tbuckley/cabot-search huggingface dataset:
Homologous recombination repair (HRR) alterations may be passenger events in patients with advanced prostate cancer (PC) with high tumor mutational burden (hTMB).
Authors: Vineel Bhatlapenumarthi, Navonil De Sarkar, Anannya Patwari, Emmanuel S. Antonarakis, Ariel Ann Nelson, Deepak Kilari
Journal: Journal of Clinical Oncology (2024)

206 Background: HRR and microsatellite instability-high (MSI-H) alterations (alt) are typically mutually exclusive in pan-cancer cohorts. However, in PC 12.8% of BRCA1 and 3.4% of BRCA2 genomic alteration(alt) (Loss of function mutation or copy loss) co-occurred with MSI-H (PMID: 35772050) but were not associated with elevated genome-wide loss of heterozygosity (gLOH), suggesting that BRCA1/2 alt are likely ‘passenger’ events in the presence of MSI-H. further characterize this potential bystander phenomenon, we hypothesized that patients (pts) with HRR alt occurring in the context of hTMB will lack functional HRD signatures. Methods: We queried the Stand Up to Cancer (SU2C) East Coast Dream Team’s exome dataset (N=429) to identify pts with hTMB and at least monoallelic HRR alterations. Demographics, treatment, and outcome data were also collected. Adopting the approach per PMID: 34877933, we derived CSig3 (a COSMIC single-base-substitution mutational signature indicative of HR dysfunction [HRD]) and iHRD (a functional signature of HR deficiency developed by our group) in this subset to evaluate HRR functional activity. Results: 18 men with hTMB (&gt;10mut/Mb) and concurrent HRR alt were identified in SU2C. Of those, 9 had biallelic, and 9 had monoallelic HRR alt. 22% had biallelic BRCA2, 22% had biallelic RAD and 39% had monoallelic BRCA2 alt. However, only 33% of these HRR-altered tumors were CSig3(+)/iHRD(+) (5 biallelic and 1 monoallelic HRR alt) and 67% were negative for both signatures (4 biallelic, 8 monoallelic HRR alt), indicating that the HRR alt in these instances are likely bystander events. In all of the CSig3(+)/iHRD(+) cases, TMB ranged between 10-20 mut/Mb, whereas when TMB was &gt;20 mut/Mb, those tumors were invariably CSig3(-)/iHRD(-). None of these pts in the SU2C cohort were treated with Immune checkpoint inhibitors or PARPi. Conclusions: In PC pts with hTMB and concurrent HRR mutations, it is more likely that the HRR alteration is a ‘passenger’ event, and the likelihood increases as TMB rises above &gt;20 mut/Mb. HRD signature (-) hTMB pts are unlikely to respond to PARPi monotherapy, even if they have a concurrent HRR alt. HR functional signatures such as CSig3 or iHRD could be utilized in treatment selection and to avoid diagnostic dilemmas.
Detection of neuroendocrine prostate cancer through plasma-based epigenomic profiling.
