tbuckley/cabot-search huggingface dataset:
Genomic characteristics of endometrial cancer in China.
Authors: Hong Zheng, Lina Cui, Bei Zhang, Xiaochen Zhao
Journal: Journal of Clinical Oncology (2021)

e17569 Background: Molecular classification of endometrial cancer has been applied in patient stratification and treatment strategy. Although the Cancer Genome Atlas project and other genomic studies have established comprehensive molecular classification, its genomic characteristics in Chinese endometrial cancer remain unclear. Methods: Tumor tissue and matched white blood cells from 316 patients with endometrial cancer underwent next-generation sequencing (NGS), which targeted the whole coding region of 733 or 381 genes. Endometrial cancer was classified into four subtypes according to genomic characteristics: polymerase (POLE) ultramutated, microsatellite instability (MSI), TP53 wild type (TP53wt), and TP53 mutant (TP53mut). Tumor mutation burden (TMB) was calculated based on the number of somatic single nucleotide variants and indels in examined coding regions. Deleterious or suspected deleterious genes were included for analysis. Genomic instability was also evaluated with Homologous Recombination Deficiency (HRD) score by over 10, 000 single-nucleotide polymorphisms distributed across human genome. HRD algorithm combined loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST). Results: The 316 endometrial cancer patients were divided into four subtypes: POLE ultramutated (16, 5.06%), MSI tumors (70, 22.2%), TP53wt (131, 41.5%), and TP53mut (99, 31.3%). Median TMB was 26.5 mut/Mb in overall cohort and POLE ultramutated subtype possessed the highest TMB (181 mut/Mb), followed by MSI (54.1 mut/Mb), TP53mut (7.11 mut/Mb) and TP53wt (6.61 mut/Mb) subtypes. POLE, PTEN, LRP1B, BRCA2 and ATRX were the top frequently mutated genes in POLE ultramutated subtype, which mutation rate are more that 80%. The most frequent mutations were detected in ARID1A, PTEN, PIK3CA in MSI subtype, TP53, PIK3CA, PTEN in TP53mut subtype, and PTEN, PIK3CA, ARID1A in TP53wt subtype. HRD score was significantly higher in TP53mut subtype, followed by TP53wt, MSI and POLE ultramutated subtype (median HRD score, 21.7, 6.15, 3.65 and 0; P &lt; 0.001). Conclusions: Our study revealed the heterogeneous genomic characteristics of four molecular subtypes in Chinese endometrial cancer. POLE ultramutated and MSI subtypes display higher TMB. TP53mut subtype showed genome features of HRD and would likely benefit from HRD-targeted therapy.
Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.
Authors: Neil J. Shah, Shuo Wang, Aquino Williams, Melinda Weber, Brittany Sinclaire, Elli Gourna Paleoudis, Adil Alaoui, Shaked lev-Ari, Shari Adams, Jordan Kaufman, Sahil B. Parikh, Emily Tonti, Eric Muller, Michael T Serzan, Divya Cheruku, Jaeil Ahn, Andrew Pecora, Andrew Ip, Michael B. Atkins
Journal: Journal of Clinical Oncology (2021)

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI &gt; 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P &lt;0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age &gt;75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI &gt;30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]
Digital PCR-based cell-free DNA K-Ras mutations analysis and clinical implication in pancreatic cancer.
Authors: Nahid Forouzandeh, Sachin Srinivasan, Katia Jurdi, John Qiang Wang, Nathan Tofteland, Wancai Yang, William Salyers, Jim Lu
Journal: Journal of Clinical Oncology (2021)

