tbuckley/cabot-search huggingface dataset:
Cellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC).
Authors: Chris Labaki, Michel Alchoueiry, Kevin Bi, Long Zhang, Charbel Hobeika, Ziad Bakouny, Nourhan El Ahmar, Sayed Matar, Carmen Priolo, Damir Khabibullin, Nicholas R. Schindler, Sabrina Yvonne Camp, Renee Maria Saliby, Eddy Saad, Sabina Signoretti, Eliezer Mendel Van Allen, Sachet A Shukla, Elizabeth Henske, Toni K. Choueiri, David A. Braun
Journal: Journal of Clinical Oncology (2024)

476 Background: ChRCC is a rare form of kidney cancer with a poor prognosis in the metastatic setting, in part due to very limited responses to immune checkpoint inhibitors (ICIs), as compared to clear cell RCC (ccRCC). The mechanisms underlying the poor response of ChRCC to ICIs remain largely uncharacterized. We therefore investigated at the single-cell resolution the cellular and molecular determinants of anti-tumor immunity in ChRCC. Methods: ChRCC samples with matched normal kidney specimens were evaluated using single-cell RNA (scRNA-seq) and single-cell T-cell receptor (scTCR-seq) sequencing. Similar data (scRNA-seq and scTCR-seq) was obtained for ccRCC samples (Braun DA. et al., 2021). T cell clonotypes were inferred and classified into their degree of expansion (poorly, moderately and highly expanded). Diversity metrics (normalized Shannon’s entropy) were calculated. Using a previously described methodology (Young M.D. et al., 2018), the cell of origin (COi) of ChRCC was inferred from scRNA-seq data of normal kidney samples, followed by differential gene expression (DGE) and pathway analysis (DPA) between the putative COi and ChRCC cells to identify potential mediators of diminished immune responses. Immunohistochemistry (IHC) of ChRCC and ccRCC samples was used to assess CD8+ and PD-1+ immune cell populations. Results: Analysis of the scTCR-seq data identified a higher proportion of poorly expanded clonotypes in ChRCC as compared to ccRCC (p=0.05), along with a lower proportion of highly expanded clonotypes (p=0.07). Normalized (Shannon’s) entropy was found to be higher in ChRCC versus ccRCC (p&lt;0.05). Analysis of annotated scRNA-seq data identified a lower proportion of CD8+ and CD4+ T-cells among immune cells in ChRCC vs. ccRCC (44.6 vs. 9.6% and 12.3 vs. 3.2%, respectively). DGE between ChRCC and its putative COi (alpha-intercalated cell) showed a lower expression of HLA class I genes in ChRCC (p&lt;0.05). DPA showed a marked downregulation of antigen presentation and protein processing pathways in ChRCC (p&lt;0.05). IHC analysis showed a markedly low infiltration of CD8+ and PD-1+ immune populations in ChRCC, as compared to ccRCC. Conclusions: ChRCC cells have marked downregulation of HLA class I genes and antigen processing pathways related to their COi. Additionally, ChRCC tumors have poor infiltration of T-cells, which show a low degree of clonal expansion. These mechanisms may help to explain the limited anti-tumor immunity and ultimately, the poor response to ICIs seen among patients with ChRCC.
PRO-WAVE1: Monitoring patient reported outcomes (PROs) in prostate cancer through Wave Health, a novel ePRO health platform.
