tbuckley/cabot-search huggingface dataset:
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: Gordon Andrew Brown, Shawn Du, Ibrahim Khilfeh, Carmine Rossi, Lilian Diaz, Frédéric Kinkead, Patrick Lefebvre, Dominic Pilon, Lorie Ellis, Benjamin H Lowentritt
Journal: Journal of Clinical Oncology (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&lt;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]
Real world data of 177 Lutetium-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC): Analysis of patients treated from 2 large reference centers.
Authors: Helena F. Bruzzi, Daniel Herchenhorn, Gabriela C. K. Lopes, Hannah Bekierman, Sergio Altino de Almeida, Camila Mosci, Chisthiane Magalhães, Isabella Palazzo, Laura Fernandes, Vinicius Freire, Juliana Tarouquella da Silva Andrade
Journal: Journal of Clinical Oncology (2024)

e17050 Background: 177 Lu-PSMA-617 was recently approved for the treatment of patients with mCRPC in the USA. While treatment is associated with improved survival, responses to therapy are lower in patients with visceral metastasis and with FDG avid disease. In this study, we aim to characterize response to the therapy trying to optimize patient selection for 177 Lu-PSMA-617. Methods: Patients treated from 2020 to 2023 in 2 large oncology centers in Brazil were analyzed. Our primary endpoint was to investigate the PSA response rate. Secondary endpoints included overall survival (OS), time to next sequential therapies (TNST) and PSA response in patients with visceral disease. Patients were treated after being submitted to a double image consisting of PET-CT PSMA and a PET-CT FDG (as indicated by the TheraP trial, Hoffman et al.) confirming disease uptake without divergent disease. Results: A total of 32 patients with mCRPC were included in this analysis. The median age was 73 years. Median number of prior lines of therapy for mCRPC was 3 with 20 receiving more than one androgen receptor signaling inhibitor (ARSI) and 5 receiving more than one taxane. The percentage with a PSA response was 48,5% and visceral disease was present in 56,3% of patients. Response rate for pts with visceral disease versus non-visceral was 21,9% vs 43,8%. The Medians of TNST and OS were respectively 7 and 9,6 months. The characteristics of patients with and without a PSA response are detailed in the table. Conclusions: Our cohort, characterized by advanced age, extensive prior treatments, and elevated PSA values, exhibited a PSA response that aligns with patients treated in randomized trials. Notably, our patients with visceral disease demonstrated a lower PSA response. [Table: see text]
A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial.
Authors: Fernando Cotait Maluf, Karine Trindade, Daniel D Almeida Preto, Fernando Sabino Marques Monteiro, Murilo Luz, Patricia Milhomem Beato, Diogo Assed Bastos, Joao Paulo Holanda Soares, Victor Marcondes Lopes dos Santos, Luis Eduardo Werneck De Carvalho, David Queiroz Borges Muniz, Douglas Racy, Susan Halabi, Taiane Francieli Rebelatto, Gustavo Werutsky, Rafaela Gomes de Jesus, Andre P. Fay
Journal: Journal of Clinical Oncology (2024)

5009 Background: Over the last six decades, platinum-based chemotherapy has been the standard of care first-line treatment for advanced penile squamous cell carcinoma (PSCC). Advanced PSCC has poor prognosis with limited treatment options. Immune checkpoint inhibitors (ICI) have been associated with improved efficacy in different types of malignancies, however the benefit in PSCC is uncertain. Methods: LACOG 0218 ( NCT04224740 ) is a phase II single arm trial evaluating pembrolizumab plus platinum-based chemotherapy as first-line treatment in advanced PSCC. Patients (pts) with metastatic or locally advanced disease (recurrent or TanyN3M0 or T4NanyM0) not amenable to curative-intent therapy received: 5-FU 1000mg/m²/day IV D1-D4; cisplatin 70mg/m² (or carboplatin AUC 5) IV D1; and pembrolizumab 200mg IV D1 every 3 weeks (Q3W) for 6 