bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in the immune microenvironment between early and late-onset colon and rectal cancer.
Authors: Gardner Ivy Hernandez , Siddharthan Ragavan , Watson Kate , Ruhl Rebecca , Anand Sudarshan , Tsikitis Vassiliki Liana 
Published: February 2020

214 Background: Over the past 35 years, there has been a significant increase in the number of patients below the recommended initial screening age (50 years old) diagnosed with colorectal cancer (CRC). Early onset colorectal cancer is more likely to occur in non-white patients, be located in the rectum, be diagnosed at a more advanced stage, and have concerning pathological features. The immune microenvironment in CRC is a key player in disease progression, therapy response, and overall survival. However, the role of the immune microenvironment in early onset CRC, particularly in rectal cancer has not been investigated. This study aims to characterize the immune microenvironment of early onset ( 50 years old) and late onset ( 65 years old) colon and rectal cancer patients. Methods: We used Nanostring immune profiling to analyze FFPE surgical specimens and identified genes that were differentially expressed between early and late onset colon and rectal cancer groups. We validate our results with qPCR. The differentially expressed genes in the rectal cancer cohort were compared to our analysis of a publically available database (GSE8721) of gene expression profiles for 203 rectal cancer and 160 matched normal mucosa samples. Immunohistochemistry (IHC) was performed on FFPE colorectal specimens for CXCL3. Results: Using Nanostring, we identified two genes that were differentially expressed between early and late onset colon cancer (IFITM1, CXCL3) and two genes in the rectal cancer cohort (FLT3, SAA1). CXCL3 has increased expression in late onset colon cancer utilizing qPCR and IHC. High expression of CXCL3 in both IHC and qPCR is associated with improved disease free survival. Analysis of the GSE8721 database also showed that FLT3 and SAA1 were differentially expressed in early versus late onset rectal cancer. Using qPCR, FLT3 is increased in early onset rectal cancer specimens compare to late onset rectal cancer, early and late onset colon cancer, and normal colon. Conclusions: There are distinct differences in the immune microenvironment between early and late onset colon and rectal cancer that may hold the potential for targeted therapeutics.
ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.
Authors: Mehrvarz Sarshekeh Amir , Roszik Jason , Manyam Ganiraju C. , Advani Shailesh M. , Willis Jason , Shen John Paul Y.C. , Morris Jeffrey , Davis Jennifer S. , Ajani Jaffer A. , Maru Dipen M. , Overman Michael J. , Kopetz Scott 
Published: February 2020

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.
Feasibility and clinical impact of routine molecular testing of gastrointestinal (GI) cancers at a tertiary center with a multigene, next generation sequencing (NGS) panel.
Authors: Bregni Giacomo , Sticca Tiberio , Akin Telli Tugba , Camera Silvia , Craciun Ligia Ioana , Shaza Leila , Deleruelle Amélie , Anciaux Maëlle , Machiels Godelieve , Deleporte Amélie , Vandeputte Caroline , Demetter Pieter , Larsimont Denis , Hendlisz Alain , Sclafani Francesco 
Published: February 2020

216 Background: High-throughput technologies have been increasingly used in research. Nevertheless, limited data are available on the feasibility and clinical value of these technologies in routine practice. Methods: All consecutive GI cancer patients (pts) who were tested with the 48-gene Truseq Amplicon Cancer Panel (Illumina) as part of routine practice at our Institution were identified from a prospectively maintained pathology database. Feasibility, results and impact on management decisions were analysed. Associations were tested with Fisher’s test. Results: From Apr 2014 to Jun 2019, 314 pts were tested. Sequencing was successful in 290 cases (92.4%; 234 colorectal (CRC), 21 gastro-esophageal, 17 bilio-pancreatic, 9 GIST, 4 appendix, 3 small intestine, 2 hepatocellular). In successful and failed cases, respectively, analyses were attempted on core biopsy (37.0% vs 66.7%), surgery (62.6% vs 16.7%), and fine needle aspiration (0.4% vs 12.4%) tumour samples (p < 0.001). Median turnaround time (TAT) was 12.5 days, reducing from 13 days in 2014 to 10 days in 2019. The majority of successfully tested pts (85.6%) had stage IV disease. TP53 was the most frequent mutation (45.9%), followed by APC (42.1%), KRAS (39.7%), PIK3CA (12.1%), SMAD4 (7.6%), BRAF (6.2%), and NRAS (5.5%). All other mutations were found in < 5% of cases. Excluding RAS/BRAF and KIT/PDGFR mutations, sequencing results impacted on the management of 4 (1.4%) pts. In 199 stage IV CRC pts, KRAS mutations were associated with lung (p = 0.020) and bone metastases (mts) (p = 0.008), NRAS mutations with liver mts (p = 0.021), BRAF mutations with peritoneal mts (p = 0.001), and APC mutations with lymph node mts (p = 0.006). Assuming a median of 25 samples per run, the estimated cost of NGS analysis per pt was €186. Conclusions: Low failure rate, short TAT and fair costs support feasibility of multi-gene NGS in routine practice. The clinical impact of this technology, however, is still limited but it could raise with the identification of new biologically relevant genetic alterations and the increased availability of novel therapeutics.
Concordance between blood- and tumor-based detection of RAS mutations to guide therapy in metastatic colorectal cancer.
Authors: Brozos Elena , Lago Ramón , Covela Rúa Marta , Montes Ana Fernández , De la camara Juan , Candamio Folgar Sonia , Muinelo Laura , Vidal Yolanda , Vazquez Maria Francisca , López Rosa , Blanco Cristina , Ferreirós Isabel , Lopez Rafael 
Published: February 2020