Authors: Diego Cacho, Belen Congregado, Ines Rivero Belenchon, Estefania Linares Espinos, Laura Basterretxea, Gemma Sancho, Nuria Lainez, David Buchser, Francesco Sanguedolce, Ibon Gurruchaga, Borja Gomez Mediavilla, Brigida Esteban, Amaia Hernandez, Matthew Lashey, Ignacio Duran
Journal: Journal of Clinical Oncology (2024)

114 Background: It is well established that the monitoring and evaluation of PROs in cancer patients has a positive impact in both quality of life and overall survival. 1 In parallel, the widespread use of electronic devices such as smart phones in the general population have increased significantly over recent years, 2 representing a unique opportunity to operationalize ePROs. However, there is uncertainty about the feasibility and applicability of these technologies in certain patient population such as prostate cancer (PC) patients. PRO-WAVE1 aims to determine the acceptability and engagement of the Wave Health patient app and healthcare provider portal, enhanced for PC patients. Specific endpoints include measuring longitudinal use of varying ePROs to impact care management, patient health literacy, and ability to identify and manage emerging risks. Methods: The study is underway across eight sites in Spain. Patient ePRO engagement is being evaluated through the administration of 19 ePRO questionnaires over the course of 13 weeks, including: health-related QoL (FACT-P); health literacy (CHLT-30-Dkspa); and weekly reviews of symptoms (WSR). Compliance rates per patient and per cohort will be reported at assessment time-points and for the entire study period. Secondary objectives evaluated include engagement with Wave Health App; changes in HRQoL; changes in health literacy; and the perceived value of the platform by patients and HCPs. Results: 98 patients were enrolled in the study. Patient cohort representation included: 44.9% mHSPC, 36.7% mCRPC, and 18.3% nmPC. Of the 98 patients, 84 successfully became active in the study and participated (85.7% acceptance). As of September 20, 2023, among the completed patients (N=46), the compliance rate for the ePRO questionnaires was 93.7%. During their participation, these patients used the app for an average of 12.2 weeks, and approximately two-thirds (67.4%) used the app for all 13 weeks. Weekly “usefulness” ratings among the HCPS averaged 3.6 (scale: 1 “not at all useful” to 5 “very useful”). Conclusions: Study results exceeded expectations for patient acceptability and engagement with the app; as well as perceived usefulness of the portal among HCPs – suggesting the platform as an impactful tool for patients working with HCPs to manage treatment journeys. A larger study using a comparator arm will help further evaluate the impact on costs and clinical outcomes. 1. Basch E., JAMA 2017. 2. Statista, 2023.
Baseline characteristics of patients with PSMA-PET–positive and –negative disease with high-risk of biochemical recurrence (BCR) after radical prostatectomy (RP) in the ongoing phase 3 PRIMORDIUM study.
Authors: Boris A. Hadaschik, Nicolas Mottet, Piet Ost, Cosimo De Nunzio, Nina Tunariu, Renata Zaucha, Klaus Brasso, Ignacio Osman-Garcia, Deniz Tural, Martin Lukac, Hind Stitou, Geneviève Pissart, Michela Efficace, Stefano Fanti
Journal: Journal of Clinical Oncology (2024)

119 Background: Positron emission tomography of radiolabeled prostate-specific membrane antigen (PSMA-PET) is more sensitive and specific than conventional imaging for the detection of lesions in patients with BCR prostate cancer. PRIMORDIUM (NCT04557059) includes standardized PSMA-PET imaging and enrolls PSMA-PET positive patients (≥1 locoregional lesion; interventional cohort) and PSMA-PET negative patients (no lesion; observational cohort); all patients are non-metastatic by conventional imaging at screening. Methods: We presented study methods at ESMO 2021 (Poster 649TiP). All patients enrolled in PRIMORDIUM have high-risk BCR (prostate specific antigen [PSA] doubling time ≤12 months or Gleason score ≥8) after RP. PSMA-PET-positive patients are randomized 1:1 to either the control arm (whole pelvic salvage radiotherapy [RT] + 6 months of luteinizing hormone-releasing hormone agonist [LHRHa]) or the interventional arm (RT + LHRHa + apalutamide 240 mg/day for 180 days); stereotactic body RT (SBRT) to ≤3 distant lesions is optional. PSMA-PET-negative patients are managed per routine clinical practice. Results: Key baseline characteristics of 198 enrolled patients at data cutoff (12-Jan-2023) are summarized in the table. Conclusions: The PRIMORDIUM study aims to evaluate the intensification of treatment with apalutamide for patients assessed with PSMA-PET. From 198 enrolled patients with high-risk BCR, positive PSMA-PET was documented in 44% of patients at a median of 39 months after RP and a median PSA of 0.51 ng/mL, while negative PSMA-PET was observed in 56% of patients at a median of 26 months after RP and a median PSA of 0.35 ng/mL. In this analysis, all PSMA-PET-positive patients had locoregional lesion(s) and 10% also had distant lesion(s) on PSMA-PET. Clinical trial information: NCT04557059 . [Table: see text]
Racial and ethnic differences in the receipt of metabolic syndrome risk factor screening and treatment among individuals with prostate cancer treated with androgen deprivation therapy.