cycles, followed by pembrolizumab 200mg IV Q3W up to 34 cycles. The primary endpoint is confirmed overall response rate (cORR) assessed by investigator (INV) according to RECIST 1.1. Considering a drop-out rate of 10%, 33 patients were required to reject the null hypothesis that ORR is 20% or less, if the true ORR is 40% (two-sided alpha level of 0.10, power 78.5%). Results: From Aug2020 to Dec2022, 37 pts were enrolled in 11 Brazilian centers and 33 pts were eligible for efficacy analysis. Median age was 56y (range, 30-76), 64.9% of pts had metastatic disease, 21.6% had recurrent disease, and 13.5% had locally advanced disease. Efficacy results are presented in the table. cORR by INV was 39.4% (95% CI 22.9-57.9); with 1 complete response and 12 partial responses. cORR INV according to PD-L1 status (66.7% in CPS 0% vs. 33.3% in CPS≥1%); TMB status (75% in high vs. 36.4% in low); and HPV16 status (HPV16 positive 55.6% vs. 35.0%). The most frequent genomic alterations detected by NGS were: TP53(57.1%), CDKN2A (51.4%), and TERT (31.4%). Treatment-related adverse events (AE) rate of any grade was 91.9% and grade 3-4 was 51.4%. Ten pts experienced Grade 5 AE, none of them related to study treatment. Immune-related AEs of any grade was 21.6% and grade 3-4 was 5.4%. 10.8% discontinued treatment due to AE. Conclusions: HERCULES is the first trial to demonstrate the efficacy of ICI in advanced PSCC with manageable safety profile. HPV16 and TMB are potential predictive biomarkers for efficacy. ICI combined with platinum-based chemotherapy is a promising treatment for advanced PSCC warranting further investigation. Clinical trial information: NCT04224740 . [Table: see text]
Triplet therapy in metastatic hormone-sensitive prostate cancer: A real-world Indian multicentre study.
Authors: Debapriya Mondal, Somnath Roy, Arnab Bhattacharjee, Rakesh Roy, Suman Meyur, Bivas Biswas
Journal: Journal of Clinical Oncology (2024)

e17086 Background: The survival benefit of upfront triplet therapy in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been demonstrated in two prospective randomised trials using a combination of androgen deprivation therapy (ADT), docetaxel and an androgen receptor signalling inhibitor (ARSi) among abiraterone or darolutamide. This study aimed to evaluate the real-world outcomes of first-line triplet therapy in treating Indian mHSPC patients. Methods: In this multicentre retrospective study, patients with mHSPC started on upfront triplet therapy at three Eastern Indian centres between May 2022 and December 2023 were included. Patients were included if they received at least one cycle of triplet therapy. Descriptive statistics were used for reporting baseline patient and disease characteristics, treatments, and adverse events. Kaplan-Meier and life-table analyses were used for survival estimates. Results: Fifty-eight patients with mHSPC were included in this study. Most of the patients had de novo metastatic disease (93.1%). The mean age was 64 years (range 49-82), and the majority had Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (90%). High-volume disease was present in 94.8%, and 69% of patients had a Gleason score of 8 or higher. Comorbidities were present in 89.7% (2 or more in 37.9%). All the patients received a triplet combination of docetaxel, ADT, and abiraterone. The median number of triplet cycles received was 6. Grade 3 or worse adverse events occurred in 22.4% of patients without any treatment-related deaths. The most common grade ≥3 adverse events were hypertension (6.9%), febrile neutropenia (5.2%), hyperglycemia (5.2%), and urinary tract infection (3.4%). Dose reduction was required in 24.1%. Undetectable PSA (&lt;0.2 ng/mL) as response was achieved in 62%. The 12-month overall survival rate was 98.3%, and the 12-month biochemical progression-free survival rate was 96.6%. Conclusions: First-line triplet therapy in Indian mHSPC patients was effective and tolerable with rare serious adverse events.
