bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and molecular landscape of metastatic colorectal cancer (mCRC) harboring ALK, ROS1, or NTRK 1, 2, 3 (NTRKs) rearrangements.
Authors: Pietrantonio Filippo , Di Nicolantonio Federica , Schrock Alexa Betzig , Lee Jeeyun , Tejpar Sabine , Siena Salvatore , Christiansen Jason H. , Hechtman Jaclyn Frances , Fucà Giovanni , Antoniotti Carlotta , Kim Seung Tae , Min Bosun , Murphy Danielle , Tebbutt Niall C. , Ross Jeffrey S. , Bardelli Alberto , Ali Siraj Mahamed , Falcone Alfredo , De Braud Filippo G. , Cremolini Chiara 
Published: March 2017

589 Background: ALK, ROS1, and NTRKs fusions occur in 0.2-2.4% of CRCs, and represent therapeutic targets, as indicated by promising reports of individual patients treated with tyrosine kinase inhibitors. Clinical and molecular features of mCRCs harboring these fusions have not been elucidated. Methods: mCRC harboring ALK, ROS1 and NTRKs fusions were identified taking advantage of screening programs worldwide (Ignyta STARTRK trials; Foundation Medicine Database; Memorial Sloan Kettering-IMPACT; Australian MAX trial post-hoc analysis). Clinicopathological and molecular characteristics of ALK, ROS1, NTRKs rearranged cases were compared with those of non-rearranged cases, included in Ignyta’s STARTRK trials program. Results: 27 ALK, ROS1 or NTRKs rearranged (including a novel SCYL3-NTRK1 fusion) and 319 not rearranged mCRCs patients were included. Rearrangements were more frequent in older patients (p = 0.024), and tumors that were right-sided (80% vs 30%; p < 0.001), RAS wild-type (93% vs 52%; p < 0.001), MSI-high (48% vs 8%; p < 0.001) and spread more frequently to lymph nodes (46% vs 25%; p = 0.03) and less frequently to the liver (42% vs 66%; p = 0.026). At a median follow-up of 28.5 months, patients bearing rearranged tumors had a shorter overall survival (OS) when compared to non-rearranged (15.6 vs 33.7 mos; HR: 2.17, 95% CI 1.03-4.57; p < 0.001). In the multivariable model including significant prognostic variables (primary site, primary resection, BRAF and MMR status), rearrangements were still associated with shorter OS (HR: 2.78, 95% CI 1.27-6.07; p = 0.011). All of the 4 patients with rearranged tumors evaluable for benefit from anti-EGFRs experienced disease progression as best response. One patient with an MSI-high EML4-ALK rearranged tumor experienced durable response to PD-1 blockade. Conclusions: ALK, ROS1 and NTRKs rearrangements define a new molecular subtype of mCRCs associated with unfavorable prognosis, and specific clinicopathological and molecular features. Since sensitivity to available treatment options, including anti-EGFRs, is very limited, targeted approaches with or without immunotherapy should be investigated in these patients.
ABCG2 and TOP1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.
Authors: Brunner Nils , Nygaard Sune Boris , Budinska Eva , Stenvang Jan 
Published: March 2017

591 Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were disease free survival (DFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, which is the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.
Role of genetic polymorphisms in CCL5/CCR5 axis to predict efficacy of regorafenib in patients with refractory metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Schirripa Marta , Cao Shu , Zhang Wu , Yang Dongyun , Marmorino Federica , Bergamo Francesca , Antoniotti Carlotta , Rossini Daniele , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Mashima Tetsuo , Yamaguchi Toshiharu , Loupakis Fotios , Lenz Heinz-Josef 
Published: March 2017