e16215 Background: Pancreatic cancer is one of the most fatal cancers worldwide. In addition to patients presenting later in the disease, limitations in current testing modalities pose a challenge to early diagnosis and treatment. Somatic mutations of the K-Ras gene have been suggested as a key driver of pancreatic carcinogenesis and thus proposed as a biomarker for diagnosis and therapy. Majority of these studies utilize tissue-based methods for analyzing K-Ras mutations. In recent years, liquid biopsy assay, in particular, analysis of cell-free DNA (cfDNA), has emerged as a promising noninvasive diagnostic approach in oncology, with the respect to the identification of minimal residual diseases, monitoring treatment response, detection recurrence and metastasis, and identification of chemo-resistance mechanisms. The application of digital PCR based plasma cfDNA K-Ras mutation assay in pancreatic cancer has not been reported. Methods: We included patients who underwent evaluation of a pancreatic lesion detected by conventional radiography (CT/MRI) and confirmed by endoscopic ultrasound (EUS) and biopsy. The biopsies from pancreatic tissues were formalin-fixed and paraffin-embedded (FFPE) for pathological diagnosis, and the total DNA was extracted from the FFPE slides. In addition, matched blood from the same patient was collected at the time of biopsy, and plasma cfDNA was extracted. Both DNA quality and concentration were evaluated. 4.0 ng of DNA was used for droplet digital PCR (ddPCR) analysis. K-Ras G12D, G12V, G12R, G12C, G12A, G12S, and G13D mutations were analyzed by multiplexed assay reagents. The sensitivity cut-off of the multiplexed K-Ras G12/G13 assay was 1.0%. Results: cfDNA could be detected in the initiation of pathological diagnosis. Among the twelve patients with pancreatic lesions, eight (67%) were pancreatic ductal adenocarcinoma (PDAC) (head (4), body (2), tail (2) of the pancreas), one was acute pancreatitis, one was a tail cyst and two were unspecified non-malignant lesions. All the eight PDAC (100%) FFPE tissues exhibited K-Ras G12/13 mutations (Scores: 4.2-41.5%), while none of the non-malignant lesions (0%) demonstrated K-Ras mutations. Interestingly, K-Ras mutations were detected from seven of the eight PDAC patient’s plasma cfDNA (87.5%) (Scores: 1.2-20.7%) while the plasma cfDNA from patients with non-malignant lesions did not show any positive K-Ras mutations. Conclusions: Digital PCR-based plasma cfDNA assay for K-Ras mutation is a promising tool for diagnosis of PDAC and is comparable to tissue-based assays. Larger prospective studies can substantiate this and explore their roles in the prediction and early detection of recurrence of PDAC.
A retrospective study on the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma.
Authors: Zhen Zeng, Linzhi Zhang, Tong Wu, Jiamin Cheng, Yan Chen, Yinying Lu
Journal: Journal of Clinical Oncology (2021)

e16127 Background: To evaluate the efficacy and safety of sorafenib or lenvatinib combined with sintilimab in patients with advanced hepatocellular carcinoma. Methods: This retrospective study included patients with advanced/metastatic hepatocellular carcinoma who received sintilimab (iv. 200 mg, Q3W) combined with sorafenib (oral, 400 mg twice-daily) (cohort A) or lenvatinib (oral, 12 mg/day for bodyweight≥60 kg or 8 mg/day for bodyweight &lt; 60 kg) (cohort B) as first line therapy between March 2019 to December 2020 in the 5 th medical center of the PLA general hospital of China. The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), Time to Progression (TTP) and safety. Results: 45 patients were enrolled, of which 29 were in the cohort A and 16 were in the cohort B. Except for the extrahepatic metastasis (62.1% vs 25.0%, P= 0.029), there were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous treatment regimens between the two cohorts. The mean (±SD) exposure cycles in the two cohorts were 7.2±6.7 vs 7.1±4.7 ( P= 0.584). The median PFS of cohort A (8.2 months, 95%CI 3.1-19.5) was longer than that of cohort B (5.2 months, 95%CI 2.0-10.8), but there was no significant difference (HR 0.55, 95%CI 0.24-1.29, P = 0.161). However, there was no significant difference between the two cohorts in ORR (24.1% vs 6.3%, P= 0.226), DCR (82.8% vs 75.0%, P= 0.700) and median TTF (8.2 vs 4.6months, HR 0.49, 95%CI 0.21- 1.10, P= 0.074). OS data were not yet mature. There was no significant difference in the incidence of all grades and grade 3-4 adverse events between the two cohorts. The most common grade 3-4 adverse events in the two cohorts were hand-foot syndrome (17.2%, 5/29) and lung infection (12.5%, 2/16). There was 1 patient (immune hepatitis) in cohort A and 2 patients (pulmonary infection) in cohort B leading to treatment interruption due to adverse events, and no deaths due to treatment. Conclusions: Sorafenib or lenvatinib combined with sintilimab showed a good efficacy and safety in patients with advanced hepatocellular carcinoma, the safety and tolerability profiles were consistent with those previously observed. Sorafenib plus sintilimab provided an improved PFS versus lenvatinib, which requires a large sample of randomized controlled trial to confirm.[Table: see text]
Tepotinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) with <i>MET</i> amplification (<i>MET</i>amp).
Authors: Xiuning Le, Luis G. Paz-Ares, Jan Van Meerbeeck, Santiago Viteri, Carlos Cabrera Galvez, David Vicente Baz, Young-Chul Kim, Jin-Hyoung Kang, Karl-Maria Schumacher, Niki Karachaliou, Svenja Adrian, Rolf Bruns, Paul K. Paik
Journal: Journal of Clinical Oncology (2021)

