bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune- and tumor-intrinsic gene expression profiles of response or resistance to tislelizumab as monotherapy or in combination with chemotherapy in non-small cell lung cancer (NSCLC).
Authors: Desai Jayesh , Wang Jie , Zhou Qing , Zhao Jun , Deva Sanjeev , Tan Wei , Ma Xiaopeng , Zhang Yun , Shen Zhirong , Wu Xikun , Leaw Shiangjiin , Wu Yanjie , Wu Yi-Long 
Published: May 2020

e15258 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, showed clinical benefit for patients (pts) with NSCLC alone (NCT02407990, CTR20160872) and in combination with chemotherapy (NCT03432598). Gene expression profiles (GEP) associated with response and resistance to tislelizumab in these studies were assessed. Methods: The GEP of baseline tumor samples from 59 nonsquamous (NSQ) and 42 squamous (SQ) NSCLC pts treated with tislelizumab monotherapy (mono) as ≥1L treatment, and 16 NSQ and 21 SQ pts treated with tislelizumab plus chemotherapy (combo) as 1L treatment were assessed using the 1392-gene HTG GEP EdgeSeq panel. NSQ and SQ cohorts were analyzed separately due to distinct GEP features shown by PCA and t-SNE clustering. Results: Tislelizumab mono and combo showed antitumor activity in NSCLC (Table). In 80 biomarker-evaluable samples, inflamed tumor signatures (inflammatory GEP; antigen presentation GEP) were associated with longer overall survival (log-rank test, NSQ mono: P=0.04, 0.003; NSQ combo: P=0.05, 0.02; SQ combo: P=0.06, 0.06). Monotherapy non-responders (NRs) were clustered into 2 subgroups (NR1, NR2) with distinct GEPs. Compared with responders, NR1 had proliferation signatures (elevated cell cycle [CC] and DNA repair) in both NSQ ( P=0.2, 0.02) and SQ ( P=0.03, 0.4) cohorts, trending toward low inflamed tumor signatures. In NR pts receiving combo, CC and DNA repair signatures were not enriched, and high CC and DNA repair scores were observed in some SQ combo responders versus NRs ( P=0.2, 0.02). NR2 had higher M2 macrophage and Treg cell signatures versus responders in both NSQ and SQ mono, despite high inflamed tumor and low proliferation signatures. NR2 also had increased expression of genes related to immune regulation and angiogenesis, including PIK3CD, CCR2, CD244, IRAK3, and MAP4K1 ( P<0.05) in NSQ, and PIK3CD, CCR2, CD40, CD163, MMP12, VEGFC, and TEK ( P<0.05) in SQ. Conclusions: Clinical benefit in pts with NSCLC receiving tislelizumab (mono or combo) was associated with high inflamed tumor signatures, while elevated immune suppressive cell signatures may indicate resistance. High proliferation signatures were associated with resistance to monotherapy, but not to combination therapy. Both immune- and tumor-intrinsic factors may be considered for validation in future clinical trials. [Table: see text]
PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.
Authors: Yang Haihua , Cui Longgang , Zhang Yuzi , Zhao Zhengyi , Bai Yuezong , Xie Wenzhuan 
Published: May 2020

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.
Real-world observation of the efficacy and prognostic factors analysis of apatinib for patients with advanced gastric cancer.
Authors: Shen Qiwen , WANG Mingyun , Peng Xiaobao , Tan Siyi , Xie Jiaqi , Du Juan , Liu Qin , Wei Jia , Liu Baorui , Yang Yang 
Published: May 2020