596 Background: CCL5/CCR5 pathway is known to mediate VEGF-A production. A recent study reported that serum VEGF-A and CCL5 levels predict efficacy of regorafenib in metastatic colorectal cancer (mCRC). We tested whether genetic polymorphisms in the CCL5/CCR5 pathway are associated with outcomes in patients with refractory mCRC treated with regorafenib. Methods: We analyzed genomic DNA extracted from 229 samples of two cohorts receiving regorafenib: an evaluation cohort of 79 patients (median age 62 years, male 47%, median follow-up time 15.3 months); and a validation cohort of 150 patients (median age 62 years, male 54%, median follow-up time 36.4 months). Nine single nucleotide polymorphisms (SNPs) of genes in CCL5/CCR5 pathway ( CCL5, CCR5, PRCKD, CCL3, CCL4, KLF13, HIF1A) were analyzed by PCR-based direct sequencing. Associations between SNPs with progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank test. Multivariable analyses including SNP and baseline characteristics were performed using the Cox proportional hazard regression model. Results: In the evaluation cohort, patients with any A allele in CCL4 rs1634517 had a significant shorter PFS compared to those with the C/C variant (2.0 vs. 2.5 months, HR 1.54, P= 0.043). Patients carrying any A allele in CCL3 rs1130371 had marginally significant shorter PFS (2.0 vs. 2.5 months, HR 1.48, P= 0.064) than those with the G/G variant. In the validation cohort, Patients with any A allele in CCL4 rs1634517 had a shorter PFS (1.8 vs. 2.3 months, HR 1.74, P= 0.001) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) compared to those with the C/C variant. It remained significant in multivariable analysis for PFS and OS ( P= 0.012 and 0.041). Patients carrying any A allele in CCL3 rs1130371 had a shorter PFS (1.8 vs. 2.3 months, HR 1.66, P= 0.002) and OS (4.4 vs. 7.9 months, HR 1.65, P= 0.004) than those with the G/G variant; these effects were significant in multivariable model (PFS: P= 0.027; OS: P= 0.047). Conclusions: Genetic variants in the CCL5/CCR5 pathway, CCL4 rs1634517 and CCL3 rs1130371, may serve as predictive and prognostic markers in refractory mCRC patients receiving regorafenib.
Comprehensive genomic sequencing of appendiceal cancer tumors to identify different genomic alterations by subtype, novel treatment opportunities, and improved outcomes.
Authors: Ang Celina , Singhi Aatur D. , Schrock Alexa Betzig , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Ali Siraj Mahamed , Millis Sherri Z. 
Published: March 2017

599 Background: Appendiceal cancers are rare and consist of mucinous (M), adenocarcinoma (A), goblet cell carcinoma (GCC), pseudomyxoma peritonei (PMP), and several even rarer histologies. Current treatment involves surgical resection or debulking; no standard exists for adjuvant chemotherapy or metastatic disease treatment. Systemic treatment is often based on chemotherapy regimens used in colorectal cancer. Methods: Tissue from 518 appendiceal cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling across all appendiceal cancer histological subtypes identified different patterns in GAs across subtypes (table), most notably in GNAS, KRAS, and TP53. No PMP exhibited microsatellite instability (MSI-H) or high TMB ( > 20 mutations/Mb); MSI-H cases included 3 M, 4 A, 1 GCC; 3-7% 12% A and 6% m had high TMB. Case reports of patients with tumors harboring GNAS alterations showed response to MEK inhibitors. Conclusions: Genomic profiles of tumors from patients with appendiceal cancers reveal differing profiles from colorectal cancers (CRC) and considerable heterogeneity between subtypes, suggesting an individualized approach to treatment. Therapeutic options include clinical trials targeting pathways involving KRAS, BRAF, GNAS, PIK3CA, FBXW7, SMAD4, APC, and ATM. Recent case reports indicate that GNAS is a clinical target for MEK inhibitors. Overall, given the poor prognosis of advanced stage appendiceal carcinoma patients, CGP may identify novel, unanticipated therapeutic targets in a significant subset of patients, including immunotherapy for high TMB patients. [Table: see text]
Anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma.
Authors: Maron Steven Brad , Alpert Lindsay , Xu David , Rendak Rachel , O'Day Emily , Setia Namrata , Catenacci Daniel V.T. 
Published: March 2017

