tbuckley/cabot-search huggingface dataset:
Corrigendum to “Sustained release hydrogel for durable locoregional chemoimmunotherapy for BRAF-mutated melanoma” [Journal of Controlled Release 357 (2023) 655–668]
Authors: Jihoon Kim, Paul A. Archer, Margaret P. Manspeaker, Alexa R.C. Avecilla, Brian P. Pollack, Susan N. Thomas
Journal: Journal of Controlled Release (2024)
Genomic correlates of response and resistance to immune checkpoint inhibitors (ICI) in patients with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Nikhil Pramod, Vladimir Makarov, Scott Dawsey, Paul G. Pavicic, Ubenthira Patgunarajah, Monica Nair, Moshe Chaim Ornstein, Timothy D. Gilligan, Christopher Eing Wee, Amanda Nizam, Omar Y. Mian, Jane Nguyen, C. Marcela Diaz-Montero, Shilpa Gupta
Journal: Journal of Clinical Oncology (2024)

670 Background: Response rates with ICI are only about 20% in mUC and we lack validated biomarkers to select patients who are most likely to derive benefit from ICI. Programmed cell death ligand 1 (PD-L1) has not proven to be a useful biomarker. We need biomarkers of response and resistance to avoid nonbeneficial treatment (Tx) and spare the majority of pts who will not respond to ICI both physical and financial toxicity. Here we report tumor genomic correlates of response and resistance to ICI in pts with mUC. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received &gt; / = 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Of the 335 pts, 49 had pre-Tx archival formalin fixed paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as responders (R) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) (N = 23) or non-responders (NR) (Progressive Disease (PD)) (N = 26). Whole exome sequencing was performed from macro dissected tumors. Raw data in FASTQ format was aligned to GRCh38 human reference genome, somatic mutations were called by Mutect2 (part of GATK4) and allele-specific copy-number analysis was performed by applying the Facets and Gistic2 package. Results: Comparison of our cohort Tumor Mutation Burden (TMB) with mutation burden of 33 the cancer genome atlas (TCGA) cohorts shows close similarity to TCGA bladder urothelial carcinoma (BCLA). Median TMB in our cohort was 6.46 muts/Mb. In our cohort, TP53 hotspot mutations were found in 52% of the (R) cohort compared to 31% in the (NR) cohort. Additionally, mutations in KMT2C and KMT2A were found in 26% and 22% of the (R) cohort compared to 8% and 12 % of the (NR) cohort. (R) also had increased mutations in the ARID1A (17% vs 4%) and ERBB2 (17% vs 4%) compared to (NR). FGFR3 missense mutations were seen in only 4% of (R) cohort compared to 15% in (NR). In our complete cohort, 49% of patients had ERBB2 copy number amplifications and 92% of patient had CREBP2 deletions. Conclusions: In our real-world cohort of mUC pts treated with ICI, we identified differential genomic alterations between (R) and (NR). High frequency of ERBB2 mutations and alterations in overall cohort and higher frequency in (R) suggests potential role for anti-HER2 therapies alone or in combination with ICI. Ongoing genomic and immunologic correlative studies in our cohort will further help understand biomarkers of response and resistance to ICI in pts with mUC.
Impact of homologous recombination repair (HRR) or nucleotide excision repair (NER) deficiency on sensitivity to antibody drug conjugate (ADC) payloads in urothelial cancer.
