bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of UGT1A’s polymorphisms and RAS: RAF mutations based on phase II study of biweekly XELIRI plus bevacizumab as a second-line therapy in patients with metastatic colorectal cancer.
Authors: Tanioka Hiroaki , Suzuki Nobuaki , Hazama Shoichi , Nagasaka Takeshi , Iwamoto Yasuo , Negoro Yuji , Nakagami Yuki , Tsunedomi Ryouichi , Nagano Hiroaki , Okajima Masazumi
Published: January 2019

565

Background: We have previously reported biweekly XELIRI + bevacizumab 10 mg/kg as second-line chemotherapy in metastatic colorectal cancer (mCRC). In this study, we investigated relationships between efficacy/toxicity and biomarkers (polymorphisms of UGT1A’s, somatic mutations of RAS, BRAF and PIK3CA). Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin based regimen were eligible for this study. Treatment protocol administrated capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan 150mg/m2 on day 1, and bevacizumab 10 mg/kg on day 1 every 2 weeks. Results: Between January 2013 and July 2015, 51 patients were enrolled in this study. The patients’ characteristics were as follows (N=51): median age, 66 years (range 41–82); male/female, 29/22; the median PFS was 5.47 months (95% CI, 4.23–7.40 months), the median OS was 13.5months (95%CI, 11.57– 20.23months), and the median TTF was 4.5 months (95%CI, 3.97–6.93 months). The response rate was 16% (95%CI, 7.2–29.1), and the disease control rate was 76% (95%CI, 61.8-86.9). Grade 3 or higher adverse events were mainly febrile neutropenia in two patients and hypertension in 14 patients (28.6%). The patients with UGT1A7 (387G<T) genotype had a trend to suffer from diarrhea ( p=0.089 by Fisher’s exact test). The summary of somatic mutations of cancer was RAS (wild/mutant = 21/23), BRAF (wild/mutant = 39/5), PIK3CA (wild/mutant = 42/0), and MSI (MSS/MSI-H = 42/2). There was no statistical association between efficacy and somatic mutations. The sample size might influenced such the results. Conclusions: In mCRC patients, biweekly XELIRI + bevacizumab 10 mg/kg is effective and feasible as second-line chemotherapy. We found several biomarkers that predict toxicities in this study. Further study is required for predicting the efficacy based on biomarkers using somatic mutations of cancer and germline polymorphisms. Clinical trial information: UMIN000009280.
Clinicopathological characteristics of patients with gastrointestinal stromal tumor according to progranulin expression.
Authors: Koo Dong-Hoe , Do In-Gu , Oh Sukjoong , Lee Yun-Gyoo , Kim Kyungeun , Sohn Jin Hee , Park Jung Ho , Sohn Chong Il , Son Byung Ho , Serrero Ginette , Yoo Chang Hak
Published: January 2019

57

Background: As an autocrine growth factor, progranulin (PGRN) has been known to stimulate tumorigenesis and proliferation of several types of cancer cells. However, little is known about the clinicopathological features of patients with gastrointestinal stromal tumor (GIST) according to the PGRN expression. Methods: A retrospective analysis was performed for patients with GIST who underwent curative surgical resection between March 2007 and March 2018. PGRN expression in tumor cells was evaluated by immunohistochemical (IHC) analysis and semi-quantitatively categorized (no expression, 0; weak, 1+; moderate, 2+; strong, 3+). High expression was considered for tumors graded 2+ or 3+ staining intensity. Results: A total of 54 patients were analyzed, and 31 patients (57%) were male. Median age at surgery was 60 years (range, 33-79), and the most common primary site was stomach (36 patients, 67%). Spindle histology was observed in 35 patients (65%). Median tumor size was 8 cm (range, 2-47), and low mitotic count (≤ 5/50 HPF) was observed in 18 patients (33%). According to the modified NIH classification, 42 patients (78%) were grouped into high risk. With IHC evaluation, KIT and CD34 expression were observed in 51 patients (94%) and 40 patients (80%), respectively, and 27 patients (50%) had high PGRN-expressing tumors. Among the 34 patients whose tumors were genotyped, 25 patients (74%) had an exon 11 mutation, and D842V was observed in 3 patients (9%). According to the PGRN expression, high PGRN-expressing tumors had more epithelioid/mixed histology (68% vs. 32%; p = 0.046), and KIT exon 11 mutation (76% vs. 24%; p = 0.037). Regarding other clinicopathological characters, such as sex, age at surgery, primary site, size, mitotic count, risk classification, and KIT/CD34 expression, there was no significant difference between high PGRN-expressing tumors and low PGRN-expressing tumors. Conclusions: High PGRN-expressing GISTs had more epithelioid/mixed histology and more KIT exon 11 mutation in GIST patients who underwent curative surgical resection.
Chemoradiation-induced alteration of programmed death-ligand 1 and CD8+ tumor-infiltrating lymphocytes in rectal cancer.
Authors: Baretti Marina , Fu Wei , Wang Hao , Anders Robert A , Azad Nilofer Saba , Zhu Qingfeng
Published: January 2019