Authors: Yazan K. Barqawi, Matthew E Borrego, Melissa H Roberts, Todd Thompson, Neda Hashemi-Sadraei
Journal: Journal of Clinical Oncology (2024)

29 Background: Racial and ethnic health disparities in prostate cancer screening, and treatment constitute the largest of all cancer disparities. Androgen deprivation therapy (ADT) is widely used in the treatment of localized or metastatic prostate cancer. However, ADT is associated with toxic cardiovascular and metabolic adverse events that may occur as early as 6 months of therapy initiation. This study aimed to assess racial/ethnic differences and longitudinal changes in metabolic syndrome risk factor (MSRF) screening/treatment among patients with prostate cancer treated with ADT at a university-affiliated comprehensive cancer center in the southwestern U.S. between 2010-2021. We also aimed to identify patient and healthcare provider factors that influence MSRF screening among study sample. Methods: A retrospective observational cohort study of 803 patients treated with ADT for at least six months at the cancer center was conducted. Patients were followed three months pre- to 12 months post-ADT initiation to evaluate MSRF screening/treatment. Determination of MSRF screening was based on primary care provider referral for MSRF screening/treatment or receipt of blood glucose, lipid profile, and blood pressure screening within six months post-treatment with ADT. Patients were considered treated for MSRF if they were started or continued therapy (within six months of ADT initiation) with science advisory guideline recommended treatments. Results: Guideline-concordant MSRF screening rate approached 23.5%; MSRF treatment rate was 76.9%. A higher treatment rate in MSRF treatment was found for NHW compared to Hispanic men ( p=0.02). We found a significant difference in the proportion of patients receiving MSRF screening across all racial/ethnic groups ( p=0.03). MSRF screening rates from 13.9% to 35.6% were observed over the 10-year data collection period. Patients with dyslipidemia at baseline had higher odds of having MSRF screening than patients without dyslipidemia ( p&lt;0.0001). Oncologists with &gt;20 years of experience had higher odds of providing MSRF screening compared with &lt;10 years of experience ( p=0.006). Conclusions: Minority populations had significantly lower odds of having MSRF screening than NHW patients after adjusting for clinical and socio-economic variables. Closer clinical attention and education, as well as the development and implementation of innovative practice tools and interventions to optimize MSRF screening and treatment are warranted to mitigate the harmful adverse effects of ADT in patients with prostate cancer.
Disparities in prostate cancer mortality and clinical trial availability across vulnerable populations.