Authors: Marc Eid, Karl Semaan, Ji-Heui Seo, Matthew P. Davidsohn, Brad Fortunato, Gitanjali Lakshminarayanan, Talal El Zarif, Hunter Savignano, John Canniff, Renee Maria Saliby, Eddy Saad, Mark Pomerantz, Sylvan Baca, Matthew Freedman, Jacob E Berchuck, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2024)

201 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive resistance phenotype that can develop in men with metastatic prostate adenocarcinoma (PRAD). Early detection of NEPC has prognostic and therapeutic implications, but is challenging due to spatial heterogeneity, sampling error associated with tissue biopsy, and a lack of distinguishing genetic mutations that can be assessed from cell-free DNA (cfDNA). Herein, we introduce a novel epigenomic-based approach to non-invasively identify NEPC from cfDNA. Methods: Plasma was collected from patients with NEPC and PRAD at the Dana-Farber Cancer Institute. Chromatin immunoprecipitation and sequencing on cfDNA (cfChIP-seq) was performed on 1mL of plasma for the post-translational histone modifications H3K4me3 and H3K27ac. Activity of gene promoters and enhancers was inferred based on H3K4me3 and H3K27ac cfChIP-seq signal normalized to signal at constitutively active regulatory elements. A classifier was built to distinguish NEPC from PRAD based on H3K27ac signal at a published set of regulatory elements with increased chromatin accessibility in neuroendocrine tumors compared to adenocarcinomas (NE-REs). The classifier performance was evaluated using the area under the receiver operating characteristic (AUROC) curve. Results: Our cohort included 30 patients, 10 with NEPC and 20 with PRAD. H3K4me3 signal at the promoter of chromogranin A ( CHGA), a diagnostic marker gene of NE-differentiation, was significantly elevated in plasma from patients with NEPC vs. PRAD (p=4x10 -11 , Wilcoxon rank-sum test). H3K27ac signal at binding sites for ASCL1, a master transcription factor driving NE-differentiation, was significantly elevated in NEPC vs. PRAD plasma samples (p=7.2x10 -5 , Wilcoxon rank-sum test). H3K27ac signal at NE-REs accurately distinguished patients with NEPC from patients with PRAD with an AUROC curve of 0.97. Conclusions: We present a non-invasive approach to identify NE-differentiation in patients with metastatic prostate cancer using 1mL of plasma. This method could help overcome practical challenges associated with NEPC detection and further guide therapy selection.
A multicohort phase 2 trial of ADT, docetaxel plus nivolumab in patients with de novo metastatic hormone-sensitive prostate cancer enriched for inflamed tumors and DNA damage repair defects.
Authors: Xiao X. Wei, Wanling Xie, Jad Chahoud, Hamid Emamekhoo, Rana R. McKay, Catherine Handy Marshall, David Johnson Einstein, Joshua Michael Lang, Sarah Raymond, Daniel Aaron Roberts, Rajitha Sunkara, Praful Ravi, Alok Tewari, Mark Pomerantz, Fei Dong, Stephanie Siegmund, Scott J. Rodig, Kathleen L. Pfaff, Christopher Sweeney, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2024)

TPS244 Background: Intensification of upfront treatment with the addition of docetaxel chemotherapy and/or a novel androgen signaling inhibitor to androgen deprivation therapy (ADT) have improved clinical outcomes for patients with de novo metastatic hormone sensitive prostate cancer (mHSPC). However, most patients develop castration resistance, the lethal form of disease. ADT early in the hormone-sensitive setting and docetaxel may have immunostimulatory effects which sensitize tumors to immune checkpoint blockade. Immunotherapy may be most effective in patients with pre-existing antitumor immunity or DNA damage repair defects (DDRD). Methods: We are conducting a multicenter, multicohort, phase 2 clinical trial of ADT, docetaxel, plus nivolumab in patients with de novo mHSPC. Cohort allocation is assigned based on tumor PD-L1 and CD8 staining by a multiplexed immunofluorescence platform (ImmunoProfile), and DDRD status on a targeted cancer next-generation sequencing panel (OncoPanel). Planned enrollment goal is 60 patients (20 patients per cohort; Table). Eligible patients must have newly diagnosed metastatic prostate cancer on conventional imaging, ECOG performance status 0-2 (ECOG 2 allowed if attributed to metastatic disease), PSA &gt;4.0 ng/mL before ADT initiation, adequate organ function, and be candidates for docetaxel chemotherapy. Patients are allowed to receive up to 140 days of ADT prior to C1D1 study treatment. All patients receive continuous ADT, docetaxel 75 mg/m 2 plus nivolumab 360mg IV Q3W for 6 cycles, followed by nivolumab 480mg IV Q4W for up to 2 years. After January 2022, the addition of standard of care abiraterone/prednisone was allowed after 7 months of study treatment at investigator discretion. The primary endpoint is PSA ≤ 0.2 ng/mL at 7 months from initiation of chemoimmunotherapy. Key secondary endpoints include PSA ≤ 0.2 ng/mL during chemoimmunotherapy, time to castration resistance, time to clinical progression, time to PSA progression, objective response rate, overall survival, and safety. Planned exploratory analysis include profiling circulating tumor cell (CTC) enumeration and analysis of PD-L1 and HLA I expression on CTCs. The first patient was enrolled on 5/4/2020, and 45/60 patients have been enrolled to date (N=7 in Cohort 1, N=18 in Cohort 2, and N=20 in Cohort 3). Study enrollment is ongoing. Clinical trial information: NCT04126070 . [Table: see text]
Outcomes of enfortumab vedotin (EV) therapy in relation to prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial cancer (aUC).