Assessing calibration and bias of a deployed machine learning malnutrition prediction model within a large healthcare system
Authors: Lathan Liou, Erick Scott, Prathamesh Parchure, Yuxia Ouyang, Natalia Egorova, Robert Freeman, Ira S. Hofer, Girish N. Nadkarni, Prem Timsina, Arash Kia, Matthew A. Levin
Journal: npj Digital Medicine (2024)

Abstract Malnutrition is a frequently underdiagnosed condition leading to increased morbidity, mortality, and healthcare costs. The Mount Sinai Health System (MSHS) deployed a machine learning model (MUST-Plus) to detect malnutrition upon hospital admission. However, in diverse patient groups, a poorly calibrated model may lead to misdiagnosis, exacerbating health care disparities. We explored the model’s calibration across different variables and methods to improve calibration. Data from adult patients admitted to five MSHS hospitals from January 1, 2021 - December 31, 2022, were analyzed. We compared MUST-Plus prediction to the registered dietitian’s formal assessment. Hierarchical calibration was assessed and compared between the recalibration sample (N = 49,562) of patients admitted between January 1, 2021 - December 31, 2022, and the hold-out sample (N = 17,278) of patients admitted between January 1, 2023 - September 30, 2023. Statistical differences in calibration metrics were tested using bootstrapping with replacement. Before recalibration, the overall model calibration intercept was −1.17 (95% CI: −1.20, −1.14), slope was 1.37 (95% CI: 1.34, 1.40), and Brier score was 0.26 (95% CI: 0.25, 0.26). Both weak and moderate measures of calibration were significantly different between White and Black patients and between male and female patients. Logistic recalibration significantly improved calibration of the model across race and gender in the hold-out sample. The original MUST-Plus model showed significant differences in calibration between White vs. Black patients. It also overestimated malnutrition in females compared to males. Logistic recalibration effectively reduced miscalibration across all patient subgroups. Continual monitoring and timely recalibration can improve model accuracy.
Revisiting Cardiac Biology in the Era of Single Cell and Spatial Omics
Authors: Jack A. Palmer, Nadia Rosenthal, Sarah A. Teichmann, Monika Litvinukova
Journal: Circulation Research (2024)

Throughout our lifetime, each beat of the heart requires the coordinated action of multiple cardiac cell types. Understanding cardiac cell biology, its intricate microenvironments, and the mechanisms that govern their function in health and disease are crucial to designing novel therapeutical and behavioral interventions. Recent advances in single-cell and spatial omics technologies have significantly propelled this understanding, offering novel insights into the cellular diversity and function and the complex interactions of cardiac tissue. This review provides a comprehensive overview of the cellular landscape of the heart, bridging the gap between suspension-based and emerging in situ approaches, focusing on the experimental and computational challenges, comparative analyses of mouse and human cardiac systems, and the rising contextualization of cardiac cells within their niches. As we explore the heart at this unprecedented resolution, integrating insights from both mouse and human studies will pave the way for novel diagnostic tools and therapeutic interventions, ultimately improving outcomes for patients with cardiovascular diseases.
Impact of alterations in tumor suppressor genes (TSG-alt) on survival outcomes in patients (pts) with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) receiving androgen deprivation therapy (ADT) with androgen receptor pathway inhibition (ARPI) or docetaxel.