Authors: Rishi Sekar, Todd Matthew Morgan, Lauren P. Wallner, Kristian Stensland, Lindsey A. Herrel
Journal: Journal of Clinical Oncology (2024)

24 Background: Clinical trials provide high-level evidence and test novel therapies that have significantly improved cancer outcomes. However, disparities in clinical trial participation and cancer mortality persist across race/ethnicity and vulnerable populations, notably in patients with prostate cancer (PCa). Adverse social determinants of health (SDOH) and systemic barriers may underlie these disparities. Identifying and overcoming these barriers may improve access to and representation in clinical trials, thereby promoting equitable advancement and applicability of science. For these reasons, we evaluate the association between clinical trial availability, cancer mortality, and population-level SDOH in PCa. Methods: Using custom data linkage from ClinicalTrials.gov, Surveillance Epidemiology and End Results (SEER) Registry, and the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), we performed a cross-sectional analysis of county-level PCa clinical trial data, cancer incidence and mortality rates, and population-level SDOH. We included Phase 2 and Phase 3 interventional PCa clinical trials with start dates from 2007 to 2022. The total number of clinical trials over the study period was calculated per county and population-adjusted for 100,000 residents. Counties were stratified into quintiles based on SVI (i.e., least vulnerable to most vulnerable). Population-adjusted clinical trial availability, cancer incidence, and cancer mortality were compared across SVI quintiles. Multivariable logistic and linear regression analyses were performed to evaluate the association between SVI and clinical trial availability and cancer mortality, respectively. Results: The mean number of PCa trials per 100,000 residents was 25.6, with the most vulnerable counties having fewer clinical trials compared to the least vulnerable counties (mean 18.1 vs. 50.0, p&lt;0.05). Further, the most vulnerable counties had a lower PCa incidence rate per 100,000 residents (mean 393.8 vs. 411.7, p&lt;0.05), but a higher PCa mortality rate per 100,000 residents (mean 85.7 vs. 72.0, p&lt;0.05). On multivariable regression analysis, the most vulnerable counties were associated with significantly decreased odds of having any PCa clinical trial (OR 0.3, 95% CI 0.2 – 0.4) and significantly increased PCa mortality (10.8, 95% CI 7.4 – 14.3), while the presence of any PCa clinical trial was associated with significantly decreased PCa mortality (-6.9, 95% CI -9.1 – -4.7). Conclusions: The most vulnerable counties were far less likely to have any PCa clinical trials despite having a significantly higher PCa mortality rate. The presence of a PCa clinical trial was associated with a reduction in PCa mortality. These vulnerable counties represent scientifically underserved populations that may benefit from equity-driven clinical trial enrollment and cancer care infrastructure expansion.
Association of HER2 expression in advanced urothelial carcinoma (aUC) and treatment outcomes with immune checkpoint inhibitors and enfortumab vedotin.
Authors: Chase Allain Shipp, Tanya Jindal, Kevin R Reyes, Xiaolin Zhu, Chien-Kuang Cornelia Ding, Emily Chan, Bradley A. Stohr, Prianka Deshmukh, Kelly N. Fitzgerald, Daniel Kwon, Rohit Bose, Arpita Desai, Ivan de Kouchkovsky, Rahul Raj Aggarwal, Eric J. Small, Lawrence Fong, Sima P. Porten, Terence W. Friedlander, Jonathan Chou, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2024)

599 Background: HER2 immunohistochemistry (IHC) is not routinely assessed in patients (pts) with aUC, but it is an emerging predictive biomarker with the advent of HER2-targeting agents. aUC outcomes with respect to HER2 status following treatment with immune checkpoint inhibitors (ICIs) and enfortumab vedotin (EV) are unknown. Methods: We retrospectively identified pts with aUC and available biopsies tested for HER2 IHC and fluorescence in situ hybridization (FISH). HER2 status was assessed using modified GI criteria as HER2 high (IHC 3+ or IHC 2+/FISH+), HER2 low (IHC 2+/FISH- or IHC 1+) or HER2 negative (IHC 0). Pt characteristics and outcomes were abstracted from chart review. We compared outcomes following ICI monotherapy and EV-based regimens in pts with HER2-high or HER2-low tumors relative to HER2-negative, and HER2-positive (≥IHC 1+) tumors relative to HER2-negative. Observed response rate (ORR) evaluated by local investigator was compared in pts with scans after ≥1 treatment cycles using logistic regression, while progression-free survival (PFS) and overall survival (OS) from treatment start were assessed using the Kaplan-Meier method and Cox proportional hazards model. Results: Biopsies from 181 pts with aUC obtained from 3/2016 – 3/2023 were tested for HER2 (34 high, 88 low, 58 negative, 1 indeterminate). In this group, 43 pts received ICI [38 (88%) pembrolizumab; 5 (12%) atezolizumab] and 37 EV [31 (82%) monotherapy; 6 (18%) combination regimen]. Pt characteristics and outcomes are shown in the Table. Among pts treated with EV, HER2-negative pts had decreased PFS (HR: 0.18, 95% CI 0.03 – 0.94, p=0.04) relative to HER2-high. No other differences were noted for any cross-group comparison. For pts treated with ICI, no differences in outcomes were observed for any comparisons based on HER2 status. Conclusions: In this single institution retrospective analysis, pts with aUC and HER2-high IHC expression had longer PFS relative to pts with HER2-negative expression when treated with EV-based regimens. No differences were observed in ICI outcomes based on HER2 expression. These hypothesis-generating results should be validated in larger cohorts. [Table: see text]
The 340B Drug Pricing Program and oral specialty drugs for advanced prostate cancer.
