bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of matched therapy in metastatic colorectal cancer on progression free survival in the phase I setting.
Authors: Lam Michael , Pereira Allan Andresson Lima , Loree Jonathan M. , Advani Shailesh M , Overman Michael J. , Bailey Ann , Johnson Amber , Holla Vijaykumar , Sanchez Nora Sylvia , Khotskaya Yekaterina , Meric-Bernstam Funda , Kopetz Scott , Pant Shubham 
Published: January 2019

619 Background: The benefits of matching targeted treatments to aberrations identified by molecular profiling (MP) is unclear. Outcomes in phase 1 settings have been traditionally reported across tumor histologies. We report outcomes based on a metastatic colorectal cancer (mCRC) population. Methods: Patients (pts) with mCRC receiving at least one dose of treatment on a phase 1 study were annotated for variants detected by MP. A precision oncology decision support (PODS) team determined variant function and actionability. A matched therapy (MT) was defined as allocation to a novel agent that targeted the aberration or predicted pathway deemed actionable by PODS. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HR). Results: A total of 370 patients enrolled onto 467 phase 1 trials were identified from January 2012 to April 2017. 106 enrolments were assigned to MT. Pts with microsatellite instability-high (MSI-H), BRAFV600E, PIK3CA mutation were more likely to be assigned a MT, while left-sided tumors and RAS mutant patients were less likely to be treated with a MT. Molecularly-targeted regimens (MTR) were utilized more frequently in MT while immune-targeting MTR was more common in non-MT. BRAFV600E mutations and HER2 amplification/overexpression made up 44.3% of MT. There was a significant difference in PFS between the MT vs non-MT group (HR 0.65, 95% CI 0.51-0.83, p = 0.016) in univariate analysis. The 6-month PFS probability was 31% (95% CI; 23-41%) versus 13% (95% CI; 10-17%) respectively. Other significant factors in univariate analysis associated with longer PFS were MSI-H, BRAFV600E and use of a regimen containing cytotoxic chemotherapy while RAS mutations were associated with shorter PFS. In multivariate analysis, after correcting for mutation status, allocation to a MT was associated with improved PFS (HR = 0.72, 95% CI 0.50-0.99, p = 0.043). Conclusions: Matching clinical trial enrollment to MP based on dedicated decision support is associated with improved outcomes in mCRC patients. The MT strategy is still hampered by a limited number of actionable variants, and is driven by a small number of active MTs.
The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.
Authors: Shepshelovich Daniel , Townsend Amanda Rose , Espin-Garcia Osvaldo , Latifovic Lidija , O'Callaghan Christopher J. , Jonker Derek J. , Tu Dongsheng , Chen Eric , Morgen Eric , Price Timothy Jay , Shapiro Jeremy David , Siu Lillian L. , Owzar Kouros , Ratain Mark J. , Kubo Michiaki , Dobrovic Alexander , Xu Wei , Mushiroda Taisei , Liu Geoffrey 
Published: January 2019

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.
The rate of novel actionable mutations in standard of care NGS panel testing in gastrointestinal malignancies.
Authors: Mehrvarz Sarshekeh Amir , Loree Jonathan , Pereira Allan Andresson Lima , Raghav Kanwal Pratap Singh , Lam Michael , Advani Shailesh M , Davis Jennifer S , Dasari A. , Morris Van Karlyle , Menter David , Eng Cathy , Shaw Kenna Rael , Broaddus Russell , Routbort Mark , Luthra Rajyalakshmi , Maru Dipen M. , Overman Michael J. , Meric-Bernstam Funda , Kopetz Scott 
Published: January 2019

640 Background: In advanced gastrointestinal (GI) malignancies, genetic profiling is often performed with the goal of facilitating enrollment of patients into clinical trials. While multigene genetic profiling has become the standard of care in many practices, the data on success rate of identifying actionable genomic alterations remain limited. In this study, we aimed to characterize the rate of actionable mutations using larger ( > 150 genes) and smaller ( < 150 genes) panels across different GI malignancies. Methods: We reviewed all reports of formalin-fixed paraffin-embedded clinical specimens sent for next-generation sequencing (NGS-using assays of at least 45 genes) for patients with advanced GI malignancies between 2012-2017 at MD Anderson Cancer Center. Actionable mutations were defined as those matching or informing the use of targeted therapies available in clinical trials, or FDA-approved. These were determined by a precision oncology support team (pct.mdanderson.org), using available literature and functional genomic screens. Novel actionable mutations were defined as those not used in current testing guidelines for GI malignancies. Results: Out of 11968 detected mutations, 3832(32.0%) were deemed to be actionable mutations and the remainder were either in non-actionable genes, deemed benign, or variants of unknown significance. Therefore, 1987 (65.1%) of assays had actionable mutations. When limited to novel actionable mutations, the rate fell to 21.5% (659/3052). Compared to CRC, other GI malignancies were 1.65 times more likely to have a novel actionable mutation (95% CI 1.35-2.00, p< .001). The use of larger and smaller panels did not differ in detecting novel actionable mutations, but larger panels resulted in a 3.5-fold higher number of mutations not deemed clinically actionable. Conclusions: Despite incorporation of NGS in oncology practice for GI malignancies, the success rate of detecting novel actionable mutations beyond those in the current guidelines remains low. Using assays with larger gene numbers does not seem to improve this detection rate. Future studies are required to evaluate the success rate of clinical interventions when actionable alterations are present.
Association of malignant potential of BRAF mutant colorectal cancer with coexpression of PD-L1.
Authors: Shinozaki Eiji , Konishi Tsuyoshi , Sakata Seiji , Osumi Hiroki , Ueno Masashi , Yamaguchi Kensei , Takeuchi Kengo 
Published: January 2019