Authors: Evangelia Vlachou, Roy Elias, Noah M. Hahn, David James McConkey, Burles Avner Johnson, Jean H. Hoffman-Censits
Journal: Journal of Clinical Oncology (2024)

570 Background: EV is FDA approved for the treatment of aUC after disease progression with chemotherapy and/or ICI, and in combination with Pembrolizumab (P) for cisplatin ineligible pts in the first line. Reported response rate (RR) for EV+P is higher than EV alone and a retrospective study showed prior ICI is associated with higher grade of EV-related skin toxicity, suggesting immunogenic interaction. Herein we evaluated whether prior ICI correlates with improved response to EV monotherapy. Methods: This single-center retrospective study compared outcomes between pts with aUC who were treated with ICI immediately prior to EV (iICI) vs pts who did not receive immediate prior ICI (niICI). We also evaluated outcomes in pts who received ICI at any time prior to EV, with or without intervening treatments, compared to pts who never received ICI. Demographics and treatment details were extracted through chart review. RR (Complete Response + Partial Response) were compared between groups using χ 2 test. Univariable and multivariable Cox regression models were used for comparing Progression free (PFS) and Overall (OS) survival. Multivariable models were adjusted for visceral metastasis presence and performance status (PS) at EV initiation (C1D1). Results: We identified 55 pts in the iICI group and 23 in the niICI. Table 1 summarizes patient characteristics. ICIs included Pembrolizumab, Atezolizumab, Nivolumab, and Avelumab. Median PFS for EV was 5.0 vs 2.0 months and OS 11.0 vs 7.1 months in iICI vs niICI group respectively. A statistically significant Hazard Ratio (HR) for PFS [HR: 1.72, 95% Confidence Interval (95CI): 1.03, 2.89, P=0.04] and OS (HR: 2.02, 95CI: 1.13, 3.60, P=0.02) was found in the univariable analysis. In the multivariable analysis HR was 1.56 (95CI: 0.91, 2.68, p= 0.11) for PFS and 1.79 (95CI: 0.97, 3.30, p=0.06) for OS. RR to EV was 43.6% (95CI: 0.33, 0.56) vs 43.5% (95CI: 0.14, 0.69), P= 0.99. In our cohort 70/78 (89.7%) pts received ICI prior to EV with or without intervening treatments. When comparing these pts to pts who never received ICI no significant difference was found in PFS, OS or RR. Conclusions: In our study, EV was associated with longer PFS and OS when given immediately after ICI compared to following other therapies. However, in the most parsimonious model examined, the p-value did not reach a significance threshold of p&lt;0.05. Larger prospective studies are needed to better understand the mechanism behind this trend and identify the optimal sequence or combination of EV with other treatments in aUC. [Table: see text]
Characterizing longitudinal molecular changes in ctDNA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Eli Tran, Chinmay Jani, Nicole Zhang, Jill Tsai, Elizabeth Pan, Justine Panian, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

205 Background: Next-generation sequencing (NGS) of ctDNA is a novel technology that can complement tumor tissue NGS and has the potential to inform prognosis, treatment (tx) selection, and real time evolution of tumor molecular alterations. While tx options for pts with mCRPC have advanced, tx resistance is inevitable. Our real-world evidence study aims to evaluate longitudinal molecular changes in ctDNA following systemic tx to inform sequential tx strategies for pts with mCRPC. Methods: We interrogated data from GuardantINFORM, a clinical-genomics database with ctDNA molecular information and structured commercial payer-claims data. We conducted genetic mutations analysis in pts diagnosed with prostate cancer both before and after Androgen Receptor Signaling Inhibitors (ARSi), Poly(ADP‐ribose) Polymerase Inhibitors (PARPi), and taxanes. The post-tx analysis was performed on samples