bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pooled analysis of multicenter cohort studies of post-surgery circulating tumor DNA (ctDNA) in early stage colorectal cancer (CRC).
Authors: Tie Jeanne , Cohen Joshua , Wang Yuxuan , Li Lu , Lee Margaret , Wong Rachel , Kosmider Suzanne , Wong Hui-Li , Lee Belinda , Burge Matthew E. , Yip Desmond , Karapetis Christos Stelios , Price Timothy Jay , Tebbutt Niall C. , Haydon Andrew Mark , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter 
Published: May 2019

3518 Background: Studies in multiple tumor types have demonstrated the prognostic impact of ctDNA analysis after curative intent surgery. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. Further review of existing study data could increase the precision of ctDNA guided adjuvant therapy decision making. Methods: We combined individual patient (pt) data from three independent prospective cohort studies that enrolled 485 pts with stage II or III CRC. Clinicians were blinded to ctDNA results. We evaluated pt outcomes over a 5-year follow-up period (median, 47.2 months). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using Safe-SeqS. Results: ctDNA was detected after surgery in 59 (12%) pts overall (11.0%, 12.5% and 13.8% respectively for samples taken at 4-6, 6-8 and 8-10 weeks; P = 0.740). ctDNA detection was associated with nodal status; 8.7%, 16.7% and 32.4% in N0, N1 and N2 disease (P < 0.001), but remained an independent adverse prognostic factor in multivariable analysis. ctDNA detection was associated with poor overall survival for pts treated (mortality ratio, 3.0; P = 0.026) or not treated with adjuvant chemotherapy (mortality ratio, 5.17; P < 0.001). The median MAF (mutant allele frequency) in pts with detectable ctDNA was 0.046%. For pts not treated with adjuvant chemotherapy, 3 year recurrence free survival (RFS) was 9% in pts with a MAF > 0.046% vs 33% with a MAF ≤ 0.046% (HR, 2.7; P = 0.032). For chemotherapy treated pts, 3 year RFS was 25% in pts with a MAF > 0.046% vs 70% with a MAF ≤ 0.046 (HR, 3.1; P = 0.025). In 90 pts with recurrence, ctDNA had been detected post surgery in 3 of 20 (15%) with locoregional recurrence, 27 of 60 (45%) with distant recurrence and 5 of 10 (50%) with both (P = 0.044). Conclusions: Where samples for ctDNA analysis were collected 4 to 10 weeks post surgery, sampling timing may not significantly impact detection rates. The prognostic significance of ctDNA detection can be further stratified by MAF level, but MAF level may not impact adjuvant treatment benefit. ctDNA analysis is most sensitive for detecting minimal residual disease at distant sites.
Recent changes in overall survival of real-life stage IV colorectal cancer patients.
Authors: Hamers Patricia , Bos Amanda C.R.K. , May Anne Maria , Punt Cornelis J. A. , Koopman Miriam , Vink Geraldine R. 
Published: May 2019

