bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between comprehensive genomic profiling (CGP) utilizing tissue-based testing (T-CGP) and cell-free DNA (cfDNA) in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).
Authors: George Ben , Haberberger James , Ferguson Naomi L , Gjoerup Ole , McGregor Kimberly , Hendifar Andrew Eugene , Laheru Daniel A. , Weekes Colin D. , Ross Jeffrey S. , Hemmerich Amanda 
Published: January 2021

422 Background: Early systemic dissemination is a salient feature of PDAC and the ability to reliably detect as well as monitor cfDNA based alterations may have predictive and/or prognostic value. However, a clear correlation between the clonality of the primary tumor and micro-metastatic disease has not been established in PDAC. We examined the correlation between T-CGP and cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of PDAC pts who had both T-CGP (October 2010 – March 2020) and cfDNA based CGP (May 2016 – March 2020), with an average of 645 days between tests (Range: 21 – 2101 days) For T-CGP, exonic regions and select intronic regions of cancer related genes were sequenced to a high uniform depth (>500X median coverage) using FoundationOne Heme (Exons: 315 genes; Select Introns: 28 genes) and FoundationOne CDx (Exons: 310 genes; Select Introns: 34 genes). cfDNA based CGP, was performed using either FoundationOne Liquid (Exons: 70 genes; Select Introns: 7 genes) or Foundation-ACT (Exons: 59 genes; Select Introns: 6 genes) platform. Results: Eighty-one pts were identified with both T-CGP and cfDNA based CGP - median age was 61 years, 59.3% (48/81) were male and 66.2% (49/74) had reported metastatic disease. The median tumor DNA content available for T-CGP analysis was 112.3 ng. The median cfDNA concentration was 1.7 ng/µL, and the number of reported ct-DNA based somatic alterations correlated significantly with the concentration of ct-DNA (Spearman’s R = 0.19, p < 10-8). 75/81 (92.6%) and 41/81 (50.6%) of pts had at least one pathogenic somatic alteration detected by T-CGP and cfDNA based CGP, respectively. KRAS, TP53 and CDKN2A were the most frequently altered genes in both T-CGP and cfDNA based CGP (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [ BRCA2, ATM, and CHEK2 alterations] were detected in 7.4% (6/81) of T-CGP and 7.4% (6/81) cfDNA based CGP, respectively. Two BRAF fusions were detected from samples tested with T-CGP, however these were not detected with the cfDNA assay. Conversely, an ALK-EML4 fusion was detected using both platforms. Conclusions: The concordance between T-CGP and cfDNA based CGP in HR-DDR gene alterations may be indicative of the germline status of some of these alterations; nevertheless, it suggests the predictive utility of cfDNA based CGP in PDAC. The differential prevalence of other gene alterations between the two modalities is likely reflective of the cfDNA yield available for CGP and to a lesser extent, clonal evolution. cfDNA based CGP holds promise as a complimentary predictive tool to T-CGP. [Table: see text]
Evaluation of a sensitive blood test for the detection of colorectal advanced adenomas in a prospective cohort using a multiomics approach.
Authors: Lin Jimmy , Ariazi Eric , Dzamba Michael , Hsu Teng-Kuei , Kothen-Hill Steven , Li Kang , Liu Tzu-Yu , Mahajan Shivani , Palaniappan Krishnan K , Pasupathy Amit , Polonskaia Alina , St. John John , Steiger Dan , Ulz Peter , Wang Irving , Xiao Jiajie , Yang Rui , Putcha Girish , Shaukat, MD, MPH Aasma 
Published: January 2021