e15508 Background: Apatinib is the first oral anti-angiogenic agent approved for the treatment of advanced gastric cancer in China. With the development of marketing promotion, the real world observation of the efficacy and prognostic factors analysis of apatinib become the urgent need for clinical decision. The aim of this study is to evaluate the efficacy and safety of apatinib in patients with advanced gastric cancer, and the association between some prognostic factors and clinical outcomes. Methods: We collected the data of 153 patients with advanced gastric cancer, who were treated with apatinib after failure of at least one regimen chemotherapy from December 2014 to June 2019. Treatment response, progression-free survival(PFS), overall survival(OS) and treatment-related adverse events were evaluated. Results: The median PFS for 153 patients was 3.1m (95% confidence interval, CI 2.863-3.337). The median OS was 6.0m (95% CI 4.392-7.608). Adverse events of grade 3 or above happened in 47.6 percent of patients and 61.7 percent of whom stopped treatment. Multivariate analysis showed that the number of metastatic sites was the independent factor simultaneously predicting DCR (disease control rate, P = 0.008) and OS (P = 0.007). Patients spending more than one year from diagnosis to treatment with apatinib had better DCR (P = 0.032) and longer PFS (P = 0.015). Liver metastasis (P = 0.007) and combined systemic therapy (P = 0.036) were significantly associated with DCR, but not associated with PFS or OS. Conclusions: Some patients with advanced gastric cancer can benefit from apatinib. This study help us to identify patients who has potential benefit from apatinib.
Association between central and peripheral circulating tumor cell (CTC) clusters in oral squamous cell carcinoma (OSCC): A prospective, observational study.
Authors: Bagadia Ritvi K , Rao Vishal Uchila Shishir , Balakrishnan Ajay , George Abhijith , Kumar Prashant 
Published: May 2020

e15548 Background: Around 90% of cancer-related mortalities are caused by tumor metastasis. CTC clusters, which constitute an intermediate stage of metastasis, have not been studied extensively in head & neck cancers. The mortality rate of oral cancers remains alarmingly high, despite multimodality treatment. The aim of the study is to identify the presence of CTC clusters in patients with Oral Squamous Cell Carcinoma (OSCC) and to correlate their presence with clinical and pathological factors. Methods: Fifty patients diagnosed with histologically proven OSCC, treatment naïve, and underwent surgery at HCG Cancer Centre, Bangalore, were consented and enrolled in the study. An IRB-approved protocol allowed for the collection of 10 ml of blood from central (jugular) and peripheral veins intra-operatively, prior to tumor removal. The culturing of CTC clusters was done using ellipsoidal microwell plates maintained at hypoxic conditions, at the Institute of Bioinformatics, Bangalore. After fourteen days of culturing, the cells were fixed and stained for DAPI, Pan-CK and CD45. The CTC clusters were classified into Loose, Tight and very Tight based on the median gray values obtained from DAPI staining on ImageJ software. Clinical data was collected from patient records and subjected to analysis using Descriptive statistics. Results: From the 50 patients included in the study, 22 (44%) patients exhibited tight clusters in central blood, while only 13 (26%) patients exhibited tight clusters in peripheral blood. A higher clinical stage was observed in a greater percentage of patients with tight clusters in central blood (early: 45.5% versus late: 54.5%), but the same findings could not be inferred with pathological staging (early stage: 59.1% versus late stage: 40.1%). No significant correlation with adverse pathological features was noted. Conclusions: This observational study provides an insight into the varying biological behaviours of similarly grouped cancers, which is based on the standard TNM staging. The study forms the basis for the hypothesis of tight clusters in the central and peripheral circulation, correlating with loco-regional and distant metastasis respectively, thus leading to poorer disease-free and overall survival rates.
Biomarker screening for the early detection of prostate cancer using an exosomal-enrichment RNA liquid biopsy test.
Authors: Roberts Douglas , Mitsock Emily , Ogunlusi Olubode , Yu Seth , Skog Johan 
Published: May 2020