collected within 3 months of tx discontinuation prior to initiation of a subsequent tx as a proxy of disease progression. Mann-Whitney test was conducted to assess the differences in mutations observed pre and post tx. We also examined the association between ctDNA burden and overall survival (OS). Results: Overall, from a database of 21,682 patients with prostate cancer, following the above filters, we analyzed 145 pts with paired pre / post-ARSI, 54 with paired pre / post-PARPi, and 115 with paired pre / post-taxane samples. Table highlights the most commonly altered genes prevalent in post-tx samples. The most frequent (%pre/%post) AR alterations post-ARSI included AR amplifications (11%/23%), AR T878A (5%/9%), AR L702H (2%/6%), AR H875Y (0.7%/1.4%), and AR F877L (0%/1.4%). The most frequent HRR alterations post PARPi included ATM (25%/25%), BRCA2 (25%/18%), BRCA1 (3%/5%), CDK12 (6%/5%), and PALB2 (3%/2%). All three tx exhibited a significantly higher prevalence of mutations post-tx (mean increase in alterations 0.3-1.3, p&lt;0.001 for all tx). Pts with higher ctDNA burden in pre-tx samples had worse OS compared to pts with low or undetectable burden. Conclusions: Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC. [Table: see text]
Peripheral blood cell counts as biomarkers of clinical benefit in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) receiving immune checkpoint inhibitor (ICI) combination (combo) therapies.
Authors: Ardit Feinaj, Kaizen Nathani, Amina Touma, Roy Elias, Maximilian Pallauf, Mark Christopher Markowski, Michael Anthony Carducci, Nirmish Singla, Yasser Ged
Journal: Journal of Clinical Oncology (2024)

446 Background: Numerous combos of ICIs and Tyrosine Kinase Inhibitors (TKIs) have received approval for the management of mccRCC. Specific peripheral blood cell counts reflect inflammation and impact anti-tumor immunity, and here we investigated their role as biomarkers of clinical benefit to ICI combos in RCC. Methods: We performed a retrospective study of 179 mccRCC patients treated with ICI combos ≥ 4 weeks (2013-2023), where we examined baseline and 6-week post-treatment Neutrophil to Lymphocyte ratio (NLR), Red cell Distribution Width (RDW), and eosinophil values. We categorized these values as High (H) or Low (L) based on baseline medians. Our analysis included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to next treatment (TNT). Kaplan-Meier methods and the log-rank test were used to evaluate time from start of ICI combos to the event of interest. Results: Our analysis included 111 eligible ICI-naïve mccRCC patients median age 63, 76% male. IMDC risk scores categorized 22% as favorable, 53% intermediate, and 25% poor risk. Treatment included 50 (45%) patients on ICI+ICI combos with a median therapy duration of 6.3 months, and 61 (55%) on ICI+TKI with a median duration of 8.8 months. In the ICI+ICI group, median OS was 28.2 months (95% CI 20.7-38.4), PFS 5.5 months (95% CI 3.7-7.8), and TNT 12.7 months (95% CI 7.4-20.4). In the ICI+TKI group, median OS was 21.7 months (95% CI 17.1-25.4), PFS 7.4 months (95% CI 5.6-11.1), and TNT 12.5 months (95% CI 9.7-16.4). The ORR was 38% in the ICI+ICI group, and 56% in the ICI+TKI group (p=0.062). No differences were seen with NLR. In the ICI+ICI group, higher baseline RDW levels were correlated with a shorter TNT, while higher eosinophil levels at week 6 were correlated with longer PFS and TNT (significant results highlighted in the table below). Conclusions: Eosinophil levels and RDW are potentially readily available biomarkers in the clinic for predicting and monitoring ICI combo treatment outcomes in mccRCC patients. Validation of these results in larger cohorts is warranted. [Table: see text]
11-Ketotestosterone and time to castration resistance in patients with recurrent non-metastatic prostate cancer receiving androgen deprivation therapy.