643 Background: PD-L1 is a member of the B7/CD28 family that regulates immune response, and also well known as targets for immune checkpoint inhibitor. On the other hand BRAF mutation (MT) is recognized as a strongly poor prognostic factor in colorectal cancer (CRC). Recently in addition to the RAS gene, a lot of new knowledge about some molecules playing an important role in the process of carcinogenesis or drug resistance, and emerging molecules as targets for new treatments have been reported. In this research, we aim to address the clinical significance of PD-L1 expression in colorectal carcinoma correlation between emerging molecules and differences through clinical stages in CRC using tissue array. Methods: Consecutive patients who underwent surgery in our hospital from June 2003 to March 2011 were enrolled in this study. Tissue array based profiling of emerging molecules was performed on archival samples using immunohistochemistry for BRAF, MLH1/MSH2/MSH6/PMS2, CDX2, HER2 and PD-L1. We analyzed PD-L1 expression and correlation with molecular profile, survival, clinicopathological findings and location of primary site. Results: A total of 1030 CRC from stage 0 to IV were analyzed. The expression rates of PD-L1 were 3.6% and increased significantly in BRAF MT, dMMR, lack of CDX-2, tumor grade3 (TG3), right sided colon of primary site (25%, 37.8%, 21.6%, 22.1%, 6.9%, respectively; P < 0.001). In the univariate analysis, lack of CDX2, BRAF MT and TG3 were identified as prognostic factors in whole population of this cohort. Furthermore the survival of BRAF MT and lack of CDX2 with co-expression of PD-L1 were extremely poor (median OS in stage IV; 2.6 months in both). In Particular the co-expression rates of PD-L1 in BRAF MT were increasing as the clinical stage progress regardless of dMMR. Conclusions: Our study comprehensively summarized the significance of PD-L1 expression associated with the recent emerging molecules and suggested that malignant potential of BRAF mutant CRC may be explained in part due to escape from immunity by co-expression of PD-L1. Immune checkpoint inhibitor could be a candidate of target of BRAF mutant CRC with PD-L1expression irrespective of MSI status.
Age-related differences in gene expression in colorectal cancer (CRC).
Authors: Byrne Raphael M , Ruhl Rebecca , Lanciault Christian , Anand Sudarshan , Nellore Abhinav , Tsikitis Vassiliki Liana 
Published: January 2019

654 Background: Colorectal cancer (CRC) in young patients is increasing in incidence and is associated with worse outcomes than CRC in older patients. While distinct molecular subtypes of CRC have been recently characterized, it is unclear whether there are molecular differences between the tumors of young and old patients. We sought to identify differences in gene expression of CRC between these two groups. Our discovery analysis identified a gene signature of several differentially expressed RNAs, from which we validated PEG10. The PEG10 gene on chromosome 7q21.3 has been implicated in liver, gallbladder, thyroid, and blood cancers, and is thought to play a role in cancer cell survival and regulation of apoptosis. In hepatocellular carcinoma, increased PEG10 expression has been associated with younger patient age. Methods: RNA sequencing data was obtained from The Cancer Genome Atlas (TCGA) and analyzed for differences in gene expression between patients ≤ 45 years old and those ≥ 65 years old. The identified differentially expressed genes were then validated with qPCR using human CRC tissue from patients ≤ 45 years old and those ≥ 65 years old. Results: RNA sequencing data from patients ≤ 45 years old (n = 29) and patients ≥ 65 years old (n = 299) identified seven genes with increased expression in younger patients: ZNF334 (log2 [fold change] = 2.30), DSC3 (1.78), PEG10 (1.67), CACNA1I (1.54), PKIA (1.33), MAP9 (1.27), and EPHX3 (1.17) (p < 0.07). Validation with qPCR for PEG10 was most promising, and was performed on both young (n = 10, mean age = 39) and old patient samples ( n= 8, mean age = 72). Two cancers (20%) in the young group received radiation treatment and five (50%) received chemotherapy. One cancer (12.5%) in the old group received radiation and two (25%) received chemotherapy. PEG10 had increased expression in the young group with log2 [fold change] = 3.16 (p < 0.02). Conclusions: We have identified a potentially unique gene expression signature for CRC in young patients, which includes PEG10. Functional analysis of PEG10 and other genes is underway using in vitro cell culture, archived human tumor tissue, and mouse tumor models.
Eukaryotic initiation factor 4A2 (EIF4A2) expression in colorectal cancer and prediction of prognosis.
Authors: Chen Zhan-Hong , Wu Qinian , Lu Jiahuan , Chen Le-zong , Wu Xiang-yuan , Wang Yun , Ju Huaiqiang , Lu Yun-xin , Chen Ya , Wang Feng , Xu Rui-hua 
Published: January 2019

