bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAS amplified colorectal cancers are enriched in RAS-WT, BRAF-WT, MSS tumors and may predict for anti-EGFR resistance.
Authors: Fakih Marwan , Sandhu Jaideep Singh , Wang Chongkai , Ali Siraj Mahamed , Schrock Alexa Betzig 
Published: January 2019

547 Background: Pre-clinical models implicate RAS amplifications ( RASa) as a mechanism of resistance to anti-Epidermal Growth Factor Receptor (EGFR) therapies. Yet, there is little guidance on the impact of RASa, as identified by next generation sequencing (NGS), on anti-EGFR response. Methods: We investigated the Foundation Medicine (FM) database for RASa in CRC and characterized this population based on patient (pt) characteristics and other concurrent genomic alterations. We subsequently investigated City of Hope (COH) mCRC molecular data set (using FoundationOne) and described the RASa population characteristics and response to anti-EGFR. Results: FM cohort included 21,315 CRC unique pt cases. 365 (1.5%) pts had RASa, of which 123 (0.6%) had ≥ 20 copy number (CN) ( RASa≥20). The incidence of MSI-H, RAS and BRAF short variant mutations in the overall, RASa, and RASa≥20 populations were (MSI-H: 5%, 0%, 0%), ( RAS: 54%, 32%, 2%), and ( BRAF: 6%, 1%, 0%), respectively. RASa≥20 tumors had higher level of genomic amplification than the overall population (29% vs. 5% had ≥ 5 genes amplified). COH cohort included 338 mCRC. 12 pts (3.6%) had RASa. The median RAS CN was 27 (7 - 72); 8/12 pts had RASa≥20. All but 2 COH pts with RASa had a RAS/BRAF-WT tumors. Both pts with concurrent RAS mutations had relatively low RAS CN (7&13). Tumors with RASa were predominantly left-sided (11/12). 7/12 pts were treated with anti-EGFR therapy. All 7 pts were RAS/BRAF wild-type: 6 left-sided; 3 pts 1st/2nd lines (1 pt oxaliplatin-based and 2 pts irinotecan-based) and 4 pts chemo-refractory (all irinotecan-based). All 4 chemo-refractory pts had RASa≥20 and progressed on anti-EGFR on 1st post-treatment CT (PFS in all pts ≤ 3 mo). One 1st line pt had SD (PFS = 4 mo). One 2nd line pt had SD (PFS = 7 mo) and one had PD as best response. Conclusions: NGS identifies RASa and RASa≥20in 1.5% and 0.6% of CRC, respectively. RASa≥20 tumors are MSS and, generally lack RAS/ BRAF mutations, and predict for resistance to anti-EGFR. This supports the potential relevance of 20-CN cut-point for the exclusion of pts from anti-EGFR. These findings would benefit from additional validation from retrospective analyses of completed prospective anti-EGFR clinical trials.
Gender and survival benefit from initial irinotecan in metastatic colorectal cancer: Analysis of the XELAVIRI (AIOKRK0110) study.
Authors: Modest Dominik Paul , Ricard Ingrid , Heinrich Kathrin , Fischer von Weikersthal Ludwig , Decker Thomas , Vehling-Kaiser Ursula , Graeven Ullrich , Stahler Arndt , Jung Andreas , Kirchner Thomas , Held Swantje , Stintzing Sebastian , Giessen-Jung Clemens , Heinemann Volker 
Published: January 2019

549 Background: XELAVIRI compared initial versus sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non inferiority of time to failure of strategy (TFS) of the sequential use could not be demonstrated (primary endpoint). Methods: The secondary endpoints overall response rate (ORR), progression-free survival (PFS) as well as overall survival (OS) were evaluated in female versus male pts as well as molecular subgroups (RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In female pts, ORR was 43% in both arms, PFS was 8.9 (95% CI 6.8-11.1) versus 10.1 (95% CI 8.5-11.8) months (HR: 1.09 (95% CI 0.76-1.55), P = 0.65) in pts with initial iri versus pts without initial iri, respectively. In females, a trend for inferior OS with initial iri was seen: 21.8 (95% CI 14.8-28.8) months with initial iri versus 28.4 (95% CI 21.9-34.9) months without initial iri (HR: 1.46 (95% CI 0.95-2.24), P = 0.08). This difference was significant in the multivariate analysis (HR: 1.73 (95% CI 1.04-2.86, P = 0.034). Male pts benefitted across all analysed endpoints from initial iri: ORR was 58.3% with initial iri and 33.6% without iri (P < 0.001), PFS was 10.1 (95% CI 9.2-11.0) versus 7.4 (95% CI 6.3-8.5) months (HR: 0.54 (95% CI 0.42-0.69) P < 0.001) and OS 23.9 (95% CI 19.1- 28.6) versus 20.5 (95% CI 18.1-22.9) months (HR: 0.63 (95% CI 0.47-0.85), P = 0.002), with initial iri versus without initial iri, respectively. Interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Additional data including treatment and toxicities will be presented at the meeting. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While male patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients. Clinical trial information: NCT01249638.
Role of enterocyte-specific gene polymorphisms in adjuvant treatment for stage III colorectal cancer.
Authors: Suenaga Mitsukuni , Cao Shu , Zhang Wu , Matsusaka Satoshi , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Schirripa Marta , Barzi Afsaneh , Ueno Masashi , Lenz Heinz-Josef 
Published: January 2019