Authors: Surish P Shanmugam, Yuzhen Zhou, Vincent D'Andrea, Timothy Hanlon, Raie Bekele, Zoltan Szallasi, Joaquim Bellmunt, Kent William Mouw
Journal: Journal of Clinical Oncology (2024)

665 Background: Approximately 10% of urothelial cancer (UC) patients have defects in the NER pathway and at least another 10% have defects in the HRR pathway. Tumors with HRR or NER defects are more sensitive to platinum-based chemotherapy due to inability repair platinum-induced DNA damage. Two ADCs, sacituzumab govitecan (SG) and enfortumab vedotin (EV) are approved for treatment of metastatic UC. The cytotoxic payload attached to SG and EV are SN-38 and MMAE respectively. SN-38 directly damages DNA through inhibition of Topoisomerase 1 activity during DNA replication whereas MMAE is a potent microtubule disruptor but does not have any direct DNA damaging effects. Given the expanding clinical roles for EV and SG in UC, we wished to test the impact of HRR or NER deficiency on sensitivity to SN-38 and MMAE. We hypothesized that HRR or NER deficiency would result in a larger increase in sensitivity to SN-38 than MMAE. We also hypothesized that SN-38, but not MMAE, would result in synergistic cell killing when delivered with a PARP inhibitor. Methods: We assembled a series of isogenic NER- and HRR-proficient/deficient cell pairs and compared sensitivity to SN-38 and MMAE, as well as other clinically relevant agents including cisplatin, gemcitabine, and the PARP inhibitors olaparib and talazoparib. Results: HRR-deficient bladder cancer cell lines were significantly more sensitive to SN38 than their respective isogenic HRR-proficient counterpart whereas there was no significant difference in MMAE sensitivity between isogenic pairs of HRR-deficient and HRR-proficient cell lines. The largest difference in sensitivity between HRR-proficient vs HRR-deficient cell lines was observed with olaparib and talazoparib respectively. In contrast, NER-deficient cell lines were not more sensitive to SN38 or MMAE than their respective isogenic NER-proficient counterparts. Conclusions: HRR deficiency significantly increases sensitivity of bladder cancer cells to SN-38 but not MMAE. These findings suggest that UC patients with HRR deficiency may be more likely to benefit from treatment with SG than EV, and more generally with an ADC that has a Topoisomerase 1 inhibitor rather than a microtubule disruptor as the cytotoxic payload.
Prostate Cancer Supportive Care (PCSC) Program: A model for meeting an unmet need for patients with PC.
Authors: Celestia S. Higano, Monita Sundar, Christine Zarowski, Meghan Lui, Nicholas Pratap, Joy Egilson, Andrea Holmes, Nikita Ivanov, Marcy Dayan, Anna Hudon-Kaide, Paul Griggs, Corinne Maurice-Dror, Rosalie Ho, Daniella Sare, Angela Hwang, Ryan Flannigan
Journal: Journal of Clinical Oncology (2024)

308 Background: Prostate cancer (PC) patients (pts) face treatment-related sequelae that affect their quality of life. The PCSC Program was created in 2013 and is located in the Vancouver Prostate Centre’s urology clinic. It is a clinical, educational, and evidence-based program that addresses challenges experienced by PC pts from the time of diagnosis onward. The program consists of 8 “modules,” each designed to support a specific concern. Methods: We describe the operational details of the PCSC Program and its metrics. Results: The program consists of a Medical Director and Program Manager who articulate the mission, oversee the day-to-day operations, and hire and manage the allied health clinicians and administrative staff. Clinicians include two sexual health RNs (1.4 FTE), two pelvic floor physiotherapists, a nurse practitioner, a registered dietitian, two clinical exercise physiologists, and two clinical counselors (all 0.2 FTE). A sexual health urologist is in the clinic, and a medical oncologist delivers the metastatic disease module. As of 09/2023, 3562 pts registered for this no-cost program (Table). Pts choose modules relevant to their interests and needs. The program supports free language interpretation services to non-English speaking pts. Translation of education session recordings is currently underway. In 4/2020, in response to the COVID-19 pandemic, the real-time group education sessions and clinic appointments transitioned from in-person to hybrid delivery, with virtual options enabling the participation of pts from throughout British Columbia. PCSC maintains high patient satisfaction, as indicated by responses to patient satisfaction questionnaires. Conclusions: The need for PC supportive care is well recognized but may be challenging when the services are fragmented, costly, and time-consuming to orchestrate. All modules offered by the PCSC Program can be accessed with one registration and are conveniently housed in one location, which also facilitates clinician communications across disciplines. We attribute the success of our program and high patient satisfaction to this model and our team approach to the individual patient’s needs. [Table: see text]
Urologist practice divestment from radiation vault ownership and treatment patterns for prostate cancer.
