tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitors in advanced malignant peritoneal mesothelioma: Clinical insights, immunopathologic profiling, and prognostic implications from a single-center study.
Authors: Gal Zvi Strauss, Helena Gondra, Ignat Schwartz, Sarit Appel, Rony Weitzen, Yaniv Berger, Almog Ben Yaacov, Aviram Nissan, Eytan Aharon Ben Ami
Journal: Journal of Clinical Oncology (2024)

e14665 Background: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the peritoneum. In patients with advanced disease, therapeutic options are limited, and prognosis is usually poor. While the role of immune-checkpoint inhibitors (ICI) in MPM is evolving, clinical data is scarce and there are currently no biomarkers to predict response to ICI therapy in this population. Methods: Patients treated at the Sheba Medical Center between 2016-2022 have been examined with the aim of delineating the clinical and immunopathologic characteristics of MPM, including programmed-death ligand-1 (PDL-1) status. Results: Forty-two patients with MPM were treated at Sheba during the study period. Eight patients (19%) have received immunotherapy as a single treatment in our cohort, all as ≥2 line of treatment. Of these patients, 3 patients (37.5%) had complete response (CR) or partial response (PR) as their best response, 3 patients (37.5%) had stable disease (SD), and 2 patients (25%) had progressive disease. Median overall survival (OS) among responding patients (CR/PR) and patients with clinical benefit (CR/PR/SD) were 6.8 years and 5.2 years, respectively, noticeably higher than the median OS for MPM (2.5 years). PDL-1 status was available for 23 patients: 17/23 (74%) had negative PDL-1 status and 6/23 (26%) had positive PDL-1 status. No correlation was observed in PDL-1 status among patients experiencing clinical benefit from treatment with ICIs. Conclusions: ICI therapy could be considered as a reasonable option for second-line therapy and beyond for MPM, with selected patients who may substantially benefit from these treatments. PDL-1 status did not correlate with treatment benefit, which highlights the limitation of this biomarker as a predictor of response in MPM patients.
Incidence of brain metastases within the VA Healthcare System.
Authors: Dominic LaBella, Joseph Kamel Salama, Matthew J. Boyer
Journal: Journal of Clinical Oncology (2024)

e14691 Background: Advancements in cancer detection and treatment are thought to underlie decreasing cancer mortality rates. The influence of these on the development of brain metastases, which can be a driving factor for mortality, has not been addressed in a modern cohort. Methods: The age adjusted incidence (AAI) of brain metastases (BMs) from any primary and those with an underlying breast, colorectal, lung, kidney, or melanoma primary were calculated by federal fiscal year from 2005 through 2019 in the VA Healthcare System (VAHS) based on the timing of the first documentation of ICD9 or ICD10 codes in the patient’s medical record, The AAI rates were calculated based on the age distribution in VAHS and US census in 2020. Incidence proportions (IPs) were calculated by dividing the number of brain metastases with an underlying primary by the number of cases of that primary from 2005-2009. Results: 36,598 new BM cases of any underlying primary were diagnosed from 2005-2019. 96.2% of diagnoses were in men, 17.9% in African-Americans. The median age at diagnosis was 66.4 years old. 67.9% of BMs cases had a prior lung cancer diagnosis. The IP of lung, colorectal, kidney, melanoma, and breast cancer were 13.7%, 1.87%, 3.67%, 4.31%, and 3.08%, respectively. Overall, the AAI of BMs in the VAHS increased from 22.5 in 2005 to 24.6 in 2012 then decreased to 16.8 in 2019. Similar trends in the AAI of BMs with a lung, colorectal, kidney, or melanoma primary were observed (Table). The AAI of BMs with a breast primary increased from 2005 to 2019 (Table 1). The decrease in BM AAI from 2005 to 2019 paralleled decreases in lung (104.6 to 73.4), colorectal (63.9 to 37.5), kidney (27.5 to 26.4) and breast (140.5 to 136.1) cancer AAI as well as melanoma (28.2 to 21.7) AAI over the same time, respectively. Conclusions: In a modern cohort from the largest integrated health care system in the United States, the IPs of BMs from five primary sites associated with BMs were lower compared to older cohorts and the AAI rates decreased over time. Future studies will assess the impact of modern screening and treatment on BM incidence. [Table: see text]
Synergistic antitumor activity of METTL3 peptide degrader and immune checkpoint inhibitor in advanced urothelial cancer.
Authors: Shihao Shang, Hong Han, Kepu Liu, Zenghui Li, Jie Zhang, Lei Zhang, Dongen Ju, Di Wei, Jianlin Yuan, Zheng Zhu, Junfeng Shi
Journal: Journal of Clinical Oncology (2024)

