bluuebunny/crossref_metadata_2025_split huggingface dataset:
Caveat emptor: A descriptive analysis of guideline-recommended biomarker inclusion in targeted NGS panels for metastatic non-small cell lung cancer (mNSCLC).
Authors: Fox John Leonard 
Published: June 2023

3124 Background: Next generation sequencing (NGS)-based panels are routinely used in the diagnosis of mNSCLC, guidelines recommending assessing 12 genes for small variants (SV), (EGFR, BRAF, KRAS, MET, ERBB2); fusions (F), (ALK, ROS1, RET, NTRK1, NTRK2, NTRK3); and copy number variants (CNV), (MET) to assess eligibility for targeted drug therapies. Reimbursement is often limited to targeted panels; yet, a comprehensive review of targeted panels’ ability to capture all recommended biomarkers has not been reported. Methods: Targeted panels were classified as ≤50 and 51-100 genes. We searched the DEX Diagnostics Exchange Registry for NGS-based lung cancer and solid tumor targeted panels. Each panel was compared against the 12 recommended genetic variants. If the type of genetic analysis (SV/F/CNV) was unclear, labs were contacted for clarification. Fusion assays by PCR or FISH with reflex testing to NGS were included. Results: 30 targeted NGS panels from 21 commercial labs were identified; 13 (43%) were specific to lung cancer. Six of 13 panels assessing fusions used FISH or PCR not NGS alone. 12 panels reported only SV, 8 small SV/F, 5 SV/CNS, and 5 all three variant types. Only 1 of the 30 panels (51-100 genes) captured all 12 biomarkers with correct variant types. Of 20 panels reporting ALK, RET, and ROS1, only 11(55%) reported fusions. Of the 5 reporting all three variant types, NTRK fusions were most commonly absent. On average, solid tumor panels sequenced twice as many genes (51 vs. 24) but were no more likely to capture all recommended biomarkers ((1/17 (6%) vs. 0/13 (0%), (p>0.05)). The average biomarkers captured in lung vs. solid tumor panels were 7.9 and 6.6, respectively (p>0.05), while in ≤50 gene panels vs. 51-100 gene panels, 7.0 and 7.6, respectively (p>0.05). Conclusions: Of 30 commercially available NGS panels with <100 genes, only one captured all recommended gene variant types for mNSCLC. Failure to capture all biomarkers was independent of panel size or specificity to lung cancer. NGS panels including small variants, fusions, and copy number variants assessed more biomarkers. Medical oncologists and clinical pathologists ordering targeted NGS panels for the management of patients with mNSCLC must ensure they assess all biomarkers relevant to targeted therapies. Insurers reimbursing targeted panels should acknowledge the inadequacy of <100 gene panels alone to provide guideline-concordant molecular diagnostic testing. [Table: see text]
Patient access to precision medicine: Identifying barriers to biomarker testing in non-small cell lung cancer.
Authors: Levent Ayse , De Richter Pieter , Bender Hope 
Published: June 2023