3522 Background: In the past decade, the reported median overall survival (mOS) in phase 3 trials of metastatic colorectal cancer (mCRC) patients increased from approximately 16 to over 36 months. However, only 2.5-20% of cancer patients participate in clinical studies and these are often patients with favourable prognostic factors. Therefore, we explored for which proportion of real-life stage IV CRC patients OS improved in recent years. Methods: Nationwide population-based data of all stage IV (synchronous metastatic) CRC patients diagnosed between 2008-2016 in the Netherlands who received local and/or systemic antitumor therapy were obtained from the Netherlands Cancer Registry (NCR). Initial treatment was registered in the NCR. Vital status was recorded until January 31st 2018. OS per incidence year was determined for various percentiles, which represent the number of months after which 10-30-50-70-80-90% of the patients had died. For some percentiles survival time exceeded follow-up duration. Results: The total study population comprised 21,047 patients. mOS remained unchanged in the period 2008-2016 at around 15 months. OS of p10 and p30 increased by 1,5 months to 3,6 and 10,0 respectively. For the ‘best’ (longest-living) patients (p70-p80) OS improved in the period 2008-2016 by 4 and 6 months to 30 and 43 months, respectively. Follow-up duration is insufficient to analyse change over time for the 10% ‘best’ patients. mOS did not change for any of the treatment subgroups except for the patients who received exclusively non-systemic therapy (e.g. metastasectomy, radiotherapy) in which mOS improved by 11 months to almost 20 months. Conclusions: mOS of real-life stage IV CRC patients has not improved since 2008. We observed a clinically relevant survival improvement in only 30% of all treated patients and in all patients who received exclusively non-systemic therapy. These data illustrate the different outcomes between trial patients and total patient population, which emphasizes that trial patients represent a selection of patients with favourable prognosis. Our results highlight the value of real-life data to determine efficacy of innovations in daily clinical practice.
A regulatory program that promotes metastasis in colorectal cancer (CRC) through modulation of mRNA stability.
Authors: Goodarzi Hani , Warren Robert S. , Yu Johnny , Fish Lisa 
Published: May 2019

3523 Background: CRC progression accompanies dysregulations in pathways of gene expression control. Regulatory pathways that govern RNA decay have emerged as key mechanisms coopted by cancer cells. Here, we have described a novel regulatory program that acts as a suppressor of metastasis in CRC. Methods: We have developed a computational approach called PRADA that identifies master regulators of aberrant mRNA stability. By applying this tool to a compendium of gene expression data collected from patient samples and colon cancer cell lines, we have identified a novel regulatory program involved in CRC metastasis. We have used xenograft models and genomic technologies to functionally dissect this pathway. We have also performed multivariate analysis in public datasets, as well as qPCR-based measurements in tumor samples to establish its clinical relevance. Results: PRADA identified the RNA-binding protein RBMS1 as a key factor in CRC metastasis. RBMS1, which is silenced in highly metastatic cells, binds and stabilizes a large regulon of mRNAs. Silencing RBMS1 in established lines resulted in increased liver colonization in xenograft models and its over-expression reduced metastasis. We also identified the set of genes that are directly bound and regulated by RBMS1 and function downstream. Loss of RBMS1 and its regulon provide a signature predictive of RFS in localized CRC (n = 574, HR = 0.48, p = 0.038) even when controlled for known prognostic factors in a multivariate analysis (Table). We also observed a 4-fold reduction (P<1e-3) in the expression of RBMS1 in stage IV tumors relative to earlier stage disease. Conclusions: In sum, we have discovered a previously unknown regulatory pathway of RNA stability that acts as a suppressor of metastasis in CRC which may inform new therapeutic targets among the RBMS1 regulon for adjuvant therapy.[Table: see text]
ROCKET: A randomized, multicenter phase 2 study of RRx-001 + irinotecan versus regorafenib in 3rd/4th line colorectal cancer.
Authors: Reid Tony R. , Fisher George A. 
Published: May 2019

3526 Background: The purpose of this study was to assess the efficacy of combination therapy with RRx-001, an aerospace-derived macrophage repolarizing agent with epigenetic and vascular normalization properties, plus irinotecan vs. regorafenib plus irinotecan in 3rd/4th line metastatic colorectal cancer that previously received treatment with irinotecan. Methods: Between June 2014 and August 2015, 34 patients were enrolled. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly until progression followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. Results: The survival follow up for RRx-001 + irinotecan range was approximately 14.5 months (mean 6.0 months, median 5.0 months, standard deviation 4.5 months). The survival follow up for regorafenib range was approximately 10.8 months (mean 4.5 months, median 4.0 months, standard deviation 3.9 months). The median survival time was 8.6 months for RRx-001 + irinotecan and 4.7 months for regorafenib. The median progression free survival was 7.5 months for RRx-001 + irinotecan vs. 1.7 months for regorafenib. In addition, the toxicity profile of RRx-001 + irinotecan was dramatically improved compared with regorafenib. The regorafenib arm was terminated for futility at interim analysis, after which any enrolled patients only received RRx-001 co-infused with an aliquot of autologous blood to evaluate the safety of that method of administration. Conclusions: The results of this trial demonstrate improved efficacy and efficacy of RRx-001 + irinotecan compared with regorafenib in patients with metastatic colorectal cancer. Clinical trial information: NCT02096354.
Metastasectomy and BRAF mutation: An analysis of survival outcome in metastatic colorectal cancer.
Authors: Prasanna Thiru , Wong Rachel , Price Timothy Jay , Shapiro Jeremy David , Tie Jeanne , Wong Hui-Li , Nott Louise M. , Roder David , Lee Margaret , Kosmider Suzanne , Jalali Azim , Burge Matthew E. , Padbury Robert , Maddern Guy , Moore James , Carruthers Scott , Sorich Michael , Karapetis Christos Stelios , Gibbs Peter , Yip Desmond 
Published: May 2019

