bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylomic classifiers of anal cancer outcomes: An NRG Oncology / RTOG 98-11 tissue study.
Authors: Siegel Erin M. , Eschrich Steven A. , Berglund Anders E. , Ajidahun Abidemi O. , Magliocco Anthony Martin , Putney Ryan , Riggs Bridget , Moughan Jennifer , Hoffe Sarah E. , Simko Jeff , Ajani Jaffer A. , Guha Chandan , Okawara Gordon S. , Clouse John W. , Becker Mark J. , Pizzolato Joseph F. , Crane Christopher H. , Shibata David 
Published: March 2017

588 Background: Genome-wide epigenetic events appear to play a role in the development and behavior of HPV+ cancers. The value of adjuvant therapy following chemoradiation for localized anal cancer (AC) remains unclear. Molecular prognostication to identify patients (pts) who may be at higher risk for recurrence would be valuable. The goal was to define methylomic profiles predictive of disease-free (DFS) and overall (OS) survival in pts with AC. Methods: Genomic DNA was extracted, processed and methylation status at ~450,000 CpG loci examined (Illumina HumanMethylation450 Array). A multistep bioinformatics methodology was applied to develop a prognostic methylomic classifier for OS and DFS: (1) feature selection for methylated regions (β-value interquartile range ≥ 0.2, ≥ 2 adjacent significant probes within a CpG Island and p < 0.05 by univariate Cox proportional hazards) (2) selected features were entered into a supervised principal component analysis (PCA) and 3 components (PC1, PC2, PC3) were derived (3) classifier was built using forward selection multivariate regression models [PC1, PC2, PC3 alone and in combination with clinical features (size: > T2 vs. ≤ T2, nodal status: N0 vs N+)] using a 10-fold cross-validation (4) final model prediction risk score was generated, dichotomized and evaluated for prognostic values in Cox regression analysis. Results: 121 AC specimens from RTOG 98-11 were examined. The methylomic-only classifier model trended towards statistical significance (log-rank p = 0.05; HR = 1.96; 95% CI 0.99-3.88) in DFS (PC1, PC3 selected). In the combined model with clinical features, the final classifier included T status and epigenetic features (PC1, PC3) and was strongly predictive for DFS (p < 0.0001, HR = 4.45; 2.02-9.76). Final OS classifier models [methylomic-only (p = 0.28 HR = 1.55; 0.70-3.44) or combined (p = 0.013 HR = 2.88; 1.20-6.89)] were not as accurate. Conclusions: Methylomic and clinical features synergize to predict DFS in AC. Multivariate modeling reveal independent contributions from clinical and methylomic variables. Epigenomic profiling may contribute to identification of high-risk pts who may benefit from adjuvant strategies. Support: U10CA180822, U10CA180868, U24CA196067
Quantitative proteomic analysis of TUBB3 to identify gastric cancer patients who may benefit from docetaxel: A reevaluation of the ITACA-S trial.
Authors: Cecchi Fabiola , Catenacci Daniel V.T. , Tian Yuan , Miceli Rosalba , Pietrantonio Filippo , Pellegrinelli Alessandro , Martinetti Antonia , Di Bartolomeo Maria , Hembrough Todd A. 
Published: March 2017

59 Background: Chemotherapy (CTX) becomes targeted therapy when biomarkers can predict a patient’s response. A relationship between resistance to taxanes and overexpression of class III b-tubulin (TUBB3) has been suggested by small clinical studies, but not confirmed in randomized trials. The Intergroup Trial of Adjuvant CTX in Adenocarcinoma of the Stomach (ITACA-S) evaluated the survival advantage of postoperative sequential CTX with FOLFIRI followed by docetaxel plus cisplatin in comparison to monotherapy with 5-FU/LV in patients with radically resected gastric cancer (N = 1106). The results showed no difference in survival between the two CTX arms. In a random subset of patients (N = 247) from the ITACA-S trial, we applied mass spectrometry-based proteomics to assess the role of TUBB3 as a predictive biomarker for response to taxane-containing therapy. Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified using a mass spectrometry-based selected reaction monitoring assay. A predetermined TUBB3 cutoff of 700 amol/µg was based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among patients treated with taxane-containing CTX (n = 125), those with TUBB3 levels below the cutoff had nearly twice the median overall survival (OS) as patients with TUBB3 levels above the cutoff (1566 vs. 801 days, p = 0.0282). TUBB3 levels made no statistical difference in survival among patients who did not receive taxane. Of note, among patients with high TUBB3 levels ( > 700 amol), those treated without taxane-containing CTX survived far longer than patients in the taxane arm (OS = 1991 vs 801 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 expression identified a subset of gastric cancer patients who benefitted from the addition of docetaxel to adjuvant CTX. Patients with high TUBB3 expression levels had worse outcomes on a taxane-containing regimen than on CTX without taxane. Personalized CTX based on the TUBB3 biomarker is promising and warrants further validation. Clinical trial information: NCT01989858.
PD-L1 and PD-1 expression profile depending on the microsatellite status and the histological subtype in colorectal carcinomas.
Authors: Bossard CÃ©line , Ott Eva , Dansette Delphine , Ouairy Adrien , Jarry Anne , Bezieau Stephane , Toquet Claire , Mosnier Jean-François 
Published: March 2017