3131 Background: The growing number of targeted therapies approved to treat non-small cell lung cancer (NSCLC) has anchored biomarker testing in clinical practice. Despite general concordance across international guidelines recommending advanced NSCLC patients be tested for oncogenic alterations and immune biomarkers, this is not always the case. This study uses real-world data to explore the barriers to testing across US, Japan, Germany and China. Methods: Ipsos’ Biomarker Testing Rate Monitor is a multi-stakeholder, physician-reported syndicated patient record database. 206 cancer-treating physicians (US=69, Japan=37, Germany=41, China=59) were screened for seniority and caseload and submitted data on 990 NSCLC patients (aggregate) in which biomarker testing had not taken place. Data were collected online January – December 2022. Results: Analyzing physician cited barriers why patients were not tested, choosing not to test at patient’s current stage was highest in the reported US patient cohort, guidelines not calling for testing at this point was more frequently cited in the Japan (27%) and Germany (25%) patient cohort and patient’s co-pay was more frequently cited in the China cohort (34%). The Japan cohort had higher mentions of tissue not being available. Country disparities in the reported metastatic (IIIB-IV) cohort included lack of tissue in Japan (48%) and Germany (25%), deferring testing to a later point in the US (21%) and high co-pay in China (50%). The top cited reasons are shown. Conclusions: Results from this study indicate that, despite guidelines, not all oncology patients receive biomarker testing. While reimbursement structures are difficult to overcome, a concerted effort is needed to raise awareness of the clinical utility of biomarker testing and of the importance of collecting sufficient tissue during the biopsy to allow patients the chance of benefiting from precision medicines. Similarly, calls for earlier testing would support efforts that ensure the best available treatment options are available to patients throughout their journey. Further investigation using comparator cohort is warranted. [Table: see text]
Pathway enrichment analysis in tumors with high mutation burdens and interferon-γ signature expression: A pancancer analysis.
Authors: Li Xuanyi , Park Ben Ho , Balko Justin M. , Johnson Douglas Buckner 
Published: June 2023

3138 Background: Tumor mutation burden (TMB) correlates with immunotherapy response, but outcomes still vary in high TMB cancers, and many high TMB tumors lack T cell infiltration. Here, we assessed gene expression signatures of high TMB, including both inflamed and non-inflamed tumors (defined by interferon-γ [IFN-γ] gene signatures). Methods: Gene set enrichment analysis (GSEA) was assessed from RNA-sequencing data in tumors in TCGA. TMB and IFN-γ signature score were assessed by previously published methods. We performed GSEA on high vs low TMB tumors, and further stratified by high vs low IFN-γ signature expression within high TMB tumors. We validated results in Tempus RNA-sequencing data from 264 patients at Vanderbilt. Results: 4020 TCGA cases in non-small cell lung, melanoma, bladder, head and neck, kidney, and colorectal cancer were included. Major signatures upregulated in the high TMB group included cell cycle signaling, nuclear protein/mRNA export, cholesterol biosynthetics, and ubiquitin signaling. High TMB/high IFN-γ signature tumors were enriched in immune-related pathways (neutrophil and monocyte chemotaxis, T cell activation and proliferation, and interleukin-1 secretion), and non-immune pathways including cAMP metabolic process and phosphatidylinositol signaling. High TMB/low IFN-γ signature tumors had enriched pathways in nonsense mediated decay, electron transport chain/oxidative phosphorylation, and mitochondrial translational disassembly. 264 tumors from Vanderbilt were used for validation; pathways including cholesterol biosynthetics also correlated with immunotherapy response. Conclusions: High TMB tumors were enriched in pathways such as ubiquitin signaling, which could regulate immune cell function in antitumor immunity. Within high TMB cancers, tumors with higher IFN-γ signatures have enriched immune-related, and metabolic pathways, which could suggest novel therapeutic targets to make high TMB/ low IFN-γ tumors more immunogenic.
A four-tier classification system for studying homologous recombination repair gene reversion mutations as a mechanism of resistance to PARP inhibitors and platinum chemotherapy.
Authors: Ou Qiuxiang , Wu Miao-fang , Ma Yutong , Wu Xiaoying , Shi Yan , Zhu Minyi , Shao Yang , Li Jing 
Published: June 2023