60 Background: Gastroesophageal cancer (GEC) is a global health problem. Multiple phase III anti-EGFR trials of unselected metastatic GEC patients (pts) were negative, yet subset analyses suggested potential benefit in pts with EGFR amplification (amp). We sought to quantify the incidence of EGFR amp in metastatic/recurrent GEC pts compared to the locally advanced TCGA rate, treat them with EGFR antagonists, quantify response/duration, and assess for mechanisms of action and resistance (MOA, MOR). Methods: 106 stage IV GEC pts in any therapy (tx) line (L) were prospectively screened for EGFR amp between 9/1/14-8/31/16 at a single site using tumor next generation sequencing (NGS). EGFR amp samples were then assessed by FISH, immunohistochemistry (IHC) and mass spectroscopy (MS) to confirm. Pts received 1L ABT-806 (1/4) or 2L+ cetux (3/4) monoclonal anti-EGFR antibodies, in combination with chemotherapy if 1L or 2L (2/4), or as monotherapy for 3L+ (2/4). Pts were followed for response (ORR) and disease control (DCR). Pre and post-treatment NGS, serial ctDNA, and EGFR/PD-L1 FISH/IHC/MS were obtained to monitor for MOA and MOR to tx. Results: Six (5.7%) pts harbored EGFR amp tumors with copies/cell ranging 54-167. Four eligible pts received >1 dose of tx with monoclonal anti-EGFR therapy: 1 FOLFOX-ABT-806 (1L), 1 FOLFIRI-cetux (2L), and 2 cetux alone (3L, 4L); ORR was 100% (4/4) by RECIST, respectively (-70%, -65%, -77%, -43%). All 3 cetux treated pts developed classic rash, which disappeared when/if progression (2/3). The 4-month DCR was 75% (3/4). No pts showed PD-L1 staining pre/post therapy. Upon progression, the 2L pt acquired de novo PTEN exon 6 deletion after 10 months, while basal NRAS mutated and HER2 amp ctDNA clones had expanded in the 4L pt after 4 months of monotherapy. Conclusions: EGFR amp incidence was similar to TCGA. Despite large negative trials with EGFR antagonists for GEC, EGFR amp predicted benefit (100%) from anti-EGFR tx, including monotherapy in 50%, albeit until various resistance mechanisms emerged, including HER2, RAS, and PTEN/AKT pathway activation. No PD-L1 expression was observed pre/post treatment, consistent with our previous data showing that EGFR-amplified cases trend towards a ‘non-T cell-inflamed’ phenotype. Clinical trial information: NCT01416714 / NCT02213289.
Polymorphisms in adipokine-related genes to predict treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy.
Authors: Miyamoto Yuji , Stintzing Sebastian , Zhang Wu , Cao Shu , Ning Yan , Okazaki Satoshi , Berger Martin D. , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Matsusaka Satoshi , Yang Dongyun , Gopez Roel , Hanna Diana L. , Barzi Afsaneh , Baba Hideo , Heinemann Volker , Lenz Heinz-Josef 
Published: March 2017

600 Background: The molecular effects of obesity are mediated by alterations in the levels of adipokines, which are produced mainly by adipose tissue. Adipokines have multiple effects, including insulin sensitivity, cell proliferation, inflammation, and angiogenesis. We previously reported that single-nucleotide polymorphisms (SNPs) in obesity-related genes were associated with the recurrence probability of CRC treated with 5-FU based adjuvant chemotherapy. This study aimed to evaluate whether SNPs in adipokine-related genes may predict clinical outcomes in bevacizumab treated mCRC pts. Methods: Genomic DNA was obtained from mCRC pts receiving bevacizumab plus FOLFIRI as first-line treatment and analyzed by using PCR-based direct sequencing. Eleven functional SNPs in 7 genes ( LEP, LEPR, ADIPOQ, ADIPOR1, RETN, TNFa and NAMPT) were tested in 291 pts in FIRE3 trial bevacizumab cohort (NCT00433927). Main characteristics were the following: male/female = 193/98; median age = 65; High BMI pts (BMI ≥ 25 Kg/m2)/low BMI pts (BMI < 25 Kg/m2) = 162/129; median PFS = 10.1 months; median OS = 24.2 months, median follow-up time = 40.8 months. Results: LEPR rs1137100 G/G variants (n = 24) showed worse PFS than any A variants (n = 246) in univariate (10.4 months (M) vs. 9.2 M, HR = 1.75, 95%CI = 1.12-2.74, P = 0.011) and multivariate analyses (HR = 1.75, 95%CI = 1.11-2.74, P = 0.016). NAMPT rs61330082 T/T (n = 24) showed worse PFS than any C variants (n = 243) in multivariate analysis (HR = 1.65, 95% = 1.02-2.67, P = 0.042). RETN rs1862513 C/C (n = 23) showed worse OS than any G variants (n = 246) in univariate analysis (14.1 m vs. 25.1 M, HR = 1.65, 95%CI = 1.04-2.60, P = 0.029). In subgroup analyses of high BMI pts, the prognostic effect of LEPR rs1137100 G/G and RETN rs1862513 C/C was confirmed and no association was observed among low BMI pts. Conclusions: Our study showed for the first time that genetic variations in adipokine-related genes are associated with prognosis of mCRC pts treated with bevacizumab based chemotherapy.
Mutation enrichment next-generation sequencing for quantitative detection of KRAS mutations in urine cell-free DNA from patients with advanced colorectal and other cancers.
Authors: Janku Filip , Barzi Afsaneh , Sartore-Bianchi Andrea , Fujii Takeo , Cassingena Andrea , Siravegna Giulia , Karp Daniel D. , Piha-Paul Sarina Anne , Subbiah Vivek , Tsimberidou Apostolia Maria , Huang Helen J. , Veronese Silvio , Di Nicolantonio Federica , Erlander Mark G. , Luthra Rajyalakshmi , Kopetz Scott , Meric-Bernstam Funda , Siena Salvatore , Lenz Heinz-Josef , Bardelli Alberto 
Published: March 2017

