bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-genome cell-free DNA (cfDNA) changes as a dynamic blood-based biomarker for early response assessment of advanced tumors.
Authors: Davis Andrew A. , Iams Wade Thomas , Chan David , Oh Michael S , Lentz Robert William , Peterman Neil , Robertson Alex , Shah Abhik , Srivas Rohith , Lambert Nicole , Wilson Timothy , George Peter , Wong Becky , Tezcan Ayse , Yalamanchili Ram , Nesmith Ken , Spinosa John C , Tezcan Haluk , Chae Young Kwang 
Published: May 2019

3041 Background: Liquid biopsies have potential clinical utility as dynamic biomarkers for treatment response. We analyzed serial changes in whole-genome (WG) cfDNA to identify patients with disease progression prior to routine imaging. Methods: We prospectively collected clinical data and blood from 69 advanced cancer patients (28 lung, 25 breast, 16 other). Blood was collected at baseline prior to initiation of a new treatment and at one or two additional timepoints (median 21 and 42 days). We isolated plasma cfDNA and prepared sequencing libraries for WG sequencing or WG bisulfite sequencing (median depth 20X). We quantified changes in the fraction of tumor-derived cfDNA over the initial course of treatment to predict progression vs. no progression. Treatment response at first post-treatment imaging was determined by RECIST 1.1 and clinical assessment. Study endpoints were agreement with first post-treatment imaging and progression-free survival (PFS) by cfDNA prediction. Results: Median age of patients was 70 and 59% were female. Patients were treated with the following therapies: chemotherapy (37), immunotherapy (17), endocrine (9), or targeted therapy (6). Patients with predicted progression by cfDNA (14), indicated by an increase in tumor fraction at either post-treatment blood collection, had shorter PFS (median 63 days) compared to patients without an increase (N = 55; median 255 days), with hazard ratio of 10.3 (95% confidence interval 4.6-23.4, log-rank P = 1x10-11). Positive predictive value was 100% for disease progression and negative predictive value was 78%. These findings were consistent in subset analyses of patients with lung (log-rank P = 2x10-5), breast (log-rank P = 3x10-4), and those treated with immunotherapy (log-rank P = 5x10-6). Conclusions: Our results show the ability to detect early disease progression with high fidelity using WG cfDNA prior to first imaging. These findings were consistent across multiple tumor types and treatments, including immunotherapy patients. Once validated, this dynamic, predictive, blood-based biomarker could aid in clinical decision making for early treatment change as a novel and cost-effective approach.
Cell-free methylated DNA (cfMeDNA) immunoprecipitation and high throughput sequencing technology (cfMeDIP-seq) in patients with clear cell renal cell carcinoma (ccRCC).
Authors: Nuzzo Pier , Spisak Sandor , Chakravarthy Ankur , Shen Shu Yi , Berchuck Jacob E , Nassar Amin , Abou Alaiwi Sarah , Steinharter John A. , Bakouny Ziad , Boccardo Francesco , Sonpavde Guru , Lee Gwo-Shu Mary , Chang Steven Lee , Pomerantz Mark , De Carvalho Daniel , Freedman Matthew , Choueiri Toni K. 