550 Background: Enterocyte subtype of the Colorectal Cancer (CRC) Assigner classifier is known as favorable to oxaliplatin-based adjuvant treatment for stage III CRC. We previously reported potential predictive value of single nucleotide polymorphisms (SNPs) in enterocyte-related genes in metastatic CRC (Suenaga, ASCO2018). In this study, we examined clinical significance of MS4A12 and CDX2 SNPs in adjuvant treatment (AT) for Stage III CRC. Methods: 350 patients with Stage III CRC were included in this study: 274 received AT (discovery cohort: median age = 62, median follow-up = 59.9 months) and 76 received surgery alone (control: median age = 75, median follow-up = 58.0 months). 68 and 206 patients received FOLFOX and oral fluoriopyrimidine, respectively. SNPs were analyzed by PCR-based direct sequencing. Disease-free survival and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: In discovery cohort, the G/G variant in MS4A12 rs4939378 was associated with lower 5-y survival rate than any A allele in uni- and multi-variate analyses (70% vs 90%, univariate: HR 2.29, 95% CI: 1.03-5.06, P = 0.035; multivariable: HR 2.58, 95% CI: 1.15-5.76, P = 0.021). Patients with the G/G variant in CDX2 rs3812863 had better OS than those with any A, though not significant in multivariable analysis (5 y-survival rate: 95% vs 82%, univariate: HR 0.34, 95% CI: 0.12-0.97, P = 0.034; multivariable: HR 0.39, 95% CI: 0.13-1.11, P = 0.078). There was no significance in the control, and significant interaction was observed between MS4A12 genotypes and groups (interaction P = 0.007). In addition, there was no interaction between MS4A12 rs4939378 and FOLFOX vs oral fluoropyrimidine. Conclusions: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in patients with Stage III CRC. However, clinical significance of the SNPs for oxaliplatin seems to differ depending on tumor stage. Further research and validation study are warranted to explore the association of the SNPs with carcinogenesis or cancer progression.
Anal melanoma: A comparative comprehensive genomic profiling study.
Authors: Ross Jeffrey S. , Gay Laurie M. , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Ali Siraj Mahamed , Chung Jon , Reddy Prasanth , Miller Vincent A. , Madison Russell , Schrock Alexa Betzig , Corona Robert John 
Published: January 2019

551 Background: Anal melanomas (AM) share histologic features with cutaneous melanomas (CM), are highly aggressive and behave in a distinct clinicopathologic pattern. We performed comprehensive genomic profiling (CGP) of AM to learn of potential matched targeted and immunotherapies that may improve clinical outcomes for the disease. Methods: FFPE tissues from late stage AM (81 cases) and CM (1804 cases) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001) (Table). Given the UV light exposure in the CM, the GA/tumor was significantly higher than AM as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). All AM and CM were MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway targets including NF1 and PTEN were commonly altered in both tumor types. Potentially targetable PDGFRA and ERBB2 GA were found in AM but not in CM. Conclusions: UV light exposure drives high GA/tumor and TMB in CM, both associated with immune checkpoint inhibitor (ICPI) responsiveness, whereas AM lacks the high TMB and therefore is far less likely to benefit from ICPI treatments. CM is classically associated with opportunities for anti-BRAF therapies and AM with an array of kinase targets including KIT, BRAF, PDGFRA and ERBB2. Finally, MTOR pathway targets are common to both tumor types. [Table: see text]
Classification of BRAF mutated colorectal cancer based on microsatellite stability.
Authors: Nakano Michitaka , Sagara Kosuke , Koreishi Sakuya , Aikawa Tomomi , Nishijima Tomohiro F. , Takayoshi Kotoe , Komoda Masato , Baba Eishi , Esaki Taito 
Published: January 2019