e14623 Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed the pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in immune escape and the progression of aUC. This study aimed to develop a novel METTL3 peptide degrader RKL and investigate its synergistic effects and underlying mechanisms in combination with ICI for aUC. Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while the prognostic implications of METTL3 expression in response to ICI were analyzed in the IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate the mechanistic insights. The METTL3 peptide degrader RKL was synthesized using Fmoc solid-phase peptide synthesis and purified with high-performance liquid chromatography. In vivo and in vitro experiments were conducted to assess the impact of RKL, ICI, and their combination on aUC inhibition. Results: In aUC, METTL3 exhibited the most significant up-regulation among m6A methyltransferases, while METTL14 and WTAP showed down-regulated expression. In the IMvigor210 cohort study, aUC patients with elevated METTL3 expression and treated with ICI demonstrated a poorer prognosis. scRNA-seq revealed that METTL3 upregulation promoted the expression of genes regulating cancer-associated fibroblast proliferation, contributing to enhanced tumor resistance to immunotherapy. RKL demonstrated high toxicity to urothelial carcinoma cell lines, inhibiting their proliferative, migratory, and invasive capacities in vitro. The combined treatment of RKL and ICI significantly reduced tumor volume (P&lt;0.001), with a complete response achieved in 87.5% (7/8) of mice in the combination group, 12.5% (1/8) in the RKL group, and 25.0% (2/8) in the ICI group. Conclusions: METTL3 overexpression in aUC is associated with immune escape and resistance to ICI therapy. The METTL3 peptide degrader RKL, when combined with ICI, demonstrates synergistic antitumor effects in aUC, warranting further exploration in clinical research.
Melanoma tumor microbiome as a predictor of anti-PD-1 and anti-CTLA-4 immunotherapy response.
Authors: Matthew Uzelac, Wei Tse Li, Yuxiang Li, Weg M. Ongkeko
Journal: Journal of Clinical Oncology (2024)

e14666 Background: In 2023, it is estimated that 97,610 melanoma diagnoses were made in the United States, resulting in 7,990 deaths. For high-risk melanomas, immune checkpoint inhibitors are often administered as an adjuvant to surgery, though they yield variable response rates. The gut microbiome’s association to these treatments’ success has been demonstrated, largely through fecal transplant and probiotic trials. In this study, we seek to determine whether tissue-resident microbes in melanoma tumors could be used to predict immunotherapy response. Methods: Sequencing data of 289 melanoma tumor tissue samples was downloaded across three distinct studies. Intratumor microbial species abundances were derived from RNA or DNA sequencing data through direct alignment to microbial reference databases. Gene expression profiling was also performed. Microbial abundance values were used to construct models predicting patients’ responses to check-point blockade immunotherapies, which were then validated on an external dataset. Results: 12 and 14 microbial species were differentially abundant in anti-PD-1 responders and anti-CTLA-4 responders, respectively. We identified significant correlations of these species to genes of the PD-1 and CTLA-4 signaling pathways. Among others, greater abundance of Corynebacterium kroppenstedtii and Streptococcus gordonii correlated to decreased expression of PD1 and CTLA-4. With the abundances of these taxa and the expressions of 37 genes known to be implicated in immunotherapy response, we developed two classifiers to predict a patient’s response to anti-PD-1 and anti-CTLA-4 therapies. When tested externally, these models successfully predicted a majority of responders and non-responders with sensitivities of 80.0% and 60.0% and specificities of 95.2% and 95.8%, respectively. Conclusions: Our study revealed that checkpoint blockade response for melanomas could be predicted with microbe abundances. Our analysis demonstrates the potentially promising clinical utility of intratumor microbiota in cancer treatment. Given their location in the tumor microenvironment and their ability to influence immune processes, intratumor microbes could play a critical role in modulating the therapeutic effects of immune checkpoint blockades. We hope that our results could also be applied to other solid tissue cancers, where a significantly smaller fraction of patients respond to immunotherapy. [Table: see text]
A new modality of anti-cancer drug: Ferritin-drug conjugates.
Authors: Jeewon Lee, Bo Ram Lee, Yong Hwan Seol, Hyun Ju Hwang
Journal: Journal of Clinical Oncology (2024)