43 Background: Blood-based screening tests for colorectal cancer (CRC) with high sensitivity and specificity are needed to improve adherence, facilitate early detection, and ultimately reduce mortality from CRC. Current stool-based tests have a sensitivity of 24-42% for colorectal advanced adenomas (AAs), while blood tests that rely on tumor-derived cell-free DNA (cfDNA) methylation signatures have shown limited sensitivity for AAs. Here we demonstrate the ability to detect AAs from blood using a multiomics test that incorporates both tumor- and immune-derived signatures, and compare it to the performance of a cfDNA methylation-only test. Methods: Participants enrolled in a prospective study (NCT03688906) were included in this analysis. The multiomics test includes signatures for cell-free nucleic acids based on next-generation sequencing, and for plasma proteins based on high-throughput multiplexed assays. Signatures are integrated computationally with a combination of convolutional neural networks and regularized logistic regression. We compared the multiomics test with one based on cfDNA methylation only. Results: This sub-study included 542 participants (AA: n = 122; colonoscopy-confirmed negative controls: n = 420). Participants with AA were 56% male with a mean age of 63 years, and colonoscopy-confirmed negative controls were 54% male with a mean age of 61 years. The multiomics test achieved a sensitivity of 41% (n = 50/122, 95% CI 34-48%) at 90% specificity (377/420). By contrast, the cfDNA methylation-only test achieved a sensitivity of 20% (24/122, 95% CI 15-25%) at 91% specificity (383/420). Performance was also analyzed by histological subtype and location, and superiority of the multiomics test to the cfDNA-methylation-only test was consistently observed. Conclusions: A novel multiomics blood test can detect colorectal AAs at a sensitivity and specificity comparable to existing stool-based tests. Combining signatures from both tumor- and immune-derived sources resulted in AA sensitivity greater than that of cfDNA-methylation alone.
Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy:Two-year clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Ka Yeung Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Luppi Gabriele , Cardin Dana Backlund , Dragovich Tomislav , Shah Usman , Yang Jing , Memaj Arteid , Overman Michael J. 
Published: January 2021

58 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up, 29.0 months [range, 24.2–33.7]) (Lenz et al. J Clin Oncol 2020;38:Abstract 4040; NCT02060188). Objective response rate (ORR) per investigator (INV) was achieved in 69% of pts (95% CI, 53–82); progressive disease rate was 13%. Median progression-free survival (PFS) and overall survival (OS) were not reached. Median duration of treatment was 19.1 months (95% CI, 11.1–29.0). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 22% of pts. We present the post hoc subgroup analyses of efficacy and safety outcomes in pts from the same follow-up based on demographics and baseline disease characteristics. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. ORR (primary endpoint, RECIST v1.1) and PFS were assessed per INV. Post hoc subgroup analyses of efficacy (by ECOG performance status [PS], stage at initial diagnosis, primary tumor location, and BRAF/KRAS mutation status) and safety (by age and ECOG PS) are presented. Results: Among 45 treated pts, efficacy (Table) and safety were generally consistent across evaluated subgroups. ORR was similar in pt subgroups by BRAF/ KRAS mutation status, stage at initial diagnosis, primary tumor location, and ECOG PS (Table). Median PFS and OS were not reached (NR) in evaluated subgroups after a minimum follow-up of 24.2 months (Table). Incidence of grade 3–4 TRAEs for subgroups by age and ECOG PS were consistent with the overall population. Conclusions: NIVO + low-dose IPI demonstrated robust, durable clinical benefit; was well tolerated with 2-year follow-up; and was consistent in evaluated subgroups in 1L MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer.
Authors: Shiu Kai-Keen , Andre Thierry , Kim Tae Won , Jensen Benny Vittrup , Jensen Lars Henrik , Punt Cornelis J. A. , Smith Denis Michel , Garcia-Carbonero Rocio , Benavides Manuel , Gibbs Peter , De La Fouchardiere Christelle , Rivera Fernando , Elez Elena , Bendell Johanna C. , Le Dung T , Yoshino Takayuki , Yang Ping , Farooqui Mohammed Zulfiqar Husain , Marinello Patricia , Diaz Luis A. 
Published: January 2021