590 Background: PD-1/PD-L1 blockade showed therapeutic efficacy in only microsatellite (MSI) colorectal carcinomas (CRC), however, the profile of PD-L1 and PD-1 expression in CRC is only partially described. Methods: We thus analyzed on FFPE whole-tissue sections of 80 CRC, the expression profile of PD-L1 by tumor and/or immune cells by immunohistochemistry (clone E1L3N) depending on the MSI status and the histological subtype, and correlated to the density of PD-1+ and Tbet+ (able to secrete IFNg known to induce PD-L1) tumor-infiltrating lymphocytes (TIL). Results: 78% of MSI CRC (32/41) overexpressed PD-L1 either by tumor or immune cells versus 46% of MSS CRC (18/39) (p 0.005). This overexpression was heterogeneous within the same tumor in most of cases. Among MSI CRC, PD-L1 was preferentially overexpressed in medullary carcinomas (MC, 19/21, 90%) compared with 65% (13/20) in non-medullary adenocarcinomas (p 0.06). PD-L1 expression by tumor cells was only observed in MSI CRC (19/41, 46% with PD-L1 expression in more than 5% of tumor cells – score 1), and preferentially in MC (57% vs 5% in no medullary adenocarcinomas, with PD-L1 expression in more than 50% of tumor cells – score 3, p 0.0005). Conversely, PD-L1 expression by immune cells was observed in MSI CRC (23/41, 56% with PD-L1 expression by more than 5 sheets of 50 positive cells) but also in MSS CRC (18/39, 43%) (p 0.5). The density of PD-1+ cells was significantly correlated to the PD-L1 expression, as well as the density of Tbet+ TIL. Conclusions: PD-L1 expression is 1) heterogeneous in CRC, among CRC but also within the same tumor, 2) preferentially observed in MSI CRC (78%), especially in MC (90%), where PD-L1 is expressed by tumor cells, 3) correlated with the density of PD-1+ or T-bet+ TIL, and 4) observed in a significant proportion of MSS CRC (46%) by immune cells only. From a clinical point of view, PD-L1 expression has to be determined at best in full tissue section and besides its preferential expression in MSI CRC, its significant frequency and expression profile (only by immune cells) in MSS CRC should be taken into account in the future clinical trials testing the efficacy of anti-PD-1/PD-L1 antibodies.
Placental growth factor and the angiogenic environment based on analysis of baseline plasma biomarkers from the VELOUR trial.
Authors: Tabernero Josep , Paccard Caroline , Chiron Marielle , Dochy Emmanuelle , Van Cutsem Eric 
Published: March 2017

592 Background: A number of available agents (e.g., bevacizumab [bev], ziv-aflibercept, ramucirumab, regorafenib) for metastatic colorectal cancer (mCRC) target the VEGF pathway; biomarkers for anti-VEGF response are thus valuable. The Ph III VELOUR study (NCT00561470) demonstrated that addition of aflibercept to FOLFIRI improved survival and response rates in mCRC patients (pts) who had failed oxaliplatin-based therapy, including pts treated with prior bev. We report the correlation between biomarkers and bev pre-treatment in baseline plasma samples from VELOUR pts. Methods: 98 biomarkers were examined in baseline plasma samples from pts enrolled in VELOUR. Biomarker concentration was determined using multiplex assays or ELISA. Results: Plasma samples were available for 553 pts (placebo n = 265; aflibercept n = 288), of whom 169 had received prior bev. Nine biomarkers implicated in angiogenesis or bev resistance correlated with prior bev therapy (Table), including VEGF-A (~5-fold higher concentration) and PlGF (~2-fold higher concentration). Conclusions: These data indicate that prior bev therapy is likely to modulate expression of biomarkers associated with acquired resistance to anti-VEGF treatment (e.g., VEGF-A & PlGF). However, the improvement in clinical outcomes with aflibercept + FOLFIRI (vs placebo + FOLFIRI) in bev pretreated pts in VELOUR suggests that aflibercept remains active despite the development of bev-induced angiogenic resistance. Clinical trial information: NCT00561470. [Table: see text]
Is the primary tumor location (PTL) associated with differential gene expression profiles in patients with metastatic colorectal cancer (mCRC)? Analysis of the FIRE1-trial.
Authors: Le Lien D. , Mansmann Ulrich Robert , Jung Andreas , Kirchner Thomas , Schäfer Reinhold , Neureiter Daniel , Holch Julian Walter , Heinemann Volker , Stintzing Sebastian 
Published: March 2017