Published: May 2019

3052 Background: CfmeDNA is a promising biomarker for non-invasive assessment of solid tumors: i) MeDNA is tissue- and tumor-specific ii) cfDNA methylation changes are stable unlike DNA alterations iii) ‘methylation target size’ is larger than identifying specific genomic alterations and, therefore, more sensitive. CfMeDIP-seq is a sensitive assay for genome-wide bisulfite-free cfMeDNA profiling, that requires 1-10 ng input DNA. We tested the feasibility of cfMeDIP-seq to detect ccRCC across TNM stages. Methods: We evaluated plasma cfDNA collected prior to nephrectomy in 46 pts with ccRCC: 25 stage I, 7 stage II, 6 stage III, 8 stage IV. cfMeDIP-seq involves four steps: 1) cfDNA end-repair, A-tailing, and adapter ligation 2) cfMeDNA immunoprecipitation and enrichment using an Ab targeting 5-methylcytosine (quality control by qPCR to ensure <1% of unMeDNA and >99% reaction specificity) 3) adapter-mediated PCR to amplify cfMeDNA 4) high-throughput NGS for cfMeDNA data. A previously-derived model (Shen et al, Nature, 2018) was used to classify pts as having ccRCC or not based on cfMeDNA. cfMeDIP-seq paired end data was reduced to 300 bp windows of the genome that map to CpG islands, shores, shelves, and FANTOM5 enhancers; a classifier was then built using the top 1,000 most variable fragments between pts with ccRCC and cancer-free controls. Statistical comparisons were performed in the R statistical environment, with the caret package being used for classifier construction and evaluation. Results: The average amount of cfDNA isolated from 1 ml of ccRCC plasma was 19.8±39.8 ng/µL [1.95-260]. Greater than 99% specificity of reaction and <1% of unMeDNA was achieved in 46/46 samples (100%). The previously-derived classifier of ccRCC correctly predicted 46/46 pts (100%) as having ccRCC. Across 3 rounds of 5-fold cross-validation, the classifier performed with a Cohen’s Kappa of 0.93. Conclusions: CfMeDIP-seq is a non-invasive, cost-effective, and sensitive assay to detect cancer-specific cfmeDNA in ccRCC pts prior to nephrectomy. With further validation, cfmeDNA may detect minimal residual disease after nephrectomy for ‘precision’ adjuvant therapy.
Efficacy of tyrosine kinase inhibitors (TKIs) based on the ALK resistance mutations on amplicon-based liquid biopsy in ALK positive non-small cell lung cancer (NSCLC) patients (pts).
Authors: Mezquita Laura , Swalduz Aurélie , Jovelet Cecile , Ortiz-Cuaran Sandra , Planchard David , Recondo Gonzalo , Benitez Jose Carlos , Howarth Karen , Morris Clive D. , Green Emma , Lacroix Ludovic , Odier Luc , Rouleau Etienne , Fournel Pierre , Caramella Caroline , Tissot Claire , Perol Maurice , Friboulet Luc , Besse Benjamin , Saintigny Pierre 
Published: May 2019

3055 Background: Acquired ALK resistance mutations (mut.) are the main mechanism of tyrosine kinase inhibitor (TKI) resistance (30-50%). While next-generation TKIs are more active on mut. than earlier TKIs, compound ALK resistance are associated with failure to next-generation TKIs. We evaluated the clinical utility of detecting ALK resistance mutations in blood to predict TKI efficacy. Methods: ALK positive advanced NSCLC pts were prospectively enrolled between Oct. 2015 and Aug. 2018 in 8 French institutions. Prospective samples were collected; ctDNA was analyzed by amplicon-based Inivata InVisionFirst-Lung. Results: A total of 101 pts with advanced ALK positive NSCLC were enrolled and 328 samples collected. In samples collected at TKI failure (N=74), we detected 9 single and 7 complex (≥2) ALK resistance mut. (22%), associated with EML4-ALK variant 3 (38%) vs. variant 2 (13%) vs. variant 1 (none); 30% had other somatic mut. (mainly TP53 and KRAS, PI3KCA, MET, etc.). No mutations were detected in 48% of samples (ctDNA neg). ALK mut. were more frequent after 2nd/3rd generation TKI (43% post-lorlatinib (7), 29% post-2nd gen. (31), 11% post-crizotinib (36)). ALKG1202R was the most common, as single (n=3) or complex mut. (n=4). The median overall survival (mOS) was 100.4 mo. (95% CI 41.9-158.9) and the median progression free-survival (mPFS) to subsequent line was 2.8 mo. (0.7-4.9). Patients with ctDNA neg had mOS of 105 mo. (39.3-172.1) vs. 58.5 mo. (33.1-84.0) if ≥1 ALK mut. vs. 44.1 mo. (20.0-68.2) if others ( P=0.001). Pts with the complex ALK mut. had worse OS compared to singles ALK mut. (mOS 26.9 mo. vs. 58.5 mo., P=0.001); ALK complex mut. were associated with poor efficacy to subsequent therapy (PFS <3 mo. in 57%; no cases with PFS >6 mo.) vs. single mut., with longer PFS (PFS >6 mo. in 56%). Detectable ALKG1202R mut. were associated with shorter median OS (58.3 mo.; 7.9-109.1) vs. overall population; 86% of cases developed rapid PD (PFS <3mo.) to subsequent therapy with only one durable response to lorlatinib (PFS >6mo.). Conclusions: The absence of ctDNA mutations at TKI failure was associated with prolonged OS, whereas complex ALK mutations at TKI failure may predict resistance to subsequent therapy. Larger and specifically designed studies should be performed to validate these findings.
