bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment and prognostic impact of a new classification using HER2 and HER3 status in resected gastric cancer in a european cohort.
Authors: Martinez Lago Nieves , Abdulkader Ihab , Santamaria Dora Insua , Nuñez Patricia Viaño , Carrera Juan Jose , Antunez Lopez Jose Ramón , Padin Iruegas Maria Elena , López López Rafael 
Published: January 2019

65 Background: HER2 status is a predictive biomarker to response to trastuzumab in metastatic gastric adenocarcinomas. However, relatively little is known about the role of HER2 and HER3 in the non-metastatic disease in European population. Methods: Immunohistochemical expression of HER2 was analyzed using DAKO-HercepTest™ and gene amplification using DAKO-DuoCISH kit; both was scored according to published reports. HER3 expressión was analyzed using HER3 clon DAK-H3-ICHER3 and scored as follows: 0 = no staining, 1+ = light staining, 2+ = moderate staining, and 3+ = strong staining. Slides with score 0 or 1+ were classified as low expression or negative and slides with score 2-3+, as high expression or positive. According HER2 and HER3 status patients were classified into six subtypes: HER2-HER3 negative, HER2 equivocal expression HER3 negative, HER2 positive – HER3 negative, HER2 negative – HER3 positive, HER2 equivocal expression – HER3 positive and HER2-HER3 positive. The relationship between this classification and the clinicopathological characteristics and survival was analyzed retrospectively. Results: We included 106 patients between January 2007 and June 2014. The HER2 positivity was 13.2% and HER3 high expression was identified in 27.4% of patients. HER2 status was significantly associated with HER3 status (p = 0.018). HER2 equivocal or positive subtypes were associated with intestinal subtype (0.020) and HER2 or HER3 positive subtypes were associated with low histological grade (0.050). Our classification have demonstrated prognostic impact (p = 0.032) with a specific mortality rate due to gastric cancer of 45-50% for patients with equivocal or positive HER2 subtypes with HER3 low expression, 30% for patients with HER3 high expression independently of HER2 status, and 18% for patients HER2-HER3 negative. Conclusions: Our classification, using HER2 and HER3 status, stratifies patients into 6 subtypes with differentiated clinical and pathological characteristics and prognostic impact.
Impact of adyuvant chemotherapy treatment according to tumor primary location in colorectal cancer: Experience at University Hospital Ramon y Cajal (HURyC) Madrid.
Authors: Barquín García Arantzazu Martínez , Martinez Saez Olga , Corral de la Fuente Elena , Serrano Domingo Juan José , Martín Huertas Roberto , Villamayor Delgado Maria , Saavedra Serrano Cristina , Rodríguez Garrote Mercedes , Pachón Olmos Vanesa , Reguera Puertas Pablo , LONGO FEDERICO , Guillen Carmen , Carrato Alfredo , Ferreiro REYES 
Published: January 2019

655 Background: Adyuvant chemotherapy is a unified therapeutic principle in colon cancer (CC). However, many prognostic factors are arising to determine who really benefits from adyuvant chemotherapy in order to avoid overtreatment. Primary tumor location of CC is emerging as an important prognostic factor owing to distinct biological features. However, there is hardly any evidence showing the benefit of treatment according to primary tumor location. Methods: We retrospectively included patients with stage II and III CC that underwent surgical resection between 2009 and 2014 HURyC. We performed a multivariable Cox model analysis to estimate the benefit of chemotherapy according to tumor location in terms of DFS and OS. The model was further adjusted by including the following confounders: ECOG-PS, number of removed nodes ( < 12 or ≥ 12), use of adyuvant chemotherapy and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied > 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (267 left sided and 297 right sided). The median follow-up of the entire cohort was 49 months. Globally, chemotherapy did not improve DFS neither in right sided or left sided CC (HR: 0.81, p: 0.58; HR 1.31, p: 0.4, respectively). As for OS, it was improved when adding chemotherapy in both sides (right sided CC HR 0.51, p: 0.061 and left sided CC HR 0.42, p: 0.009). By stages, chemotherapy did not improve DFS or OS according to tumor localization in stage II. In right sided stage III, there was a trend to improve both DFS and OS (HR: 0.54, p: 0.14; HR: 0.39, p: 0.1, respectively). In left sided stage III, there was a trend to improve DFS (HR: 0.66, p: 0.36) and there was an improvement in OS (HR: 0.23, p < 0.001). Conclusions: The multivariable analysis showed benefit of chemotherapy in both right and left sided CC in terms of OS, exhibiting more benefit those patients with left sided CC.
Association of differential mucosal microbiome composition with clinicopathologic characteristics of rectal adenocarcinoma.
Authors: Lee Michael Sangmin , Carlson Cheryl Ann , Calvo Benjamin F. , O'Neil Bert H. , McCoy Nicole Amber , Keku Temitope O 
Published: January 2019

