51.2). Median OS was 7.4 months for patients receiving targeted therapy (95% CI 4.7–12.0), 11.2 months for patients receiving chemotherapy (95% CI 6.9–14.7) and 10.6 months for patients receiving immunotherapy (95% CI 4.4–13.2]. 12-month OS was 30.4% (95% CI 15.9-58.3) for patients receiving targeted therapy, 45.4% (95% CI 33.7-61.2) for patients receiving chemotherapy and 45.3% (95% CI 36.2-56.6) for patients receiving immunotherapy. Conclusions: This study found that current treatments strategies confer limited survival and response benefit in mACC and highlight the need for research into the pathogenesis and novel strategies in the disease. Immunotherapy and chemotherapy demonstrate modest benefits for patients and future trials should attempt to surpass the survival benchmarks set in this study.
First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study.
Authors: Martin H Voss, Howard Gurney, Vagif Atduev, Cristina Suárez, Miguel Ángel Climent, David William Pook, Piotr Tomczak, Philippe Barthelemy, Jae-Lyun Lee, Taron Nalbandian, Viktor Stus, Thomas Ferguson, Pawel Wiechno, Erhan Gokmen, Louis Lacombe, Craig Gedye, Joseph E. Burgents, Manish Sharma, Jerry Cornell, Laurence Albiges
Journal: Journal of Clinical Oncology (2024)

2 Background: Pembrolizumab (pembro) + lenvatinib (lenva) is approved for first-line treatment of advanced/metastatic RCC based on results of the phase 3 KEYNOTE-581/CLEAR study. Previously reported results from the phase 2 KEYNOTE-B61 (NCT04704219) study with a median follow-up of 15 months further support the use of pembro + lenva in the first-line setting specifically across nccRCC. We now report updated results from KEYNOTE-B61 with median follow-up of 23 months. Methods: Adults with previously untreated, advanced nccRCC (histology assessed by investigator) and measurable disease per RECIST v1.1 received pembro 400 mg IV Q6W for ≤18 cycles (~2 years) + lenva 20 mg orally once daily until intolerable toxicity, progressive disease, or patient (pt) withdrawal from the study. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DCR, DOR, and PFS per RECIST v1.1 by BICR, OS, and safety. Results: A total of 158 pts received pembro + lenva. Median age was 60 years (range, 24-87), and the most common histologic variants of RCC were papillary (n = 93; 59%), chromophobe (n = 29; 18%), and unclassified (n = 20; 13%). Median time from first dose to the data cutoff date of July 5, 2023, was 22.8 months (range, 16.6-27.6). 86 pts had discontinued treatment (most commonly due to progressive disease, n = 56 [35%]). In all pts, ORR was 51% (95% CI, 43-59; 13 CRs [8%]; 67 PRs [42%]) and DCR was 82% (95% CI, 75-88). Median DOR was 19.5 months (range, 15.3-not reached [NR]). An estimated 51% of responses had a duration of ≥18 months. ORR and DCR by histology are shown in the table. In all pts, median PFS and OS were 17.9 months (95% CI, 15.1-22.1) and NR (95% CI, NR-NR); estimated 18-month PFS and OS rates were 48% and 73%. Treatment-related AEs (TRAEs) occurred in 151 pts (96%), most commonly hypertension (56%), diarrhea (46%), hypothyroidism (41%), and proteinuria (30%). Grade 3-4 TRAEs occurred in 92 pts (58%), most commonly hypertension (25%), and diarrhea, proteinuria, and decreased weight (5% each). No deaths due to TRAEs were reported. Discontinuation due to TRAEs for pembro, lenva, or both pembro and lenva occurred in 15%, 13% and 4% of pts, respectively. Conclusions: Consistent with prior reports, pembro + lenva had durable antitumor activity and a manageable safety profile in pts with advanced nccRCC. These results continue to support pembro + lenva as a first-line treatment option for pts with variant histologies of nccRCC. Clinical trial information: NCT04704219 . [Table: see text]
Quality of treatment with targeted agents for advanced prostate cancer by treating specialist.