e14590 Background: Success criteria of ADCs is the target overexpression in tumor, i.e. in general ~ 14-fold in tumor vs. normal cells, which is the reason why it is hardly possible to develop clinically potent ADCs against several cancers with low target expression, which remains a major challenge yet, although fam-trastuzumab deruxtecan-nxki (Enhertu; AZN) and sacituzumab govitecan-hziy (Trodelvy; Gilead) recently exhibit an exceptionally enhanced efficacy for TNBC. Methods: Payloads were conjugated to a human apoferritin-derived, cancer-targeting scaffold (a self-assembled 24-mer protein with a diameter of ~ 12 nm, showing a high avidity for cancer cells) via a particular payload-releasing linker based on thiol-maleimide/imidazole-metal ion/EDC-NHS chemistry. Results: A new modality of anti-cancer drug - ferritin-drug conjugates (FDCs) - was developed, demonstrating a notably enhanced performance in cancer treatment as compared to current, clinically available anti-cancer drugs such as fam-trastuzumab deruxtecan-nxki, which is due to the important advantages such as far lowered EC 50 , high cancer-targeting efficiency, excellent structural stability (even in DMSO (up to 30%)), high loading capacity (high drug to ferritin ratio (DFR &gt; 20)) and consistent homogeneity in drug conjugation, no immune side effects, reduced drug resistance, and/or reduced off-target toxicity. Conclusions: FDCs are believed to open up a novel, attractive clinical route for both potent and safe therapy of a broad range of cancers.
Re-irradiation in recurrent glioblastoma: PET- or MRI-based? Results of a prospective randomized clinical trial.
Authors: Ilinca Popp, Wolfgang A. Weber, Erika Graf, Michael Mix, Rolf Wiehle, Ursula Nestle, Tanja Schimek-Jasch, Maximilian Niyazi, Claus Belka, Frank Paulsen, Franziska Eckert, Michael J. Eble, Liane König, Frank Anton Giordano, Elena Sperk, Felix Momm, Irina Spehl, Stephanie E. Combs, Denise Bernhardt, Anca L. Grosu
Journal: Journal of Clinical Oncology (2024)

2021 Background: Re-irradiation is an important treatment option for recurrent glioblastoma (rGBM). Here, we aimed to compare the oncological outcome of a re-irradiation target volume delineation based on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) with the one of a treatment based on contrast enhanced T1-weighted magnetic resonance imaging (T1Gd-MRI). Methods: GLIAA was a prospective, multicenter, randomized trial (NOA 10/ARO 2013-1, DKTK-a.). Patients with rGBM recurrence of 1-6 cm following initial radiotherapy were recruited at 14 centers in Germany and randomized 1:1 between a FET-PET- (arm A) and a T1Gd-MRI-based target volume delineation (arm B). The treatment consisted in a high-precision stereotactic re-irradiation with 39 Gy in 13 fractions. The primary endpoint was progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), local tumor control, and toxicity. Results: From November 26, 2013, to September 2, 2021, 271 patients were assessed for eligibility and 200 were randomized. 98 patients in the FET-PET arm and 97 patients in the T1Gd-MRI arm were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRI arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39). Median OS was 9.4 months (95% CI 7.8-11.1) in arm A and 9.0 months (95% CI 7.6-10.5) in arm B (HR 1.01 [95% CI 0.75-1.37], p=0.92). Local control rate at 12 months was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). Radiation necrosis as adverse event was documented in 25.5% of cases in arm A and in 21.6% in arm B. Of the 239 patients who received the FET tracer, 3 reported 5 severe adverse events in the timespan of 7 days after PET. No event was related to the application of the tracer. Conclusions: In this trial, FET-PET-based re-irradiation of rGBM was not superior to the GdT1-MRI-based treatment. Consequently, both options remain valid in this setting. Stereotactic re-irradiation with 39 Gy in 3 Gy fractions was shown to be safe and the FET-PET investigation was well tolerated in all cases. Due to the inclusion of FET-PET-positive patients only, our results do not impact the known diagnostic role of FET-PET in differentiating rGBM progression from post-therapeutic changes. Clinical trial information: NCT01252459 .
Effect of breast cancer receptor subtypes and CSF cytology status on survival for patients with leptomeningeal disease.
Authors: Sujan Niraula, Sugam Gouli, Andrea M. Baran, Haley Tyburski, Huina Zhang, Ruth O'Regan, Nimish Mohile, Carey K. Anders, Sara Hardy, Ajay Dhakal
Journal: Journal of Clinical Oncology (2024)