Authors: Kassem S Faraj, Samuel Kaufman, Lindsey A. Herrel, Avinash Maganty, Mary Oerline, Megan Veresh Caram, Vahakn B. Shahinian, Brent K. Hollenbeck
Journal: Journal of Clinical Oncology (2024)

304 Background: Urologists practicing in single-specialty groups with ownership in radiation vaults are more likely to treat men with prostate cancer. The effect of urology practice divestment in radiation vault ownership on treatment patterns of men with prostate cancer is unclear. Methods: A 20% sample of national Medicare claims was used to perform a retrospective cohort study of men with prostate cancer, diagnosed between 2010 and 2019, managed by single specialty urology groups. All men were followed through December 31, 2020. Urology groups were categorized by radiation vault ownership for each year as nonowners, owners, and divested owners. The primary outcome was use of treatment and the secondary outcome was use of intensity-modulated radiation therapy (IMRT). Both outcomes were assessed for the 12-month period after diagnosis. Using a difference-in-differences design, multivariable logistic regression was used to measure the effect of radiation vault divestment on outcomes. Subgroup analyses assessed outcomes by non-cancer mortality risk (high (&gt; 50%) vs. low (≤ 50%)) within 10 years of diagnosis. Results: Among 72 urology practices that owned radiation vaults, six divested during the study. Divestment led to a decrease in treatment compared with those managed at continuously owning practices (difference-in-differences estimate, -13%, p=0.03). The use of IMRT also decreased, but this change was not statistically significant (difference-in-differences estimate, -8%, p=0.21). In men with a high non-cancer mortality risk, treatment (difference-in-differences estimate, -28%, p&lt;0.001) and use of IMRT (difference-in-differences estimate, -27%, p&lt;0.001) decreased after divestment. Conclusions: Urology single specialty group divestment in radiation vault ownership leads to a decrease in prostate cancer treatment. This decrease was most pronounced in newly diagnosed men that had a high non-cancer mortality risk. This has important implications for healthcare reform, suggesting that programs that can incentive constraints on utilization may be effective in reducing prostate cancer overtreatment.
Development of a novel RNA-based immune checkpoint inhibitor response signature (ICI-PRS) that avoids standard-of-care (SOC) prognostic signal for use in patients with urothelial cancer (UC).
Authors: Jonathan Shepherd, Gregory Mayhew, John Guo, Kirk Beebe, Joel Robert Eisner, Michael Vance Milburn
Journal: Journal of Clinical Oncology (2024)

549 Background: Immune checkpoint inhibition (ICI) shows great promise, including approval of pembrolizumab, nivolumab and avelumab in urothelial cancer (UC). However, the overall percentage of UC patients with clinical benefit is relatively small, despite biomarker use to select patients (e.g., PD-1 expression and TMB). Recently, several accelerated approvals (atezolizumab and durvalumab) were subsequently withdrawn following failure to show improved survival compared to standard of care (SOC) treatment in Phase 3 +/- biomarker use. To address the need for better ICI biomarkers, we developed an RNA-based predictive response signature (ICI-PRS) with the primary objective of being prognostic for ICI-treated patients, but not for SOC treatment. Methods: A survival-based model trained on 2/3 of the combined IMVigor210 dataset (n=298 locally advanced or metastatic UC patients treated with atezolizumab) and TCGA BLCA cohort (n=405 patients treated with non-ICI SOC) identified genes associated with survival across these data sets (prognostic agnostic to therapy) and genes distinctly associated with survival with ICI treatment (candidate ICI-predictive). Candidate ICI-predictive genes were developed into a model that was applied to the remaining IMVigor210 and TCGA BLCA samples, UC-GENOME urothelial carcinoma samples, and an ICI-treated melanoma dataset (Gide et al, 2019 : DOI: 10.1016/j.ccell.2019.01.003). Associations with tumor mutation burden (TMB) were examined. Expanded models incorporating this signature with additional immune markers were also investigated. Results: The ICI-PRS shows consistent associations with overall survival (OS) dependent on ICI treatment status. A higher hazard ratio (HR) was found for cohorts with ICI-therapy [HR (95% CI): IMVigor test 1.23 (0.96-1.57); UCGENOME 1.35 (0.99-1.85); Gide 1.50 (1.02-2.2)]. By comparison, no association was seen in the TCGA test set in which patients received non-ICI SOC treatment (HR = 0.96 (0.73-1.3). Patients with high TMB had extended survival in both IMVigor210 and non-ICI SOC TCGA datasets (P = 0.02 and 0.001). Conclusions: Herein we describe the development of a novel ICI-PRS and initial demonstration that it provides ICI-treatment specific prognostic value for bladder cancer patients. ICI-PRS status was associated with extended survival in patients treated with anti-PD-L1 but not non-ICI SOC therapy. These results support the further evaluation of the ICI-PRS and potential development as a diagnostic test for selecting UC patients most likely to benefit from ICI therapy.