Authors: Kassem S Faraj, Mary Oerline, Samuel Kaufman, Megan Veresh Caram, Vahakn B. Shahinian, Brent K. Hollenbeck
Journal: Journal of Clinical Oncology (2024)

88 Background: Urologists are increasingly prescribing oral targeted agents to men with advanced prostate cancer, who traditionally have been cared for by medical oncologists. These agents require close monitoring, since they mechanistically affect androgen biosynthesis and can lead to cardiovascular and metabolic adverse events. It is unclear whether patients treated by urologists—whose practice scope typically does not involve systemic therapies—experience more frequent therapy-related adverse events. Further, these medications are expensive, often subjecting patients to high out-of-pocket costs, which can lead to coping strategies like treatment non-adherence. Urologists may have less experience discussing these costs and exploring cheaper alternatives. Methods: A 20% sample of National Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer between 2012-2020 who were treated with a targeted agent (abiraterone or androgen receptor blocker). The primary outcome was the composite of any hospital or emergency department visit for a cardiometabolic event within 1 year of starting a targeted agent. Secondary outcomes included monthly out-of-pocket costs in those without low-income subsidies and adherence to treatment in first 6 months after initiating treatment. Multivariable regression models were fitted to assess the association between prescribing specialist (urologist or medical oncologist) and each outcome. Results: There were 1,462 (25%) and 4,501 (75%) patients who were prescribed a targeted agent by a urologist and medical oncologist. Men who were managed by urologists were more often started on an androgen receptor blocker, compared to those managed by medical oncologists (67% vs 36%, p&lt;0.001).There were no differences in the adjusted frequencies of composite adverse events of patients managed by urologists and medical oncologists in those who were started on abiraterone (7.7 % vs 8.1%, P=0.79) or an androgen receptor blocker (6.4% vs 6.2%, p=0.91). Out-of-pocket costs did not vary between patients who were managed by urologists vs medical oncologists in those who were started on abiraterone ($748 % vs $778%, P=0.48) or an androgen receptor blocker ($795 vs $834, p=0.33). Adherence to treatment was similar between the specialties in those prescribed abiraterone (67% vs 64%, P=0.15), but the likelihood of adherence was higher in men prescribed an androgen receptor blocker by a urologist (65% vs 61%, p=0.04). Conclusions: Although urologists may be less accustomed to primarily managing advanced prostate cancer than medical oncologists, patients fared no worse when assessing adverse events, out-of-pocket costs, or adherence to treatment. This study provides further support for urologists’ increased role in managing advanced prostate cancer.
A safety net for safety net hospitals: Affiliation with cancer centers and survival outcomes in patients with metastatic genitourinary cancers.
Authors: Raj Ramnik Bhanvadia, Jacob Taylor, Kris Gaston, Solomon L. Woldu, Yair Lotan, Vitaly Margulis
Journal: Journal of Clinical Oncology (2024)

543 Background: Safety net hospitals (SNH) care for a substantial proportion of medically vulnerable populations (MVP). Addressing health disparities at a hospital level through partnerships with cancer centers is a potential strategy to improve outcomes of MVPs. We thus compared outcomes for metastatic prostate (mPCa), kidney (mKCa), and urothelial cancer (mUCC) among National Cancer Institute centers (NCI), NCI affiliated SNH (NCI-SNH), and non-affiliated SNH using the Texas Cancer Registry (TCR). Methods: The TCR has 98% case ascertainment of all cancers diagnosed in Texas. The TCR can identify each facility where a patient was diagnosed and treated, allowing detailed hospital level comparisons of outcomes. The TCR was queried from 2004-2017 for mPCa, mKCa, and mUCC. Publicly available data identified Texas NCIs. The top quartile of Disproportionate Share Hospital Index values identified SNH. SNH with established relationships to NCI were designated NCI-SNH and remainder were SNH. Non-SNH were hospitals not affiliated with NCI nor SNH. MVPs were defined as age &gt; 75, non-US natives, non-whites, and uninsured or Medicaid patients. Cox multivariable regression was used to assess overall mortality (OM). Results: Of the 1,048,464 patients in TCR, MVPs accounted for 44.7% of cases. The SNHs and NCI-SNHs accounted for 53.1% of all MVP cancer care statewide. MVPs were the majority of cases within NCI-SNH compared to other SNH or NCI (80% vs 45% vs 37.1%, p&lt;0.01). TCR identified 20,503 metastatic genitourinary (GU) cancers. For mPCa, rates of hormone therapy were similar between NCI-SNH (76.7%) and NCI (76.2%), but greater than SNH (51.5%) or non-SNH (49.7%) ( p&lt;0.01). Receipt of chemotherapy or immunotherapy was greater at NCI-SNH compared to other SNH or non-SNH for both mKCa (36.1% vs 31.1% vs 27.1%, p&lt;0.01) and mUCC (44.0% vs 36.7% vs 33.2%, p&lt;0.01). On multivariable cox analysis, equivalent OM between NCI and NCI-SNH for any metastatic GU cancer (Table). OM was worse at other SNH and non-SNH compared to NCI (Table). Conclusions: Medically vulnerable patients made up almost half of cancer care in Texas and majority were cared for at SNH. NCI-SNHs had equivalent OM to NCI and superior OM compared to other SNH. Future initiatives to improve cancer care should focus on strengthening existing relationships between NCI and SNH, and examine mechanisms to centralize care of MVPs to these facilities.[Table: see text]
Defining molecular features associated with microsatellite instability and response to immune checkpoint blockade in urothelial carcinoma.