Baseline cfDNA characteristics and evolution of cfDNA profile during treatment with selective FGFR inhibitor TAS-120.
Authors: Moss Tyler J. , Rodon Ahnert Jordi , Oakley Holly D. , Kahle Michael , Karp Daniel D. , Pant Shubham , Jacob Jeena , Raymond Victoria M. , Lanman Richard B. , Kwong Lawrence , Routbort Mark , Soni Nital , Huang Jerry , Javle Milind M. , Meric-Bernstam Funda 
Published: May 2019

3056 Background: There is an increasing role for cfDNA in monitoring response and mechanisms of resistance. We performed cfDNA analysis in a subset of patients enrolled on a Phase I trial with an irreversible, selective FGFR1-4 inhibitor, TAS-120. Methods: 58 plasma samples from 17 patients (13 with cholangiocarcinoma) were analyzed on a 73-gene, next-generation sequencing panel. Selected patients(pts) had longitudinal samples. Results: At least one alteration was detected in 46 cfDNA samples, in 16 (94%) of 17 pts – a pt with GBM had no alterations detected. 14 pts had alterations in FGFR2/3 by genomic testing of archival tumor samples, comprising 20 total alterations (18 unique). 10 of 20 FGFR2/3 alterations were also detected by cfDNA testing: 4/5 SNVs, 1/2 amplifications, 5/13 fusions. Three pts had FGFR/FGF alterations not included (thus not detected) in the cfDNA panel: 2 with FGF ligand amplification, and one FGFR4 mutation. 6 pts (35%) had PR, 5 (29%) had SD and 6 (35%) PD as a best response to TAS-120. Four pts had prior FGFRi: 2 had a PR, 1 SD, and 1 PD on TAS-120. Baseline cfDNA mutations became undetectable during treatment in 4/6 pts with PR. 4 of 6 PD pts had other driver mutations at baseline including mutations in PIK3CA, KRAS, IDH1, BRCA2, or amplifications in PIK3CA, PDGFR. 9 pts with cfDNA available at progression after SD/PR: 3 had acquired FGFR2 mutations (one each of V564L, V564F, or N549K). Two also acquired alterations in other candidate resistance genes ( PTEN and MAP2K1). Another pt had low variant allele frequency (VAF) NRAS G12D and BRAF A694T pretreatment and had SD. At progression, cfDNA revealed an increase in NRAS VAF and mutations acquired in the MAPK pathway . One pt with prior FGFRi acquired FGFR2 V564I and V564K detected by cfDNA prior to initiation of TAS-120, and had a PR on TAS-120. There was a drop in FGFR2 V564I VAF with response that subsequently increased with progression. The patient also acquired a FGFR2 V564L mutation at progression. Conclusions: FGFR alterations can be detected by cfDNA. cfDNA may detect potential resistance mechanisms, including PI3K or MAPK pathway alterations and acquired FGFR2 mutations. Patients with gatekeeper mutations in cfDNA at baseline may still respond to TAS-120. Further study is needed to determine the impact of FGFR2 mutations and co-alterations on TAS-120 sensitivity.
No-cost next generation sequencing of advanced cancer patients within the Strata Precision Oncology Network supports clinical trial enrollment.