217 Background: The study of RAS using circulating tumor DNA (ctDNA) provides a good alternative for the detection and monitoring of RAS mutations during therapy course. Liquid biopsy has the advantage of being less invasive than conventional tissue biopsy. Therefore, it is necessary to determine the degree of concordance of RAS status between plasma and tissue samples from mCRC patients. Methods: We conducted a study to evaluate RAS concordance in several hospitals in Galicia, Northwest of Spain. We analyzed samples from 380 patients with mCRC in Galicia. RAS genotyping in plasma was performed using OncoBEAM RAS CRC kit, Sysmex and compared with the PyroMark Q24 System, Qiagen for FFPE-tissue analysis. Clinical data were collected from electronical reports from each patient. We analyzed the clinical features that can be related with discordant cases. Results: The overall percent of agreement was 83%, with a positive concordance of 79% (143/180 patients) and a negative concordance of 87% (116/132 patients). Taking into account the clinical features of the patients, those with only liver metastasis showed a higher level of concordance (88,8%) and the highest level was in the group of patients that presented liver metastasis and another location (91,3%). On the other hand, patients with only peritoneal disease showed the lowest level of agreement (68,2%), and the absence of liver metastasis was a significant factor of discordance of RAS (71% vs 28%, p<0.0001). Conclusions: The high overall concordance between plasma and tissue RAS mutation support the liquid biopsy technology as an alternative to tissue testing for RAS characterization in mCRC patients, especially in patients with liver metastasis and less in those with peritoneal disease. These results reinforce the use of liquid biopsy as a non-invasive tool for guiding targeted therapy in our patients. [Table: see text]
Distinct genomic landscape in colorectal mucinous carcinoma via comprehensive genomic profiling.
Authors: Huang Liang , Luo Shuangling , Xue FangQin , Xiao Yi , Wang Ziqiang , Lai Sicong , Liu Zhanzhen , Hu Huanxin , Zeng Ziwei , Lin Tengjiao , Zhang Shiyue , Wang Jian , Wang Kai , Chen Gong , Kang Liang 
Published: February 2020