656 Background: Alterations in gut microbial composition are associated with development and progression of colorectal cancer (CRC), and may contribute to interpatient biologic and clinical heterogeneity. While recent studies have emphasized primary CRC tumor site as explaining much of these differences, there is still marked heterogeneity in clinical outcomes among the more homogeneous subgroup of rectal cancers. As such, we hypothesized that differential mucosal microbial populations are associated with distinct clinicopathologic characteristics among patients with locally advanced rectal cancer. Methods: Patients with T3-4 or N+ rectal adenocarcinoma were prospectively identified and underwent endoscopic tumor biopsy before starting neoadjuvant chemoradiation. Tumor samples were fresh frozen, bacterial DNA was extracted, and the V1-V2 region of the 16S bacterial ribosomal RNA was sequenced (IonTorrent). Sequences were processed through QIIME and an average of 16,189 reads per sample was obtained after quality filtering. Multivariate analyses were conducted using PRIMER VII and SPSS v24 software. P-values were determined using Mann-Whitney tests, and Benjamini-Hochberg procedure for false discovery rate was used and only results with false discovery rate < 0.25 are presented. Results: Among the 37 patients, mean age at diagnosis was 54 (range 30-77) and pre-treatment clinical stage was II (30%) vs. III-IV (70%). Younger patients (age < 50) had samples underrepresented for Streptococcus (0.9% vs 7.1%, p = 0.016, FDR 0.224) genus. Higher clinical stage was associated with enrichment of Fusobacterium (16.2% vs 5.6%, p = 0.019) and Parvimonas (4.6% vs 1.4%, p = 0.033) genera. Conclusions: Differential composition of tumor mucosal microbiota is associated with key clinical features among rectal adenocarcinomas, including age of diagnosis and tumor stage. Further investigation to determine associations between gut dysbiosis and transcriptomic subtypes may shed light on etiology of interpatient heterogeneity of rectal cancers.
Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined by methylation analyses and its prognostic significance in gastric cancer.
Authors: Suh Koung Jin , Kim Jin Won , Kim Ji Eun , Koh Jiwon , Kim Ji-Won , Lee Hye Seung , Lee Keun-Wook 
Published: January 2019

66 Background: Peripheral regulatory T cells (pTregs) might involve in tumor immune microenvironment. We aim to evaluate the correlation between pTregs and tumor immune microenvironment. Methods: pTregs status was determined from assessment of the pTreg/total T cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation) through epigenetic pattern of bisulfite pyrosequencing in long-term stored peripheral blood of 442 gastric cancer patients who received curative surgery. Immunohistochemical staining of multiple immune-related markers including CD3, CD4, CD8, Foxp3, 1-selectin arginase, ADAM metallopeptidase domain 17, CD163 and CD45RO within tumor microenvironment were performed in resected gastric tumor specimen. Results: The median value of FoxP3-TSDR and CD3G/CD3D demethylation was 5.8% and 32.3%, respectively. When pTreg/total T cell ratio was divided into eight equal groups from the lowest to the highest value, the extreme pTreg/total T cell ratio of the upper eighth and the lower eighth was significantly associated with lower CD45RO expressed cell counts within tumor microenvironment. In terms of arginase and CD163, inverse results were observed. Patients with extreme pTreg/total T cell ratio had significantly shorter disease-free survival (DFS) and overall survival (OS) compared to the patients with non-extreme pTreg/total T cell ratio. Multivariate analysis which included age, stage, lymphatic invasion, vascular invasion, and perineural invasion as covariates demonstrated that the extreme pTreg/total T cell ratio was an independent predictor for shorter DFS (HR 1.740, 95% CI 1.128 – 2.682; p = 0.012) and OS (HR 1.900, 95% CI 1.175 – 3.070; p = 0.003). Conclusions: Our results suggest that the pTreg/total T cell ratio determined by epigenetic methylation analysis is correlated with specific immune cell infiltration within tumor microenvironment in resected gastric tumors, and gives prognostic information in gastric cancer patients. pTreg/total T cell ratio could be an easy-obtained potential biomarker for prognosis and future immunotherapeutic treatment strategies.
A precision medicine strategy to identify the FGFR pathway as a novel target in colorectal cancer liver metastasis.
Authors: Altunel Erdem , Somarelli Jason , Kim So Young , Glover Wayne , Rupprecht Gabrielle , Hsu Shiaowen David 
Published: January 2019