Authors: Arshit Narang, Ryon P Graf, Georges Gebrael, Chadi Hage Chehade, Gerald Li, Zeynep Irem Ozay, Archisman Mazumder, Vinay Mathew Thomas, Benjamin L. Maughan, Rana R. McKay, Emmanuel S. Antonarakis, Umang Swami, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

5091 Background: TSG-alt have been associated with poor survival in the mCRPC setting (PMID: 31061129) and in the mCSPC setting from small single institution cohorts (PMID: 34294873). However, large studies evaluating their impact on survival outcomes with ADT intensification in mCSPC setting are lacking. Herein, we evaluate the impact of TSG-alt on outcomes in a large real-world patient population with dn-mCSPC receiving ADT treatment (Rx) with ARPI or docetaxel. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine Prostate Cancer clinical-genomic database (FH-FMI CGDB), with de-identified data originating from approximately 800 US cancer clinics. Inclusion criteria: dn-mCSPC, tissue biopsy within 90 days of diagnosis, and initiation of ARPI or docetaxel + ADT within 120 days of diagnosis. Time to castration-resistance (TTCR) and overall survival (OS), indexed from metastatic diagnosis, were evaluated with Cox proportional hazards models adjusted for baseline prognostic factors (PSA, Gleason score, age, ECOG, hemoglobin, alkaline phosphatase, and albumin). OS risk intervals were left truncated to date of comprehensive genomic profiling report to adjust for immortal time bias. Results: Of 5356 pts in FH-FMI CGDB, 571 met inclusion criteria. Of these, 321 received ADT + ARPI and 250 ADT + docetaxel. Pts with pathogenic TSG alt were: 214 TP53 (37%), 154 PTEN (27%), and 37 RB1 (6%). Results are summarized in Table. Conclusions: In this real-world analysis, alt RB1 and alt TP53 had worse OS than their respective wild-type (wt) counterparts with both ARPI and docetaxel whereas alt PTEN had similar OS with ARPI and Docetaxel in dn-mCSPC pts. Based on these results, RB1 and TP53 may represent prognostic biomarkers guiding treatment selection and clinical trial enrollment in dn-mCSPC and may assist with counseling and prognostication. [Table: see text]
Clinical and genomic landscape of neuroendocrine prostate cancer (NEC) vs. prostate adenocarcinoma (AdenoK).
Authors: Georges Gebrael, Micah Ostrowski, Jessica Williams, Chadi Hage Chehade, Arshit Narang, Zeynep Irem Ozay, Neal Shiv Chawla, Vinay Mathew Thomas, Alex Chehrazi-Raffle, Umang Swami, Neeraj Agarwal, Benjamin L. Maughan
Journal: Journal of Clinical Oncology (2024)

5026 Background: NEC represents an aggressive form of prostate cancer, characterized by a high incidence of visceral metastases and a poor prognosis [PMID: 23169519]. A previous study has shown that, in a cohort of 30 patients (pts) with NEC, there was a significant enrichment for the loss of RB1 and the mutation or deletion of TP53 in these pts compared to those with AdenoK [PMID: 26855148]. Herein, we sought to compare the genomic landscape of pts with NEC to those with AdenoK using a large real-world genomic dataset. Methods: In this IRB-approved retrospective study, the de-identified Tempus Lens dataset was used to identify patients diagnosed with NEC and AdenoK across all stages and having comprehensive genomic profiling (CGP). Baseline demographic information was collected. Pathological variables were summarized using descriptive statistics to compare the NEC and AdenoK groups, using the Chi-square test with a significance threshold of P &lt; 0.05. Genomic alterations with an incidence of ≥ 5% were included in the analysis. Homologous recombination repair (HRR) alterations in 14 pre-specified genes per the olaparib FDA label were also compared between both groups. Results: A total of 13,683 pts (AdenoK: 13472; NEC: 211) were included in the analysis. The median age of the NEC cohort was 65 [24 – 90+], with 55.9% of pts identified as White. Of pts with NEC, 37.9% were never smokers, while 32.7% were ex-smokers. In the AdenoK cohort, the median age was 66 [21- 90+], with 45.4% of patients identified as White. 36.62% of pts never smoked and 29.33% were ex-smokers. In the NEC cohort, the three most common alterations were TP53(63.98%), RB1(53.08%), and PTEN(28.91%). Compared to AdenoK, the NEC cohort had a significantly higher prevalence of TP53 (63.98 vs 34.97%; P&lt;0.001), RB1 (53.08 vs 6.09%; P&lt;0.001), PTEN (28.91 vs 18.1%; P&lt;0.001), BRCA2(15.17 vs. 10.05%; P=0.01), TMPRSS2-ERG(25.12 vs. 19.29%; P=0.03), MYC(7.11 vs. 2.78%; P &lt; 0.001), CDKN1B(6.16 vs. 2.11%; P &lt; 0.001), and a lower frequency of SPOP (2.84 vs 9.22%; P=0.01), and ATM (6.64 vs 12.33%; P=0.01). HRR alterations frequency was similar between the NEC and AdenoK, respectively (38.83 vs. 38.66%, P=0.73). Conclusions: This is the largest real-world study characterizing the genomic features of prostate NEC compared to AdenoK. Our findings are consistent with prior studies suggesting a distinct genomic profile of NEC. These data can help in an improved understanding of the genetic drivers of this aggressive form of prostate cancer.
