bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognosis and chemosensitivity of non-V600E BRAF mutations in metastatic colorectal carcinoma (mCRC): An AGEO French multicenter retrospective cohort.
Authors: Derosiere Aline , Nicolai Vincent , Malka David , Pozet Astrid , Lazartigues Julien , Turpin Anthony , Tougeron David , Walter Thomas , Artru Pascal , Bachet Jean-Baptiste , Phelip Jean Marc , Lepage Come , Lievre Astrid , Caulet Morgane , Norguet Emmanuelle , Lourenco Nelson , Coriat Romain , Sefrioui David , Dremaux Julie , Hautefeuille Vincent 
Published: May 2019

3575 Background: BRAF mutations are present in 5-15% of mCRC. V600E BRAF mutations account for ~80% of cases and are mostly found in right-sided tumors. Non-V600E BRAF mutations are rare (~2% of mCRC), mostly left-sided. Although BRAF V600E mutations are associated with a dismal prognosis, some studies suggest that non-V600E BRAF mutations may be associated with a favorable outcome. The chemosensitivity of non-V600E BRAF-mutated mCRC has never been studied. Methods: From 2017 to 2018, all consecutive patients (pts) with non-V600E BRAF-mutated mCRC (next generation sequencing) treated in the participating centers were included. Survival analyses were performed using Kaplan-Meier method and LogRank test. Results: A total of 108 pts in 34 centers in France were included between October 2017 and August 2018 (median age, 66 years [range, 58-77]; ECOG performance status 0-1, 86%). The primary was mostly left-sided (66%). Main metastatic sites were the liver (73%), lungs (33%), lymph nodes (39%) and peritoneum (26%). D594 (34%), G469 (15%), K601 (11%), N581 (7%) and L597 (7%) were the most frequent mutations. A concomitant RAS mutation was found in 22% of pts. Microsatellite instability (MSI) was found in 3/67 pts (4.5%). First-line chemotherapy (CTx) (n = 69) efficacy was (overall response rate/disease control rate) 49%/77% (anti-EGFR-containing CTx [n = 20], 75%/85%; antiangiogenic-containing CTx [n = 22], 55%/73%). Median overall survival (mOS) was 25.6 months (95% CI : 17.1-43.8) overall; it was 8.0 months with best supportive care alone (n = 10), 16.0 months with palliative CTx alone (n = 63), and attained 105.1 months with curative-intent management of metastases (n = 35). mOS did not differ according to sidedness (p = 0.22), type of mutation (p = 0.52), or its functional impact on BRAF (p = 0.19). Conclusions: Non-V600E BRAF-mutated mCRC retain sensitivity to CTx + biologics and harbor a good prognosis (especially when amenable to curative-intent surgery), regardless of the type of mutation and its impact on BRAF kinase function. Contrarily to BRAF V600E mutations, non-V600E mutations may occur along with RAS mutations, but uncommonly with MSI.
High incidence of advanced stage cancer and prolonged rectal bleeding history before diagnosis in young-onset patients with colorectal cancer.
Authors: Sandhu Gurprataap Singh , Anders Rebekah , Walde Amy , Leal Alexis Diane , King Gentry Teng , Leong Stephen , Davis S. Lindsey , Purcell William T. , Goodman Karyn A. , Herter Whitney , Meguid Cheryl Lauren , Birnbaum Elisa H , Ahrendt Steven Arthur , Gleisner Ana , Schulick Richard D. , Delchiaro Marco , McCarter Martin , Patel Swati , Messersmith Wells A. , Lieu Christopher Hanyoung 
Published: May 2019