Authors: Chantal Guillemette, Cylia Dahmani, Patrick Caron, David Simonyan, Louis Lacombe, Armen G. Aprikian, Fred Saad, Michel Carmel, Simone Chevalier, Eric Levesque
Journal: Journal of Clinical Oncology (2024)

209 Background: The contribution of 11-oxygenated androgens to disease progression in men receiving androgen deprivation therapy (ADT) for recurrent non-metastatic prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the potent androgen receptor (AR) agonist 11-ketotestosterone (11KT), could serve as a potential predictor for the onset of castration resistance (CRPC). Methods: The multi-institutional prospective PROCURE cohort involves 2,026 patients who underwent radical prostatectomy for localized PCa. In this cohort, a subset of 145 patients who received ADT therapy for recurrent disease and had available plasma samples post-surgery were included in this study. The effect of therapy on steroid levels was assessed in paired samples obtained before and after the initiation of ADT (n=50), and samples from patients under combined ADT with AR pathway inhibitors, enzalutamide (n=10) and abiraterone (n =15). 11-oxygenated androgens (n=7) and canonical steroids, such as testosterone (T) and dihydrotestosterone (DHT), were quantified by mass spectrometry. Kaplan-Meier survival analyses were used to investigate relationships of androgen levels with the occurrence of CRPC. Results: 11-oxygenated androgens remained unaffected by ADT, which stands in contrast to the observed changes in T, DHT and other steroids. In men with castrated T levels, 11KT was the most abundant androgen. Elevated 11KT was associated with a sooner time to CRPC ( P=0.023). The 10-year CRPC event-free rate was 63% vs. 84% for 11KT levels above and below the median, respectively. The initiation of enzalutamide had no impact on 11-oxygenated androgen levels, whereas abiraterone significantly reduced 11KT levels owing to the adrenal origin of its precursor. Conclusions: Our findings indicate that 11KT is a significant component of the hormonal profile predictive of an earlier onset of CRPC and inhibition of its production by the CYP17A1 inhibitor abiraterone.
Avelumab first-line maintenance therapy for locally advanced/metastatic urothelial carcinoma: Results from the real-world US PATRIOT-II study.
Authors: Petros Grivas, Pedro C. Barata, Helen H. Moon, Shilpa Gupta, Thomas E. Hutson, Cora N. Sternberg, Jason Brown, Vaidehi Dave, Chad Downey, Alicia C. Shillington, Howard Katzenstein, Melissa Kirker, Sarah Hanson, Frank X. Liu, Valerie A. Morris, Abhijeet Bhanegaonkar, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2024)

697 Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance (AVE 1LM) + best supportive care (BSC) improved overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) with no disease progression following 4-6 cycles of platinum-based chemotherapy (PBC). PATRIOT-II aimed to describe real-world outcomes in pts with la/mUC treated with AVE 1LM who were progression-free after 1L PBC. We hypothesized that outcomes would be similar to those of JAVELIN Bladder 100. Methods: PATRIOT-II is an observational, retrospective study in US pts with la/mUC treated in geographically dispersed community and academic centers. Pts receiving AVE 1LM were eligible. Data were collected via medical records for a minimum of 52 weeks (wks) from AVE 1LM initiation. This analysis focuses on ≥24 wks post AVE 1LM initiation. Survival and safety outcomes were assessed; analyses are descriptive in nature. Results: 160 pts from 37 sites, a mix of oncology practices and community/academic centers, were included with median age, 70 (range, 40-90) years; 123 (77%) male; 118 (74%) White, non-Hispanic; 77 (49%) lower tract and 49 (31%) upper tract tumors; 119 (74%) ECOG PS 0/1; 70 (44%) and 51 (32%) known visceral (excluding bone) or non-visceral metastases (mets), respectively; 31 (19%) liver mets; and 64 (40%) creatinine clearance &gt;60 mL/min. 100 (62.5%) and 60 (37.5%) pts had received 1L cisplatin or carboplatin, respectively. 