664 Background: Eukaryotic initiation factor 4A2(EIF4A2) is a member of the eukaryotic initiation factor 4A family and it is one of the protein-synthesis initiation factors, which are involved in the binding of messenger RNA to the ribosome. The prognostic roles of EIF4A2 in breast cancer, melanoma and lung cancer have been studied. However, the clinical significance and biologic role of EIF4A2 in colorectal cancer remain unknown. Methods: We used quantitative real-time polymerase chain reaction to compare expression of eIF4A2 mRNA between 72 paired colorectal cancer tissues and non-tumor colorectal tissues. We used immunohistochemistry to study the expression of EIF4A2 in 310 colorectal cancer patients under surgical resection, 247 of them received curative surgery. We also analyzed correlation between EIF4A2 expression and clinicopathological characteristics. The biological function of EIF4A2 on colorectal cancer cells were determined in vitro by knock-downing EIF4A2 in HCT116 and DLD1 cell lines. We performed MTT tests, colony formation assays, transwell and wound healing assays. Results: EIF4A2 mRNA was significantly higher in colorectal cancer tissues compared to the paired non-tumor colorectal tissues(P = 0.0034). Over-expression of EIF4A2 was prognostic of shorter overall survival(P = 0.002) and shorter disease-free survival(P = 0.042). Over-expression of EIF4A2 was significantly correlated with more TNM stage IV(P = 0.012). Multivariate analysis suggested EIF4A2 as an independent predictor of overall survival (hazard ratio 2.041[95% CI 1.385 to 3.008], P < 0.001) and disease-free survival (hazard ratio 1.537[95% CI 1.003 to 2.355], P = 0.049). Functionally, knockdown of EIF4A2 in HCT116 and DLD1 cell lines exerted tumor-suppressive effects by significantly inhibiting cell proliferation, colony formation,migration and invasion(P < 0.05). Conclusions: EIF4A2 is highly expressed in colorectal cancer and predicts poor prognosis. EIF4A2 could be served as a potential prognostic marker for colorectal cancer patients.
Dynamics and characteristics of KRAS mutated circulating tumor DNA in patients with metastatic colorectal cancer during various treatments.
Authors: Takayama Yuji , Suzuki Koichi , Ichida Kosuke , Fukui Taro , Kakizawa Nao , Watanabe Fumiaki , Kikugawa Rina , Hasegawa Fumi , Tsujinaka Shingo , Miyakura Yasuyuki , Konishi Fumio , Rikiyama Toshiki 
Published: January 2019

665 Background: KRAS mutated circulating tumor DNA (MctDNA) can be detected in blood of patients with metastatic colorectal cancer (mCRC) but its dynamics and characteristics during anti-EGFR and other treatments are not well known. Methods: Four hundred and fifty-one plasma samples were collected prospectively from 85 patients who underwent chemotherapy due to mCRC in 2014 - 2017. KRAS mutation in codon12/13/61 was explored in tumor tissues and plasma. Results: KRAS assessment in tumor tissues showed 29 patients with KRAS mutation (MT), 56 patients without mutation (WT). Sensitivity and specificity of MctDNA was 86.4% and 100%, respectively. In 29 patients with MT, significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (3.0 months vs.15.0 months; p = 0.005). In 56 patients with WT, 27 patients showed MctDNA during various treatments. Different characteristics in appearance were recognized during several treatments including anti-VEGF, TAS-102 and regorafenib. KRAS mutation in codon12/13 was appeared before and after disease progression. KRAS mutation in codon 61 was, however, frequently detected before disease progression. A spike like appearance of KRAS mutation in codon12/13 was likely seen in response to induction of the sequential treatment. Significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (6.0 months vs. 13.0 months; p = 0.0017), as was observed in patients with MT. Conclusions: Dynamics and characteristics of KRAS status in blood may be involved in the treatment response and outcome in mCRC patients.
Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.
Authors: Murcia Oscar , Juárez Miriam , Hernández-Illán Eva , Rodriguez-Soler Maria , Giner-Calabuig Mar , Alustiza Miren , Egoavil Cecilia , Castillejo Adela , Alenda Cristina , Mangas Carolina , Barberá Victor , Yuste Ana , Bujanda Luís , Clofent Joan , Andreu Montserrat , Castells Antoni , Llor Xavier , Zapater Pedro , Jover Rodrigo 
Published: January 2019

