bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS mutation methylation clonality in early-stage pancreatic cancer.
Authors: Kowalski Jeanne , Xu Qi , Chao Hsueh Ping , Gandhi Heta , Aung Kyaw Lwin , Matsui William H. 
Published: January 2022

614 Background: KRAS is mutated in 90% of pancreatic cancers making it a seemingly ideal target for treatment and yet, with the exception of the rare G12C mutation, KRAS is undruggable for the vast majority of pancreatic patients. Herein, we characterize, in silico, KRAS methylation-derived mutation clonal and subclonal diversity in PDAC and examine their impact upon clinical outcomes. Methods: We developed a mutation methylation (MM) clonality workflow for gene mutation assignment as clonal versus subclonal and applied it genome-wide to TCGA data. For comparison, we used the cancer cell fraction (CCF) clonality prediction. We examined clinical outcomes by comparing in months (mos), Kaplan-Meier estimated overall survival (OS) using a log-rank test and a cox model for testing several features. We performed differential gene expression, differential gene correlation, and gene set enrichment analyses (GSEA) between KRAS MM clonal versus subclonal early stage pancreatic patients. Results: Using 104 TCGA early stage pancreatic cancer patient tumors from TCGA with mutation, methylation and clinical outcomes data, we defined KRAS MM clonality (n = 70 clonal, n = 34 subclonal) and CCF clonality (n = 74 clonal, n = 28 subclonal) tumors. Clonality assignment between methods was 53% clonal and 17% subclonal concordant, and 19% discordant among samples. KRAS MM clonality was associated with significantly (p = 0.046) shorter OS (median OS = 11.5 mos) as compared to the KRAS subclonal group (median OS = 15 mos). By comparison, KRAS CCF clonal and subclonal patient groups did not differ in their OS. When RNA-Seq derived subtypes for pancreatic cancer were included in a model with our KRAS MM clonality marker, only our marker remained as significantly associated with OS. Median KRAS gene expression was significantly (p = 0.01) higher in the KRAS MM clonal versus subclonal group. A GSEA showed enrichment of MYC targets in the KRAS clonal group. We identified 72, mostly protein coding genes residing on chromosomes 5q, 7p and 8p that correlated with KRAS gene expression only in the subclonal group. Conclusions: Our analyses shows a potential clonality dissection of the established 90% KRAS mutation rate in pancreatic cancer, which based on our MM workflow, may be dissected into 61% KRAS clonal and 30% KRAS subclonal. By assigning clonality based on another DNA data type using CCF, we obtain 65% KRAS clonal and 25% KRAS subclonal. Thus, regardless of which DNA-based workflow, overall, the KRAS clonality rates are similar. There is a notable difference however in patient-level assignment of KRAS clonality as only our workflow showed poor OS associated with KRAS clonality. The introduction of a methylation-based mutation clonality marker could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for patient and treatment selection, and clinical trial monitoring of tumor responses.
Disparities in comprehensive genomic profiling in older patients with gastrointestinal malignancies.