The potential of transcriptomic profiling to predict immune-checkpoint inhibitor (ICIs) response in locally advanced (La) and metastatic urothelial carcinoma (mUC).
Authors: Belen Caramelo, Nerea Muñoz Unceta, Javier Freire, Ignacio Varela, David Martin, Sofía Del Carmen, Ainara Azueta, Pilar Diaz, Pilar Garcia-Berbel, Naiara Sagastibelza Marinelarena, Macarena Rey-Cárdenas, Daniel Castellano, Miguel Ángel Climent, Javier Puente, Juan Irure, Laura Revuelta, Fernanda Genre, Diego Cacho, Javier Gómez, Ignacio Duran
Journal: Journal of Clinical Oncology (2024)

668 Background: Immune checkpoint inhibitors (ICIs) have proven to be an effective therapy for locally advanced (La) and metastatic (mUC) urothelial carcinoma. However, response rates are typically modest, and patient (pt) selection remains a challenge, especially in the era of ICIs-based combos. The current study analyzes the differential RNA expression as a predictor of ICI response or resistance in La/mUC. Methods: Clinical information and formalin-fixed paraffin embedded (FFPE) samples from pts with La/mUC treated with single agent ICIs [2014 -2021] were obtained and RNA sequencing (RNA-seq) analysis performed. According to response, pts were assigned to one of these three groups: Primary resistant [PR] (progressive disease (PD) as the best response); Secondary resistant [SR] (initial response followed by PD); and Long responders [LR] (stable disease/partial or complete response maintained &gt; 16 months). Results: Clinical data and FFPE samples from 46 patients were available. Nineteen, twelve and fifteen pts respectively were in the PR, SR and LR groups. Clinical characteristics were well-balanced among groups, except for higher percentage of liver metastasis in PR and SR pts. The median overall survival was 11.2 and 18.2 months for the PR and the SR groups and has not yet been reached for the LR cohort, where 80% of the pts remain alive, with 50% achieving complete response. RNA-seq analysis unveiled distinct patterns of differential gene expression in the resistance groups compared to the LR. Notably, an upregulation of the epithelial-mesenchymal transition pathway was observed, with interleukin 2 emerging as a potential surrogate marker of this activity. Additionally, an overactivation of the KRAS pathway was evident, irrespective of its mutational status. Furthermore, in a comparison between the two resistance groups, the SR group displayed increased activation of DNA damage control mechanisms. Conclusions: Our RNA-seq analysis could provide relevant information and holds promise as a valuable tool for predicting responses to ICIs in La-mUC. Nonetheless, further validation on a larger cohort of patients is required.
Universal Risk Prediction for Individuals With and Without Atherosclerotic Cardiovascular Disease
Authors: Yejin Mok, Zeina Dardari, Yingying Sang, Xiao Hu, Michael P. Bancks, Lena Mathews, Ron C. Hoogeveen, Silvia Koton, Michael J. Blaha, Wendy S. Post, Christie M. Ballantyne, Josef Coresh, Wayne Rosamond, Kunihiro Matsushita
Journal: Journal of the American College of Cardiology (2024)
Clinical and patient-reported outcomes of fully adaptive MR-guided stereotactic radiotherapy to prostate: Real-world experience from the UK.