Authors: Syed Muneeb Alam, Min Yuen Teo, Jun Woo, Michal Sarfaty, Samuel A Funt, David H Aggen, Chung-Han Lee, Marie Isabel Carlo, Jatin Gandhi, Neha Ratna, Ashley M. Regazzi, Mark Donoghue, Dean F. Bajorin, Jonathan Coleman, Jonathan E. Rosenberg, Hikmat A. Al-Ahmadie, David B. Solit, Gopa Iyer
Journal: Journal of Clinical Oncology (2024)

536 Background: Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are associated with sensitivity to immune checkpoint blockade (ICB) in urothelial carcinoma (UC). MSI status may only partially explain this sensitivity, and the molecular features that distinguish MSI-high (MSI-H) UC are not well described. Methods: Retrospective review of UC patients having undergone targeted exome sequencing of up to 505 genes was performed. Using the previously validated MSIsensor score, we identified MSI-H (score ≥10) and MSI stable (MSS) (score &lt;3) UC tumors. Tumor mutational burden (TMB) was quantified. Gene alterations enriched in MSI-H UC were evaluated using the false discovery method with q&lt;0.05 considered statistically significant. Mutational process signatures (MPS) were characterized using COSMIC v3.3. Survival analysis was performed using the Kaplan-Meier method with Cox proportional-hazards to determine progression-free (PFS) and overall survival (OS) based on molecular features. Results: Targeted exome sequencing data were available for 3,811 UC specimens representing 2,608 patients, of which 471 carried a diagnosis of upper tract UC. Of the total, 60 (1.6%) MSI-H tumors from 55 (2.1%) patients were identified. Germline testing (n=52) revealed dMMR mutations in 24 cases (46.2%) with MSH2 (59.6%) being most common. Median MSIsensor score was 19.8 (IQR 15.5, 27) and median TMB was 52.7 mut/Mb (IQR 39.7, 63.2). Notable gene alterations enriched in MSI-H tumors are summarized in Table 1. Dominant MPS in MSI-H UC included dMMR (85.0%), APOBEC (8.3%), and Aging (6.7%). MSI-H tumors clustered with dMMR mutational signatures SBS6 and SBS44. A total of 21 MSI-H and 160 MSS patients having received ICB for metastatic disease were identified for survival analysis. Median follow-up was 18.4 months (IQR 6.6, 58.5). MSI-H UC demonstrated superior PFS (HR 0.34, 95% CI 0.22-0.55) and OS (HR 0.48, 95% CI 0.28-0.80) following ICB. There was no association between TMB or MPS and survival following ICB in MSI-H UC. In MSS UC, TMB ≥10 mut/mB was associated with improved PFS (HR 0.56, 95% CI 0.40-0.79) and OS (HR 0.71, 95% CI 0.50-1.0). Conclusions: Targeted sequencing reveals distinct genomic features of MSI-H UC. The findings from this relatively large clinical cohort of MSI-H UC patients affirm previous associations between MSI status, TMB, and response to ICB in metastatic UC. [Table: see text]