3140 Background: Pathogenic mutations in homologous recombination repair (HRR) genes are highly associated with the oncogenesis of multiple cancers and represent favorable biomarkers for platinum (Pt)-based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi). While the development of drug resistance by restoring protein function via secondary mutation is commonly observed, a thorough analysis of the landscape of HRR gene reversion mutation is lacking. Methods: A real-world database with ~13,000 pan-cancer patients who underwent targeted next-generation sequencing and contained a primary germline or somatic pathogenic mutation of 25 pre-defined HRR genes, including ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, ERCC3, FANCA, FANCC, FANCD2, FANCI, FANCL, MRE11A, NBN, PALB2, RAD51, RAD51C, RAD51B, RAD51D, RAD54L, and WRN, was used to identify HRR secondary mutations, which were further classified into four tiers by mutation type and intended reversion mechanism. Patient’s clinical data and treatment history were retrospectively reviewed. Results: The potential mechanism of HRR gene reversion was categorized into four tiers, including Tier 1 (single nucleotide variation, SNV), Tier 2 (frameshift), Tier 3 (deletion), and Tier 4 of other mutation types that were not further discussed in this study. A total of 42 patients were identified with Tier 1/2/3 secondary HRR gene mutations in the presence of a primary pathogenic germline (N = 32) or somatic (N = 10) mutation. BRCA1 (15/42, 35.7%) and BRCA2 (23/42, 54.8%) were most frequently observed in this cohort with significant enrichment of exon 11 aberrations of both genes. The other HRR genes identified of Tier 1/2/3 reversion mutations included PALB2 (N = 3, Tier 3) and RAD51D (N = 1, Tier 1). More specifically, a majority of BRCA1 reversion mutations (8/15) were Tier 1 SNV, while the most prevalent reversion mechanism for BRCA2 was Tier 3 deletion, which accounted for 60.9% (14/23) of all BRCA2 cases with a median deleted length of 1164 bp (range: 153 – 6745 bp). Furthermore, we reported the treatment history data of three cancer patients (pancreatic, prostate, and lung, respectively) demonstrated the acquisition of BRCA2 reversion mutations (Tier 2 and Tier 3) at post-Pt/Olaparib in the presence of a primary germline BRCA2 pathogenic mutation, strongly suggestive of the role of reversion mutations in driving resistance to Olaparib or Pt-chemotherapy. Conclusions: Owing to a large-scale real-world dataset, we retrospectively investigated the landscape of the reversion mechanism of HRR genes and established a four-tier classification system for secondary HRR mutations in the presence of primary germline/somatic pathogenic HRR mutations. This study is of great clinical value in studying mechanisms of drug resistance to Pt-chemotherapy and PARPi.
Long-term outcome of neoadjuvant mFOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: A multicenter, randomized phase III trial.
Authors: Zhang Jianwei , Chi Pan , Lan Ping , Cui Long , Wei Hongbo , Zhao Ren , Huang Zhongcheng , Zhang Hao , Cai Yue , Wang Jianping , Deng Yanhong 
Published: June 2023

3505 Background: Pevisous results of phase III FOWARC trial demonstrated that mFOLFOX6, with or without radiation, did not significantly improve survival versus fluorouracil with radiation in patients with locally advanced rectal cancer at 3 yeas. Here, we presented the data of long-term disease free survival (DFS) and overall survival (OS). Methods: In this multicenter, phase III trial, patients with stage II/III rectal cancer were randomly assigned (1:1:1) to receive 5 cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil adjuvant treatment, mFOLFOX6 plus radiotherapy, or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Results: Totally, 495 patients were enrolled,165 pateints in each group. 445 patients underwent surgery. After a median follow-up of 9.5 years, DFS events were observed in 56, 54, and 55 patients in fluorouracil plus radiotherapy, mFOLFOX6 plusradiotherapy, and mFOLFOX6 goups. The 10-year DFS rate were 55.5%, 63.0% and 62.8% (P = 0.934 by the log-rank test). OS evets were reported in 39, 38, and 40 patientts in the 3 group. The 10-year OS rate was 66.2%, 73.2% and 73.0% (P = 0.919 by the log-rank test), respectively. Conclusions: With long-term follow up, no significant difference in was found in survival outcome between mFOLFOX6, with and without radiation. Comparing with fluorouracil plus radiation, mFOLFOX6 plus radiation also failed to improve long-term survival. Clinical trial information: NCT01211210 .
Transcriptional metabolic profiling young onset colorectal cancer (CRC) patients.
Authors: Vadehra Deepak , Rosario Spencer , Wang Jianmin , Zhang Yali , Hsiao Hua-Hsin , Kolesar Jill , McDonald Patricia , Spakowicz Daniel , Ibrahimi Sami , Tabung Fred , Owen Dwight Hall , Mukherjee Sarbajit 
Published: June 2023