6 Background: KEYNOTE-177 (NCT02563002) evaluated the antitumor activity of pembrolizumab (pembro) vs chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We present results of the final PFS analysis and analysis of PFS2. Methods: Patients with locally-determined MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chosen before randomization). Treatment continued until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembro only). Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were PFS (RECIST v1.1, central review) and OS. Secondary end points included ORR (RECIST v1.1, central review) and safety. Exploratory endpoints included duration of response (DOR), PFS2 (time from randomization to progression on next line of therapy or any cause death), and health-related quality of life (HRQoL). Data cutoff was Feb 19, 2020. Results: At data cutoff a total of 307 patients were randomized (153 to pembro, 154 to chemo). Median (range) study follow-up was 32.4 mo (24.0-48.3). Pembro was superior to chemo for PFS (median 16.5 mo vs 8.2 mo; HR 0.60; 95% CI, 0.45-0.80; P= 0.0002). The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Confirmed ORR was 43.8% vs 33.1%; median (range) DOR was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. PFS2 was longer with pembro vs chemo (median not reached vs 23.5 mo [HR 0.63; 95% CI, 0.45-0.88]). OS analysis is ongoing. Grade ≥3 treatment related adverse event (TRAE) rates were 22% vs 66% for pembro vs chemo. There were no grade 5 TRAEs in the pembro arm and 1 grade 5 intestinal perforation in the chemo arm. HRQoL scores were improved with pembro vs chemo. Conclusions: Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed. Furthermore, pembro provided a clinically meaningful improvement in PFS2 for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002.
Targeted multiplex proteomics (TMP) and genomics of early-onset colorectal cancer (EO-CRC).
Authors: Kam Audrey E. , Khaliq Ateeq M. , Alam Nida , Hayden Dana , Bhama Anuradha R. , Govekar Henry , Pappas Sam , Ritz Ethan M. , Singh Ajaypal , Thyparambil Sheeno P. , Liao Wei-Li , Bhalkikar Anuja , Ling Xuefeng B. , Levy Mia Alyce , Kuzel Timothy , Masood Ashiq 
Published: January 2021

97 Background: The incidence and mortality of early-onset colorectal cancer (EO-CRC) is on the rise. Consequently, there is an urgent unmet need to better understand their unique tumor biology to expand therapeutic options and improve clinical outcomes. Methods: Exploratory Targeted multiplex proteomics (TMP) and targeted 648 gene panel was performed on specimens from 35 patients with resected colon cancer diagnosed at age < = 40 years. TMP panel consisted of 72 proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Clinicopathologic and genomic data were also collected. Results: The median age of diagnosis was 33 years. The cohort included 15 male and 20 female patients. 20 (57%) had left-sided tumors and 6 (17%) had stage IV disease. Notable genomic alterations included mutations in: BRAF V600E (2/35); RAS (15/35); PIK3CA exon 9 or 20 (5/35); and ERBB2 (2/35). One patient exhibited ERBB2 amplification. 9/35 tumors were MSI-H. TMP analysis revealed overexpression of chemotherapy resistance proteins in several patients: ALDH1A1:16/35; ERCC1:1/35; GART:26/35; MDR1:9/35; MGMT:5/35; RRM1:6/35; TUBB3:1/35; TYMS:2/35; XRCC1:11/35. In contrast, some tumors exhibited elevated biomarkers of chemosensitivity: hENT1:8/35; DHFR:12/35; TYMP:15/35; OPRT:8/35; SLFN11:1/35; TLE:11/35; TOPO1:12/35; TOPO2A:1/35. Protein targets of cell signaling pathways were overexpressed in a number of tumors: CAT:16/35; CAV-1: 6/35; CBL:2/35; E-Cadherin: 19/35; HSP90A:16/35; HSP90B:18/35; MET:5/35; NQO1:18/35; paxillin:4/35; SRC:21/35; STAT3:11/35. Regarding EGFR and KRAS, none of the tumors exhibited elevated protein expression level. Furthermore, RAS mutational status did not correlate with the level of EGFR or KRAS protein expression. Antibody drug conjugate biomarkers were observed. HER2 overexpression was noted in one patient who had a confirmed ERBB2 amplification. Regarding immunotherapy targets, PDL-1 protein was not overexpressed in any tumor, whereas MSLN and TROP2 were elevated in 1/35 and 2/35 patients, respectively. Conclusions: TMP analysis of EO-CRC patients revealed marked heterogeneity in the expression of proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Differential protein expression may provide insight into therapeutic vulnerabilities for EO-CRC. Furthermore, the discordance between detected genomic alterations and protein expression levels highlights the complementary nature of genomic sequencing and TMP analysis.
Evaluation of the ctDNA LUNAR-2 Test In an Average Patient Screening Episode (ECLIPSE).
Authors: Raymond Victoria M. , Higashi Linda , Marino Enrique , Lang Kathryn 
Published: January 2021

