tbuckley/cabot-search huggingface dataset:
Interim analysis of a phase I study using cryopreserved non-genetically modified allogeneic natural killer cells with enhanced cytotoxicity (SNK02) in patients with advanced solid tumors without lymphodepletion.
Authors: Victoria Chua, Sant P. Chawla, Erlinda Maria Gordon, William Feske, Lucia Hui, Hank Lee, Yoonmi Kang, Juan Mata, Katia Betito, Paul Y. Chang, Paul Y. Song
Journal: Journal of Clinical Oncology (2024)

e14515 Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. A leading approach to boost NK cell-mediated anti-tumor activity is via the adoptive transfer of ex vivo activated NK cells. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells by the recipient and ensure adequate cell delivery of the product cells to the target. However, lymphodepletion can negatively impact combination therapies where a robust T cell response is desired. SNK02 is a first-in-kind, cryopreserved allogeneic non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced on a large commercial scale. We hypothesized that higher doses of SNK02 (to overcome autodigestion) could be delivered frequently without the need for lymphodepletion and that it might demonstrate activity against solid tumors that have failed multiple prior standard-of-care treatment options. Methods: In this Phase 1 dose escalation study (NCT05990920), SNK02 was administered intravenously (IV) weekly for 8 consecutive weeks in patients with advanced solid tumors. The starting dose was 6 x 10 9 SNK02 cells. The primary endpoint was safety based on adverse events (AEs), vitals, laboratory tests, and physical exams. Results: As of Feb 1, 2023, 5 patients with advanced refractory solid tumors have been enrolled. Median age was 64 (range 44 – 71) and 3 were male. The subtypes were 1 leiomyosarcoma, 1 angiosarcoma, 1 endometrial adenocarcinoma, 1 undifferentiated pleomorphic sarcoma, and 1 colorectal adenocarcinoma. Four of five patients completed 8 cycles of SNK02. There was 1 death on study, which was deemed unrelated to the investigational product (IP). Out of the 36 doses administered through Cycle 8, there were 17 Grade 1, 3 Grade 2, and 1 Grade 3 adverse AEs related to IP. The Grade 3 AE of increased fatigue resolved after 1 day with no intervention required. Antibodies appeared to develop around cycle 5 and appeared to correlate with AEs. The best objective response of SD was demonstrated in 100% of patients that completed the 8 cycles. Conclusions: SNK02 was well tolerated as a monotherapy and appears to have some clinical activity against pretreated solid tumors despite the lack of lymphodepletion. SNK02 will continue to be studied as a monotherapy and in potential combination treatment regimens with monoclonal antibodies and immune checkpoint inhibitors. Clinical trial information: NCT05990920 .
Multimodal imaging-based prediction of recurrence for unresectable HCC after downstage and resection-cohort study
Authors: Hanyu Jiang, Mengxuan Zuo, Wang Li, Shuiqing Zhuo, Peihong Wu, Chao An
Journal: International Journal of Surgery (2024)

Background: Surgical resection (SR) following transarterial chemoembolization (TACE)-based downstaging is a promising treatment for unresectable hepatocellular carcinoma (uHCC), and identification of patients at high-risk of postoperative recurrence may assist individualized treatment. Purpose: To develop and externally validate preoperative and postoperative prognostic models integrating multimodal CT and digital subtraction angiography features as well as clinico-therapeutic-pathological features for predicting disease-free survival (DFS) after TACE-based downstaging therapy. Materials and methods: From March 2008 to August 2022, 488 consecutive patients with Barcelona Clinic Liver Cancer (BCLC) A/B uHCC receiving TACE-based downstaging therapy and subsequent SR were included from four tertiary-care hospitals. All CT and digital subtraction angiography images were independently evaluated by two blinded radiologists. In the derivation cohort ( n =390), the XGBoost algorithm was used for feature selection, and Cox regression analysis for developing nomograms for DFS (time from downstaging to postoperative recurrence or death). In the external testing cohort ( n =98), model performances were compared with five major staging systems. Results: The preoperative nomogram included over three tumors [hazard ratio (HR), 1.42; P =0.003], intratumoral artery (HR, 1.38; P =0.006), TACE combined with tyrosine kinase inhibitor (HR, 0.46; P &lt;0.001) and objective response to downstaging therapy (HR, 1.60; P &lt;0.001); while the postoperative nomogram included over three tumors (HR, 1.43; P =0.013), intratumoral artery (HR, 1.38; P =0.020), TACE combined with tyrosine kinase inhibitor (HR, 0.48; P &lt;0.001), objective response to downstaging therapy (HR, 1.69; P &lt;0.001) and microvascular invasion (HR, 2.20; P &lt;0.001). The testing dataset C-indexes of the preoperative (0.651) and postoperative (0.687) nomograms were higher than all five staging systems (0.472–0.542; all P &lt;0.001). Two prognostically distinct risk strata were identified according to these nomograms (all P &lt;0.001). Conclusion: Based on 488 patients receiving TACE-based downstaging therapy and subsequent SR for BCLC A/B uHCCs, the authors developed and externally validated two nomograms for predicting DFS, with superior performances than five major staging systems and effective survival stratification.
MSK-ACCESS powered with SOPHiA DDM: Performance analysis of a decentralized MSK-ACCESS solution.
Authors: Florian Klemm, Fabio De Martino, Fuad Mohammad, Yvan Wenger, Jacklyn Casanova-Murphy, Anita S. Bowman, Brian Houck-Loomis, Angela Rose Brannon, Michael F. Berger, Zhenyu Xu
Journal: Journal of Clinical Oncology (2024)