598 Background: Site-differential molecular characteristics of PTL as well as its influence on overall survival have been reported. In our study, we investigated the association of PTL with gene- and pathway-wise RNA expression as well as its representation in RAS mutational status subgroups. Methods: The phase-III-trial FIRE-1 compared the efficacy of FuFIRI and mIROX in patients with mCRC. Formalin-fixed, paraffin-embedded pretreatment samples from 166 FIRE-I patients were collected. The splenic flexure was used for differentiation between left colon cancer (LC) and right colon cancer (RC). RAS mutated PTs (RASmut) had PCR confirmed mutations in KRAS gene (Exon 2, 3, or 4) or in NRAS gene (Exon 2, 3, or 4). RNA expression profiling used the nCounter(R) PanCancer Pathways Panel including DNA damage control and TGF-β. We also studied a set of selected genes (Aprataxin, AREG, CD3EAP, CES1, CES2, CMPK1, DPD, DUT, ERCC1, ERCC5, EREG, FGF2, GSTP1, KLC3, MTHFR, PPP1R13L, RCC1, TOPO1, TP, TS, and UGT1A1). The gene-wise analyses used Limma and the permutated t-test with appropriate multiple testing adjustment. Holistic pathway investigation used GlobalAncova and the global tests. RAS mutation status and its correlation with tumor side were included as factors in both analyses. Additionally, gene- and pathway-wise analyses were performed in RASmut and RASWTsubgroups. Results: A total of 83 (50%) of 166 patients had any RAS mutation. A total of 28 (17%) patients had PTs on the right side and 13 of those (46%) were RASmut. The top ten differentially expressed genes between LC and RC are MMP9, ERCC3, MAP3K1, RRAS2, SOCS3, RB1, TGFβ1, LEFTY1, NKD1, and CDC25B (unadjusted p-values < 0.005). Potential enrichment in the DNA damage control pathway was found (p = 0.008). The RAS subgroup analyses showed a non-overlapping top ten list. Side specific effects may exist for the TGF-β pathway and the selected gene set in RASWTpatients. Conclusions: No strong association between PTL and gene expression showed up in mCRC tumors nor RAS subgroups. Potentially differential gene expression may exist for specific genes, two pathways and our selected gene set.
A prospective multicenter observational study of surgical palliation examining postoperative quality of life in patients treated for malignant gastric outlet obstruction caused by incurable advanced gastric cancer.
Authors: Fujitani Kazumasa , Ando Masahiko , Sakamaki Kentaro , Terashima Masanori , Kawabata Ryohei , Ito Yuichi , Yoshikawa Takaki , Kondo Masato , Kodera Yasuhiro , Kaji Masahide , Oka Yoshio , Imamura Hiroshi , Kawada Junji , Takagane Akinori , Shimada Hideaki , Tanizawa Yutaka , Yamanaka Takeharu , Morita Satoshi , Ninomiya Motoki , Yoshida Kazuhiro 
Published: March 2017