660 Background: Colorectal cancer liver metastasis (CRCLM) continues to be a major health problem and despite extensive efforts to develop new drugs, median survival remains at a mere 30 months. The purpose of our study is 1. Develop a precision medicine strategy for patients with CRCLM and 2. Discover novel pathways and treatments to improve outcomes. Methods: In order to develop a precision medicine strategy, 6 matched patient derived xenografts (PDX) and cell lines were established from patients undergoing resection of their CRCLM. A high-throughput drug screen containing over 100 FDA approved drugs was first used in vitro on 3 cell lines to identify therapeutic targets. The top therapeutic targets were validated in vivo. RNA seq was then performed to identify potential predictive markers of response. Results: Our high-throughput drug screen performed on 3 early passage CRC cell lines (CRC057, CRC119 and CRC240) identified ponatinib, a multi TKI, as the only agent to inhibit all 3 cell lines. Subsequent growth inhibition analysis identified the fibroblast growth factor receptor (FGFR) as the main target of ponatinib. In vitro findings were confirmed in vivo in matched PDXs. Western blot analysis post treatment showed evidence of decreased phospho-FGFRs. Further analysis of the main downstream signaling pathways of FGFR (RAS/PI3K/AKT, RAS/MEK/ERK and STAT) demonstrated that the STAT pathway was effectively targeted in all 3 cell lines. In contrast, the ERK pathway was targeted in CRC240 and CRC057 while the p-AKT was targeted in CRC119. Finally, RNAseq revealed different isoforms and mutations in these samples. Conclusions: We have developed a precision medicine strategy for patients with CRCLM using matched cell lines and PDXs coupled with high throughput drug screens and genomic analysis to identify novel targets and specifically identified the FGFR/STAT axis as a therapeutic target. Furthermore, co-targeting FGFR and its downstream pathways may provide synergy and lead to combinatorial therapies that can improve patient outcomes. Finally, RNAseq data can be used to develop predictive markers of therapy.
Detection and description of ERBB2 amplification using circulating cell free tumor DNA (ctDNA) genomic analysis in metastatic colorectal cancer (mCRC).
Authors: Raghav Kanwal Pratap Singh , Loree Jonathan M. , Morris Jeffrey , Manuel Shanequa , Crosby Shadarra , Meric-Bernstam Funda , Menter David , Raymond Victoria , Lanman Richard B. , Talasaz AmirAli , Kopetz Scott 
Published: January 2019

661 Background: ERBB2 amplification (HER2amp) is evolving as a distinct subset of mCRC with therapeutic implications. Although seen in 3-4% of mCRC in tumor tissue, little is known about occurrence of HER2amp in ctDNA. The purpose of this study was to assess the value of ctDNA in detection of HER2amp in blood and to delineate its landscape in mCRC. Methods: We performed a retrospective analysis of mCRC patients (pts) who underwent plasma-derived NGS of ctDNA in a CLIA-certified lab (Guardant Health, Inc.) using a high sensitivity assay that reports copy-number variations using pre-specified algorithms. Pts with no detectable alterations were excluded. The cohort was divided into 2 groups: HER2amp and ERBB2 non-amplified (HER2NA). Descriptive statistics and Fisher’s exact test were used. Results: Between 5/2014 and 5/2016, 1625 mCRC pts had a ctDNA NGS assay and of these 1387 met our inclusion criteria. Among these, HER2amp was seen in 69 pts (4.9%, 95%CI: 3.9 – 6.3). HER2amp were found to be enriched in RAS wild-type (WT) (6.4% v 2.9%, OR 2.3, P = 0.002) and RAS/BRAFV600E WT (6.9% v 2.7%; OR 2.7, P < 0.001). When co-existing with RAS mutations, HER2amps were seen more with sub-clonal ( < 50% relative mutation allele frequency) RAS mutations than clonal RAS mutations (6.6% v 2.1%, OR 3.1, P = 0.03). The most common co-occurring mutations were TP53 (77%), APC (59%), EGFR (25%), PIK3CA (25%) and KRAS (23%). HER2 (13% v 5%, OR 2.6, P = 0.017) and TP53 (77% v 62%, OR 2.1, P = 0.011) mutations co-occurred more frequently with HER2amp than with HER2NA cases. No significant association was seen with PIK3CA, EGFR and APC mutation status. Conclusions: In one of the largest series of CRC pts with ctDNA NGS, ERBB2 amplification were confirmed to be enriched in RAS/BRAF WT mCRC. In these pts, co-existing clonal RAS mutations are uncommon, but concurrent PIK3CA and ERBB2 mutations are present in a sizable minority of cases. These findings may have implications for anticipated innate/acquired resistance mechanisms to HER2-targeting therapies under evaluation for CRC.
Polymorphisms in beta-defensin pathways and clinical outcomes in metastatic colorectal cancer patients treated with FOLFIRI-bevacizumab in two randomized phase III trials.
Authors: Naseem Madiha , Berger Martin D , Puccini Alberto , Tokunaga Ryuma , BATTAGLIN FRANCESCA , Barzi Afsaneh , Soni Shivani , McSkane Michelle , Cao Shu , Millstein Joshua , Zhang Wu , Loupakis Fotios , Stintzing Sebastian , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2019