e15063 Background: Blood plasma cell-free DNA (cfDNA) testing of cancer patients allows for genomic profiling when tissue sampling is too invasive or of insufficient quality. This approach has demonstrated clinical utility to identify treatment targets, screen for resistance and monitor disease burden. MSK-ACCESS (Memorial Sloan Kettering – Analysis of Circulating cfDNA to Evaluate Somatic Status) is a validated, high sensitivity cfDNA assay employed at MSK to identify biologically actionable tumor alterations in clinical care. SOPHiA GENETICS is developing a decentralized solution of this assay that incorporates major features of MSK-ACCESS such as molecular barcoding, duplex-based variant calling, the inclusion of tumor-informed prior knowledge and identification of somatic alterations through the removal of both germline and clonal hematopoiesis (CH) variants. Here, we present the results of a performance study obtained during product development. Methods: A cohort of 24 plasma cfDNA and matched white blood cell (WBC) DNA samples were collected from patients with solid tumors and processed at MSK according to the validated standard operating procedures and bioinformatic analyses. In parallel, for the same set of materials libraries were constructed at SOPHiA GENETICS using the proprietary CUMIN molecular identifiers, captured with probes targeting the updated MSK-ACCESS v2 set of 146 genes and sequenced on an Illumina NovaSeq 6000. Variants were called using a duplex-aware approach by SOPHiA GENETICS and germline and CH variants were identified and filtered by paired cfDNA – WBC DNA analysis. Accuracy of the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution was assessed through concordance to the orthogonal results obtained by MSK. Results: A total of 104 somatic SNV/Indels were detected with variant allele fractions (VAF) ranging from 0.1% to 97.0% with a median of 5 variants per sample. The positive percent agreement (PPA) for all variants above the limit of detection of the original MSK-ACCESS assay was 98.9% with 99.98% specificity. For the subset of prior-knowledge variants PPA was 95.6% down to 0.1% VAF. A total of additional 59 variants with ≤ 15% VAF were found both in cfDNA and WBC and assigned as CH-derived. Importantly, these occurred not only in CH-associated genes but also in common oncogenes such as BRCA1/2 and ERBB2, highlighting the utility of matched WBC analysis to correctly identify somatic variants. Conclusions: The results demonstrate that the decentralized “MSK-ACCESS powered with SOPHiA DDM” solution exhibits a high degree of agreement to the results achieved by MSK. Further studies will be conducted to expand the analytical performance evaluation.
Niraparib efficacy in patients with newly-diagnosed glioblastoma: Clinical readout of a phase 0/2 "trigger" trial.
Authors: Nader Sanai, Yoshie Umemura, Tigran Margaryan, Jennifer Molloy, Hualin Zhang, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, Kelly Braun, William R. Kennedy, Michael A. Garcia, Igor J. Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Journal of Clinical Oncology (2024)