e15553 Background: Prostate cancer is one of the most common cancers in men, with approximately 10% of all new cancer cases and ~5% of all cancer deaths in 2019. The standard test for prostate cancer is the Prostate Serum Antigen (PSA) test. The PSA test suffers from low specificity (20-40%) in patients including ‘grey zone’ levels (4-10 ng/mL); moreover, the PSA test fails to identify patients with high-risk cancers. Previously we developed ExoDx Prostate Intelliscore (EPI), a urine-based exosome prostate cancer test optimized to rule out the need for a biopsy (risk stratification for high-grade prostate cancer). This study utilized a next generation exosome-based test that specifically enriches a subtype of prostate cancer exosomes from urine. Early detection of prostate cancer via a non-invasive method is desirable and the identification of patients with high-risk cancer is critical. Here we describe the development of a prostate-specific urinary exosome test for the identification of patients with prostate cancer. Methods: We have developed a prostate-specific enrichment method to isolate exosomes of prostate origin from urine samples. Using an affinity-based method against surface marker proteins found on prostate cells, we were able to selectively enrich for exosomes shed by the prostate gland with demonstrated specificity. Subsequent analysis of exosomal nucleic acids enables a promising panel of gene expression biomarkers capable of distinguishing patients with prostate cancer from healthy individuals. Results: RNA from prostate cancer enriched exosomes was compared to total exosomes from urine. Enrichment of prostate cancer specific exosomes significantly enhanced the RNA signature compared to total urine exosomes. Conclusions: Prostate cancer tests have recently been developed for RNA signatures in urine. Exosomes provide a source of nucleic acids as they are actively shed continuously from living cells as part of their normal life cycle. The urine exosomes can be used for total RNA transcriptome analysis and are therefore a very rich source of biomarkers for prostate cancer that can be tailored to different clinical indications. An affinity-based enrichment for tissue-specific exosomes allow for better resolution of the gene expression profile from the tissue of interest and reduces the RNA targets from non-relevant processes of the bladder and kidneys. The gene signature identified in this ongoing study could potentially provide a non-invasive molecular means for the early diagnosis of prostate cancer.
Identification of germline cancer predisposition variants during clinical ctDNA testing.
Authors: Stout Leigh Anne Anne , Kassem Nawal , Hunter Cynthia , Philips Santosh , Radovich Milan , Schneider Bryan P. 
Published: May 2020

e15555 Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. Identification of inherited germline cancer predisposition mutations that have significant implications for at-risk relatives may be missed during routine ctDNA testing. Allele frequency has the potential to enhance the likelihood that a mutation is germline; and is often reported in many NGS tests from ctDNA. Here, we report on the fidelity of allele frequency in ctDNA as a predictor for pathogenic germline variant carriage. Methods: ctDNA sequencing of patients with metastatic cancer from the Indiana University Health Precision Genomics Program was performed using the FoundationOne Liquid assay. All variants detected by the ctDNA assay report were considered. All patients also had germline testing information and pathogenicity of germline variants were determined using ClinVar. Germline variants with conflicting interpretations were manually reviewed to determine pathogenicity. Comparisons between ctDNA results with known germline status were performed. Results: Of 91 previously identified germline cancer predisposition variants, 36 (40%) were also identified by ctDNA analysis. All germline variants that were tested for in the ctDNA assay (n = 36, 100%) were identified. When detected, the allele frequencies of detected germline variants in the ctDNA ranged from 39-87.6% with an average of 52.1%. Conversely, 111 of 160 (69%) variants identified by ctDNA analysis with allele frequency between 40-60% in a cancer predisposition gene were found to be germline in origin (regardless of pathogenicity). Variants in the BRCA2, BRCA1, and CDH1 genes were most likely to be germline in origin (26/27 [96%], 20/22 [91%], 13/15 [87%], respectively). Variants in the TP53 and APC genes were least likely to be germline in origin (9/36 [25%] and 1/6 [17%], respectively). There was an 85% (95/111) concordance in actionability between the somatic testing lab and ClinVar germline classifications. Of the 16 discordant variants, 100% were determined to be actionable by the somatic testing lab but not actionable in ClinVar. Conclusions: ctDNA allele frequency can alter the likelihood that a variant is germline. Importantly, however, this testing is far from comprehensive and should not be used as a replacement for germline testing. Variants with allele frequency between 40-60% in cancer predisposition genes should induce a high level of suspicion for germline status.
Detection of residual disease and recurrence in early-stage non-small cell lung cancer (NSCLC) patients using sensitive personalized ctDNA sequencing assays.
Authors: Heider Katrin , Gale Davina Gillian , Marsico Giovanni , Ruiz-Valdepeñas Andrea , Sharma Garima , Perry Malcolm , Osborne Robert , Howarth Karen , Rundell Viona , Belic Jelena , Wulff Jerome , Harden Susan , Rassl Doris M , Rintoul Robert , Rosenfeld Nitzan 
Published: May 2020