2025 Background: Leptomeningeal disease (LMD) in metastatic breast cancer (MBC) carries a poor prognosis. Data on the effect of BC sub types and CSF cytology results on overall survival (OS) are lacking. This single institution retrospective study compares OS among MBC with LMD across BC sub types and CSF cytology results. Methods: This study included patients (pts) diagnosed with MBC LMD from Jan 2010 to Jan 2023. BC sub types were defined as (1) ER positive (+)/HER2 negative (-), HER2+, triple-negative BC (TNBC), (2) HER2 0 [immunohistochemistry (IHC) score 0], HER 2 low [ IHC 2+ with fluorescence in-situ hybridization negative OR IHC 1+], HER2+. ER and HER2 positivity were defined per ASCO/CAP criteria. CSF cytology sub types were CSF+ (for malignant cells), CSF-, and CSF not tested. Baseline characteristics were compared using Fisher’s Exact and Wilcoxon rank-sum tests. OS among sub types was evaluated using Kaplan-Meier analysis and compared using log rank test. For multivariate analysis, a step wise model selection was performed after inclusion of sub type of interest; and variables meeting entry (p&lt;0.10) and staying criteria (p&lt;0.05) were included in final Cox model. Results: Out of 219 patients screened, 69 pts were registered. Median OS and associated 95% confidence interval (CI) within BC sub types in analyses 1 and 2 and CSF sub type analysis are shown in the table. OS in analysis 1 was not significantly different by BC sub types. In multivariate analysis, TNBC sub type had significantly shorter OS than ER+/HER2- group [Hazard Ratio (HR) 2.64, 95% CI (1.23, 5.80) (p=0.04)] after adjusting for interval from MBC to LMD diagnosis and CSF cytology status. OS by BC sub types in analysis 2 was not significantly different in unadjusted and multivariate analyses. CSF- group had significantly better OS compared to CSF+ or CSF not tested group in unadjusted analysis (Table) and multivariate analysis [CSF+ vs CSF- HR 4.5 95% CI (1.75-12.11); CSF not tested vs CSF- HR 2.91 95% CI (1.45-6.26), overall p=0.002]. Conclusions: This single institution study on MBC pts with LMD showed that BC receptor sub types were significantly associated with OS when adjusted for the interval from MBC to LMD diagnosis and CSF cytology group. This study showed significantly improved OS among patients with negative CSF cytology compared to those with positive cytology or those not tested, indicating a novel prognostic value of CSF cytology (currently on diagnostic value) for MBC LMD. These findings will be further validated. [Table: see text]
Optimizing patient (pt) care through pt-focused resources to prevent and manage hand-foot skin reaction (HFSR).
Authors: Meera Patel, Arti Patel, Ana Cinthia Gonçalves Silva, Pooja S. Merchant, Yaswant K. Dayaram
Journal: Journal of Clinical Oncology (2024)