9021 Background: METamp is an oncogenic driver occurring in 1–5% of NSCLCs that confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in NSCLC with MET exon 14 ( METex14) skipping in Cohort A of the Phase II VISION trial (NCT02864992). VISION Cohort B evaluated tepotinib in pts with advanced NSCLC and METamp, as detected by a convenient and minimally invasive liquid biopsy assay, in the absence of METex14 skipping. Methods: Pts with locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, 0–2 prior lines of therapy, EGFR/ ALK wild-type status, no METex14 skipping, and METamp by liquid biopsy (Guardant360 ® ; MET gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). The primary endpoint was objective response (RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. The data cut-off was July 1, 2020. Results: Among 24 enrolled pts, median age was 63.4 years (range: 38–73), 21 pts (88%) were male, 21 (88%) had ECOG PS 1 and 21 (88%) were smokers. Tepotinib was given to 7 pts (29%) in first line (1L), 10 pts (42%) in second line (2L) and 7 pts (29%) in third line (3L). As of November 2020, treatment was ongoing for &gt; 1 year in 5 pts (1L, n = 2; 2L, n = 2; 3L, n = 1). Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L (Table). Median DOR by IRC was not estimable (NE; 95% confidence interval [CI]: 2.8 months–NE). Investigator-assessed outcomes were similar. Five pts (20.8%) discontinued due to adverse events (AEs), which were considered unrelated to tepotinib. Treatment-related AEs were reported in 16 pts (67%; Grade 3/4, 7 pts [29%]) and included peripheral edema (9 pts [38%]; Grade 3/4, 2 pts [8%]), generalized edema (4 pts [17%]; Grade 3/4, 2 pts [8%]) and constipation (4 pts [17%]; Grade 3/4, 0 pts). Conclusions: In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in NSCLC with METamp. Clinical trial information: NCT02864992. [Table: see text]
A surface-eroding poly(1,3-trimethylene carbonate) coating for magnesium based cardiovascular stents with stable drug release and improved corrosion resistance
Authors: Hongyan Tang, Shuangshuang Li, Yuan Zhao, Cunli Liu, Xuenan Gu, Yubo Fan
Journal: Bioactive Materials (2021)

Magnesium alloys with integration of degradability and good mechanical performance are desired for vascular stent application. Drug-eluting coatings may optimize the corrosion profiles of magnesium substrate and reduce the incidence of restenosis simultaneously. In this paper, poly (trimethylene carbonate) (PTMC) with different molecular weight (50,000 g/mol named as PTMC5 and 350,000 g/mol named as PTMC35) was applied as drug-eluting coatings on magnesium alloys. A conventional antiproliferative drug, paclitaxel (PTX), was incorporated in the PTMC coating. The adhesive strength, corrosion behavior, drug release and biocompatibility were investigated. Compared with the PLGA control group, PTMC coating was uniform and gradually degraded from surface to inside, which could provide long-term protection for the magnesium substrate. PTMC35 coated samples exhibited much slower corrosion rate 0.05 μA/cm
Robust prediction of response to immunotherapy in a mixed cohort of previously treated and immunotherapy-naive melanoma patients.
Authors: Charles Abbott, Lee McDaniel, Rachel Pyke, Eric Levy, Fabio Navarro, Simo V. Zhang, Jing Wang, Rena McClory, Michael Snyder, Sekwon Jang, Sean Michael Boyle, Richard Chen
Journal: Journal of Clinical Oncology (2021)

e21548 Background: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers. Methods: Pre-treatment samples from 51 unresectable, stage III/IV melanoma patients who underwent anti-PD-1 therapy were characterized to assess factors influencing response. RECIST criteria were used to evaluate tumor response to therapy, with a median follow-up of 24 months. For each patient, a single paired FFPE tumor and normal blood sample was collected and profiled using Personalis’ ImmunoID NeXT Platform; an augmented exome/transcriptome platform and analysis pipeline which produces comprehensive tumor mutation information, gene expression profiling, neoantigen characterization, HLA typing and LOH, TCR repertoire profiling, and tumor microenvironment profiling. These data were then integrated to form a composite neoantigen presentation score (NEOPS) for each patient. Results: We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. Neoantigen burden score (NBS) was derived from SHERPA, our exome and transcriptome integrative neoantigen prediction model. We found that NBS more significantly stratified responders and non-responders (P = 0.016) than TMB alone (P = 0.049). A broader score, NEOPS, incorporated DASH, to capture HLA allele-specific loss of heterozygosity and additional antigen presenting machinery resistance mechanisms. NEOPS consequently demonstrated a stronger association with response (p = 0.002). We used area under the curve (AUC) to benchmark NEOPS performance against established mutational and transcriptomic predictive models, demonstrating the model was more predictive of response in both the treatment naive setting, as well as in a mixed cohort of treatment-naive and experienced patients. These findings were confirmed in an independent cohort of patients (n = 110), suggesting that NEOPS is a robust, novel biomarker of ICB response in melanoma. Conclusions: Given the complex nature of resistance to immunotherapy, as well as potential toxicities associated with treatment, there is a need for biomarkers that can more accurately predict response. Here we demonstrate that NEOPS can significantly improve stratification of patient response. We also demonstrate that data intensive biomarkers like NEOPS can be clinically practical, with comprehensive tumor profiling in our clinical cohort achieved using very limited tumor tissue.
The impact of radiological assessment schedules on progression-free survival in metastatic breast cancer: A systemic review and meta-analysis.
Authors: Dor Reuven Dabush, Daniel Shepshelovich, Tzippy Shochat, Eitan Amir, Ariadna Tibau, Hadar Goldvaser
Journal: Journal of Clinical Oncology (2021)