3531 Background: Surgical resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether such benefit is consistently observed for BRAF V600E mutant (MT) and wild type (WT) mCRC. We conducted a retrospective analysis to explore the influence of BRAF mutation status on survival outcomes after metastasectomy. Methods: Data collected from two large prospective population databases in Australia (Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and South Australian cancer registry). Overall survival (OS) and recurrence free survival (RFS) for BRAF MT and WT mCRC were evaluated by Kaplan-Meier method and compared by log-rank test. Results: 513 patients who had undergone metastasectomy were identified, 6% were BRAF MT. Median age 63. Metastasectomy rate was lower in BRAF MT (13 v 27%). In BRAF WT, 4% underwent resection of metastases (mets) in >1 organ at diagnosis and 5% had 3 or 4 metastasectomies versus none in BRAF MT. Median OS in BRAF MT v WT: 25.7 v 48.5 months (HR 1.95; 1.18-3.22). In a multivariate model adjusting for variables which were significant on univariate analysis, OS differences were not statistically significant. Right primary tumor, intact primary, >1 metastatic sites at diagnosis, non R0 resection, peritoneal mets and synchronous mets were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 v 19 months, p=0.09). Rate of downsizing was higher with triplet chemo than doublet +/- bevacizumab or doublet/EGFR in BRAF WT (50 v 30%) as well as MT (33 v 11%). Conclusions: Median OS was > 2 years in BRAF MT V600E after metastasectomy in this study consistent with an OS benefit. OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Presence of BRAF MT should not impact patient selection for metastasectomy.[Table: see text]
Comprehensive transcriptome analysis reveals link between epigenetic dysregulation, endogenous retrovirus expression and immunogenicity in metastatic colorectal carcinoma.
Authors: Mendis Shehara Ramyalini , Topham James Thomas , Titmuss Emma , Williamson Laura , Pleasance Erin D. , Culibrk Luka , Karasinska Joanna , Liu Shiru Lucy , Lee Michael , Aird John , Moore Richard A , Mungall Andrew J. , Laskin Janessa J. , Jones Steven J. M. , Marra Marco A. , Schaeffer David F. , Renouf Daniel John , Loree Jonathan M. 
Published: May 2019