6 Background: Decision-making for surgical palliation remains one of the most challenging clinical scenarios since quality of life (QOL) is a key component of cancer care. We conducted this study to examine the impacts of surgical palliation on postoperative QOL in patients (pts) with malignant gastric outlet obstruction (GOO) caused by incurable primary gastric cancer (GC). Methods: Eligibility included (1) no oral intake or liquids only requiring parenteral nutrition (2) aged ≥20 (3) surgically fit (4) ECOG PS of 0-2 and (5) written IC. Patients underwent either palliative distal/total gastrectomy (DG/TG) or gastrojejunostomy (GJS). Treatment choice was left to the discretion of the physician. Validated QOL instruments (EORTC QLQ-STO22 and EuroQol-5D) assessed QOL at baseline, 2 weeks (wks), 1 month (m), and 3 months following the surgical palliation, and two observational outcomes (postoperative improvement of oral intake, and safety of surgical intervention) were evaluated. Results: 104 pts, 71 males and 33 females with a median age of 68 years, were enrolled. The types of surgery were DG in 23 pts, TG in 9 pts, GJS in 70 in pts, and exploratory laparotomy in 2 pts. Baseline QOL questionnaires were completed by 103 (99.0%) pts. Among the 104 pts, 98 (94.2%), 100 (96.1%), and 81 (77.9%) completed the 2-wk, 1-m, and 3-m follow-up survey, respectively. The mean baseline EQ-5D score was 0.74 (SD, 0.21). During the follow-up period, the mean scores remained consistent with the baseline scores; the change from baseline score was within ± 0.05 for the index. Many pts came to eat solid food at 2 wks postsurgery and remained tolerable thereafter (from 0 at baseline to 82, 85, 75 pts at 2 wks, 1 m, and 3 ms, respectively). Overall morbidity rate of ≥grade 3 on Clavien-Dindo classification and 30-day postoperative mortality rate was 9.6% (10 pts) and 2.0% (2 pts) with a median hospital stay of 13 days and re-operation rate of 3.9% (4 pts). Conclusions: In pts with malignant GOO caused by advanced GC, surgical palliation maintained patient QOL while improving solid food intake with an acceptable surgical safety. Clinical trial information: UMIN000023494.
Effect of polymorphisms of genes encoding regulatory proteins in the coagulation cascade on outcome for mCRC patients treated with FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Berger Martin D. , Stintzing Sebastian , Yang Dongyun , Suenaga Mitsukuni , Miyamoto Yuji , Cao Shu , Soni Shivani , Gopez Roel , Hanna Diana L. , Zhang Wu , Heinemann Volker , Lenz Heinz-Josef 
Published: March 2017

601 Background: Components of the coagulation cascade and surface proteins of platelets are involved in the regulation of angiogenesis. There are preliminary data suggesting that antithrombin III (ATIII), beside its anti-angiogenic effects, might also inhibit cancer cell migration and invasion. We therefore hypothesize that genes encoding regulatory proteins within the coagulation cascade and surface proteins of platelets may predict outcome in patients with metastatic colorectal cancer (mCRC). Methods: 295patients with mCRC enrolled in the randomized phase III FIRE-3 trial and treated with FOLFIRI and bevacizumab were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 6 functional SNPs in 6 genes (FGB, F2, F2R, SERPINC1, ITGA2B, ITGB3) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y (31-76) and median PFS/OS = 10.1/24.2 months. The SERPINC1 variant rs5877 encoding ATIII and the FGB SNP rs4220 encoding fibrinogen showed significant association with overall survival (OS). Patients with a C/C genotype of the SERPINC1 SNP rs5877 had a significantly worse OS than those harboring any T alleles (17.6 vs 25 months) in both univariate (HR 1.66, 95% CI 1.11-2.48, p = 0.011) and multivariate analysis (HR 1.74, 95% CI 1.15-2.64, p = 0.009). Similarly, A/A genotype carriers of the FGB SNP rs4220 showed a shorter OS compared to those with any G alleles (14.7 vs 24.8 months) in univariate (HR 1.90, 95% CI 1.05-3.42, p = 0.028) and multivariate analysis (HR 2.83, 95% CI 1.49-5.40, p = 0.002). Conclusions: This is the first report demonstrating that the SERPINC1 polymorphism rs5877 and the FGB SNP rs4220 might serve as predictive/prognostic biomarkers in patients with mCRC treated with FOLFIRI and bevacizumab in the first line setting.
Clinical applications of extended ctDNA RAS mutation determination in metastatic colorectal cancer.
Authors: Vidal Barrull Joana , Muinelo Laura , Dalmases Alba , Abalo Alicia , Vela Maria Carmen , Brozos EM , Muset Maria Merce , Ruiz BaÃ±obre Juan , Iglesias Mar , Blanco Cristina , Lopez Eva , Rodriguez Lopez Carmela , Jones Frederick S. , Edelstein Dan , Lukas Antje , Albanell Joan , Bellosillo Beatriz , Candamio Sonia , Montagut Clara , Lopez Rafael 
Published: March 2017