3576 Background: In contrast to the older population, the incidence of colorectal cancer (CRC) in younger patients (aged < 50 years) has been increasing in the last three decades. Younger patients tend to present with more advanced disease, thought to be in part related to lack of routine screening colonoscopies. The goal of this study was to examine characteristics of young-onset CRC and potentially identify factors that may aid in earlier diagnosis and treatment. Methods: We collected data for patients available through the University of Colorado Cancer Center Cancer Registry. Inclusion criteria included: 1) Diagnosis of colon or rectal cancer between the years 2012-2018 and 2) age at diagnosis of less than 50 years. Pertinent data including baseline characteristics, clinical presentation, family history, pathology, molecular testing, staging, and treatment were collected. Results: 211 patients with young-onset CRC were available for review. Mean age at diagnosis was 42.4 years and 55.5% were males. A total of 42.1% had rectal cancer and a majority of the colon cancer diagnoses had left-sided tumors (66%). Regarding clinical presentation, 52.2% presented with rectal bleeding prior to diagnosis. Of those who presented with rectal bleeding, the average time from the onset of bleeding to diagnosis was 271.17 days. 42.9% of young-onset CRC were stage IV at the time of initial diagnosis. Evaluation of the pathology specimens showed that 89.6% were adenocarcinomas and 63.5% were grade 2 or higher. At diagnosis, the mean BMI was 26.6 and the mean CEA was 135.5. A total of 72.5% of young-onset patients had a positive family history of any cancer. KRAS or NRAS mutations were present in 49.6% of patients, BRAF V600E mutations were present in 3.8%, and 10.8% were MSI-H. Conclusions: Prolonged rectal bleeding history prior to diagnosis was noted in a significant proportion of young-onset patients with colorectal cancer. Patients and primary care physicians should be made aware of this finding in order to facilitate timely referral for colonoscopy which may lead to earlier diagnosis, less advanced disease at diagnosis, and improved outcomes.
Retrospective analysis of overall survival (OS) by subsequent therapy in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving irinotecan ± cetuximab in the EPIC study.
Authors: Sobrero Alberto F. , Lenz Heinz-Josef , Eng Cathy , Scheithauer Werner , Middleton Gary William , Chen Wen-Feng , Esser Regina , Nippgen Johannes , Burris Howard A. 
Published: May 2019

3580 Background: The multicenter, open-label, randomized, phase 3 EPIC study (EMR 062202-025) investigated cetuximab + irinotecan vs irinotecan as a second-line (2L) therapy in pts with EGFR-detectable mCRC. A retrospective analysis in the EPIC RAS wt population showed improved overall response rate (29.4% vs 5.0%) and progression-free survival (5.4 vs 2.6 mo) upon the addition of cetuximab to irinotecan. Median OS (mOS) was similar in both treatment arms, possibly due to differences in subsequent therapies. We present OS by post-study therapy in the RAS wt population. Methods: 1298 RAS-unselected pts were enrolled from May 2003 to February 2006. The primary endpoint was OS. RAS status was determined retrospectively in 2018 from existing DNA samples using BEAMing technology; wt status was defined as having a sum of mutated RAS allele frequencies of ≤5%, with all relevant alleles being analyzable. Results: Among the 452 pts with RAS wt mCRC, 231 received cetuximab + irinotecan and 221 received irinotecan. Baseline characteristics were similar in both arms. OS data by post-study therapy are summarized in the Table. No new or unexpected safety signals were observed. Conclusions: Post-study cetuximab was associated with improved OS in both treatment arms compared with post-study therapy without cetuximab and no subsequent therapy, suggesting that cetuximab-based therapy may be suitable as a standard treatment for pts with RAS wt mCRC in the rechallenge setting. Study limitations include a potential bias due to the differences in proportion of subsequent therapies with and without cetuximab between arms (almost 50% of pts in the irinotecan arm received post-study cetuximab) as well as the likelihood for pts who live longer to receive cetuximab in any subsequent therapy line. [Table: see text]
Is the predictive and prognostic impact of sporadic and familial microsatellite instable stage III colon cancer different? A pooled analysis of the PETACC8 and NCCTG N0147 (Alliance) trials.
Authors: Zaanan Aziz , Shi Qian , Taieb Julien , Alberts Steven R , Meyers Jeffrey P. , Smyrk Thomas C. , Julié Catherine , Zawadi Ayman , Tabernero Josep , Mini Enrico , Goldberg Richard M. , Folprecht Gunnar , VAN Laethem Jean Luc , Le Malicot Karine , Sargent Daniel J. , Laurent-Puig Pierre , Sinicrope Frank A. 
Published: May 2019