3509 Background: Patients diagnosed with colorectal cancer (CRC) at age < 50 years typically present with more advanced disease, resulting in poor therapeutic response and clinical outcomes. Therefore, there is an unmet need to understand the differences in transcriptional profiles between younger (<50) and older ( > 50) CRC patients. Methods: Using TCGA (n = 397; > 50 = 349; < 50 = 48) and Oncology Research Information Exchange network (ORIEN) CRC datasets (n = 460; > 50 = 364 ; < 50 = 96), patients were separated into younger and older populations. Baseline characteristics of the patients in this analysis are provided in the accompanying table. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Comparisons of older and younger groups revealed a large number of significantly differentially expressed transcripts (n = 2629), enrichment in younger groups of metabolic pathways (amino acids and lipids), oncogenes (MYC targets and NRAS targets), and cellular processes. In the older group we found enrichment of methylation and histone modification, immune response, and other metabolic pathways, like androgens. Metabolic pathway analysis revealed consistent alterations in steroid hormone metabolism and kynurenine metabolism, which were largely upregulated in the over 50 group. Additionally, pathways associated with response to both CTLA4 and PDL1 treatment were largely upregulated in the over 50 group. This transcriptional signature may be associated with a pre-disposition to different clinical outcomes and therapeutic response for agents targeting these pathways. Conclusions: Overall, this study has revealed differences in transcriptional metabolic profiles and other drivers of disease, as well as immune profiles, between younger and older CRC populations. This biology should be explored in the future, as new avenues for treatment in younger CRC populations. [Table: see text]
15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.
Authors: Larsen Stein G , Graf Wilhelm , Sørensen Olaf , Mariathasan Anthony Burton , Spasojevic Milan , Ghanipour Lana , Cashin Peter , Bruland Øyvind 
Published: June 2023

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .
HPV integration as a prognostic biomarker for metastatic anal cancer: A next-generation sequencing ctDNA-based approach.
Authors: Johnson Benny , Pelicano Helene , Huey Ryan W , Wolff Robert A. , Wistuba Ignacio Ivan , Duose Dzifa Yawa , Mallampati Saradhi , Luthra Rajyalakshmi , Morris Van K. 
Published: June 2023