607 Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but detection of circulating tumor (ct) DNA in plasma is being actively investigated as an alternative for detection and monitoring RAS mutations during therapy. Methods: Concordance of RAS testing in plasma using the OncoBEAM RAS CRC test and RAS testing in tissue using standard-of-care RAS detection techniques was evaluated in 114 mCRC antiEGFR-naïve patients. In discordant cases, tissue samples were re-examined by BEAMing. OncoBEAM RAS CRC assay was also used to monitor RAS mutation status in serial plasma samples from 34 patients treated with anti-VEGF +/- chemotherapy or anti-EGFR based therapy. Results: The overall agreement of the two methods was 93% (106/114 patients), with positive agreement of 96.2% (51/53) and negative agreement of 90.2% (55/61). Longitudinal monitoring of plasma samples from 13 patients with RAS mutated tumors treated with chemotherapy +/- anti-VEGF, showed a significant decrease (or disappearance) of RAS mutant allele fraction (MAF) in all cases at the time of CT-scan (8-12 weeks after onset of treatment). In 3 patients, plasma was also analyzed at week 4 showing the same dramatic decrease in MAF. RAS decline mirrored clinical and radiological response to treatment. Interestingly, RAS decline was also observed in patients with stable disease in CT-scan by RECIST1.1. In 7 of 9 patients that subsequently progressed, RAS ctDNA fraction increased accordingly. On the other hand, among 22 patients RAS wt treated with cetuximab, 6 showed emergence of RAS mutations at progression. In two cases, multiple RAS mutations were concomitantly present. Conclusions: The high overall agreement between basal plasma and tissue RAS mutation status indicates that blood-based testing with OncoBEAM RAS CRC is a viable alternative to tissue RAS testing in mCRC patients. Moreover, this study highlights the utility of OncoBEAM RAS CRC to monitor treatment of mCRC patients in two setting: (a) evaluation of response to anti-VEGF +/- chemotherapy in RAS mutant patients, as a complement to RECIST radiological criteria and (b) to monitor emergence of resistant clones during anti-EGFR treatment in RAS wt patients.
Association of chromosome 17 copy number instability with favorable prognosis in nonsurgically treated gastroesophageal adenocarinoma and impaired response to trastuzumab.
Authors: Spada Neal , Birkness Jacqueline , Dacic Sanja , Luketich James D. , Nason Katie Sue , Sun Weijing , Davison Jon M. 
Published: March 2017

61 Background: Chromosomal instability (CIN), defined as cell to cell variation in copy number, is a feature of solid tumors that has been shown in experimental systems to result in aneuploidy, DNA damage, changes in gene expression, and genetically heterogeneous cell populations. In esophageal adenocarcinoma, chromosome 17 (Chr17) aneusomy is associated with heterogeneous HER2 amplification, a marker of poor prognosis (Yoon et al., J Clin Oncol 2012), but the association between CIN, HER2 amplification and clinical outcome has not been well studied. Methods: We retrospectively analyzed individual cell Chr17 centromere counts in 348 gastroesophageal adenocarcinomas that were tested for HER2 amplification. As an estimate of Chr17 CIN (CIN-17), we calculated the percentage of cells with centromere counts differing from the mode (modal centromere deviation, MCD, Roylance et al. Cancer Epidemiol Biomarkers Prev, 2011). We analyzed the association of CIN-17 with Chr17 aneusomy, HER2 amplification, pathologic tumor characteristics and clinical outcome. Results: Using pre-established cutoffs, we found CIN-17 (MCD > 30%) in 45% (158/348) and extreme CIN-17 (MCD > 45%) in 28% (99/348) of cases. Compared to CIN-17 negative tumors, CIN-17 positive tumors were more likely to be polysomic (77% vs 0.5%, P < 0.001) and Lauren intestinal type (84% vs 70%, P = 0.005). HER2 amplification was detected in 23% (80/348) of tumors, but there was no association with CIN-17 (P = 0.493). In patients who received pharmacologic therapy (n = 77), there was a 58% reduction in overall mortality associated with extreme CIN-17 (HR = 0.42, 0.25-0.72) independent of age, stage and addition of trastuzumab. Addition of trastuzumab to pharmacologic therapy showed a trend toward improved clinical outcome only in the subgroup without extreme CIN (n = 50, HR = 0.37, 0.13-1.06). CIN-17 was not associated with differences in patient survival after surgical resection. Conclusions: In this retrospective study, extreme CIN-17 was a favorable prognostic factor in patients who receive chemotherapy but could impair response to trastuzumab. These findings warrant further study.