662 Background: Beta defensin 1 (DEFB1) and 2 (DEFB4A) are antimicrobial peptides secreted from colonic epithelial cells in response to inflammation. DEFB1 has been shown to serve as a tumor suppressor, whereas high concentrations of DEFB4A are linked with angiogenesis. This study examines the impact of single nucleotide polymorphisms (SNPs) in beta-defensin pathways in two independent phase III trials: FIRE-3 and TRIBE. Methods: The OncoArray database containing 530K SNP markers provided by Illumina was used to find associations between clinical outcomes and 10 functional SNPs from DEFB1, DEFB4A, PPARG, NFKB1, MUC2, and TLR4 genes. Patients treated with first-line FOLFIRI/bevacizumab (bev) in the randomized phase III FIRE-3 trial (n = 107) and TRIBE trial (n = 215) served as discovery and validation cohorts respectively. The FIRE-3 FOLFIRI and cetuximab (cet) arm served as a negative control (n = 129). Results: A total of 451 patients were included. The NFKB1 rs3821958 SNP showed significant association with OS and PFS in overall pts and those with left-sided CRC. Compared to pts carrying the mutant A allele, those with the wild-type G/G genotype had a shorter median OS (19 vs 40 mts) and PFS (9.2 vs 11.7 mts) in both univariate ((OS: HR = 2.32, 95%CI 1.21-4.42, p = 0.006) (PFS: HR = 1.93, 95%CI: 1.11-3.37, p = 0.014)) and multivariable analysis ((OS: HR = 2.90, 95%CI 1.47-5.70, p = 0.002) (PFS: HR = 2.08, 95%CI:1.18-3.67, p = 0.012)). This finding was validated in TRIBE, where carriers of G allele had shorter PFS in univariate analysis (HR = 1.44, p = 0.019). Opposite results were observed in pts receiving cet, where G/G carriers had improved OS in univariate analysis (HR = 0.46, p = 0.048). Pts with left-sided CRC who carried the wild-type allele had poorer OS and PFS in both trials. Conclusions: NFKB1 rs3821958 SNP is known to activate DEFB1 and is downstream of EGFR. Harboring a mutant allele in this SNP confers a mortality benefit in left-sided and overall pts treated with bev, and worsens OS in pts receiving cet. Hence, NFKB1 could serve as an important predictive biomarker. Future studies are warranted to further elucidate its role in colorectal cancer.
Single nucleotide polymorphisms in miRNA binding sites of nucleotide excision repair-related genes to predict clinical benefit of oxaliplatin in FOLFOXIRI plus bevacizumab in TRIBE trial.
Authors: Suenaga Mitsukuni , Schirripa Marta , Cao Shu , Zhang Wu , Yang Dongyun , Cremolini Chiara , Murgioni Sabina , Lonardi Sara , Ning Yan , Okazaki Satoshi , Berger Martin D , Miyamoto Yuji , Gopez Roel , Barzi Afsaneh , Loupakis Fotios , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2019