2002 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met. Methods: Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort2) following the last dose. Tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the Phase 2 component of the study and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors in excess of the PK threshold were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib monotherapy. Results: All Phase 0 patients (n=46) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 335.1 nM (n=43) for cohort 1 and 331.9 nM (n=3) for cohort 2. PAR suppression after ex vivo radiation was observed in 73% of the patients (24/33). Nineteen of 27 (70.3%) patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib. All adverse events resolved without sequelae. At time of data cutoff, median progression-free survival was 11.7 months. Mature overall survival (OS) data will be reported for the first time. Conclusions: Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Accompanying PD effects were observed in patient tumor tissue. For the first time, we report on the clinical efficacy of the study. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT unmethylated glioblastoma is being planned. Clinical trial information: NCT05076513 .
Closing classification gaps in luminal breast cancer with single-cell RNA-seq insights from normal breast lineages.
Authors: Oleg Baranov, Polina Turova, Vladimir Kushnarev, Linda Balabanian, Nikita Kotlov, Konstantin Chernyshov, Nathan Hale Fowler, Jochen K. Lennerz
Journal: Journal of Clinical Oncology (2024)

e13168 Background: Almost two decades ago, invasive breast cancer was classified into five subgroups based on expression patterns, each with distinct biological and prognostic characteristics. Advances in single-cell RNA sequencing offers insights into the expression profiles of normal luminal epithelial cells. Here, we investigate the connection between breast cancer (BC) classification and luminal expression profiles. Methods: We applied single-cell data from recent studies (Table) to compile gene signatures corresponding to expression profiles of luminal epithelial cell clusters in normal breast tissue. Normalized enrichment scores (ESs) of these signatures were calculated for bulk RNA-seq gene expression data from open source cohorts (TCGA-BRCA, SCAN-B, METABRIC). The BC molecular subtype of each tumor sample was predicted based on a modified PAM50 classification using gene expression profiling (1); LumA and LumB subtypes were combined into Luminal. ESs of signatures were compared between the BC subtypes (Table). Results: The ESs of all signatures differed significantly across BC subtypes (p &lt; 0.001, Kruskal-Wallis test, Table 1). The ESs of signatures for LumSec-major and Luminal progenitor clusters are the highest in subtypes HER2-low and Basal-like (p &lt; 0.001, Dwass-Steel-Critchlow-Fligner test [DSCF]). Basal-like also had the highest enrichment of the ductal signature (p &lt; 0.001, DSCF). Luminal subtype showed the highest ESs of signatures corresponding to HR+ clusters of mature luminal cells and of the TDLU signature (p &lt; 0.001, DSCF). HER2-low subtype showed the highest ES of the LumSec-lac signature (p &lt; 0.001, DSCF). Conclusions: Our analyses challenge traditional classifications by showing that luminal breast cancers are less similar to most luminal epithelial clusters in normal breast tissue than other breast cancer subtypes. These findings suggest traditional expression classification may not fully capture the complexity of this largest subset of luminal-type breast cancers. 1. Turova et al., SABCS, 2023. [Table: see text]
Social vulnerability and clinical trial enrollment: The next frontier of health equity.
Authors: Shruthi Reddy Perati, Sana M. Mohayya, Ernie Shippey, Howard S. Hochster, Coral Oghenerukevwe Omene, Henry A. Pitt, Mariam F. Eskander
Journal: Journal of Clinical Oncology (2024)

1508 Background: Clinical trials are the basis for novel therapies but may not be representative of disadvantaged groups, particularly low-income individuals. This study assesses how social vulnerability impacts enrollment and explores the interaction between race and social vulnerability among patients with the top five leading causes of cancer death. Methods: The national Vizient Clinical Database was queried for outpatients with lung, breast, prostate, colorectal or pancreas cancer from 2022-2023. This includes data from 98% of academic medical centers and more than 110 cancer hospitals. The exposures of interest were Medicaid insurance and social vulnerability as measured by the Vizient Vulnerability Index (VVI), a novel marker of social drivers of health at the census tract level. Participation in a clinical trial was the primary outcome. A multivariable analysis was performed evaluating the association of social vulnerability quartiles with clinical trial participation. Interaction tests were performed for race and VVI. Results: 2,660,566 patients were identified. Of these, 36,456 (1.4%) enrolled in a clinical trial: 28.6% with breast cancer, 26.3% prostate, 22.8% lung, 12.8% colorectal and 9.5% pancreas. Trial participants were more likely to be young, White, privately insured, have metastatic disease, and live in a less vulnerable census tract.5.3% of trial participants were insured by Medicaid (12.2% of Black participants, 8.5% of Asian participants, and 3.5% of White participants), compared to 6.2% of non-participants (p&lt;0.0001).22.6% of participants lived in highly vulnerable neighborhoods (53.5% of Black participants, 19.7% of White participants, and 5.6% of Asian participants), compared to 25.0% of non-participants (p&lt;0.0001). Living in the most vulnerable VVI quartile was associated with decreased odds of clinical trial enrollment (OR 0.86; 95% CI 0.82-0.91, p=0.0442), as was having Medicaid insurance vs. private insurance (OR 0.76; 95% CI 0.73-0.80, p&lt;0.0001). The highest social vulnerability quartiles in the VVI domains for education, neighborhood resources and transportation were associated with decreased enrollment (Table). High social vulnerability decreased the odds of enrollment for Black patients (OR 0.80; 95% CI 0.68-0.88, p&lt;0.0001) more than White patients (OR 0.88; 95% CI 0.89-0.96, p=0.0028); p=0.0054 for interaction. Conclusions: 1.4% of patients in this contemporary, cross-sectional cohort enrolled in a clinical trial. Patients with Medicaid have a 24% lower odds of enrollment than privately insured patients. Neighborhood social vulnerability is also barrier to enrollment, even more so among Black patients. Interventions to address social determinants of health may increase racial diversity in clinical trials. [Table: see text]
Body composition measures as a determinant of alpelisib-related toxicity.
Authors: Eliya Shachar, Ari Raphael, Uriel Katz, Rivka Kessner, Shlomit Strulov Shachar
Journal: Journal of Clinical Oncology (2024)