Targeting the CD47/TSP-1 axis: A promising strategy for patients with ovarian cancer (OC) that relapses on PARP inhibitors (PARPi).
Authors: Alexandra Leary, Albin Jeanne, Marion Etiennot, Aubéri Henry, Coralie Drelon, Christophe Schneider, Aurélie Moniot, Stéphane Dedieu
Journal: Journal of Clinical Oncology (2024)

5568 Background: There is an urgent need for novel therapies for patients relapsing post-PARPi. CD47 is an attractive target due to its overexpression in OC, particularly under PARPi treatment, and its association with shorter survival and immune evasion. While most studies have focused on the CD47/SIRPa interaction (“don’t eat me” signal), our recent data from the randomized CHIVA trial (NCT01583322) uncovered the relevance of TSP-1, a matrix glycoprotein associated with poor prognosis, as a primary CD47-interacting ligand [ASCO 2023]. The TAX2 peptide selectively disrupts TSP-1 binding to CD47. Our aim was to investigate whether inhibiting the CD47/TSP-1 axis with TAX2 could overcome PARPi resistance in a syngeneic mouse model of BRCA2 mutant OC. Methods: Biodistribution studies of fluorescent TAX2 peptide were carried out in mice bearing ovarian tumors tracked through fluorescence molecular tomography. To assess the efficacy of TAX2 and/or PARPi (olaparib) treatment, we used ID8 cells harboring Trp53 -/- and Brca2 -/- mutations, as a pertinent syngeneic representation of intraperitoneal high-grade serous TP53 and BRCA2 mutated OC. Olaparib was administrated at 50 mg/kg orally daily, while TAX2 was administrated at 30 to 100 mg/kg intravenously thrice weekly. Survival curves were compared using the Gehan-Breslow-Wilcoxon's test. Results: We confirmed that TAX2 peptide binds directly to human TSP-1 with K D of 11 µM. In mice bearing tumors, TAX2 correlated with TSP-1 expression with prolonged accumulation at tumor sites, but none in healthy tissues. Using a relevant peritoneal carcinomatosis model exhibiting PARP inhibitor resistance, we demonstrated that administration of TAX2 alone significantly extended survival. Interestingly, post-olaparib administration of TAX2 substantially reduced tumor burden, even at the lowest TAX2 dosing, and prolonged survival (median survival: 44 vs 38 days). Remarkably, sequential use of TAX2 increased animal survival even under treatment conditions allowing olaparib efficacy. Indeed, post-olaparib discontinuation, mice survival increased from 10.6 to 15.7 days with administration of TAX2. This sequential approach improved the median survival to 56 days. Conclusions: Our findings propose TAX2 as a promising strategy for patients relapsing on PARP inhibitors. TAX2 displayed a selective biodistribution pattern in mice, concentrating at tumor sites. Our study showcased that while TAX2 alone exhibited significant but modest activity in PARPi-naive mice, its efficacy significantly increased post-PARPi exposure, irrespective of PARPi duration. A first in human trial in the post-PARP setting is planned.