TPS142 Background: Population-wide colorectal cancer (CRC) screening has been recommended by the United States Preventive Task Force (USPSTF) since 2008. Despite multiple CRC screening options, screening compliance rates have plateaued well below the 80% compliance goal set by leading health organizations. Almost 1 in 3 Americans are non-compliant with screening recommendations, citing reasons that screening is time consuming, unpleasant, and in the case of colonoscopy, invasive. The potential exists for a blood-based CRC screening test with high sensitivity and specificity to improve uptake and adherence to CRC screening. Methods: ECLIPSE (Evaluation of the ctDNA LUNAR-2 Test In an Average Patient Screening Episode; NCT# 04136002) is a prospective, observational, multi-center study being conducted in the United States. The primary objective is performance of a proprietary blood-based circulating tumor DNA (ctDNA) test (LUNAR-2, Guardant Health, Redwood City, CA) developed to detect CRC in a screen-relevant, average risk population as compared to colonoscopy reference. ECLIPSE involves collection of whole blood prior to a standard of care screening colonoscopy and associated preparation from 10,000 subjects. Eligibility criteria include average risk adults age 45-84 without prior history of cancer, inflammatory bowel disease, or familial predisposition to CRC, and have not received recent CRC screening. Primary outcomes are sensitivity of CRC detection and specificity of advanced neoplasia (AN) detection. Health-related outcomes at one and two-years will be collected as secondary endpoints to investigate the possibility of incidental non-CRC cases and interval CRC cases that had not reached a clinical threshold for detection at time of colonoscopy. Additional secondary objectives are positive predictive value and negative predictive value for AN detection and sensitivity of advanced adenoma detection. Enrollment began in October 2019, continues at over 130 sites nationwide, and is on track for the 24-month enrollment goal. Study enrollment remained open despite the COVID-19 pandemic. Study features including mobile phlebotomy and remote site monitoring were implemented. This contributed to successful study execution during COVID-19, as demonstrated by the enrollment rebound observed as early as June 2020 which saw higher enrollment than prior months, even pre-COVID. Clinical trial information: NCT# 04136002.
A randomized controlled phase III trial of comparing local field with additional prophylactic irradiation in chemoradiotherapy for clinical-T1bN0M0 esophageal cancer:JCOG1904/ARMADILLO study.
Authors: Nomura Motoo , Sakanaka Katsuyuki , Kato Ken , Kadota Tomohiro , Ito Yoshinori , Machida Ryunosuke , Sasaki Keita , Kataoka Tomoko , Nishimura Yasumasa , Kitagawa Yuko 
Published: January 2021

TPS257 Background:Parallel-group controlled trial of esophagectomy versus chemoradiotherapy (JCOG0502) showed chemoradiotherapy (CRT) is considered as a standard treatment option for clinical-T1bN0M0 esophageal squamous cell carcinoma (ESCC) with organ preservation. However, locoregional recurrence after CRT occurs in 20% of patients and requires salvage treatment including salvage surgery, chemo(radio)therapy, and endoscopic resection. Salvage treatments can cause complications and treatment-related death. CRT with elective nodal irradiation (ENI) have been reported to reduce the locoregional recurrence of esophageal cancer. We conduct the clinical trial to evaluate the efficacy of modified CRT with ENI compared with CRT without ENI for the patients with cTbN0M0 ESCC. The primary purpose of this study is to investigate whether modified CRT with ENI reduces the locoregional recurrence that cannot be completely resected by salvage endoscopic resection and preserve esophagus without compromising overall survival. Methods:Eligibility criteria include the followings; thoracic ESCC, adenosquamous, or basaloid cell carcinoma with clinical-T1bN0M0, age 20 or older, performance status 0 or 1, adequate organ function, and patient who do not have a preference to receive a surgical resection as an initial therapy. Patients are randomly assigned to following two arms using the minimization method with a random component to balance institution, tumor length (≤4cm versus > 4cm), and age (≤65 years old versus > 65 years old). Patients in arm A receive CRT consisted of CDDP (70 mg/m2/day, days 1 and 29) and 5-FU (700 mg/m2/day, days 1-4 and 29-32, civ) with concurrent radiotherapy (60 Gy/30 fr without ENI). Patients in arm B receive CRT consisted of CDDP (75 mg/m2/day, days 1 and 29) and 5-FU (1000 mg/m2/day, days 1-4 and 29-32, civ) with concurrent radiotherapy (50.4 Gy/ 28 fr with ENI of 41.4 Gy/23 fr). Primary endpoint is major progression-free survival (MPFS), defined as the time from randomization to the date of death or disease progression except achieving curative resection by salvage endoscopic resection. We assumed 5-year MPFS with arm A to be 70% and expected a 10% improvement for arm B. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 5%, power of 70%, an accrual period of 4 years, and a follow-up period of 5 years. This trial was activated in July 2020. The study was also registered at the Japan Registry of Clinical Trials (jRCT) as study number jRCTs031200067. Clinical trial information: jRCTs031200067.
Phase II trial of the CDK4/6 inhibitor abemaciclib in patients (pts) with advanced and refractory well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs).
Authors: Wong Kit Man , Askovich Bojana Irene , Ramachandran Harini , Hensel Jeniece , Ottermiller Susan , Alidina Annie , Hibbert Reina , Coveler Andrew L. , Thompson John A. , Chiorean Elena Gabriela 
Published: January 2021