Authors: Matrana Marc Ryan , Tomlins Scott A. , Kwiatkowski Kat , Mitchell Khalis , Suga Jennifer Marie , Dees Elizabeth Claire , Burkard Mark E. , Khatri Jamil , Safa Malek M. , Yang Eddy Shih-Hsin , Parsons Benjamin , Menter Alex R. , Thompson Michael A. , Gonzalez Anneliese O. , Wassenaar Timothy Robert , Rhodes Dan 
Published: May 2019

3073 Background: Widespread integration of systematized next generation sequencing (NGS)-based precision oncology is hindered by numerous barriers. Hence, we developed the Strata trial (NCT03061305), a screening protocol to determine the impact of scaled precision oncology. Methods: We implemented no-cost NGS on formalin fixed paraffin embedded (FFPE) clinical samples for all patients with advanced tumors, a common portfolio of partnered therapeutic clinical trials, and robust infrastructure development across the Strata Precision Oncology Network. Results: Across the network of 17 centers, specimens from 8673/9222 (94%) patients were successfully tested in the Strata CLIA/CAP/NCI-MATCH accredited laboratory using comprehensive amplicon-based DNA and RNA NGS. Patients were tested with one of three StrataNGS test versions; the most recent panel assesses all classes of actionable alterations (mutations, copy number alterations, gene fusions, microsatellite instability, tumor mutation burden and PD-L1 expression). Median surface area of received FFPE tumor samples was 25mm2 (interquartile range 9-95mm2), and the median turnaround time from sample receipt to report was 6 business days. 2577 (27.9%) patients had highly actionable alterations, defined as alterations associated with within-cancer type FDA approved or NCCN guideline recommended therapies (1072 patients), NCI-MATCH trial arms (1467 patients), Strata-partnered therapeutic trials (327 patients), or specific alteration-matched FDA approved therapies in patients with cancers of unknown primary (71 patients). Of the 1467 patients matched to an NCI-MATCH trial arm, 15 enrolled. Of the 327 patients matched to one of nine Strata-partnered clinical trials, 77 (24%) were screen failures, while 250 (76%) have either enrolled or are being actively followed for enrollment upon progression. Conclusions: Through streamlined consent methods, electronic medical record queries, and high throughput laboratory testing at no cost to patients, we demonstrate that scaled precision oncology is feasible across a diverse network of healthcare systems when paired with access to relevant clinical trials. Clinical trial information: NCT03061305.
Comparison of an automated cartridge-based system for mRNA assessment with central immunohistochemistry in the neoadjuvant GeparX trial.
Authors: Denkert Carsten , Link Theresa , Jank Paul , Just Marianne , Hanusch Claus , Brasch Frank , van Mackelenbergh Marion , Küster Willi , Marme Frederik , Karn Thomas , Müller Volkmar , Kümmel Sherko , Nekljudova Valentina , Loibl Sibylle , Blohmer Jens U. 