Authors: Elias Rawad , Kuang Zheng , Murphy Jo-Ellen , Yu Peter Paul 
Published: January 2022

646 Background: Limited data guides the management of older adults with cancer, a patient population that continues to be under-represented in clinical trials. Comprehensive Genomic Profiling (CGP) drives the enrollment on biomarker-based trials and may inform treatment selection. This analysis aims to evaluate the use of CGP in older patients with gastrointestinal (GI) malignancies and to compare results of genomic profiling across age groups. Methods: Clinical CGP results derived from Next Generation Sequencing (NGS) of tumor tissue (n=92802) were reviewed for patients with GI malignancies. Genomic alterations (GAs) and complex signatures were identified, based on hybridization-captured, adapter ligation-based sequencing. Association between age group (< 65: n=51652; 65-74: n=28972; 75+: n=12178) and biomarkers of interests was evaluated using Chi-square test, adjusting for multiple testing using Bonferroni correction. Delay-adjusted incidence rates in populations included in the study were acquired from SEER Databases. Results: The majority of patients in the CGP cohort were <65 yrs (55.7%). Patients aged 75 and above were underrepresented as compared to the SEER database incidence rates (15.2% vs. 31.6%, p <0.0005). Overall, the incidence of known or likely pathogenic GAs was similar across all age groups (>99%). An analysis of specific GAs among all the GI cancers analyzed showed an age-associated increase of high tumor mutational burden (≥10 mut/Mb) (TMB-H) (5.6% vs 6.6% vs 10.7% for respective age groups, p<0.0005). The overall incidence of mismatch repair deficiency or microsatellite instability (dMMR/MSI) (3.6% vs 4.0% vs 7.5%, p<0.0005) and DNA damage repair mutations (DDR mut) (13.2% vs 13.9% vs 16.4%, p<0.0005) also increased with age. The magnitude of the CGP findings varied by GI cancer type, as summarized for select significant findings (p <0.0005) in Table. Detailed results for each GI subtype and relevant biomarkers will be presented. Conclusions: This large scale analysis of CGP done for patients with GI cancers showed that genomic profiling is under utilized in older adults who constitute the majority of patients with GI malignancies. These findings may improve access to clinical trials and guide the development of older adult-specific studies.[Table: see text]
Poorly differentiated histology as a predictive biomarker in patients with advanced gastrointestinal (GI) cancers treated with immunotherapy.
Authors: Draper Amber , Jung Emily , Cao Yichun , Atallah Rami , Switchenko Jeffrey M. , Alese Olatunji B. 
Published: January 2022

664 Background: Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have showed a correlation between immune cell infiltration and poorly differentiated cancers. We evaluated the impact of poorly differentiated histology on survival in patients with advanced GI malignancies treated with immunotherapy. Methods: We performed a retrospective, single institution analysis of patients with poorly differentiated GI tumors treated with CPI between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics, progression free survival (PFS) and overall survival (OS). Results: A total of 123 patients were included. Median age was 66years. Majority had stage IV disease (88.2%), were White (65.5%) and male (64.5%). Most common diagnoses were HCC (28.5%), gastric (15.4%) and esophageal (14.6%) adenocarcinomas. About 32% were MSI-H, with 10% BRAF mutation rate. About 25% received CPI as initial treatment and 35.5% received 2 or more prior lines of therapy. Compared with well and moderately differentiated histology, poorly differentiated tumors had shorter mPFS (3.4 vs 2.5 vs. 2.2months; p = 0.29) and mOS (not reached [NR] vs. 20.9 vs. 14.2 months; p = 0.14) respectively. On UVA, the degree of tumor differentiation did not correlate with mPFS or mOS. Female patients (HR: 0.55, CI: 0.34-0.90, p = 0.018) and ECOG of 1 vs. ≥2 had significantly longer mPFS (HR: 0.58, CI: 0.35-0.97, p = 0.036). ECOG 1 correlated with better mOS (HR: 0.47, CI: 0.23-0.94, p = 0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, CI: 2.41-13.63, p < 0.001) and mOS (HR: 5.45, CI: 1.64-18.12, p = 0.006). Number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, CI: 1.03-1.39, p = 0.022) and mOS (HR: 1.23, CI: 1.01-1.50, p = 0.045). On MVA, ECOG status of 0/1 vs. ≥2 and MSI-H vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with race or mutations such as BRAF or KRAS. Conclusions: Poorly differentiated histology did not predict for PFS or OS. Treatment naïve patients, female gender, ECOG 1 and MSI-H were most likely to benefit from CPI.
A proof-of-concept formative trial evaluating the interest of multiple connected devices for the early detection of hand-foot skin reactions in patients treated with regorafenib therapy (FACET).