602 Background: Molecular testing of cell-free (cf) DNA from urine is a completely non-invasive approach for detection of actionable mutations in cancer. Methods: A quantitative mutation enrichment next-generation sequencing (NGS) urine cell-free (cf) DNA KRASG12/G13mutation test was developed and results compared to clinical testing of archival tumor tissue and research testing of plasma cfDNA from patients with advanced colorectal (n=56, 79%) and other advanced cancers (n=15, 21%). Results: The analytical sensitivity of the KRASG12/G13 cfDNA test was 0.002%-0.006% mutant copies in wild-type background. In 71 patients, the agreement between urine cfDNA and tumor was 73% (sensitivity 63%; specificity 96%); the agreement increased to 89% for patients with recommended 90-110mL of urine. In 33 patients with available plasma samples, the agreement with tumor was 94% (sensitivity 92%; specificity 100%). In patients treated with systemic therapy there was lower number of KRASG12/G13 copies in urine and plasma cfDNA on therapy compared to baseline and progression ( P<0.003). Decrease in urine and plasma cfDNA KRASG12/G13 copies on therapy compared to no change/increase was associated with longer median time to treatment failure ( P<0.05). Conclusions: Mutation enrichment NGS detection of KRASG12/G13 mutations in urine cfDNA has good concordance with archival tumor tissue. Changes in urine cfDNA correspond with time to treatment failure.
Soluble CD87 (s-uPAR) predicts bevacizumab-based first line treatment of metastatic colorectal cancer (mCRC): Results from a prospective multi-center study.
Authors: Unseld Matthias , Kornek Gabriele , Gleiss Andreas , Demyantes Svitlana , Schwarzwald Jost , Bianconi Daniela , Andel Johannes , Tinchon Christoph , Pecherstorfer Martin , Eisterer Wolfgang , Jagdt Björn , Kretschmer Andreas , Gerger Armin , Greil Richard , Seebacher Adelheid , Krippl Peter , Laengle Friedrich , Zielinski Christoph , Scheithauer Werner , Prager Gerald W. 
Published: March 2017

604 Background: Bevacizumab-combined chemotherapy is well established in the induction treatment of metastatic colorectal cancer (mCRC). Despite tremendous efforts, no valid predictive marker for anti-VEGF treatment has so far been defined. CD87, the urokinase plasminogen activator receptor (uPAR), is centrally regulating VEGF-induced angiogenesis via adapting endothelial cell migration and invasion (Unseld et al.; ThrombHaem,2015, Brunner et al.; Blood 2011, Prager et al; Blood 2009; Prager et al; Blood 2004). Preoperative plasma s-uPAR levels were shown to independently predicted survival of patients resectable colorectal cancer. This study aimed to identify any prognostic or predictive value of s-uPAR in front-line bevacizumab-treated mCRC patients. Methods: In this prospective multi-center trial (NCT02119026), patients were either treated with bevacizumab plus FOLFOX or bevacizumab plus FOLFIRI. Baseline s-uPAR levels were assessed in 80 patients (40 ea. group) using respective CE-certified electro-chemiluminescence immunoassay (ECLIA). Biomarkers were explored using Kaplan-Meier curves and were log transformed for survival analysis by Cox proportional hazards models. All P values reported are two-sided. Results: Data from eighty patients were available for analysis. Progression free survival (PFS) and overall survival (OS) were assessed. Data indicate significance for the angiogenic biomarker uPAR to determine prognostic (HR = 3.06, CI 1.45 - 6.53, p = 0.003) and predictive (HR = 3.41, CI 2.03 - 5.74, p < 0.001) value in the treatment of Bevacizumab. Conclusions: This is the first prospective analysis of baseline s-uPAR. High baseline-s-uPAR levels were an independent predictive marker for worse bevacizumab-based first-line treatment response.
Signet ring cell colorectal cancer: Genomic insights into a rare subpopulation of colorectal adenocarcinoma.
Authors: Korphaisarn Krittiya , Morris Van Karlyle , Overman Michael J. , Fogelman David R. , Shureiqui Imad , Kee Bryan K. , Wolff Robert A. , Eng Cathy , Menter David , Hamilton Stanley R. , Dasari A. , Raghav Kanwal Pratap Singh , Mehta Trupti R. , Manuel Shanequa , Kopetz Scott 
Published: March 2017