553 Background: BRAF mutated metastastic colorectal cancer (CRC) shows poor outcome in spite of development of the treatment. Thus, classification of BRAF mutated CRC based on therapeutic target is warranted. Particularly, about half of the BRAF mutated CRC reveals high microsatellite instability (MSI-H) that is characterized by high mutation burden and frequent infiltration of lymphocytes. Hence, the patients with BRAF mutation carrying MSI-H would potentially benefit from immune-check point inhibitor. However, the precise evaluation of immune status of these patients has not been clarified. Furthermore, the character of BRAF mutation with microsatellite stability (MSS) is not fully investigated. Methods: Transcriptomic information of BRAF mutated CRC with MSS/MSI-H was downloaded from open database, Gene Expression Omnibus (GEO); GSE75316 (n = 59), GSE35896 (n = 62), GSE39582 (n = 585). Gene expression of BRAF mutation with MSI-H/MSS (GSE75316: n = 5/3, GSE35896: n = 1/5, GSE39582: n = 31/14) were normalized and differentially expressed genes were identified by using GeneSpring (Agilent technologies). Pathway analysis was performed by GSEA. Results: Pathway analysis revealed datasets regarding cytotoxic T cell (FDR q value: 0.09), helper T cell (FDR q value: 0.05), natural killer T cell (FDR q value: 0.11), and activated inflammatory response (FDR q value: 0.16) were significantly enriched in BRAF mutation with MSI-H. (FDR q value < 0.25 means significant). The differentially expressed genes were identified in both of 2 groups. Significantly high expression of Granzyme A, Granzyme B, and Perforin were observed in BRAF mutated MSI-H. At the same time, highly expressed genes including MLH1 were identified in BRAF mutated MSS. Conclusions: High infiltration of cytotoxic T cells was suggested by the pathway analysis and expression of Granzayme A, B, and Perforin among BRAF mutated MSI-H. The activated immune status within these patients suggested the potential response of immune-checkpoint inhibitors. Furthermore, our data would give us a clue in considering the therapeutic strategy against BRAF mutated MSS, that will be the remained population among BRAF mutated CRC to which effective treatment have not been established.
Prognostic value of genomic alterations (GA) on overall survival in appendiceal adenocarcinoma (AA).
Authors: Jacome Alexandre A , Raghav Kanwal Pratap Singh , Shaw Kenna Rael , Fournier Keith F. , Royal Richard Eldon , Taggart Melissa , Foo Wai Chin , Matamoros Aurelio Aurelio , Ahmed Shahab U. , Guerra Jennifer L. , Overman Michael J. , Eng Cathy 
Published: January 2019

554 Background: AA are extremely rare tumors, with potentially aggressive clinical behavior. The characterization of the molecular alterations of the disease is poorly described, as well as its association with clinical outcomes. The present study aims to evaluate the prognostic influence of GA on overall survival (OS) of AA patients (pts). Methods: We performed a retrospective study involving AA pts at MD Anderson Cancer Center between October 2012 and April 2017 who underwent next-generation sequencing (NGS) (at least 45 genes), using either tumor tissue specimens or peripheral blood for cell-free DNA (cfDNA). GA identified by NGS and clinicopathological variables were correlated with OS. Survival curves were performed by the Kaplan-Meier method and compared with log-rank test. Multivariate analysis of prognostic factors was performed by the Cox model. Results: A total of 78 pts were identified, of which 35 had died (45%) in a median follow-up time of 4.8 y. The majority of pts presented with stage IV disease (72%); 46% underwent cytoreductive surgery (CRS) + HIPEC. Tissue-based and cfDNA-based sequencing were performed on 73% and 23% of the pts, respectively, and 4% had both. The most frequent GA were KRAS (62%), TP53 (36%), GNAS (28%), SMAD4 (18%), PIK3CA (16%), and APC (15%). By univariate analysis, stage, tumor grade, and CRS + HIPEC demonstrated prognostic value (p < 0.05). Multivariate subset analysis of stage IV pts adjusting for age, tumor grade (TG), CRS + HIPEC, KRAS, GNAS, and p53, demonstrated that poorly differentiated tumors and a KRAS mutated tumor resulted in worse OS (HR: 12.1 and HR: 3.9, respectively, both with p < 0.05) and CRS + HIPEC resulted in an improved OS (HR: 0.32, p < 0.05). Conclusions: Our analysis indicates that TG and the presence of the KRAS mutation are poor prognostic factors in the OS of pts with AA. CRS + HIPEC offers survival advantage . Molecular characterization and prognostication of these rare tumors may help guide therapy. These findings need validation, thereby continued evaluation in a larger population and utilizing a wider molecular platform is ongoing.
Nrf2 metagene as a prognostic biomarker across all stages of colorectal cancer (CRC).
Authors: O'Cathail Sean Micheal , Wu Chieh-Hsi , Lewis Annabelle , Maughan Tim , Hawkins Maria A 
Published: January 2019