Published: May 2019

3075 Background: Hormone receptors, HER2 and Ki-67 are prognostic values typically determined for breast cancer (BC) outcome and prediction of therapy response. A RT-qPCR based system, the Xpert Breast Cancer STRAT4, can be used to classify BC tissues regarding their hormone receptor status, HER2 and proliferation via Ki-67. We compared mRNA expression analysis of ER, PR, HER2, and Ki-67 by this automated in-vitro diagnostic platform (GeneXpert) (GX) with central immunohistochemistry (IHC) in a large clinical trial cohort. Methods: BC patients from the prospective GBG neoadjuvant trial GeparX (NCT02682693) (still recruiting) were included in this biomarker project. We used formalin-fixed paraffin embedded (FFPE) pretherapeutical core biopsies with a tumor content > 10%. One 4 µm FFPE tissue section was first processed with the Xpert FFPE Lysis Kit, the sample lysate was placed in the STRAT4 cartridge system and then tested on the GX system in which the purification, amplification and real-time detection took place within two hours automatically. Results: A total of 503 (99%) of the 509 samples had a valid measurement of all four genes. 258 samples (51.3%) of the cohort were classified in central pathology as ER positive, 196 (39%) as PR positive and 78 (15.5%) as HER2-positive, and 421 samples (83.7%) were Ki-67-high ( > 20%). The simple kappa coefficient was for ER = 0.7938, PR = 0.6540, HER2 = 0.8172 and Ki-67 = 0.3655. This indicates, that the measurements for ER, PR and HER2 showed a high correlation between both methods, whereas the measurement of Ki-67 does not. The accuracy between the STRAT4 and IHC was 89.7% for ER, 83.3% for PR, 94.6% for HER2 and 86.7% for Ki-67. According to molecular subgroups, highest accuracy regarding Ki-67, was determined in TNBC (96.2%; luminal: 81.1%; HER2-positive: 76.9%). Conclusions: Our results show a high concordance between standardized central IHC and automated mRNA expression analysis for the most important BC biomarkers ER, PR and HER2. For the proliferation marker Ki-67, the concordance is slightly lower. The STRAT4 assay might offer additional option to conventional methods for BC biomarker assessment, in particular in settings where IHC is not feasible. To determine the clinical validity, additional outcome analyses are necessary. Clinical trial information: NCT02682693.
Utility of somatic mutation panel testing in patients with advanced cancer receiving treatment in an Irish teaching hospital.
Authors: Khan Hadia , O' Callaghan Louise , Ahmed Gul , Bird Brian Richard , O'Connor Derbrenn , Murphy Conleth G. 
Published: May 2019

3076 Background: Tumor testing for potentially actionable somatic mutations via commercially available panel tests has entered routine clinical practice in many countries. In Ireland the cost of these tests is not covered by insurance companies and must be paid for by patients. Use of these tests is sporadic and depends on patient and clinician factors (including ability to pay). Existing data suggest that such testing results in a direct impact on patient therapy in a minority of patients only. We reviewed the impact of somatic mutation testing on treatment selection and outcomes in patients attending a medical oncology service in a teaching hospital in Ireland. Methods: We performed a retrospective study of patients who had commercial panel testing performed as part of routine oncology care. All patients opportunistically tested between 2013 and 2018 were included. Patients having focused molecular tests for approved therapies (e.g. RAS mutations in colon cancer, EGFR and ALK mutations in non-small cell lung cancer) were excluded.We reviewed medical records to assess the frequency and utility of mutations detected, the impact of testing on next and subsequent lines of therapy, and the effectiveness of therapy. Results: 74 panel tests were performed in 71 patients. 39 tests (53%) detected mutations, of which 21 (28%) were potentially actionable. 36 patients (51%) had further treatment after testing was performed. 9 tests (12%) led to test-based treatment. The mean duration of test-based treatment was 34 days (range 1-90 days). No patients had benefit from test based treatment, defined as tumour response or disease stabilisation on restaging scans. 23 patients died within 90 days of panel tests being requested. Among patients starting and completing a subsequent line of therapy after testing, the mean duration of therapy with test-based treatment was 39 days (range 6-90) and for standard of care treatment was 56 days (range 1-262 days). Conclusions: While testing for tumor-specific somatic mutations with proven predictive benefit is very useful, somatic mutation panel testing for non standard of care genetic alterations is not of utility in this real world setting. Its role in Ireland should be limited to identification of suitable early phase clinical trials. Discussions of panel testing should include frank discussion of expected benefits, and should also address factors such as patient ability to travel for clinical trials. [Table: see text]
Proteomic profile of high-risk luminal A early breast cancers.