Authors: Prantik Das, Killian Nugent, Nicola Louise Dallas, Carla Perna, Ami Sabharwal, Daniel Ford, Philip Camilleri
Journal: Journal of Clinical Oncology (2024)

303 Background: Stereotactic MR-guided adaptive radiotherapy (SMART) brings several advancements including enhanced soft tissue definition, adaptation of individual fractions based on daily anatomy, real time tracking of prostate coupled with beam gating that prevents treatment delivery if the prostate is outside the treatment boundary and negating the need for invasive fiducial markers. Here we evaluate treatment response and acute and intermediate patient adverse events amongst prostate cancer patients who underwent SMART. Methods: A total of 197 patients with localised prostate cancer were treated with SMART. Patients were assessed for eligibility against robust institutional criteria. SMART consisted of MR- and computed tomography (CT) simulation scan, inverse intensity-modulated radiotherapy (IMRT) treatment planning and daily plan re-optimization prior to treatment delivery with editing CTVs (as per daily variation) and OAR recontouring within the first 3 cm outside the PTV. Prescription dose was 36.25 Gy in 5 fractions delivered on alternate days. Patients who completed a baseline 12 item PRO-CTC AE, before treatment, were subsequently followed up with the same graded questionnaire at set time points. Results: Median follow up was 12 months (inter quartile range 6 – 36). Patients included low (6%), intermediate (86%) and high risk (8%). Median pre-treatment PSA was 7.09 ng/ml (interquartile range IQR 1 – 133.2). At first follow up at 6 months, median drop in PSA was 97.09 % from base line (range 27.7– 99.9 %, SD 15.04). At second follow up at 12 months, median change in PSA was 96.92% (range 5.88– 233.3%, SD 12.41). At 24 months median PSA was 0.28 ng/ml (IQR 0.03 -3.26) with a median drop from baseline of 95.98%. ADT was used in 88% of patients and median duration of ADT was 6 months (IQR 3-30). 69 patients, who completed baseline and subsequent PRO CTC AE questionnaires in different time frames were included in analysis. More than 80% of men reported no change from baseline urinary toxicity during follow up apart from urinary urgency. Regarding GI toxicities, new ≥ frequent/severe patient reported adverse events were diarrhoea (9%), constipation (3%) and pain on opening bowels (6%) in the first 3 months but were all absent after 33 months. No patient reported frequent GI bleeding. No grade ≥4 toxicity was seen. Conclusions: SMART shows low acute and intermediate toxicities and excellent short-term outcomes.
The role of cytoreductive nephrectomy (CN) in the immune checkpoint inhibitor (ICI) era of metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 2319 patients.
Authors: Dimitrios Makrakis, Pavlos Msaouel, Jose A. Karam, Stepan M. Esagian
Journal: Journal of Clinical Oncology (2024)

425 Background: The combination of CN and systemic therapy has been established as one of the mainstay treatments for mRCC during the targeted therapy era. However, the role of CN in the ICI era remains unclear. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing the combination of CN + ICI vs. ICI alone in mRCC. Using published Kaplan-Meier overall survival (OS) curves, we reconstructed IPD and then performed one-stage and two-stage meta-analyses with both parametric and non-parametric effect estimates. To account for immortal time bias, we performed 6-month and 12-month landmark analyses. We also performed a subgroup analysis according to ICI line of treatment. The risk of bias was assessed using the ROBINS-I tool. Results: We identified eight retrospective cohort studies fulfilling our inclusion criteria. Only two out of eight studies adjusted for immortal time bias and none of them adequately adjusted for all predetermined confounding factors. A total of 2319 (1264 CN + ICI and 1055 ICI only) patients were included in our analysis. Patients in CN + ICI group were younger (median age 58.2 vs. 62.8), had lower proportions of non-clear cell histology (8.8% vs. 15.2%), ≥2 metastatic sites (60.0% vs. 68.5%), liver metastases (9.0% vs. 21.9%), and poor IMDC risk score (21.7% vs. 43.9%), but had higher proportions of sarcomatoid histology (15.6% vs. 10.6%) and ≥2nd line treatment (38.1% vs. 17.1%). The combination of CN + ICI was associated with superior OS in the one stage (HR: 0.45, 95% CI 0.38–0.52), 6-month landmark (HR: 0.45, 95% CI 0.37–0.54), 12-month landmark (HR: 0.50, 95% CI 0.31–0.50) and two-stage (HR: 0.38, 95% CI 0.29–0.49) meta-analyses. Similarly, the combination of CN + ICI was associated with superior OS in the subgroup of patients receiving first-line ICI (HR 0.39, 95% CI: 0.30–0.48). Conclusions: The combination of CN + ICI for mRCC may be associated with superior OS compared to ICI alone, but currently available data are subject to selection bias. More studies, including well-designed randomized controlled trials, are needed to determine the role of CN in the ICI era. [Table: see text]