e15560 Background: Detection of residual circulating tumour DNA (ctDNA) in patient plasma following curative intervention for localized non-small cell lung cancer (NSCLC) could identify patients who are at higher risk of relapse. These patients may benefit from adjuvant treatment, even if they have no macroscopic disease identified by radiographic imaging, which is the current standard of care. Here we evaluate the performance of the Inivata personalized sequencing assays to detect ctDNA in a cohort of 90 patients with early-stage NSCLC undergoing treatment with curative intent. Methods: The Inivata assay uses a highly sensitive next-generation sequencing platform, to identify tumor-specific variants from exome sequencing of tumor tissue and to track up to 48 patient-specific mutations in plasma specimens by multiplex PCR and ultra-high-depth next-generation sequencing. Samples from 90 patients with Stage I-III NSCLC who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy, were collected as part of the LUng cancer - CIrculating tumor DNA (LUCID) study. Results: 350 plasma samples from 90 patients were analyzed using the Inivata assay, including samples collected before and after treatment and at subsequent follow-up visits. ctDNA was detected in pre-treatment samples in 38% of 32 patients (12/32) with Stage I NSCLC and in 90% of 21 patients (19/21) with Stage II/III disease, at allele fractions ranging from 6 parts per million (ppm, equivalent to 0.0006%) to over 20,000 ppm (equivalent to 2%). In plasma samples collected post-treatment, ctDNA was detected in close to 50% of cases. Conclusions: These findings highlight the Inivata assay is a sensitive method for detection of residual ctDNA and recurrence in early stage NSCLC. Initial detection rates ranged from 38% in Stage I disease to 90% for patients with Stage II/III disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. ctDNA was detected in at least one post-treatment timepoint in close to 50% patients. Together with additional data to be presented from the full 90 patient cohort, this suggests a possible route to improving treatment and designs of adjuvant trials for early stage NSCLC by detection of residual disease post-treatment and monitoring for early detection of relapse.
A phase I study of the novel immunotoxin, MT-5111, in subjects (subj) with HER-2 positive tumors: Interim results.
Authors: Wainberg Zev A. , Barve Minal A. , Hamilton Erika Paige , Brenner Andrew Jacob , Valdes Frances , Mita Monica M. , González Valeria , Anand Banmeet S. , Burnett Christine , Pelham Joshua , Waltzman Roger J. , Strack Thomas , Van Tine Brian A. 
Published: May 2020