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.
Plasma ICAM-1 (pICAM-1) and plasma IL-8 (pIL-8) level as biomarker of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).
Authors: Yamamoto Yoshiyuki , Okamoto Wataru , Makiyama Akitaka , Shitara Kohei , Denda Tadamichi , Ogura Takashi , Nakano Yasuyuki , Nishina Tomohiro , Komoda Masato , Hara Hiroki , Ozaki Yukinori , Kawakami HIsato , Boku Narikazu , Hyodo Ichinosuke , Yamazaki Kentaro , Hironaka Shuichi , Sakai Kazuko , Yamanaka Takeharu , Muro Kei , Nishio Kazuto 
Published: January 2019

670 Background: Bevacizumab (BV)-containing chemotherapy has been established as the standard first-line treatment for metastatic colorectal cancer (mCRC). However, no biomarkers have been established to predict the clinical benefit of BV for patients (pts) with mCRC. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). Median values of pICAM-1 and pIL-8 were used as cut-off points to categorize pts into the low and high groups. Progression free survival (PFS) and overall survival (OS) were compared between two groups, using Cox proportional hazards model. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0]. Response rate was 64.6 % [53.3-74.9]. pICAM-1 and pIL-8 were measured in 99 pts and the median values were 190.0 ng/ml [range, 58.0- 1080.1] and 311.5 pg/ml [range, 83.2-4541.4], respectively. The hazard ratios of PFS and OS between the high and low pICAM-1 groups were 2.08 [95%CI, 1.28-3.40, p = 0.003] and 2.04 [0.92-4.50, p = 0.079], respectively. The hazard ratios of PFS and OS between the high and low pIL-8 groups were 1.63 [95%CI, 1.00-2.65, p = 0.048] and 3.42[1.57-7.44, p = 0.002], respectively. Conclusions: High pICAM-1 and pIL-8 were associated with short PFS and OS of mCRC pts treated with BV-containing chemotherapy, suggesting that pICAM-1 and pIL-8 could be predictive markers for prognosis of mCRC treated with BV. Clinical trial information: UMIN000012442.
Somatic mutation landscape of appendiceal cancer.
Authors: Shen John P. , Jacobs Miriam T. , Fuh Ingrid L , Baumgartner Joel Micah , Fanta Paul T. , Lowy Andrew M. , Harismendy Olivier 
Published: January 2019

671 Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, which has prevented the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease. Standard treatment generally follows consensus guidelines for colorectal cancer; however, there are currently no standards to guide chemotherapy selection in the adjuvant or metastatic setting. Methods: Somatic mutation profiles covering ~300 frequently mutated genes were obtained for 385 primary appendiceal tumors (Foundation Medicine). A retrospective review was performed to gather clinico-pathologic data. The primary objective was to assess the somatic mutation profile of each subtype of appendiceal cancer and to compare these to colorectal cancer. Colorectal data was obtained from TCGA cohort via cBioPortal. Results: Appendiceal adenocarcinoma (non-mucinous) and mucinous adenocarcinoma had shared somatic mutations albeit with differing frequencies. The most common mutations were KRAS (60.1% and 80.5%, respectively), GNAS (32.4%, 58.5%), TP53 (42.8%, 19.5%), and SMAD4 (14.8%, 14.6%). Tumors with goblet cell (adenocarcinoid) histology had lower prevalence of KRAS (16.0%) and GNAS mutations (8.0%), but similar prevalence of TP53 mutation (24.0%) and a greater prevalence of ARID1A mutation (20.0%). The mutation profiles of all appendiceal histologies differed from colorectal adenocarcinoma with markedly lower prevalence of ATM (7.9% vs. 71.0%). Chemotherapy data was available for 30 metastatic patients; these patients received an average of 1.76 lines of therapy (range 1-4). All 30 were treated with either 5-FU or capecitabine, 11 (36.7%) with oxaliplatin, 23 (76.7%) with irinotecan and 19 (63.3%) with bevacizumab. Analysis of survival data and correlation with molecular and histologic features is ongoing. Conclusions: Despite clear molecular differences between appendiceal and colorectal tumors, appendiceal tumors are primarily treated with colorectal chemotherapy regimens. There remains a pressing need for both pre-clinical and clinical investigation to develop treatment regimens specific to appendix cancer.