Authors: Coriat Romain , Sibaud Vincent , Dochy Emmanuelle , Leturgez Thibaut , Arvis Pierre , Kremliovsky Michael , Reeves John A. , Di Palma Mario 
Published: January 2022

TPS207 Background: Hand-foot skin reaction (HFSR) is a common skin toxicity associated with regorafenib that may lead to drug withdrawal, dose reduction, or drug interruption. Predicting or recognizing early symptoms of HFSR could allow for better care. Digital solutions for ambulatory monitoring of patients provide an opportunity for monitoring and early detection of HFSR in home conditions. Methods: FACET is a phase 4, prospective, open-label, multicenter, interventional trial designed to assess the clinical utility, technical feasibility and usability of a system including a camera, FeetMe Connected insoles for gait assessment, ePRO questionnaires (HFS-14, EQ-5D-5L, FAS and VAS), and educational materials to detect and grade the severity of HFSR. During the study, enrolled patients developing an HFSR will be assigned to the HFSR group and patients without any sign of HFSR, they will be assigned to non-HFSR group. Study registration number at ANSM (French Authority): ID-RCB 2020-A03080-39. Patients will have metastatic colorectal cancer requiring initiation of regorafenib in accordance with clinical practice standard. Other key inclusion criteria are ECOG Performance Status 0-2, ability to understand the instructions and complete the ePRO questionnaires, ability to understand and communicate in French language, familiarity in using mobile communication devices and mobile application software, no previous episode of HFSR or HFS. The primary objective is to explore fit-for-purpose, and usability of the ePRO instruments and the data collecting devices. The primary endpoint is participants’ compliance with data collection measured by ePRO questionnaires completion, use of camera to take images vs expected and number of device days of insoles usage vs expected. Secondary objectives are to characterize variables exhibiting significant associations with development of HFSR. Secondary endpoints include summary statistics of ePRO questionnaires scores at the HFSR worst grade event in the HFSR group vs at 3 weeks in the non-HFSR group; Summary statistics for Feetme Connected insoles variables; Regorafenib dose modifications and treatment discontinuation; Participant’s device daily use to generate data; Participants ability to reach a hotline for technical issues or usability complaints. For HFSR related secondary endpoints, a blinded and independent Preliminary Adjudication Committee (PAC) will retrospectively assign participants to two groups (HFSR vs. no-HFSR) based on a case-by-case blinded assessment. An independent Final Adjudication Committee will compare the PAC assessment and investigators’ assessments done on site. It is planned to include a total of 38 participants from 4 centers. As of September 2021, all sites are open and ready to enroll. Study funded by Bayer.
Prevention of colorectal cancer through multiomics blood testing: The PREEMPT CRC study.
Authors: Putcha Girish , Xu Chuanbo , Shaukat, MD, MPH Aasma , Levin Theodore R. 
Published: January 2022

TPS208 Background: The USPSTF recently recommended colorectal cancer (CRC) screening for adults aged 45 to 49 years in addition to those aged 50 to 75 years. This guideline update, which increases the number of screen-eligible individuals by ̃19 million, is similar to the recommendation in 2018 by the American Cancer Society (ACS) and is based on the modeling studies that reflect rising CRC incidence rates in younger adults. Currently, only 67% of average-risk individuals over the age of 50 years are up-to-date on CRC screening, and adherence to screening is lower in younger individuals (e.g., 50-54 years). Despite the non-invasive nature of existing stool-based CRC tests, barriers remain to adoption, including a dislike for manipulating stool and a requirement for substantial navigational support. Blood tests may overcome these barriers through ease of sample collection and integration into routine blood work. Methods: Here we describe our prospective, multi-center registrational study for validating a blood-based multiomics test for average-risk CRC screening: PREEMPT CRC. Eligible participants include those aged 45-85 with no known history of CRC or colorectal adenomas who are undergoing CRC screening by colonoscopy. The target enrollment is 25,000 participants, and primary outcome measures are sensitivity for CRC and specificity for advanced colorectal neoplasia, which includes CRC and advanced adenomas. Secondary outcome measures include positive predictive value for CRC, negative predictive value for advanced colorectal neoplasia, and sensitivity for advanced adenomas. Novel recruitment methods have been implemented by combining traditional, site-based recruitment and virtual recruitment using an online web portal, coupled with mobile phlebotomy, to make participation broadly accessible, especially during the COVID-19 pandemic. Participants have been enrolled from 40 states as of August 2021, and virtual recruitment has enabled widespread participation, potentially from any zip code in the continental US. To ensure adequate representation of the intended use population, community organizations, federally qualified health centers (FQHCs), and universities have been engaged to reach underserved and minority patient populations. The study was initiated in May 2020 and to our knowledge will be the largest prospective, multi-center registrational validation study of an average-risk CRC screening test to date. Clinical trial information: NCT04369053.
Neoadjuvant chemoradiotherapy with or without Pd-1 antibody sintilimab for pMMR/MSS/MSI-L locally advanced rectal cancer: A randomized controlled study (cohort B).
Authors: Xiao Weiwei , Lin Jun-zhong , Chen Gong , Wu Xiao-Jun , LU Zhen-Hai , Wang Qiaoxuan , Cai Peiqiang , Liu Min , He LongJun , Xi ShaoYan , Wang Feng , Zhang Huizhong , Gao Yuan-Hong , Pan Zhi-Zhong , Xu Rui-hua 
Published: January 2022

TPS210 Background: Neoadjuvant chemoradiotherapy (NACRT) could bring tumor downstaging and pathological response (pCR), and also survival benefit for locally advanced rectal cancer (LARC) patients. Several single arm prospective clinical trials have investigated combination effect of immunotherapy (PD-1 or PD-L1 antibody) and NACRT in LARC patients, such as the VOLTAGE clinical trial. A randomized trial is needed to confirm the benefit of immunotherapy in this setting and explore predictive biomarkers. This is a clinical trial with two cohorts according the MMR/MSI status (clinicalTrials.gov, NCT04304209). Methods: In this study, LARC patients with pMMR/MSS/MSI-L tumor will enter cohort B and be randomized into two arms. Main inclusion criteria include: cT3-4N0M0 or cTxN+M0 rectal adenocarcinoma, pMMR/MSS/MSI-L confirmed by immunohistochemistry or gene test, aged 18-75y; ECOG performance 0-1; no previous anti-tumor treatment for rectal adenocarcinoma. Main exclusion criteria include: active autoimmune diseases or a history of autoimmune diseases, and inadequate main organ functions. Patients in the experimental arm will receive four cycles of neoadjuvant PD1 antibody Sintilimab, Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy. Patients in the control arm will receive four cycles of neoadjuvant Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy Primary outcome measure is pCR rate. Secondary outcome measures include acute toxicity, tumor regression grade, R0 resection rate, local recurrence, distant metastasis. Sample size for this cohort is 134. Whole exome sequencing, RNA sequencing and immunohistochemistry of the rectal primary tumor are planned for biomarker searching and synergy effect mechanism investigation. The first patient has been enrolled in June, 2020. Clinical trial information: NCT04304209.
REVERCEII (ACCRU-GI-1809): A randomized phase II study of regorafenib followed by anti-EGFR monoclonal antibody therapy versus the reverse sequencing for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin and irinotecan.
Authors: Ahn Daniel H. , Ou Fang-Shu , Sonbol Bassam Bassam , Wender Donald , Klute Kelsey , Jin Zhaohui , Jones Jeremy Clifton , Ulrich Angela , Waechter Blake , Young Heather , Weinberg Benjamin Adam , Lenz Heinz-Josef , Strickler John H. , Bekaii-Saab Tanios S. 
Published: January 2022

TPS213 Background: Regorafenib (R) is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis; it has a survival benefit in refractory metastatic colorectal cancer (mCRC). The current standard (std) treatment in patients (pts) with RAS wildtype (WT) mCRC is sequential treatment with an anti-EGFR antibody (AEA) followed by R. However, R, which is orally administered once daily, may be more convenient and thus preferable for pts than AEA. REVERCE, a Japanese trial, demonstrated a significant 5.8 month (mo.) survival benefit with regorafenib administered prior to AEA compared to the std sequence. Based off these findings, the proposed phase II trial is to confirm the observed survival benefit from regorafenib sequencing prior to anti-EGFR monoclonal antibody therapy in REVERCE in a US patient population. Methods: REVERCEII is an Academic and Community Cancer Research United (ACCRU) network-led randomized phase II study of R (dose escalation from 80mg to 160mg based on tolerance) prior to AEA (R+AEA) compared to standard sequencing (AEA+R) in pts with refractory RAS WT mCRC. Patients are randomized 1:1 to receive R (Arm A) vs. AEA (with or without irinotecan per investigator choice) (Arm B). At the time of disease progression or intolerance, patients will receive sequential treatment until disease progression. Eligibility criteria include histologically confirmed mCRC, ECOG ≤ 2, acceptable organ function, and patients must have had prior fluoropyrimidine, oxaliplatin and irinotecan, and no prior AEA nor R. The primary objective is to compare the overall survival (OS), the primary endpoint, between evaluable patients (eligible, consented, started protocol treatment) who were randomized to R+AEA (arm A) and AEA+R (arm B). With 83 OS events, we have 87% power to detect an improvement in median OS from 9 months to 14.5 mo., assuming 1-sided significance level of 0.15, and exponential distribution. The total sample size is 124 patients. Secondary endpoints include progression-free survival, objective response, and adverse events. The total study duration is expected to be 3 years. Clinical trial information: NCT04117945. Clinical trial information: 04117945.
REGINA: A phase II trial of neoadjuvant regorafenib (Rego) in combination with nivolumab (Nivo) and short-course radiotherapy (SCRT) in intermediate-risk, stage II-III rectal cancer (RC).
Authors: Bregni Giacomo , Senti Chiara , Acedo Reina Elena , Gkolfakis Paraskevas , Moretti Luigi , Veron Ana , Demetter Pieter , Liberale Gabriel , Carrasco Javier , Geboes Karen Paula , Gokburun Yeter , Peeters Marc , Van Den Eynde Marc , Van Laethem Jean-Luc , Vergauwe Philippe , Buyse Marc E. , Deleporte Amélie , Hendlisz Alain , Sclafani Francesco 
Published: January 2022

TPS226 Background: Despite recent improvements, management of locally advanced rectal cancer (LARC) remains challenging, and many patients (pts) still experience recurrence. In preclinical models, combining Rego with an anti-PD-1 inhibitor led to superior tumour growth suppression as compared with either treatment alone. In a phase I clinical trial, remarkable results were reported for the combination of Rego and Nivo in advanced MSS colorectal cancer. This synergistic effect is thought to be secondary to the anti-angiogenic effects of Rego and its potential to reduce TAMs, promote M1 macrophage conversion, and down-regulate expression of immunosuppressive factors. Building on these data, we designed a trial of Rego-Nivo with standard SCRT in the neoadjuvant setting of RC. Methods: REGINA is an academic, multicentre, single-arm, phase II trial sponsored by Institut Jules Bordet. Eligible patients are treated according to the following plan: induction phase (Nivo 240 mg IV D1&15, and Rego 80 mg PO D1-14), SCRT (D22-26), consolidation phase (Nivo 240 mg IV D29,43&57, and Rego 80 mg PO D29-49), and surgery (7-8 weeks after SCRT). Key eligibility criteria include age ≥18 years, ECOG PS ≤1, adenocarcinomas below the peritoneal reflection, intermediate-risk, stage II-III tumour (ie, cT3/T4aNany or cT1-2N+, no involvement/threatening of the mesorectal fascia, no involvement of lateral pelvic lymph nodes) irrespective of microsatellite instability status. The primary endpoint is pathological complete response (pCR). Secondary endpoints include, among others, toxicity, compliance to treatment, pathological tumour regression grade, event-free survival, and overall survival. Subjects will be followed for recurrence and survival for 5 years after end of treatment visit. The study follows a Simon’s two-stage design (null hypothesis pCR = 12%, alternative hypothesis pCR = 24%; α= 5%, β= 20%) with a maximum of 60 pts to be enrolled. A safety interim analysis is planned after the first 6 pts have completed treatment. Serial collection of tumour, blood, and stool samples is mandatory at pre-specified time points for exploratory correlative biomarker analyses. The trial is planned to be run at 8-10 centres across Belgium. Study recruitment started in Q1 2021 and is anticipated to complete in Q3 2023. The study is funded by Bayer. Clinical trial information: NCT04503694.