557 Background: Keap1/Nrf2 is an important intracellular canonical stress response pathway, with Nrf2 acting as a potent transcription factor. Lung cancer is known to acquire constitutive activation of the pathway thus promoting survival, resisting chemo-radiation and dysregulating metabolism. Mechanisms of pathway activation include methylation of KEAP1, somatic mutation and direct activation by KRAS, BRAF and MYC. Its role in CRC is unknown. Due to its role as a transcription factor, activated in many ways, we hypothesise a metagene of Nrf2 regulated genes would act as a prognostic biomarker in CRC. Methods: Using a candidate gene approach and publicly available data (GSE17536), we derived and trained a 36 gene metagene to aggregate Nrf2 pathway expression, using principal component analysis and cox proportional hazard models. GSE14333 was used for validation in stage I/II/III CRC. The first line metastatic FOCUS trial was used for validation in Stage IV disease. Results: 601 patients are included in the validation analysis. Nrf2 metagene expression is associated with worse DFS outcomes in stage I/II/III disease in Cox PH model comparisons (LRT, p = 0.00175) and worse OS in stage IV disease (LRT, p = 0.00574). On multivariate analysis, Nrf2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and Duke’s stage in stage I/II/III disease (ANOVA, p = 0.03), BRAF V600E and sidedness in stage IV disease (ANOVA, p = 0.00255). Using the median cut point, high expression has a HR 2.36 (C.I 1.27-4.38) in stage I/II/III disease and HR 1.39 (C.I 1.12-1.72) in metastatic disease. Conclusions: Nrf2 expression is a novel, robust prognostic biomarker of poor prognosis across all stages of colorectal cancer. Greater understanding of its mechanistic role could lead to targeted strategies to improve outcomes in CRC. [Table: see text]
Somatic POLE proofreading domain mutations by next generation sequencing to predict outcomes in stage II colorectal cancer.
Authors: Mo Shaobo , Li Yaqi , Peng Junjie 
Published: January 2019

559 Background: Stage II colorectal cancers (CRC) exhibit unique molecular heterogeneity and patients with somatic POLE mutations are defined as a distinct tumor subgroup. The aim of this study was to clarify the characteristics and prognostic effect of somatic POLE proofreading domain mutations by Next Generation Sequencing in stage II CRC. Methods: Recurrent patients were 1:1 matched to patient with no recurrence for stage II CRC patients diagnosed between 2008 and 2013 in Fudan University Shanghai Cancer Center (FUSCC). All patients were pathologically confirmed and received radical resection. Microsatellite instability status and POLE mutation status were determined by NGS using ColonCore panel (Burning Rock, Guangzhou, China). Groups based on NGS-POLE mutation status were compared in terms of patient demographics and pathologic features using chi-squared tests. Survival curves were plotted using the Kaplan-Meier method. Results: In total, 245 stage II CRC patients were enrolled. POLE mutations were detected in 25 (10.2%) of 245 stage II CRC, while only 9 (3.7%) was located in proofreading domain (NGS-POLE EDM-mutations) and other 16 were found in non-proofreading domain (non-NGS-POLE mutations). Compared to cases with wild-type POLE, cases with NGS-POLE EDM-mutations were more prone to be microsatellite instability-high (MSI-H) (3 of 9 [33.3%] vs. 23 of 236 [9.7%], p = 0.024), younger at diagnosis (median 46 years vs. 62 years, p < 0.001), and more frequently with right-sided tumor location (6 of 9 [66.7%] vs. 54 of 236 [22.9%]; p = 0.003). All tumors with NGS-POLE EDM-mutations presented with a surprisingly high tumor mutation burden (TMB) (median 145.2 per Mb). Patients with NGS-POLE EDM-mutations have favorable 5-year disease-free survival (DFS) compared with those with non-NGS-POLE EDM-mutations and wild-type POLE (100% vs. 62.5% vs. 52.5%, p = 0.037). Though there is DFS difference between patients with non-NGS-POLE EDM-mutations and wild-type POLE, the difference was not statistically significant (p = 0.412). Conclusions: Stage II CRC patients with NGS-POLE EDM-mutation identify a special cancer subset with better immune environment predicting excellent outcomes.
Development of a liquid-biopsy-based technique for the supplementary diagnosis of highly advanced lymph node metastasis in patients with locally advanced gastric cancer.
Authors: Oshima Takashi , Miyagi Yohei , Oue Naohide , Masuda Munetaka , Kimura Yayoi 
Published: January 2019