Authors: Hajjaji Nawale , Aboulouard Soulaimane , Robin Yves-Marie , Bertin Delphine , Fournier Isabelle , Bonneterre Jacques , Salzet Michel 
Published: May 2019

3077 Background: Breast cancer is a heterogeneous disease with a wide range of outcomes. Among the intrinsic breast cancer subtypes, luminal A tumors are considered to have a favorable prognosis. However, molecular studies characterizing the genomic landscape of luminal A tumors revealed a molecular heterogeneity within this subtype, which also translated to variability in survival. A better understanding of the biology of this tumor subgroup is therefore needed to determine the appropriate therapeutic strategy. The aims of the study were to determine the frequency of high-risk luminal A tumors in a real life cohort of early breast cancers and provide a proteomic characterization of this subgroup using a mass spectrometry approach. Methods: 222 early breast cancer patients with hormone receptor positive and HER2 negative tumors treated at our institution had a PAM50-based genomic assay Prosigna to estimate their risk of recurrence. This assay assigned each tumor sample to an intrinsic molecular subtype of breast cancer. Luminal A and B tumors were analyzed with MALDI mass spectrometry imaging combined with microproteomics, a spatially-resolved on-tissue shotgun proteomic technology, to determine the proteomic profiles of both cancer cells and stroma. Results: Among the 129 luminal A breast cancers identified in our cohort, 67 (51%) had a risk of distant recurrence of 10% or more (32% had a 10% to 15% risk, and 19% a risk greater than 15%). High-risk luminal A tumors had a distinctive proteomic profile compared to low-risk luminal A or to luminal B tumors. Overexpression of the methionine biosynthesis pathway was the main differential protein expression observed in cancer cells and stroma of high-risk luminal A. Inflammation mediated by chemokine and cytokine signaling pathway and integrin signaling were also overexpressed in high risk luminal A compared to luminal B. In the stroma of luminal B tumors, EGR signaling, Ras and FGF pathways and angiogenesis were overexpressed compared to high-risk luminal A tumors. Conclusions: Real life data showed a significant proportion of high-risk luminal A breast cancers. MALDI mass spectrometry proteomics revealed distinctive tumor and microenvironment profiles in this breast cancer subgroup.
MET kinase domain rearrangements across 10 cancer types.
Authors: Zhao Jun , Chen Jin , Ma Haitao , Ye Ke , Shi Yue , Yi Yuting , Zeng Xiaoling , Guan Yan-Fang , Wang Jiayin , Yi Xin , Xia Xuefeng 
Published: May 2019

3078 Background: MET is a transmembrane receptor tyrosine kinase and deregulated in many kinds of tumors by mutation, rearrangement and amplification. Since the first c onstitutively active MET rearrangement ( TPR-MET) was discovered, many other MET rearrangements have been identified in various tumor types. However, the frequency and characteristic of MET rearrangement in Chinese cancer patients is still unclear. Methods: Targeted sequencing using 1021-gene panel or 59-gene panel was performed on 3952 tissue samples and 5100 blood-based ctDNA samples from 9052 unique patients across 10 cancer types. All MET exons were sequenced, but MET intronic breakpoints were not specifically baited. Results: 24 (0.27%) MET kinase domain rearrangements (KDRE) were identified in 9052 patients. Specifically, 0.25% (16/6284) in non-small cell lung cancer (NSCLC), 0.69% (2/290) in gastric adenocarcinoma, 0.32% (2/897) in colorectal cancer, 0.33% (2/610) in breast cancer, 0.3% (1/330) in hepatocellular carcinoma and 0.69% (1/145) in ovarian cancer, none in 139 pancreatic cancer, 136 thyroid cancer, 111 renal cell carcinoma and 110 esophageal squamous cell carcinoma. Among all of the MET KDRE, 17 were fusions with 5’ identified partner, 3 were kinase domain duplication (KDD) and 4 were probable fusions with unidentified partner. The most common 5 ’partner gene was CAPZA2, followed by CD47 and TES. In the MET KDRE cases in NSCLC, 56.25% (9/16) did not found any clinical actionable variants referring to the NCCN guideline. In addition, MET amplification, EGFR L858R or exon 19 deletion and KRAS mutation co-occurred in 25% (4/16), 18.75% (3/16) and 12.5% (2/16) of NSCLC MET KDRE cases respectively. Conclusions: Our results, for the first time, illustrate the MET KDRE across 10 cancer types among Chinese population and might provide some novel targets to develop new therapies for patients with MET KDRE. MET KDRE across different tumor types. [Table: see text]