3583 Background: The Microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually taken as a single biological entity whereas no data are available concerning prognosis and response to chemotherapy between sporadic and familial dMMR cases. Methods: Resected KRAS exon 2 wild-type (WT) tumor stage III colon cancers (N = 4596) from patients (pts) randomly assigned to FOLFOX +/- cetuximab in two adjuvant large phase III trials were prospectively analyzed for MSI status and dMMR mechanism (sporadic vs familial). Stratified Cox models were used to assess prognostic and predictive values of dMMR mechanism by treatment arms, adjusting for age, gender, tumor grade, ECOG PS, pT/pN stage and primary tumor location. Results: Among dMMR patients with complete data for dMMR mechanism analysis (N = 354), there were 255 (72%) sporadic ( BRAF mutated or WT with MLH1 methylation) and 99 (28%) familial (loss of MSH2 or MSH6, or loss MLH1 with BRAF WT and unmethylated MLH1) cases. A large proportion of dMMR sporadic cases were mutated for BRAF (n = 200; 80%). In pts treated with FOLFOX, the disease-free survival (DFS) was not statistically different by dMMR mechanism, while for pts treated with FOLFOX + cetuximab, the sporadic cases did worse than familial cases (DFS; adjusted (adj) HR, 2.69; 95% CI, 1.02-7.08; P= 0.04). Considering the predictive value, a deleterious effect of adding cetuximab to FOLFOX was observed in sporadic (DFS; adjHR, 1.68; 95% CI, 1.01-2.79; P= 0.04) but not in familial dMMR pts (interaction P value regarding treatment effect = 0.03). Furthermore, a non-significant trend to a deleterious effect of adding cetuximab to FOLFOX was observed in BRAF mutant (DFS; adjHR, 1.66; 95% CI, 0.95-2.92; P= 0.07) but not in BRAF WT pts. Conclusions: The addition of cetuximab to FOLFOX was associated with reduced DFS in patients with sporadic dMMR cases. Further studies including the methylator phenotype (CIMP) analysis are needed to validate these results. Clinical trial information: NCT00265811 and NCT00079274.
Association of MAPK signaling subtypes with prognostic benefit for bevacizumab in left-sided metastatic colorectal cancer (mCRC) patients treated with FOLFIRI + cetuximab / bevacizumab (FIRE-3 trial).
Authors: Stahler Arndt , Stintzing Sebastian , Modest Dominik Paul , Jelas Ivan , Heinrich Kathrin , Miller-Phillips Lisa , von Einem Jobst C. , Vehling-Kaiser Ursula , Decker Thomas , Kiani Alexander , Fischer von Weikersthal Ludwig , Heintges Tobias , Kahl Christoph , Kullmann Frank , Scheithauer Werner , Moehler Markus H. , Wirapati Pratyaksha , Kirchner Thomas , Jung Andreas , Heinemann Volker 
Published: May 2019

3584 Background: We investigated the role of the MAPK pathway by mRNA expression profiles in microarrays of the FIRE-3 trial as it was formerly associated with prognosis. Methods: 451 patients provided eligible mRNA material for subsequent analyses of the MAPK pathway (295 genes). Non-negative matrix factorized (NMF) clustering for normalized mRNA microarray data (Almac Inc, Xcel Array) was performed for 2 to 6 ranks against randomized controls. Linear models with adjustment for multiple testing showed differential gene expression between groups. Single sample gene set enrichment analysis (ssGSEA) was used to compare differentially enriched hallmarks of cancer gene sets. Kaplan Meier method, log rank test and Cox regression analyses were performed to estimate overall (OS) and progression free survival (PFS) between MAPK subtypes. Results: NMF clustering built two groups of MAPK mRNA expression (coph: 0.91, silh: 1.00) without cohort-based bias in principal component analysis. Group MAPK1 (n = 238) was significantly associated with CMS2 (66.4 %), group MAPK2 (n = 213) with CMS4 (67.6 %, p < 0.0001). 5.551 of 23.561 genes were significantly differentially expressed between MAPK subtypes. 49 cancer hallmark gene sets were significantly differentially enriched in ssGSEA ( MAPK1: myc targets, DNA repair, cell cycle, PI3K- AKT- mTOR pathway upregulation; MAPK2: EMT-related signatures, TGFß pathway, angiogenesis upregulation among others). In overall analysis, MAPK1 showed slightly better outcome than MAPK2 (OS: HR: 0.80, 95% CI: 0.65 – 0.99, p = 0.049; PFS: HR: 0.81, 95% CI: 0.66 – 1.00, p = 0.05). However, MAPK1 was significantly more favourable for bevacizumab treatment in OS ( MAPK1: 30.8 m, MAPK2: 19.4 m, HR: 0.56, 95% CI: 0.39 – 0.81, p = 0.002) and PFS ( MAPK1: 11.7 m, MAPK2: 9.8 m, HR: 0.68, 95% CI: 0.48 – 0.98, p = 0.038) in left sided tumors, while no difference was seen for cetuximab treatment, RAS and BRAF status. Conclusions: mCRC subtypes by MAPK mRNA expression might contain prognostic information for the treatment with bevacizumab beyond mutational status in patients with left sided tumors of the FIRE-3 trial.
Molecular landscape of colorectal cancers harboring R-spondin fusions.
Authors: Seeber Andreas , Kocher Florian , Xiu Joanne , Spizzo Gilbert , Puccini Alberto , Swensen Jeffrey , Ellis Michelle , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Battaglin Francesca , El-Deiry Wafik S. , Tokunaga Ryuma , Naseem Madiha , Philip Philip Agop , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef , Gatalica Zoran 
Published: May 2019