222 Background: Mucinous carcinoma (MC), accounting for 10-15% of colorectal cancer (CRC), has long been associated with an inferior response to treatment. MC as an unfavorable prognostic factor in early stage CRC remains questionable. In this study, we used a large CRC cohort to define the genomic landscape of MC and identify prognostic and clinically actionable information. Methods: The 1226 CRC patient cohort included 997 adenocarcinomas (AC), 129 MC, and 110 adenocarcinomas with mucous composition (AMC). All of the pathological sections were verified by an experienced pathologist. FFPE tumor samples and matched peripheral blood were sequenced using a 450-cancer-related gene panel. Results: MC was significantly associated with right colon (p<0.001) and regional lymph node metastasis (p=0.004) compared to AC. We found a higher mutation rate of BRAF V600E (10.9% vs. 3.3%), PIK3CA (28.7% vs. 19.2%), SMAD4 (34.1% vs. 19.1%), BRCA1/2 (16.3% vs. 6.8%) and homology recombination pathway (40.3% vs. 22.7%), and a lower rate of TP53 (53.5% vs. 79.5%), APC (46.5% vs. 75.1%,), and HER2 amplification (0% vs. 2.1%,) in MC than in AC. MC had a significantly higher proportion of microsatellite instability-high (MSI-H) tumors (22.5% vs. 6.8%, p<0.001). Furthermore, in tumors with MSI stable, POLE mutation was more frequent in MC than in AC (7.0% vs. 2.6%, p=0.094) and resulted in dramatic elevated tumor mutational burden (TMB, range 79.5-591.5 muts/Mb), indicating up to 30% of MC patients may benefit from immunotherapy. MSI-H was associated with better prognosis (5-y DFS, MSI-H 86.7% vs. MSS 56.7%) in stage II/III CRC patients with MC. Importantly, AMC mimicked the genomic features of MC rather than AC. Conclusions: For the first time, comprehensive genomic analysis revealed that MC had distinct molecular features, indicating promising clinically application for both immunotherapy and targeted therapy. Early stage MC had a diverse prognosis due to MSI status and should be interpreted differently. The similarity of molecular profile between AMC and MC suggested the possible usage of MC, but not AC, clinical strategy for AMC.
Vascular endothelial growth factor (VEGF)-D and clinical outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line FOLFIRI plus bevacizumab (Bev): A biomarker study of the WJOG 6210G trial.
Authors: Izawa Naoki , Shitara Kohei , Masuishi Toshiki , Denda Tadamichi , Yamazaki Kentaro , Moriwaki Toshikazu , Okuda Hiroyuki , Kondoh Chihiro , Nishina Tomohiro , Makiyama Akitaka , Baba Hideo , Yamaguchi Hironori , Nakamura Masato , Sunakawa Yu , Akiyoshi Kohei , Sato Mikio , Yonesaka Kimio , Yoshino Takayuki , Yamanaka Takeharu , Muro Kei 
Published: February 2020

226 Background: The WJOG 6210G trial demonstrated a similar efficacy between FOLFIRI plus Bev and FOLFIRI plus panitumumab (Pani) at 2nd-line treatment in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). Recently, angiogenesis biomarker studies of clinical trials have identified VEGF-D as a potential predictor for angiogenesis inhibitors in mCRC. We evaluated whether VEGF-D level are associated with clinical outcomes in the WJOG 6210G trial. Methods: Plasma samples which were collected at pre-treatment were analyzed. VEGF-D level in plasma was measured by means of magnetic bead panel (G & G SCIENCE CO., LTD.). The correlations of VEGF-D level with progression-free survival (PFS) and overall survival (OS) were evaluated by cox regression analyses. Results: Ninety-nine pts were evaluable for VEGF-D level (Bev, n = 51; Pani, n = 48) among 121 pts enrolled in the WJOG6210G. The median VEGF-D level was 441 pg/ml (range 60-1570). VEGF-D level was not affected by the period from last administration of 1st-line Bev to start of 2nd-line treatment. When the median VEGF-D level was adopted as cut-off value, pts with high VEGF-D achieved a shorter PFS and OS than pts with low VEGF-D in the Bev arm [HR: 0.58 (95%CI 0.32-1.07), p = 0.08; HR: 0.62 (95%CI 0.34-1.11), p = 0.10]. In pts with high VEGF-D, the Bev arm tended to have a shorter OS and PFS compared to Pani arm [median: 12.4 m vs. 17.5 m, HR: 1.58 (95%CI 0.87-2.88); median: 4.7 m vs. 5.5 m, HR: 1.31 (95%CI 0.72-2.40)]; whereas, comparable OS and PFS in pts with low VEGF-D [median: 18.9 m vs. 16.5 m, HR: 1.08 (95%CI 0.59-2.01); median: 5.9 m vs. 7.2 m, HR: 1.10 (95%CI 0.62-1.99)]. OS was stratified by VEGF-D level quartile, then OS of Bev arm in each quartile was compared with that of Pani arm (Table). Clinical trial information: UMIN000031621. Conclusions: Our study suggests clinically meaningful association between VEGF-D level and clinical outcomes in mCRC pts treated with 2nd-line FOLFIRI plus Bev. [Table: see text]
Overall survival of cetuximab administered every two weeks versus weekly in real-world data of U.S. patients with metastatic colorectal cancer.
Authors: Pescott Chris , Batech Michael , Boutmy Emmanuelle , Ronga Philippe , Lamy Francois-Xavier 
Published: February 2020