3525 Background: Anal cancer is an HPV-associated malignancy with increasing prevalence in the United States. Immune checkpoint blockade demonstrates limited efficacy in patients with metastatic squamous cell cancer of the anal canal (mSCCA), and no prognostic or predictive biomarkers have demonstrated clinical utility in this population. Available circulating tumor DNA (ctDNA) assays have utilized ddPCR methodologies to report only the most common HPV types (HPV-16 and HPV-18) and HPV copy numbers. To extend the utility of an HPV ctDNA assay, we created a novel next-generation sequencing HPV ctDNA assay to analyze HPV integration as a prognostic biomarker for patients with mSCCA. Methods: Using an IRB-approved protocol, ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types. HPV type, HPV copy number, and HPV integration status/locus were determined using a bioinformatic pipeline developed in-house. A Fisher's exact test was used to compare radiographic and ctDNA changes in response to systemic treatment. Unpaired t-tests were used to compare demographics between patients with HPV integration (I) or no integration (NI) status in the ctDNA. Median survival was estimated (Kaplan Meier) and compared according to integration status using a log-rank test. Results: 68 plasma samples from 27 patients with mSCCA were analyzed. While HPV-16 was detected in ctDNA of all 27 patients, five patients had additional oncogenic HPV types [HPV-18 (2), HPV-45 (2), HPV-73 (1)]. Radiographic changes in metastatic disease volume were concordant with HPV copy number changes in the ctDNA (odds ratio 12.2, 95% confidence interval (CI) 2.0-75; p = .007). HPV integration events were detected in the ctDNA for 16 (59%) patients (median 2, range 1-7 unique events per patient). For the 23 patients with mSCCA who received anti-PD1 immunotherapy (15 I, 8 NI), there were no differences in age (60 vs 59 years, p = .88) or prior lines of treatment (3.0 vs 3.5, p = .72). There was a trend towards improved median progression-free survival for NI ctDNA status (5.8 vs 3.2 months, hazard ratio (HR) 1.8, 95% CI .71-4.5). Relative to NI status, I status was associated with worse overall survival rates (OS) (22.5 vs 44.9 months, HR 5.0, 95% CI 1.5-17, p = .005). Conclusions: Detection of HPV integration status for all HPV types is feasible using a ctDNA-based approach for patients with SCCA. HPV integration was prognostic for worse OS in patients with mSCCA. Identification of HPV integration as a novel prognostic biomarker for survival outcomes in mSCCA warrants further evaluation in larger clinical trials.
A prospective, cross-sectional, multicentre study to evaluate the clinical performance of the ColoSTAT in vitro diagnostic for the detection of biomarkers associated with colorectal cancer.
Authors: He Emily , Van Hazel Guy A. , Sloss Andrew , Pianko Stephen , Brown Gregor , Clingan Philip R. , Singh Rajvinder , Solterbeck Ann , Traficante Robert , Lockett Trevor , Formby-Miller Louise , Macrae Finlay 
Published: June 2023

3529 Background: Colorectal cancer (CRC) survival rates could be improved if more cancers were detected early. The ColoSTAT blood test and algorithm combines concentrations of 5 protein biomarkers with age and sex to provide an alternative to current CRC screening methods like the faecal immunochemical test (FIT). We compared the performance of ColoSTAT to colonoscopy in detecting CRC. Methods: Patients in this Australian study were either recently diagnosed with CRC using colonoscopy and progressing to surgery or neoadjuvant treatment (Cohort 1) or had no CRC history and were scheduled for colonoscopy (Cohort 2). Due to COVID-19 pandemic-related recruitment delays, the samples from Cohort 1 were supplemented with bio-banked blood samples (BBS) from patients with clinically confirmed CRC. Patients provided a 17 mL blood sample and were followed until start of cancer treatment or colonoscopy. All blood samples were de-identified prior to testing by an independent laboratory. The primary endpoints were ColoSTAT sensitivity of ≥73% (lower 95% confidence limit [LCL] > 60%), and specificity ≥90% (LCL > 80%). Sensitivity by TNM stage was an exploratory endpoint (ACTRN12619000301167). Results: Cohort 1 enrolled 29 patients, Cohort 2 enrolled 768 patients and 192 BBS were included. Patient demographic characteristics were similar in Cohorts 1, 2 and BBS. Overall, the median age of the patients (n = 989) was 64 years (range 40 to 88) and 53.4% were female. Definitive ColoSTAT results were obtained for 22 patients in Cohort 1, 554 in Cohort 2 and 81 in BBS. Overall, the estimated sensitivity of ColoSTAT for detection of CRC compared with colonoscopy was 81.3% (95%CL 73.0%-87.4%) and estimated specificity 91.0% (95%CL 87.7%-93.5%) (Table). Conclusions: The ColoSTAT test met the primary endpoints of performance based on sensitivity and specificity in detecting CRC compared to colonoscopy. ColoSTAT sensitivity and specificity for CRC were comparable with published performance parameters for FIT which range from 74-93% (sensitivity) and 85-96% (specificity).1 Clinical trial information: ACTRN12619000301167 . Clinical trial information: ACTRN12619000301167 . [Table: see text]