56 Background: The outcomes of patients with locally advanced gastric cancer who have highly advanced lymph node metastasis such as N3 remain poor despite radical resection. If the preoperative diagnoses of such patients improve, further improvement in treatment outcomes is expected to be obtained by means of personalized therapies such as preoperative chemotherapy; however, the accuracy of diagnosis remains unsatisfactory. Therefore, exploratory proteome analysis using sera was performed with the aim of developing a supplementary liquid-biopsy-based technique to diagnose highly advanced lymph node metastasis in patients with locally advanced gastric cancer. We report the results obtained thus far. Methods: The subjects were 24 patients with pT4a gastric cancer (12 with pN0 disease and 12 with pN3 disease). Proteins that had significantly different (P<0.001) expression levels in the preoperative serum on exploratory proteome analysis by liquid chromatography and mass spectrometry were identified. These proteins were verified by Enzyme-Linked ImmunoSorbent Assay (ELISA) using a different cohort (20 patients with pN0 disease and 13 with pN3 disease) from that described above. Results: In the exploratory proteome analysis, 2,357 kinds of proteins were identified and examined. Six these proteins were identified as candidate predictive markers of highly advanced lymph node metastasis. These proteins were verified using existing and newly developed ELISA kits, and reproducibility was verified for one protein (Protein V) (P = 0.003). Conclusions: The possibility of the supplementary diagnosis of highly advanced lymph node metastasis by liquid biopsy was suggested in patients with locally advanced gastric cancer. Further evaluations by prospective studies are now in progress, with the ultimate goal of clinical application.
Impact of genomic alterations (GAs) on outcomes and their distribution by age groups in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Sahin Ibrahim Halil , Chen Wanqi H , Chen Zhengjia , Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , El-Rayes Bassel F. , Wu Christina 
Published: January 2019

560 Background: Although clinical outcomes has substantially improved over the last decade, long term survival in mCRC remains rare. Molecular profiling (MP) of CRC is routinely conducted to identify potential therapeutic targets. The aim of this project is to evaluate the impact of uncommon GAs on outcomes and characterize their distribution by age. Methods: Pts were eligible if they had mCRC (synchronous or metachronous) and underwent MP between 01/2013 and 05/2018. GAs were obtained from Foundation Medicine reports. Clinical data were collected by trained personnel by detailed chart review. Multivariable survival analyses (MA) with Cox model were conducted for survival outcomes and Fisher’s exact test was used to assess the differences among age groups (< 45, 45-60, > 60). The study was reviewed by Institutional IRB ( IRB00097021 ). Results: 161 patients with mCRC had MP, and 159 of those patients had survival data. The most commonly detected GAs were APC (133/161, 82.6%) TP53 (128/161, 79.5%). In univariate analyses mutations in BRCA 1/2, RB1, SOX9, CDK8, FLT3, and IRS2 amplification were associated with worse survival outcomes. In MA, including initial stage of disease, GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 remained statistically significant (Table). When we performed MA by age groups, mutations SOX9 in age group < 45 and BRCA1/2 in age group 45-60 were significant predictors of worse outcomes. We also compared the frequency of mutations among age groups and FAM123B was significantly more common in age group 45-60 (P = 0.038). Conclusions: Our data suggests that GAs in BRCA1/2, RB1, FLT3, SOX9, and IRS2 may predict worse outcomes in mCRC. Therapeutic approaches targeting these pathways should be investigated. Differences in distribution and prognostic significance of mutations were observed based on age. [Table: see text]