TPS376 Background: Despite advances in the treatment of advanced GEP NETs, long‐term disease control remains a challenge. Overexpression and altered regulation of cyclin-dependent kinases (CDK) 4 and 6 have been observed in multiple subtypes of GEP NETs. Preclinical studies have demonstrated that the CDK 4/6 inhibitor palbociclib reduces growth of pancreatic NET cell lines and levels of phosphorylated retinoblastoma protein in vitro. Moreover, the drug significantly inhibited tumor growth in vivo in pancreatic NET xenograft models. Abemaciclib is a selective small molecule CDK 4/6 inhibitor, approved for the treatment of HR+ HER2– metastatic breast cancer. Clinical activity and central nervous system penetration of the drug have been observed in several tumor types in clinical trials, including partial response in one pt with metastatic small intestinal NET. We have developed a Phase 2 trial of abemaciclib in GEP NETs to evaluate its efficacy and safety in these rare cancers. Methods: This is an investigator-initiated non-randomized phase 2 trial using a two-stage design. Eligible pts have metastatic or locally advanced unresectable well-differentiated grade 1-2 GEP NETs, ECOG PS 0-2, and must have progressed on at least one line of systemic therapy. Prior or concurrent treatment with somatostatin analogs is allowed,. Abemaciclib is administered at a dose of 200 mg orally every 12 hours continuously in 28-day cycles. Dose reductions for toxicities are allowed to level -1 (150 mg) and -2 (100 mg). Primary endpoint is objective response rate (ORR) by RECIST v1.1. Secondary endpoints include progression free survival (PFS), overall survival (OS), and toxicity. A two‐stage design with 88% power to detect an increase in ORR to 20% with abemaciclib at the 1‐sided 0.05 level would require a total of 37 patients. Stage 1 will include 20 patients, and if one response is seen among these patients, the study will continue to enroll another 17 patients. The trial was activated in January 2020, and 3 patients have been enrolled to date. Available archival tumor tissue and molecular profiling data are collected for future correlative studies including assessment of response biomarkers.
Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study
Authors: Männistö Jonna M E , Jääskeläinen Jarmo , Otonkoski Timo , Huopio Hanna 
Published: January 2021

AbstractContextThe management of congenital hyperinsulinism (CHI) has improved.ObjectiveTo examine the treatment and long-term outcome of Finnish patients with persistent and transient CHI (P-CHI and T-CHI).DesignA population-based retrospective study of CHI patients treated from 1972 to 2015.Patients106 patients with P-CHI and 132 patients with T-CHI (in total, 42 diagnosed before and 196 after year 2000) with median follow-up durations of 12.5 and 6.2 years, respectively.Main Outcome MeasuresRecovery, diabetes, pancreatic exocrine dysfunction, neurodevelopment.ResultsThe overall incidence of CHI (n = 238) was 1:11 300 live births (1972-2015). From 2000 to 2015, the incidence of P-CHI (n = 69) was 1:13 500 and of T-CHI (n = 127) 1:7400 live births. In the 21st century P-CHI group, hyperinsulinemic medication was initiated and normoglycemia achieved faster relative to earlier. Of the 74 medically treated P-CHI patients, 68% had discontinued medication. Thirteen (12%) P-CHI patients had partial pancreatic resection and 19 (18%) underwent near-total pancreatectomy. Of these, 0% and 84% developed diabetes and 23% and 58% had clinical pancreatic exocrine dysfunction, respectively. Mild neurological difficulties (21% vs 16%, respectively) and intellectual disability (9% vs 5%, respectively) were as common in the P-CHI and T-CHI groups. However, the 21st century P-CHI patients had significantly more frequent normal neurodevelopment and significantly more infrequent diabetes and pancreatic exocrine dysfunction compared with those diagnosed earlier.ConclusionsOur results demonstrated improved treatment and long-term outcome in the 21st century P-CHI patients relative to earlier.