1086 Background: The impact of the interval of radiological assessment on the magnitude of benefit observed in randomized trials (RCTs) in metastatic breast cancer is undefined. Methods: All RCTs investigating anti-neoplastic drugs for metastatic breast cancer published between 2006 and 2019 were identified. Intervals for restaging were categorized as short ( &lt; 9 weeks) or long (≥9 weeks). Hazard ratios (HRs) and 95% confidence intervals for progression-free survival (PFS) and overall-survival (OS) were pooled in a meta-analysis and compared between trials employing short and long restaging intervals assessed as subgroup analyses. Analyses were repeated for pre-specified subgroups according to disease subtype, drug type, whether experimental therapy was added to or replaced standard treatment and whether HR for PFS was &lt; 1 or ≥1. Results: Eighty-nine studies comprising 95 comparisons and 44,901 patients were included. The magnitude of PFS benefit was non-significantly larger in trials which employed short compared to long restaging intervals (HR 0.79 vs. 0.86, p = 0.15). Short restaging interval was associated with significantly higher magnitude of effect on PFS in pre-specified subgroups including non-first line studies (HR 0.78 vs. 0.92, p = 0.04), studies with drugs replacing standard treatment (HR 0.86 vs. 1.04, p = 0.02) and studies performed exclusively in human epidermal growth factor receptor 2 (HER2) positive disease (HR 0.72 vs. 0.90, p = 0.02). Restaging interval was not associated with OS for all included studies (HR 0.92 vs. 0.93, p = 0.66) or for any of the pre-specified subgroups. Conclusions: Shorter restaging intervals are associated with a higher magnitude of effect of PFS, but not OS. Awareness of the impact of the restaging interval on quantification of intermediate endpoints such as PFS is important for the design and interpretation of RCTs.
Association of serum brain-specific protein fragments and brain metastases in patients with metastatic breast cancer.
Authors: Sara Damaso, Nicholas Willumsen, Ana C. Martins Cavaco, Patrícia Corredeira, Teresa Raquel Duarte Pacheco, Ana Lucia Costa, Claudia C Faria, Ourania Tzara, Kim Henriksen, Morten A. Karsdal, Suhail M. Ali, Kim Leitzel, Allan Lipton, Luis Costa
Journal: Journal of Clinical Oncology (2021)

e14007 Background: Brain metastases (BrMs) occur frequently in patients with breast cancer (BC) and represent one of the most difficult-to-treat events. Novel clinical tools are needed to identify BC patients at high risk of developing BrMs. Blood-based liquid biopsies represent a minimally invasive procedure that may detect surrogate markers of pathological changes occuring in the brain as a result of BrMs. Here we evaluated serum levels of a panel of brain-specific protein fragments in metastatic BC patients with BrMs, with no-BrMs and controls. Methods: Our cohort includes stage IV BC patients with BrMs (n= 27; median age 51 y.o.) and no-BrMs (n=50; median age 53.5 y.o.), and healthy controls (H) (n=23, median age 50 y.o.). Serum levels of 5 brain-specific protein fragments were measured by immunoassays and compared between groups. No-BrMs samples were collected at the time of metastatic disease diagnosis; BrMs samples were collected at BrMs diagnosis and before local treatment. Association with overall survival (OS) was evaluated by univariate Cox regression analysis. Results: All markers were significantly higher in patients with no-BrMs compared to H. Only Neurocan, Tenascin-R and GFAP were significantly higher in patients with BrMs compared to H. When comparing metastatic BC patients, significantly higher levels of Tau-A, Tau-C, Neurocan and GFAP were found in no-BrMs patients versus BrMs (Table). Association with OS was not found in BrMs patients, although a trend for high Tau-A levels to predict poor OS was detected in the no-BrMs group (HR 4.4, 95%CI 0.9-21.3, p=0.068). Conclusions: Protein fragments expected to be derived from brain remodeling consequent to BrMs were elevated in BC patients both with BrMs and no-BrMs at the time of sampling, with an overall trend for the highest levels to be found in patients with no-BrMs. This may suggest that brain remodeling processes are associated with BC and could partly explain the relatively high incidence of BrMs relapse in BC. Further studies requiring samples collected pre- and post-treatment are needed to further validate the diagnostic and prognostic value of these non-invasive biomarkers in BC BrMs setting. [Table: see text]