663 Background: Nucleotide excision repair (NER) is known as part of the DNA damage response (DDR) against platinum-induced DNA damage. Polymorphisms in miRNA binding sites of replication protein A ( RPA2) and General Transcription Factor IIH Subunit 1 ( GTF2H1) genes in NER pathway have shown to correlate with colorectal cancer risk. We tested whether the NER-related single nucleotide polymorphisms (SNPs) predict oxaliplatin efficacy in FOLFOXIRI regimen in patients (pts) with metastatic colorectal cancer (mCRC). Methods: Genomic DNA was extracted from 457 blood samples of mCRC pts enrolled in the TRIBE trial: 230 pts received first-line (1L) FOLFOXIRI plus bevacizumab (discovery cohort: median age, 60 yrs; median follow-up, 46.6 mos); and 227 pts received 1L FOLFIRI plus bevacizumab (control cohort: median age, 60 yrs; median follow-up, 49.0 mos). SNPs were analyzed by PCR-based direct sequencing. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: In KRAS wild-type population among the discovery cohort, the C/C variant in RPA2 rs7356 was associated with shorter PFS and OS than any T allele (9.1 vs 13.3 mos, HR 2.32, 95%CI: 1.07-5.03, P= 0.020; 20.8 vs 37.1 mos, HR 1.94, 95%CI: 0.94-3.99, P= 0.059). Any C allele in GTF2H1 rs4596 was associated with shorter PFS than the G/G variant (10.8 vs 13.3 mos, HR1.64, 95%CI: 0.95-2.81, P= 0.045). In multivariable analysis, RPA2 rs7356 remained significant for PFS and OS (HR 2.97, 95%CI: 1.27-6.94, P= 0.012; HR 2.58, 95%CI: 1.19-5.58, P= 0.016). In all population of the discovery cohort, pts with any GTF2H1 rs4596 C allele had remarkably shorter PFS and OS than those with the G/G variant (11.3 vs 13.2 mos, HR 1.32, P= 0.087; 28.6 vs 34.3 mos, HR 1.36, P= 0.076). The findings remained in multivariable analysis. These findings were not confirmed in the control cohort. Conclusions: We suggest that miRNA binding sites of NER-related genes regulate DDR for oxaliplatin-related DNA damage. Germline RPA2 and GTF2H1 polymorphisms may predict oxaliplatin efficacy in mCRC pts.
Comparison of the real-world adherence and compliance patterns with trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) for the treatment of metastatic colorectal cancer (mCRC).
Authors: Patel Anuj K. , Duh Mei Sheng , Barghout Victoria , Yenikomshian Mihran Ara , Xiao Yongling , Wynant Willy , Tabesh Majid , Fuchs Charles S. 
Published: January 2019

666 Background: FTD/TPI and REG both prolong survival in refractory mCRC and have similar indications with different side effect profiles. This study compares real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database. Methods: Retrospective data from 10/2014 to 7/2016 from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for patients receiving FTD/TPI or REG. The index date was the date of first FTD/TPI or REG prescription. Patients were included if: 1) age ≥18 years old, 2) ≥1 CRC diagnosis, 3) no diagnosis of gastric cancer or gastrointestinal stromal tumor, and 4) continuous clinical activity for ≥3 months before and after index date. The observation period spanned from index date to end of data, end of continuous clinical activity, or switch to another mCRC treatment. Adherence was assessed using medication possession ratio (MPR) ≥0.80 and proportion of days covered (PDC) ≥0.80 at 3 months. Compliance was assessed using time to discontinuation over the observation period using allowable gaps of 45, 60, or 90 days. Patients who never discontinued therapy were censored at the end of the observation period. Outcomes were compared between FTD/TPI and REG using multivariate logistic regression and Cox proportional hazards models, adjusting for demographic and clinical baseline characteristics. Results: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. Mean ± standard deviation (SD) age of FTD/TPI patients was 61.0 ± 11.0 compared to 62.8 ± 10.9 for REG patients (p < 0.001). FTD/TPI patients were 80% more likely to have a MPR ≥0.80 compared to those on REG (Odds Ratio [OR] = 1.80, p < 0.001) and more than twice as likely to have a PDC ≥0.80 (OR = 2.66, p < 0.001) at 3 months. FTD/TPI patients were 37% less likely to discontinue their treatment compared to those on REG when using gaps of 60 days (Hazard Ratio = 0.63, p < 0.001). Similar results were found with 45 and 90 days. Conclusions: In this retrospective study of mCRC patients, patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.