606 Background: Colorectal signet ring cell carcinoma (SRCC) has been shown to be associated with advanced tumor stage at presentation and worse outcomes. Due to the rarity of this subtype, 1% of all colorectal adenocarcinoma (CRC), little is known about its molecular characteristics. We aimed to characterize the molecular alterations of this subgroup. Methods: Metastatic CRC (mCRC) patients (pts) with signet ring cell (SC) histology who had tumors evaluated with next generation sequencing between February 2009 and November 2015 were reviewed. SC mCRC were classified into 2 groups; SRCC (>50% of signet cells) and adenocarcinoma (AC) with SC component. Genomic alterations, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) status noted in SC mCRC were compared to non-SC mCRC pts from the Assessment of Targeted Therapies Against Colorectal Cancer program at MD Anderson Cancer Center using Pearson’s χ 2 test. Results: A total of 665 mCRC pts were included in this study. 93 pts (14%) had SC histology of which 30 (32.3%) pts were SRCC. The Table below shows key cancer genes mutation frequencies. Conclusions: Colorectal SRCC has distinct molecular features compared with non-SC and AC with SC component CRC. The frequencies of KRAS, PIK3CA and APC mutations were lower than the frequencies reported in non-SC CRC. SRCC was not associated with MSI-H or CIMP-H tumor in this study. Further studies on identification of activated pathways underlying this worse prognosis and potential therapeutic targets are required. [Table: see text]
Rational combination therapy in young vs older patients with advanced colorectal cancer (CRC).
Authors: Capasso Anna , Pitts Todd M. , Tentler John J. , Klauck Peter J , Bagby Stacey M , Nguyen Anna , Arcaroli John , Cattaruzza Fiore , Meyer Joshua E. , Connelly Caitlin , Eckhardt S. Gail , Lieu Christopher Hanyoung 
Published: March 2017

612 Background: Although CRC is rare in young adults, the incidence has increased recently and patients present more commonly with Stage III or IV disease which may reflect differing biology. Prior analyses revealed a statistically significant increase in the risk of death in young patients with metastatic CRC compared to older patients. Methods: To assess age-dependent genetic changes, DNA and RNA from younger ( < 40) and older ( > 65) CRC were isolated, and whole exome and transcriptome sequencing analysis from 4699 FFPE CRC clinical specimens were performed. Hybridization capture was performed on up to 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Samples were sequenced to high (average 688X) uniform coverage. CRC PDXs were injected into athymic nude mice and randomized into vehicle control, refametinib (MEKi), OMP-18R5 (monoclonal Ab against FZD 1, 2, 5, 7, and 8), or the combination and treated for at least 28 days. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. Alterations in CTNNB1 [p < 0.001, False Discovery Rate (FDR) = 0.07] and MLH1 (p < 0.001, FDR = 0.017) were found to be more common in younger patients. Older patients were more likely to have alterations in APC (p < 0.01, FDR < 0.01) and FAM123B (p < 0.01, FDR = 0.03). The CTNNB1 data provided support to explore the WNT pathway as a potential target for younger patients. Therefore, we conducted an in vivo study of MEKi and OMP-18R5 to assess efficacy in molecularly defined young CRC PDX models. In a young PDX models, we observed enhanced combination effects with tumor growth inhibition index (treated/control) of 13% in the combination arm (compared to tumor growth of 150 %, and 116%, respectively with MEKi and OMP-18R5 alone). Interestingly, in this PDX models, RNA sequencing data showed baseline enrichment in the WNT and mTOR pathway, not observed in the older PDX models. Conclusions: The combination of refametinib and OMP-18R5 showed enhanced antitumor activity in combination compared to the single agent arms. Studies investigating predictive biomarkers of response are currently underway.