130 pts (objective response rate, 81% [complete response, 21; partial response, 109]) had an investigator-assessed response to 1L PBC. Pts initiated AVE 1LM at a median of 4 wks (IQR, 3-6) after PBC completion. At data cutoff, 120 pts (75%) had discontinued AVE 1LM, 89 (74% of 120) due to progression/adverse events (AEs)/other non-death related reasons. Median time on AVE 1LM was 4.1 months (mo) (IQR, 2.3-8.7); median follow-up time post AVE 1LM initiation was 11.5 mo (IQR, 7.5-16.3). Table shows OS and PFS data. Most common documented treatment-related AEs (any grade) included hypothyroidism (n=7 [4%]), anemia (n=6 [4%]), blood creatinine increased (n=6 [4%]), fatigue (n=6 [4%]), and nausea (n=6 [4%]). Grade 3+ AEs occurred in 19 (12%), with no Grade 5 AEs. No new safety signals were noted. Conclusions: Results complement JAVELIN Bladder 100 and align with other AVE 1LM real-world studies. Limitations include retrospective data, lack of randomization and central scan review, missing data, selection bias, and confounders. PATRIOT-II further supports the level I evidence for AVE 1LM as standard of care in la/mUC not progressing on 1L PBC. [Table: see text]
Dicycloplatin: Assessing the efficacy of a novel platinum analog for treatment of urothelial carcinoma of the bladder.
Authors: David Zekan, Barbara Jackson, Thomas F. Hogan, Stanley Kandzari
Journal: Journal of Clinical Oncology (2024)

689 Background: Platinum-based chemotherapies are a component of standard-of-care regimens for urothelial carcinoma (UC). These nephrotoxic drugs are often dose-limiting, with cisplatin and carboplatin most used. Dicycloplatin (DCP) has better solubility and stability, with comparable efficacy and better tolerability. Some suggest use of DCP as primary treatment for non-muscle-invasive bladder cancer. We exposed UC cell lines to DCP in vitro to assess efficacy. Methods: A high grade (IV) in vitro UC cell line (TCCSUP) was exposed to varying concentrations of cisplatin (0-600 ug/mL), carboplatin (0-600 ug/mL), oxaliplatin (0-4.0 ug/mL), and DCP (0-350 ug/mL). Grade II-IV cells were exposed to concentrations of DCP (0-350 ug/mL) to assess time- and concentration-dependence of growth inhibition, and intravesical simulation. Growth inhibition was determined following exposures of 24, 48, and 72 hours using exposure to a tetrazolium dye assessing mitochondrial dehydrogenase activity. Results: DCP, cisplatin, and carboplatin effectively achieved &gt;90% cell-kill at 72 hours. Concentrations of 325 ug/mL DCP, 50 ug/mL cisplatin, and 600 ug/mL carboplatin are sufficient for &gt;90% cell-kill, with cisplatin boasting highest kills at lowest concentration/time intervals. Dose- and time-dependent cell-kill were demonstrated at varying concentrations of DCP in grade II-IV cell lines, including cells exposed in a intravesical fashion. Conclusions: DCP has in vitro cell-kill efficacy in a time- and concentration-dependent manner in grade II-IV UC cell lines, showing promise for its IV, PO, and intravesical use for UC of the bladder in the primary and adjuvant/neoadjuvant setting. Animal studies are forthcoming to assess in vivo efficacy prior to proceeding with clinical trials.