e15567 Background: Engineered toxin bodies (ETBs), composed of a Shiga-like Toxin A subunit genetically fused to antibody-like binding domains, can force receptor internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, binds to an epitope distinct from and non-competitive with trastuzumab and pertuzumab. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adults with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics, efficacy, and immunogenicity. Part 1 will identify the MTD via MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10 µg/kg/dose) according to a modified 3+3 design. Part 2 will further evaluate the safety of MT-5111 at the recommended phase 2 dose (RP2D) in 3 separate cohorts of subjs with a HER2 immunohistochemistry score ≥2 in a metastatic lesion of primary breast, gastroesophageal, or other cancers. All subjs receive MT-5111 as a 30-minute IV infusion on Days 1, 8, and 15 of each 21-day treatment (tx) cycle (C) until disease progression, unacceptable toxicity, death, or withdrawn consent. Details can be found on clinicaltrials.gov (NCT04029922). Results: The first cohort (0.5 µg/kg/dose) enrolled 4 subjs (metastatic breast cancer, n = 2; metastatic cholangiocarcinoma, n = 2). Three subjs were female and the mean age was 69 years (median 65, range 64-78). Subjs received a mean of 5 prior lines of therapy (median 4.5, range 3-8). Three subjs completed C1 of tx without dose-limiting toxicities; 1 subj was inevaluable. Two subjs had progressive disease in C2. A total of 23 AEs occurred in 4 subjs; all were grade (G) 1-2 except one G3 event of hypertension in a subj with a history of hypertension. There were 2 tx-related AEs (G1 chills; G2 aspartate aminotransferase increased in the setting of progressive liver metastases). There was 1 serious, non-tx-related AE (G2 dyspnea) that occurred in the inevaluable subj. No cardiac AEs were noted, nor clinically significant changes in cardiac biomarkers, an important safety parameter given non-human primate toxicity. Conclusions: MT-5111 appears to be well tolerated at the lowest dose with no apparent cardiotoxicity to date. Drug concentrations are expected to be below the level required for in vitro tumor cell killing. Safety and efficacy data from subsequent dose escalation cohorts are expected by May 2020. Clinical trial information: NCT04029922.
Validation of an exome and transcriptome based diagnostic platform enabling clinical cancer therapy selection and emerging composite biomarkers for immunotherapy.
Authors: Saldivar Juan-Sebstian , Harris Jason , Desai Sejal , Ayash Erin , Tandon Prateek , Marfatia Twinkal , Power Robert , Morra Massimo , Chinnappa Manju , Clark Michael James , McClory Rena , Chen Richard 
Published: May 2020

e15583 Background: While immunotherapy has become a pillar of cancer treatment, diagnostic biomarkers that consistently predict patient response to these therapies have remained elusive. There is an increasing need for the development of integrative, composite biomarkers that can model the complex biology driving response and/or resistance to immunotherapy more effectively than existing single-analyte approaches. However, the majority of current cancer diagnostic panels, with their focus on a small set of genes, provide limited ability to support these emerging advanced biomarkers. Methods: To address these limitations, we developed and validated NeXT Dx, a comprehensive enhanced exome and transcriptome based diagnostic platform designed to simultaneously characterize tumor and immune genomics from a single limited FFPE sample. To achieve higher accuracy and sensitivity for an exome scale diagnostic platform, we developed an augmented exome assay that improves uniformity of coverage across all ~20,000 genes, including boosted coverage of 248 clinically-relevant cancer genes. We validated this assay using genomic DNA and RNA extracted from tumor-derived cell-lines, constructs, clinical FFPE samples, and proficiency testing samples. The assay utilizes > = 25ng of co-extracted DNA and RNA which were sequenced using Illumina NovaSeq instruments at our CAP-accredited, CLIA-certified laboratory. Additional assay enhancements for HLA, immune repertoire, and oncoviruses were designed to further optimize the platform for immunotherapy biomarker discovery applications. Results: Validation of NeXT Dx demonstrated a performance of 99.5% sensitivity and 99.8% positive predictive value (PPV) for SNVs with > = 5% AF; 98.7% sensitivity and 97.4% PPV for indels with > = 10% AF; 97.2% sensitivity and 94.6% PPV for CNAs in samples with > = 30% tumor content; 94.9% sensitivity and 94.9% PPV for fusions; and a 2.1% error rate for MSI classification. TMB was calculated using gold-standard whole exome data from SNVs and indels. Typical median coverage depth was > 1,000X for 248 clinically-relevant genes, ~300X for the remaining (whole exome) footprint. Conclusions: With NeXT Dx, we demonstrate a exome/transcriptome scale diagnostic platform that can detect current clinical biomarkers with high sensitivity as well as support emerging, advanced biomarkers that integrate across both tumor and immune features.