e24144 Background: Research has shown that pts and caregivers (non-HCPs) seek medical and disease-related information more than once a month, and this has accelerated due to the COVID-19 pandemic. However, they find it difficult to understand the information they receive and thus, can be misinformed. By understanding the use of fair-balanced medical information (MI) resources by non-HCPs, pharmaceutical companies can develop scientifically accurate yet pt-friendly resources to meet their needs (Goettner, 2022; Rai, 2022). Upon reviewing the unsolicited oncology inquiries received by our MI department, approximately 25% of inquiries were from non-HCPs seeking information. Over the past 3 years, non-HCPs have submitted almost 10,000 inquiries regarding our oncology products, in which 191 inquiries were specifically regarding HFSR and regorafenib and sorafenib. Historically, our MI department responded to non-HCP inquiries by sharing the product label information. However, we identified an unmet need for trustworthy, comprehensive, and accurate pt resources in plain language. Methods: A full literature review was performed, and the relevant data were summarized in plain language for pts. Both HCPs and pts participated in developing the global pt resource on the prevention and management of HFSR for regorafenib and sorafenib. The seven-page interactive brochure was written in 4 th to 6 th grade reading level which included images and graphics to enhance the understanding of data, easy navigation to the content of interest, and glossary to define key terms. Furthermore, these materials were translated for pts who participated in the regorafenib and sorafenib Patient Support Program in Brazil to further educate and support pts who have started therapy. Results: As of June 2023, the global pt medical resource has been deployed 28 times in Brazil, delivering key information to non-HCPs on their disease and treatment while emphasizing its practical utility and addressing health literacy challenges. We collected feedback from pts who utilized the translated material, and they described it to be “informative” and “helpful” since it empowered them to effectively navigate and address HFSR-associated discomforts during their treatment journey. The feedback has also been utilized to further enhance the resource’s feasibility. Conclusions: The pt feedback on the brochures showcases the value of pt-focused approach in oncology and the positive impact of collective efforts across all stakeholders including pts, pharmaceutical MI departments and pt programs. Furthermore, it demonstrates how MI can bridge the gap between pt insights and clinical knowledge by addressing their needs and providing practical and trustworthy tools. Not only does this initiative enhance pt understanding but also empowers pts to take a more active role in their treatment and fosters shared-decision making.
Quality of life for older patients with metastatic cancer in Brazil: A telehealth-based geriatric assessment and supportive care intervention (GAIN-S).
Authors: Cristiane Decat Bergerot, Paulo Gustavo Bergerot, Marianne Razavi, Jonas Ribeiro Gomes Silva, Jose Adolfo Cerveira, Marcos V S Franca, William Hiromi Fuzita, Vitor Fiorin de Vasconcellos, Joao Nunes Matos Neto, Carolina Bezerra Patriota, Aline Lury Hada, Gabriel dos Anjos, Murilo Buso, Mariana Laloni, Carlos G. M. Ferreira, Ryan David Nipp, Areej El-Jawahri, Enrique Soto Pérez de Celis, William Dale
Journal: Journal of Clinical Oncology (2024)

1514 Background: Older adults with cancer often present unique geriatric and supportive care needs. We sought to evaluate the impact of a telehealth-based multimodal geriatric assessment (GA)-guided supportive care interventions (GAIN-S) program among older patients with metastatic cancer in a Brazilian cancer center. Methods: This is a randomized trial. Patients aged 65+ years with metastatic cancer, undergoing treatment, regardless of ECOG status, were enrolled. Following the baseline assessment, patients were randomized 1:1 to receive usual care or GAIN-S. The GAIN-S intervention provided remote, telehealth-based consultations with a nutritionist, psychologist, psychiatrist, and certified fitness trainer. At baseline and 3-months, patients were assessed for emotional symptoms (Geriatric Depression Scale), functional status (Instrumental Activities of Daily Living), coping (BriefCope), and quality of life (Functional Assessment of Cancer Therapy-General). Independent t-tests and linear mixed model were used. Results: Out of 86 approached patients, 80 were enrolled (40 per arm), with 3 deceased during treatment (usual care: 2, GAIN-S: 1). Most patients were female (56%), with a median age of 73 years (range, 65-68). Most common cancers were genitourinary (28%) and breast (23%). At baseline, there were no differences in the outcome measures between arms. However, from baseline to 3-months, patients assigned to GAIN-S had improvements in emotional symptoms, functional status, and quality of life compared to usual care (Table). Additionally, those assigned to GAIN-S reported increased utilization of active coping, acceptance, and positive reframing at 3-months. Conclusions: GAIN-S demonstrated significant improvements in emotional well-being, functional status, and quality of life among older patients with metastatic cancer. These findings underscore the potential of such telehealth-driven approaches to enhance the supportive care experience in diverse healthcare settings. [Table: see text]