3535 Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated increases in ERV mRNA as a result of DNA hypomethylation, and ERV transcription has been associated with increased immunogenicity in metastatic renal cell carcinoma. We performed comprehensive bioinformatics analysis of ERV transcription in metastatic colorectal carcinoma (mCRC), to identify novel links between ERV transcription, epigenetic dysregulation and immunogenicity in metastatic colorectal carcinoma (mCRC). Methods: Tumour samples from 63 patients with mCRC were subjected to RNA sequencing as part of the Personalized OncoGenomics program (POG; NCT02155621) at BC Cancer. Patients were enrolled between 07/2012-07/2017. ERV transcription was quantified across 702,533 distinct loci. Tumors were classified ERV-hi if their total ERV expression (RPKM) was greater than the mean across all samples. High antiviral gene expression tumors (AVG-hi) were designated as having a mean expression of IFIH1, DDX58, TLR3, TANK, TBKBP1, TBK1, IRF3 and IRF7 that was greater than the mean across all samples. All pairwise comparisons of gene expression were subjected to multiple hypothesis correction. Results: Median age was 59 years, with 34 (54%) male and 1 tumor microsatellite unstable. ERV-hi tumors showed increased expression of DNA demethylators TET2 ( q=0.0045) and TET3 ( q<0.0001). Significant overlap existed between ERV-hi and AVG-hi tumors (18/27, p=0.016). Tumors both ERV-hi and AVG-hi trended towards increased PD-L1 expression (p=0.055) and showed a significant increase in survival compared to tumors with high antiviral expression in the absence of high ERV transcription (p=0.0043). Conclusions: Our results suggest DNA demethylation drives increased ERV transcription and ERV-associated immunogenicity in mCRC. Moreover, we provide novel insight into the impact of ERV transcription on the biology of mCRC, highlighting ERV transcription as a potential biomarker and target for precision immunotherapy. Clinical trial information: NCT02155621.
A phase II study of lenvatinib in patients with metastatic colorectal cancer refractory to standard chemotherapy: LEMON study (NCCH1503).
Authors: Shoji Hirokazu , Iwasa Satoru , Kuchiba Aya , Ogawa Gakuto , Kawasaki Mamiko , Nakamura Kenichi , Mori Mikio , Honma Yoshitaka , Takashima Atsuo , Kato Ken , Boku Narikazu , Okita Natsuko , Yamada Yasuhide 
Published: May 2019

3538 Background: Although regorafenib significantly improved overall survival compared with placebo for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies in the global phase III CORRECT trial, regorafenib is often discontinued due to toxicity. Lenvatinib is an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptors α, RET, and KIT, showing receptor inhibition profile and kinetics different from regorafenib. This phase II study was conducted to evaluate the efficacy and safety of lenvatinib in patients with mCRC refractory to standard chemotherapies. Methods: mCRC patients with measurable lesions, PS 0-1, and refractory to standard chemotherapies including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab (if RAS wild-type), and TAS-102 (trifluridine/tipiracil) were eligible. Prior treatment with regorafenib was not allowed. Patients received lenvatinib orally at a dose of 24 mg once daily in 28-day cycles until unacceptable toxicity or disease progression. The primary endpoint was disease control rate (DCR) assessed by independent central review. Secondary endpoints included safety, response rate, progression-free survival (PFS), and overall survival. The planned sample size was 30 patients to expect a DCR of 60% with a threshold DCR of 35%, one-sided alpha of 5% and power of 80%. Results: Between October 2016 to January 2018, 30 patients were enrolled. All had received prior chemotherapy; 14 (47%) and 16 (53%) had received 3 or ≥ 4 prior lines for advanced disease, respectively. The median number of lenvatinib cycles was 4 (range 1-13). Two patients achieved partial response and 19 patients had stable disease, resulting in a response rate of 6.7% and DCR of 70.0% (95% CI: 50.6-85.3%). Median PFS was 3.6 months (95% CI: 2.6-3.7). The most common grade ≥ 3 adverse events were hypertension (53%), elevated serum aspartate aminotransferase (13%), thrombocytopenia (10%), and anorexia (7%) without unexpected safety signals. Conclusions: Lenvatinib showed promising antitumor activity with acceptable toxicity for patients with mCRC refractory to standard chemotherapies. Clinical trial information: UMIN000023446.
Effect of patient age on efficacy of FOLFIRI plus cetuximab vs bevacizumab in 1st-line treatment of metastatic colorectal cancer: An analysis of FIRE-3 (AIO KRK 0306).
Authors: Heinemann Volker , Modest Dominik Paul , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Kaiser Florian , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Stauch Martina , Scheithauer Werner , Held Swantje , Jung Andreas , Kirchner Thomas , Stintzing Sebastian 
Published: May 2019