e13093 Background: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. Methods: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, and hospitalizations. Results: Sarcopenia was observed in half of the patients (n=19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P=0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P=0.04) and hospitalizations (P=0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. Conclusions: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to predict toxicity, allowing for personalized therapeutic observation and intervention.
Clinical and molecular features and survival in thyroid cancer with brain metastases.
Authors: Carly C. Barron, Thais Baccili Cury Megid, Yangqing Deng, Erick Figueiredo Saldanha, Gordon Taylor Moffat, Richard Thomas O'Dwyer, Aruz Mesci, Jelena Lukovic, Richard Tsang, Ozgur Mete, Monika K. Krzyzanowska, Lucy Xiaolu Ma
Journal: Journal of Clinical Oncology (2024)

2023 Background: Brain metastases (BM) in advanced thyroid cancer are rare; however, they may be underreported as staging brain imaging is not routine. Prognostic features and molecular alterations for this group are poorly described. We characterized the clinical and molecular features of thyroid cancer with BM and evaluated differences in survival. Methods: In this single-center retrospective analysis, patients with metastatic radioactive iodine refractory well-differentiated, poorly-differentiated, or medullary thyroid carcinoma seen at the Princess Margaret Cancer Center from 2007-2022 were included. Electronic medical records were reviewed to collect clinicopathologic and treatment data. All patients had tumor next-generation sequencing (NGS) by a targeted gene panel. Overall survival (OS) from initial medical oncology consultation was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazards models. Results: Of 248 patients with advanced thyroid cancer, 41(17%) were diagnosed with BM. The median interval from thyroid cancer diagnosis to BM development was 6.49 years (y) (IQR 3.51- 14.35 y). The median age at the time of BM diagnosis was 63.6 y and 23 (56%) were male. Most (76%) were asymptomatic at the diagnosis of BM and 80% had an ECOG of 0-1. Among patients with well-differentiated histology, 27 (18%) developed BM, while 7 (12%) with poorly-differentiated and 7 (19%) with medullary thyroid cancer developed BM. The most common molecular alterations included BRAFV600E (n=19), TERT (n=11), RAS (n=9), RET (n=8), and FANCA (n=3). Patients were treated with surgery (n=5), stereotactic radiation (n=21), whole brain radiation therapy (n=12), or a combination of both (n=2). OS was similar in patients with BM compared to those without (6.05 vs 6.45 y). There were no differences in histology or molecular alterations between patients that developed BM compared to those who did not. The median survival from the time of BM was 3.23 y. Patients with BM with ≥4 lesions had worse survival (0.52 vs 5.09 y, p=0.01). There were no differences in survival based on histology, symptoms, treatment or molecular alterations among those with BM. Conclusions: This is one of the largest reported thyroid BM cohorts and the first with complete NGS. The prevalence of BM in our cohort was higher than previously described, often diagnosed incidentally. Screening for BM in advanced thyroid cancer may detect higher rates, offering prognostic insights. While the number of BM was predictive of survival, molecular alterations did not predict BM development or survival and larger studies are needed.