23 Background: Cetuximab (CET) administered weekly (q1w) at 250 mg/m², after an initial dose of 400 mg/m², is approved in combination with chemotherapy (CT) for the treatment of (K) RAS wild-type metastatic colorectal cancer (mCRC). The use of CET 500 mg/m2 administered with CT every 2 weeks (q2w) is according to US clinical practice guidelines and observed routinely. In this study, we compared q2w vs q1w regimens on overall survival (OS) in a presumed first-line (1L) treatment subcohort and present updated data on the noninferiority of q2w vs q1w in line-agnostic (1L+) treatment using US real-world data. Methods: Using IBM MarketScan, a large US insurance claims database, we classified a cohort of mCRC patients treated between 07/2010 and 12/2016 with CET+CT as q1w or q2w based on observed infusion patterns. Absence of mCRC-related treatment claims preceding CET initiation date (defined as the index date) qualified as CET treated in 1L. A validated algorithm was used to determine patient death. Confounding was accounted for using high-dimensional propensity scoring (hdPS) with inverse probability of treatment weights. OS was compared using Cox proportional hazards regression. Imbalanced confounders after hdPS were added to the Cox model. In 1L+, noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25. However, noninferiority could not be tested in 1L due to the small sample size; a test for difference was used instead. Results: Of 2,730 CET-exposed mCRC patients (updated), 1,779 (65.2%) and 951 (34.8%) were classified in q1w and q2w groups, respectively, among which 557 (31.3%) and 316 (33.2%) received CET in 1L. The HR (95% CI) for OS of q2w vs q1w in 1L was 1.10 (0.92-1.31; crude), and 1.05 (0.86-1.29; adjusted; p for difference: 0.625). In 1L+, crude and adjusted HRs were 1.05 (0.94-1.18) and 0.94 (0.85-1.03), respectively, rejecting the inferiority hypothesis at p < 0.001. Conclusions: Only a third of patients received CET in 1L in this study. OS was statistically noninferior in q2w vs q1w in 1L+, and adjusted results in 1L suggest no differences between both treatment schedules. However, more data would be needed to formally test the noninferiority hypothesis in 1L.
Clinical utility of targeted next generation sequencing (NGS) to predict response to neoadjuvant therapy (NT) in rectal cancer (RC).
Authors: Carroll Kristen , Burns Michael C. , Jones Ryan , Kocherginsky Masha , Burdett Kirsten Bell , Yang Guang-Yu , Benson Al Bowen , Mahalingam Devalingam 
Published: February 2020

237 Background: NGS analysis has identified molecular alterations that have predictive and prognostic implications in advanced RC. However, its role in identifying predictive signatures of chemoradiotherapy response in RC remains largely unexplored. Neoadjuvant rectal cancer (NAR) score, a composite score available after resection, is a validated short-term surrogate endpoint for long-term outcomes. Herein, we identified gene alterations in early stage RC with NGS analysis and correlated mutations with tumor response using the NAR scoring system. Methods: Patients (pts) with stage I-III RC completing NT followed by resection (2011-2018) had their tumor prospectively sequenced by an ion torrent targeted 22 gene NGS panel ( AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53). NAR scores were calculated based on clinical and pathologic staging data input, yielding 3 cohorts: low (score < 8, pCR or near CR), intermediate (8-16), or high ( > 16, poor or no response) NAR scores. Associations were drawn using Two-sided Fisher’s exact. Both unadjusted (p) and Benjamini & Hochberg adjusted (BHp) p-values are shown. Results: 51 pts with RC were analyzed: median age 59 (24-81), male (59%), clinical stage I (6%), II (25%) and III (69%). Pathological mutations were found in 94% of pts, including TP53 (76%), KRAS (49%), PIK3CA (10%), NRAS (6%), FGFR3 (4%), MET (4%). Post NT 8 (16%) pts had low NAR scores, including 6 (12%) cases with pCR, 26 (51%) intermediate, and 17 (33%) high NAR scores. Gene alterations in FGFR3 (p =0.022, BHp = 0.15) and NRAS (p =0.026, BHp = 0.15) were associated with NAR score, while no differences were observed with mutations in TP53 or KRAS. Additionally, 17 (33%) pts had recurrences [13% of pts with low NAR scores, 31% intermediate, 47% high], with metastases primarily to lung (53%) and/or liver (35%). Conclusions: This study suggests that pts with RC who derived favorable responses to standard NT could have a targeted molecular profile, namely alterations in FGFR3 and NRAS. Conversely, pts that lack this profile may benefit from novel therapeutic approaches to improve NAR scores and long-term outcomes.
Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.
Authors: Fricke Stephanie Leigh , Kratz Jeremy D. , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Matkowskyj Kristina A. , Eickhoff Jens C. , Deming Dustin A. 
Published: February 2020

252 Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR > 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size > 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR > 0.67 with median effect size 1.0±3.8 (p < 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR > 0.67 with median effect size 0.9±1.4 (p < 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.