3541 Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. The subgroup of extended RASwt patients consisted of 400 patients. The median age of patients treated in FIRE-3 was 64 years. Analyses of efficacy of doublet-chemotherapy in patients >70 years have shown inconsistent results. Methods: In this exploratory analysis, patients were grouped into cohorts with 65 years and 70 years as a cut-off for age-related analysis of the FIRE-3 study population. ORR was compared using Fisher´s exact test, Survival analyses were done using Kaplan-Meier estimation and median survival times were compared using log-rank testing. Results: Within the RAS wt population, patients older than 70 years had a significantly shorter OS when compared to patients ≤70 years of age in both arms (p= 0.02 for cetuximab arm, p= 0.02 for bevacizumab arm). Patients ≤65 years and ≤70 years had a significantly longer OS when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab (p= 0.01 and 0.02 respectively). The OS benefit of cetuximab treated patients compared to bevacizumab treated patients was consistent for patients ≤65 years (p=0.005) and patients ≤70 years (p= 0.009) of age. In patients older than 70 years, however, comparable efficacy of bevacizumab and cetuximab was observed. This effect of age on outcome appears to be affected by sidedness. RAS wt population (n=400). Conclusions: In the overall RAS wt population, younger patients have a significant OS benefit when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab, while this was not the case in patients older than 70 years.[Table: see text]
Blood-based genomic profiling of cell-free DNA (cfDNA) to identify microsatellite instability (MSI-H), tumor mutational burden (TMB) and Wnt/B-Catenin pathway alterations in patients with gastrointestinal (GI) tract cancers.
Authors: Isaacs James , Nixon Andrew B. , Bolch Emily , Quinn Katie , Banks Kimberly , Hanks Brent Allen , Strickler John H. 
Published: May 2019

3552 Background: MSI-H cancers are responsive to immune checkpoint blockade (ICB), but nearly half of all patients experience primary or early treatment resistance. Activation of the WNT/B-Catenin pathway can lead to immune exclusion and may drive resistance to ICB. Methods: 12 patients had stage III (N = 1) or IV (N = 11) MSI-H GI tract (small bowl, colon, or rectal) cancers. Blood samples were obtained after (N = 5) or during (N = 5) ICB. 2 patients did not receive ICB. Blood samples from 8 patients with microsatellite stable (MSS) metastatic colorectal cancer were included as controls. The Guardant Health (Redwood City, CA) Omni 2.0 mb panel was used to analyze cfDNA. We analyzed MSI-H status, TMB, and mutations within the WNT/B-Catenin pathway, including APC, RNF43 and CTNNB1. Results: Of 12 patients with MSI-H GI cancers, 1 sample failed enrichment due to hemolysis. MSI-H was not detected in 2 patients with a history of MSI-H in tissue; however these patients had a complete response to ICB at the time of blood collection. The Omni panel identified MSI-H in the remaining 9 patients with MSI-H disease in tissue. Among 8 control patients with MSS disease in tissue, MSI-H was not detected. Median TMB (mutations/Mb) was greater for MSI-H specimens (109; range 30-807) than for MSS specimens (13; range 6-24). All 8 patients with MSS GI cancers were identified to have APC mutations, and none were found to have CTNNB1 or RNF43 mutations. Of 9 evaluable MSI-H GI cancers, 2 had APC mutations alone. The remaining 7 carried RNF43 mutations (G659fs). All patients with RNF43 mutations were found to have disease progression while on ICB. Among these 7 patients with RNF43 mutations, 6 had additional mutations in APC or CTNNB1. Conclusions: Blood based genomic profiling can identify MSI-H cancers. Patients with MSI-H cancers resistant to ICB in this cohort have mutations in RNF43 as well as additional mutations in APC or CTNNB1, suggesting that co-activation of the WNT/B-Catenin pathway may be biologically important. Further study of the role of WNT/B-Catenin pathway activation in ICB resistance will be pursued using tumor tissue from this cohort.