3588 Background: Gene fusions involving R-spondin ( RSPO) family members have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Therapies targeting Wnt pathway are being actively investigated for tumors harboring RSPO2/3 fusions. Here we set out to characterize the molecular features of CRC with and without RSPO fusions to gain insight into potential rationale combination therapy strategies. Methods: Tumor DNA sequencing of 592 genes (NextSeq, Illumina), RNA sequencing of 53 gene fusions (ArcherDx FusionPlex) and immunohistochemistry for PD-L1 on tumor cells (SP142) were tested on CRC tumors at Caris Life Sciences, Phoenix, AZ. Molecular profiles of RSPO2/3 positive (pos) were compared with negative (neg) tumors, Fisher-Exact was used for comparative analysis. Results: A total of 1356 CRC samples were analyzed. RSPO3 and RSPO2 fusions were detected in 42 (3.1%) and 4 (0.3%) samples, respectively, including 5 fusion events not previously reported (e.g., IFNGR1-RSPO3). A female predominance was seen in RSPO fusion pos vs. neg tumors (71.7% vs 45.0%, p < 0.001); no association with age or tumor sidedness was seen. RSPO2/3 fusions were mutually exclusive of MSI-high (0 vs. 5%), ERBB2 alterations (0 vs. 1% mutation, 4% amplification) and other Wnt pathway activation drivers including APC (2 vs. 75%), CTNNB1 (0 vs. 1.4%) and RNF43 (0 vs. 5.3%) mutations. Significantly higher BRAF (26 vs. 7%), RAF1 (4.5 vs. 0.4%) and SMAD4 (30 vs. 11%) mutation rates were seen in RSPO pos vs. neg tumors (p < 0.05). A universal co-activation of MAPK pathway ( KRAS, NRAS or BRAF) was seen with RSPO fusions. There was a significantly elevated PD-L1 expression in RSPO3 pos tumors (14%) compared to RSPO neg (6%, p = 0.04) and APC-mutated (5%, p = 0.02) tumors that are MSS. Conclusions: This is the largest series of CRC cases harboring an RSPO rearrangement reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO fusions in CRC and suggested potential combinatorial approach to target Wnt/MAPK pathway. The immune modulatory effects specific to RSPO2/3 fusion revealed by PD-L1 expression suggest co-targeting Wnt pathway with PD1/PDL1 inhibitors in RSPO pos tumors.
Prediction model for detecting circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).
Authors: Pereira Allan Andresson Lima , Parikh Aparna Raj , Van Seventer Emily E. , Jia Jingquan , Loree Jonathan M. , Kanikarla Marie Preeti , Raghav Kanwal Pratap Singh , Morris Van K. , Overman Michael J. , Raymond Victoria M. , Lanman Richard B. , Talasaz AmirAli , Strickler John H. , Corcoran Ryan Bruce , Kopetz Scott 
Published: May 2019

3590 Background: While tissue-based assays have yields above 90% in solid tumors, there is less known about factors that influence the sensitivity of ctDNA for detecting mutations. Methods:We retrospectively evaluated mCRC patients (pts) who had plasma-derived NGS utilizing a highly-sensitive targeted 68-73-gene ctDNA assay. In a case-control design, pts with a known mutation on tissue and radiologic evidence of metastatic disease but no detectable ctDNA mutation were matched 1:3 with randomly selected pts with detectable mutations and compared according to clinical, laboratory, and radiologic characteristics. A prediction score for ctDNA detection was built using a binary logistic backward stepwise regression analysis and tested in two independent data sets from different institutions. Area under the curve (AUC) from receiver operating characteristics curves (ROC) were used for internal and external validation. Results: From 416 pts who met inclusion criteria, plasma-derived NGS did not find tumor mutations in 66 cases (15.9%); 198 pts with detectable alterations were selected as controls. After multivariate analysis, the detection of ctDNA was associated with increasing age (OR 1.05; 95%CI 1.02-1.09; p = .001), presence of liver (OR 5.82; 95%CI 2.55-12.49; p < .001) and lymph node metastases (OR 3.28; 95%CI 1.51-7.60; p = .004), archival TP53 mutations (OR = 2.88; 95%CI 1.37-6.17; p = .006). A key determinant was timing of collection relative to disease status: plasma collected in newly diagnosed metastatic disease or after evidence of progression was substantially more likely to have detectable alterations (OR 9.24; 95%CI 4.11-22.40; p < .001); The simplified prediction model performed well in internal (AUC = 0.88) and external validation (AUC = 0.95; 163 pts). Conclusions: Our validated prediction model provides clinicians and researchers with a tool to screen for patients in whom ctDNA testing can outperform tissue-based testing in detecting genomic alterations.
Preoperative platelet leukocyte ratio as an independent risk factor for postoperative outcomes in colorectal cancers.
Authors: Ryan Carrie E , Gajdos Csaba , Pourafkari Leili , Nader Nader D. 
Published: May 2019

3591 Background: Although preoperative platelet/leukocyte ratio (PLR) is a predictor of postoperative outcomes in various neoplasms, data is lacking for colorectal cancer (CRC). We hypothesized that elevated preoperative PLR would be an independent risk factor for postoperative complications and increased 30-day mortality in patients with surgically resected CRC. Methods: Patients undergoing resections for CRC were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2016 dataset. Logistic regression models for 30-day morbidity and mortality for PLR ≤28.4 and >28.4 (calculated from ROC analyses) were completed. Univariate log-rank test, and multivariate Cox proportional hazards regression were used for time-to-event analyses and data are presented as odds/hazard ratio with confidence interval. Results: 98,398 patients were included in the study. Elevated PLR was an independent predictor of 30-day morbidity and mortality. Patients with high PLR were more likely to have a wound infection (1.022, 1.01-1.04), pneumonia (1.2, 1.17-1.23), require reintubation (1.23, 1.19-127), prolonged ventilation (1.31, 1.26-1.36), have renal insufficiency (1.17, 1.11-1.22), and have a postoperative myocardial infarction (1.23, 1.9-127). PLR value > 28.4 was among independent predictors of mortality (1.67, 1.47–1.87), along with the ASA class, age, perioperative use of steroids, serum albumin and INR. (Table). Conclusions: Elevated PLR is a significant preoperative risk factor for 30-day morbidity and mortality. PLR may be considered as a potential risk assessment tool that predicts postoperative outcome following CRC resections. Multivariate analysis. [Table: see text]
Exploring the genetic basis of Lynch-like syndrome through paired germline and tumor exome sequencing.
Authors: Willis Jason , Mork Maureen E , Chang Kyle , Kinnison Jenniffer , Rodriguez-Bigas Miguel A. , Thirumurthi Selvi , Borras Ester , Taggart Melissa , Lynch Patrick M. , You Y. Nancy , Vilar Sanchez Eduardo 
Published: May 2019

3592 Background: Lynch-like syndrome (LLS) is characterized by a diagnosis of mismatch repair deficient (dMMR) malignancy where somatic bi-allelic mutations in canonical MMR pathway genes ( MLH1, MSH2, MSH6, PMS2) have been identified as the main cause. Yet, a substantial proportion of cases remain unexplained by MMR somatic bi-allelic events or germline mutations. We hypothesize that LLS cases with young-onset cancers carry cryptic germline alterations in other pathways. To explore this contribution, we performed analyses of the germline and tumor mutation landscapes in LLS patients diagnosed with dMMR cancers. Methods: 18 probands with young-onset (age <50 years) dMMR colorectal or uterine cancers were selected from a familial cancer registry. The absence of deleterious germline MMR mutation and/or somatic MLH1inactivation was confirmed by standard clinical testing. We performed whole-exome sequencing (Illumina HiSeq) of germline (peripheral blood) DNA. Variant calls, quality-control, allele-frequency filtering (<1% in reference cohorts), and in silicoannotation were performed using the GATK and polyphen/SIFT tools. Pathway analysis was performed using the DAVID suite. For 16 of 18 patients, targeted exon sequencing of 408 cancer-related genes was performed on paired tumor/normal tissue samples (Ion Torrent AmpliSeq) and analyzed with VarScan 2. Results: 237,055 rare germline variants were detected in our cohort. We enriched a subset of 758 variants with putative frameshift (45.1%), stop gain or loss (25%), or splice site alteration (29.9%). Pathway analysis of genes altered by this subset revealed excess events in DNA damage repair (e.g. ERCC5, POLM, POLN, EXO5) and mRNA splicing (e.g. SCAF1, SRSF4) pathways. Preliminary analysis of somatic mutations profiles shows frequent alteration of known drivers including APC(64%) and NOTCH1(36%). Conclusions: Our exploratory analysis provides novel evidence that LLS patients may harbor an excess of deleterious germline mutations in DNA damage repair- and mRNA splicing-related genes. Future studies will identify genes which are targeted by both germline and somatic mutation with the goal of nominating putative causal genes. Defining additional mechanisms of dMMR in LLS cancers may help to refine prevention strategies for (un)affected individuals.