Authors: Kassem S Faraj, Samuel Kaufman, Lindsey A. Herrel, Mary Oerline, Megan Veresh Caram, Vahakn B. Shahinian, Brent K. Hollenbeck
Journal: Journal of Clinical Oncology (2024)

26 Background: Oral specialty drugs like abiraterone and enzalutamide are increasingly used in the management of men with advanced prostate cancer. However, the costs of these drugs can pose barriers to access and continued use, particularly in the socioeconomically disadvantaged population. The 340B program allows participating hospitals to purchase these medications at steep discounts, generating millions of dollars in savings per hospital. These savings afford them the opportunity to invest in programs (e.g., drug discounts) aimed at expanding their safety net. We assessed the effect of 340B participation on the care of men with advanced prostate cancer. Methods: A 20% sample of national Medicare claims data was used to perform a retrospective cohort study of men with advanced prostate cancer from 2012 through 2019 who received their care at a hospital. The primary outcome was the initial use of an oral specialty drug for prostate cancer and secondary outcomes included associated monthly out-of-pocket costs and adherence to treatment. To account for heterogeneity, we evaluated the effects of 1) hospital 340B participation, 2) socioeconomic status, using the social vulnerability index (SVI), and 3) the interaction between hospital 340B participation and SVI on each outcome. Results: Of the men with advanced prostate cancer, 2,237 (67%) and 1,100 (33%) received care at 340B participating and non-participating hospitals. There was no difference in the use of an oral specialty drug in men who received care at a hospital participating and not participating in the 340B program (22% vs 23% p=0.63). Conversely, when assessing variation across SVI, use of an oral specialty drug decreased with increased SVI (i.e., increased vulnerability; OR 0.95, p=0.038). However, the interaction between hospital 340B participation and SVI did not affect oral specialty drug use. Neither 340B participation, SVI, nor their interaction affected patient out-of-pocket costs. Additionally, although neither hospital 340B participation or SVI affected adherence to treatment, the interaction between 340B participation and SVI was significant (OR 1.2, p=0.040). This demonstrated that 340B was associated with better adherence to treatment among more socially vulnerable men. Conclusions: The 340B program did not affect the frequency of men with advanced prostate cancer who were started on an oral specialty drug. However, among those who were already started on therapy, 340B was associated with increased adherence to treatment in more socially vulnerable men. The underlying mechanism by which this occurred was unclear. In light of growing calls from policymakers to reform the 340B program, due to concerns regarding its effectiveness, policymakers could initially shift focus towards providing hospitals with guidance on how to effectively use savings to benefit those most in need.
Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.
Authors: Ugo De Giorgi, Arun Azad, Karim Fizazi, Nobuaki Matsubara, Fred Saad, Jae Young Joung, Peter C.C. Fong, Robert J. Jones, Stefanie Zschaebitz, Jan Oldenburg, Neal D. Shore, Curtis Dunshee, Joan Carles, Andre P. Fay, Paul Cislo, Melissa Kirker, Cynthia G. Healy, Alexander Niyazov, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .