bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment: Results from the randomized FOCUS4-N trial.
Authors: Adams Richard , Fisher David , Graham Janet , Seligmann Jenny F. , Seymour Matthew , Kaplan Richard S. , Yates Emma , Richman Susan D , Quirke Philip , Butler Rachel , Brown Ewan , Falk Stephen , Collinson Fiona Jane , Wilson Richard H. , Brown Louise C. , Maughan Tim ,   FOCUS4 Investigators
Published: June 2021

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]
Multi-omics characterization of left-right colorectal cancer.
Authors: Marshall John , Yoshino Takayuki , Rha Sun Young , Church David N. , Coutinho Anelisa Kruschewsky , Sampaio-Filho Carlos Alberto , Gallagher David James , García-Foncillas Jesús , von der Heyde Silvia , Juhl Hartmut , Woodsmith Jonathan , Kerr David J. 
Published: June 2021

3542 Background: Right (R) vs left (L) sided colorectal cancers are clinically distinguishable based on prognosis and response to certain therapies, but as of yet, limited data have emerged to explain these differences. The science of molecular testing has evolved rapidly. Enabled by improved technologies and computing power, it is now feasible to obtain to systematic multi-omic datasets covering DNA, RNA, proteins, phospho-proteins and metabolomics on large numbers of patients. Multi-omic analysis can further define disease specific subgroups but pre-analytic quality of the tissues (ischemia time) and comparison to normal tissue controls is paramount to optimize results. Methods: Following informed consent, 450 colorectal cancer primary tumors and paired normal tissues were collected following an SOP to minimize ischemia time, and were analyzed using comprehensive genomics, transcriptomics, proteomics, phosphoproteomics, morphology and annual clinical information. Right (C18.0,2,3) and left (C18.6,7) CRC tumors, normal tissue were compared using machine learning tools to unravel the molecular mechanisms that underpin these clinically distinguishable phenotypes as well as correlating with known genomic metrics such MSI and KRAS mutation status. Results: Through leveraging the tumor and paired normal patient samples, systematic differences between left and right tumor samples were observed including specific molecular events associated with these anatomical differences. The detailed results will be presented at the meeting. Conclusions: Progress in precision medicine requires the inclusion of multi-omics which in turn requires changes to our current SOPs of tissue collection. The ability to define molecular distinctions such as between R and L colon cancer will permit the rapid discovery of clinically useful prognostic and predictive markers, dramatically adding to our fundamental understanding to colon cancer biology. Future work will focus on the discovery of novel targets and signatures, creating innovative tools that depict multi-omic results for clinicians.
PMC: A more precise classifier of POLE mutations to identify candidates for immune therapy.
Authors: Zeineddine Fadl , Garmezy Benjamin , Yap Timothy A. , Shen John Paul Y.C. 
Published: June 2021

3548 Background: Specific somatic mutations in DNA polymerase epsilon ( POLE) can cause a hypermutant phenotype with tumor mutation burden (TMB) in excess of 100 mutations per megabase. It has been reported that POLE mutant tumors are enriched in response to immune therapy and this association is being tested in multiple active clinical trials. However, most POLE mutations are passenger mutations and have no pathogenic role. Current methods to classify POLE mutations are limited in both accuracy and completeness, which could lead to inappropriate use of immune agents in tumor such as MSS CRC, where response rate is 5% or less. Here we present a new classifier, POLE Mutation Classifier or PMC, based on the unique trinucleotide mutation signature caused by selective loss of the proofreading function (LOP) of POLE. Methods: cBioPortal was queried to identify all tumors with POLE mutation. TMB was calculated for each, additionally, trinucleotide mutation signatures were obtained for all POLE mutant tumors in TCGA. Using OncoKB to identify a gold standard of 12 functional POLE mutations (n = 98 tumors) a POLE mutational signature was created. A combination of mutational signature, amino acid location, and TMB was used to classify each POLE variant. Results: Among all 48035 unique tumors the overall frequency of POLE mutations was 2.5% (n = 1184), however only 9.2% (n = 110) were determined to cause the selective LOP. The incidence of LOP POLE mutation was highest in uterine carcinoma and CRC, these tumors also had the highest ratio of LOP to passenger mutations. In a pan-cancer analysis the overall survival of LOP POLE patients was significantly better than those with passenger mutations (not-yet-reached vs. 51 mo, HR = 4.4, p < 0.0001). A similar analysis performed using the polyphen-2 classifier to identify functional POLE mutations did not show a difference in overall survival (HR = 1.0, p-value = 0.57). To further validate the improved specificity of the PMC classifier TMB was used as a surrogate marker, using the PMC classifier 98% of tumors with LOP showed hypermutation (TMB > 20mut/Mb), vs. 53% called functional by polyphen-2. A retrospective analysis of MD Anderson CRC patients identified 25 patients with LOP POLE mutation, who had improved OS relative to 267 CRC patients with passenger POLE mutation (not-yet-reached vs. 70 mo, HR:4.2, p = 0.028). Four metastatic CRC patients with LOP POLE mutation were treated with immune therapy (nivolumab, or ipilimumab/nivolumab) in 2nd or 3rd line, all four achieved objective response and remain on therapy (mean time on treatment 15 mo). Conclusions: The PMC classifier specifically identifies mutations in POLE that cause loss of the proofreading function, outperforming both manually curated databases and machine learning-based methods. Clinical trials that use POLE mutation as a selection criteria for immune therapy should be restricted to just those POLE mutations that cause LOP.
Consensus molecular subtypes and RAS status as biomarker of treatment intensity with fluoropyrimidine, bevacizumab, and irinotecan in metastatic colorectal cancer (XELAVIRI, AIO KRK 0110).
Authors: Stahler Arndt , Heinemann Volker , Schuster Veronika , Alig Annabel Helga Sophie , Fischer Laura Elisabeth , Weiss Lena , Heinrich Kathrin , Kurreck Annika , Jelas Ivan , von Einem Jobst C. , Giessen-Jung Clemens , Fischer von Weikersthal Ludwig , Vehling-Kaiser Ursula , Decker Thomas , Neumann Jens , Kirchner Thomas , Jung Andreas , Kumbrink Joerg , Stintzing Sebastian , Modest Dominik Paul 
Published: June 2021

3552 Background: Prognostic biomarkers beside RAS/BRAF status are necessary to identify metastatic colorectal cancer (mCRC) patients who benefit from combined (COMB) versus sequential (SEQ) treatment with fluoropyrimidine, bevacizumab and irinotecan (randomized phase III XELAVIRI trial). Methods: mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue of 337 patients, gene expression was measured by the Nanostring PanCancer Progression Panel. Consensus molecular subtypes (CMS) classification was re-derived using a multinomial regression model. Data of Guinney et al. (Nat. Med. 2015. 21:1350-6) and FIRE-3 served as training and validation set. RAS/BRAF MUT were assessed by pyrosequencing. Median overall (OS) and progression free survival (PFS), hazard ratios (HR) and 95% confidence interval (CI) were estimated by Kaplan-Meier method and univariate Cox regression. Results: The multinomial regression model employed in the present analysis correctly predicted CMS labels in 98.3 % of the original Guinney- and 100.0 % of FIRE-3 population. In XELAVIRI, CMS subgroups were predicted as follows: CMS1: n = 62 (18.4 %); CMS2: n = 174 (51.6 %); CMS3: n = 9 (2.7 %); CMS4: n = 92 (27.3 %). A general prognostic impact of CMS was not observed when all patients were analysed. In RAS/BRAF WT mCRC patients, substantial benefit of COMB versus SEQ treatment was shown for OS and PFS in CMS2 and CMS4, but not in CMS1. Conversely, OS was significantly longer for COMB treatment in patients with RAS MUT and CMS1 mCRC, while SEQ treatment was not inferior in RAS MUT and CMS2 or CMS4 subgroups (see TABLE). Additional data for overall response rates, early tumor shrinkage and sidedness might be presented at the meeting. Conclusions: This retrospective analysis of XELAVIRI suggests that CMS may serve as biomarker that predicts response to initially combined versus less intensive sequential chemotherapy in patients with RAS/BRAF WT mCRC.[Table: see text]
LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.
Authors: Gomez-Roca Carlos A. , Yanez Eduardo , Im Seock-Ah , Castanon Alvarez Eduardo , Senellart Hélène , Doherty Mark , Garcia-Corbacho Javier , Lopez Juanita Suzanne , Basu Bristi , Maurice-Dror Corinne , Gill Sanjeev Singh , Ghori Razi , Kubiak Peter , Jin Fan , Norwood Kevin Glen , Chung Hyun Cheol Cheol 
Published: June 2021

3564 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326. [Table: see text]
Treatment responses and disease dynamics in patients with untreated metastatic colorectal cancer receiving bevacizumab-based sequential versus combination chemotherapy: Analysis of a phase 3 trial (AIO KRK0110, XELAVIRI study).
Authors: Kurreck Annika , Heinemann Volker , Fischer von Weikersthal Ludwig , Decker Thomas , Kaiser Florian , Uhlig Jens , Schenk Michael , Freiberg-Richter Jens , Peuser Bettina , Denzlinger Claudio , Graeven Ullrich , Heinrich Kathrin , Held Swantje , Stahler Arndt , Alig Annabel Helga Sophie , Jelas Ivan , von Einem Jobst C. , Stintzing Sebastian , Giessen-Jung Clemens , Modest Dominik Paul 
Published: June 2021

3571 Background: Early response parameters such as early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy endpoints and potential predictors of long-term outcome. We analyzed the association of these endpoints with bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within a randomized phase III trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR-image) were analyzed in the XELAVIRI-trial. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated with ETS as stratification parameter (ETS vs. no ETS) according to treatment arm, molecular subgroup, and sex. Results: 370 patients were available for analysis of early treatment response parameters. A higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination compared to the sequential therapy arm, respectively. The improvement of ETS and DpR was pronounced in the subpopulation of RAS/ BRAF wildtype patients. Male in contrast to female patients significantly benefitted from initial combination treatment in terms of median DpR (male: -40.0% vs. -22.2%; p < 0.001; female: -34.0% vs. -24.4%; p = 0.13) and rate of ETS (male: 64.8% vs. 40.2%; p < 0.001; female: 52.5% vs. 49.3%; p = 0.73). Achievement of ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Whereas the survival benefit in male patients achieving ETS was statistically significant (PFS: p < 0.001, HR 0.532 (0.409-0.692); OS: p < 0.001, HR 0.574 (0.437-0.756)), there were no significant differences in PFS (p = 0.107) and OS (p = 0.965) of female patients depending on ETS. Conclusions: In the XELAVIRI trial, initial irinotecan-based combination therapy with bevacizumab improves ETS and DpR in mCRC patients. Improvement in early response parameters appears pronounced in patients with RAS/ BRAF wildtype tumors suggesting a high sensitivity to irinotecan-based treatment. ETS was predictive of PFS and OS regardless of treatment arm. This finding was rather driven by male than female patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population.
ENSURE: An international multicenter study exploring whether surveillance after esophageal cancer surgery impacts oncological and quality-of-life outcomes.
Authors: Elliott Jessie A , Markar Sheraz , Klevebro Fredrik , Johar Asif , Goense Lucas , Lowery Maeve Aine , Lagergren Pernilla , Zaninotto Giovanni , van Hillegersberg Richard , Nilsson Magnus , Hanna George , Reynolds John V. ,   ENSURE Study Group
Published: June 2021

4032 Background: Although established and emerging therapies for recurrent esophageal cancer (EC) may impact on survival and health related quality of life (HRQL), surveillance protocols after the primary curative treatment of EC are varied and inconsistent, reflecting a limited evidence-base to guide an optimum approach. Specifically, whether advantages exist for an intensive surveillance protocol is unknown and was the focus of this study. Methods: European iNvestigation of SUrveillance after Resection for Esophageal cancer (ENSURE) is an international multicenter retrospective observational study of consecutive patients undergoing surgery with curative intent for esophageal and gastroesophageal junction cancers (2009 – 2015) across 20 European and North American cancer centers (NCT03461341). Intensive surveillance (IS) was defined as routine annual CT/PET-CT along with clinical assessment during the first three postoperative years, and compared with standard surveillance (SS) with investigation as clinically indicated. The primary outcome measure was overall survival (OS), secondary outcomes included treatment administered, disease-specific survival (DSS), disease-free survival (DFS), recurrence pattern, and HRQL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance on oncologic outcomes and HRQL. Results: 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). 45.5% underwent IS. At a median follow-up of 60 months, 47.5% developed disease recurrence. Oligometastatic recurrence occurred in 39% of cases, with 31% receiving best supportive care, 60% chemotherapy and/or radiation, and 8% surgical resection. IS was associated with reduced symptomatic recurrence (odds ratio [OR] 0.17 [0.12–0.25]), increased tumor-directed therapy (OR 2.09 [1.58–2.77]), and improved OS (HR 0.90 [0.82–0.98], 5-year OS 47.9±1.2% versus 43.2±1.1%). After adjusting for confounders, significantly improved overall survival with IS was maintained for patients who underwent surgery alone as initial therapy (HR 0.60 [0.47–0.78]) and in those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58–0.89]). IS was associated with greater anxiety ( P= 0.016), but similar overall HRQL. Conclusions: These data suggest that IS may improve oncologic outcomes, particularly in patients with early stage disease at presentation or with a favorable pathological stage post induction therapy. This may be relevant to guideline development and provide a framework and rationale for RCTs. It may also inform shared decision-making with patients at a time where therapeutic options for recurrence are expanding.
Circulating tumor DNA (ctDNA) analysis by low-coverage whole genome sequencing (lcWGS) of resectable esophageal adenocarcinoma (rEAC) patients.
Authors: van den Ende Tom , Creemers Aafke , van der Pol Ymke , Boers Dries , Van Berge Henegouwen Mark I. , Gisbertz Suzanne S. , Geijsen E. Debby , Hulshof Maarten C.C.M. , Dijk Frederike , van Grieken Nicole C.T. , Pegtel D. Michiel , Derks Sarah , Bijlsma Maarten F. , Moulière Florent , Van Laarhoven Hanneke W.M. 
Published: June 2021

4033 Background: ctDNA is becoming an established marker to assess tumor burden, relapse after surgery, and to identify responders in immunotherapy studies. In the phase II PERFECT trial rEAC patients were treated with neoadjuvant chemoradiotherapy (nCRT) and a PD-L1 inhibitor (van den Ende et al. CCR. 2021). Here we evaluated the potential of cell-free DNA (cfDNA) to predict pathological complete response (pCR) and recurrence. Methods: The cohort consisted of 40 patients and 145 plasma samples. EDTA blood samples were drawn at baseline (B, N = 40), in week 5 of nCRT (W5, N = 40), before surgery (OR, N = 33) and 3 months after surgery (FU, N = 32). cfDNA was isolated by affinity columns (CNAkit, QIAgen) quantified by spectrofluorometer (BioAnalyzer, Agilent), sequencing libraries were prepared for lcWGS ( < 5-fold coverage, Tag-seq, Takara) and sequenced on a NovaSeq (S4, PE150). Sequencing data were processed with an in-house pipeline. Copy number aberrations (CNA) and the tumor fraction were estimated using the ichorCNA tool. Insert sizes were recovered and we determined a Tumor Enriched Fragment Fraction (TEFF), calculated by doing the ratio of fragments between 90-150 bp and 250-320 bp (enriched in tumor signal) and fragments between 150-250 bp and 320-360 bp (poor in tumor signal). ichorCNA and TEFF were used to quantify the ctDNA fraction in plasma samples. pCR was defined as ypT0N0. Residual tumor, progression or death before surgery were considered non-pCR. Relapse-free survival (RFS) was defined as the time after surgery until recurrence. Results: The pCR rate was 25% (10/40). The median fold change TEFF between B and W5 was -0.15 (range -0.67 to 0.44) in the pCR group and 0.16 (range -1.40 to 0.76) in the non-pCR group (Mann–Whitney U; p = 0.047). Of the 17 patients in whom ctDNA was detected (TEFF≥0.3 and/or ichorCNA≥0.03) in the FU sample, 13 (76%) showed a recurrence. Of the 15 patients with no ctDNA detected 5 (33%) showed a recurrence. Patients with ctDNA detected at FU had worse RFS, HR = 2.72 (95%CI 0.96-7.71; p = 0.050). Recurrences were detected earlier by FU ctDNA than by imaging due to physical complaints with a median of 312 days (163-798 days). Conclusions: lcWGS appears to be a useful tool to predict pCR and recurrence in resectable esophageal cancer. These lcWGS results will be further combined with fragmentomics analysis and targeted mutational data (Ion Torrent next-generation sequencing) in order to assess response to immunotherapy. Clinical trial information: NCT03087864.