570

Background: DNA damage and subsequent neoantigen formation has been hypothesized as a mechanismfor radiotherapy and PD-1/PD-L1 pathway inhibition to synergize in an antitumor immune response. We investigated neoadjuvant chemoradiotherapy (nCRT)-induced changes in CD8+ tumor infiltrating lymphocyte, PD-L1 and mucin expression in rectal cancer patients as compared to patients who did not receive nCRT. Methods: Tumor samples were collected from rectal adenocarcinoma patients who had undergone resection between 2008-2014 with (n = 62) or without (n = 17) nCRT treatment. Tissue sections were stained with CD8 and PD-L1 antibodies for immunohistochemistry. Whole slides images were acquired at 20x magnification. The prevalence of positive CD8 stained cells was recorded in tumor, interface tumor side, interface background rectal side. Image analysis (HALO Indica Labs) was used to determine the density (# of cells/surface area analyzed) of CD8 expressing lymphocytes. The percentage of PD-L1 membranous expression was manually counted in tumor cells (TC), tumor stroma (TS) and invasive front (IF). Mucin expression was determined as the percentage of the mucin area in the whole tumor mass area. Results: PD-L1 expression on TCs was identified in 7.7 % (6/78) of specimens. All 6 cases had received nCRT (p = 0.33). 80% and 75.5% of the nCRT cases showed PD-L1 expression on TS and IF respectively, versus 20% (p = 0.55) and 24.5% (p = 0.56) in non-nCRT cases. The median densities of CD8+ infiltrating T lymphocytes in tumor, interface tumor side, interface background rectal side did not differ significantly between the two groups (p = 0.79, p = 0.47, p = 0.22). No nCRT-changes in mucin expression observed in the 28 evaluable cases (p = 0.25). Conclusions: nCRT exposure was associated with a non-significant difference in PD-L1 expression on TS and IF cells in patients with rectal adenocarcinoma as compared to non-nCRT case, possibly due to sample size limitations. Further mechanistic investigations and comprehensive analysis of other immune checkpoints are needed to understand nCRT-induced immunologic shift in rectal cancer and to expand the potential applicability of checkpoint inhibitors in this setting.
The relationship between tumor budding, tumor microenvironment, and survival in patients with primary operable colorectal cancer.
Authors: Van Wyk Hester Catharina , Roseweir Antonia K. , Anderson Ditte , Sutton Elizabeth , Horgan Paul G. , McMillan Donald C , Edwards Joanne
Published: January 2019

581

Background: Tumour budding is an independent prognostic factor in colorectal cancer and has recently been defined by the International Consensus Conference on Tumour Budding. The aim was to use the ITBCC budding evaluation method to examine relationships between tumour budding, tumour factors, tumour microenvironment, gene expression profiles and survival in patients with primary operable CRC. Methods: Hematoxylin and Eosin (H&E) stained slides of 953 CRC patients, diagnosed between 1997 and 2007 were evaluated for tumour budding according to the ITBCC-criteria. The tumour microenvironment was evaluated using tumour stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumour inflammatory cell infiltrate. Differential gene expression was assessed using TempO-Seq gene expression profiling (BioSpyder Technologies Inc., CA, USA) using the Surrogate+Tox targeted panel (2,733 genes selected for biological diversity, maximal information content, and widespread pathway coverage). Results: High budding (n = 269/ 28%) was significantly associated with TNM stage (P < 0.001), venous invasion (P < 0.001), weak KM grade (P < 0.001), high TSP (P < 0.001) and reduced cancer specific survival (CSS) (HR = 5.04; 95% confidence interval [CI], 3.50-9.51; P < 0.001) and was independent of venous invasion, KM grade, and Ki67 proliferation index. RNA expression analysis was employed using TempO-Seq to determine differential gene expression between tumours with (n = 8) and without budding (n = 18). Three genes were identified as significantly differentially expressed: S100A2 (S100 calcium binding protein A2) was upregulated by 2.9 fold (padj < 0.00001); REG1A (regenerating family member 1 alpha) was downregulated by 4.7 fold (padj < 0.01) and LCN2 (lipocalin 2) was downregulated by 2.2 fold (padj < 0.01). Conclusions: Tumour budding stratifies patients’ survival in primary operable colorectal cancer and associates with differing gene expression profiles and factors of the tumour. Therefore, the ITBCC budding evaluation method should be used to assess tumour budding as supplement the TNM staging system and can help to further subdivide colorectal cancer into new prognostic groups.
Blood-based biomarkers in metastatic colorectal cancer patients treated with FOLFIRI plus regorafenib or placebo: Results from LCCC1029.
Authors: Liu Yingmiao , Burdett Kirsten , Starr Mark D. , Brady J. Chris , Hatch Ace Joseph , Ivanova Anastasia , Moore Dominic T. , Hammond Kelli , Lee Michael Sangmin , O'Neil Bert , Innocenti Federico , Owzar Kouros , Sanoff Hanna Kelly , Nixon Andrew B.
Published: January 2019

587

Background: The LCCC1029 trial demonstrated that addition of the multitargeted kinase inhibitor regorafenib (Rego) to FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) modestly prolonged progression-free survival (PFS). In this preplanned analysis, circulating angiogenic and inflammatory proteins were explored as potential prognostic and predictive biomarkers of Rego benefit. Methods: Plasma samples from 149 mCRC pts (107 in Rego + FOLFIRI and 42 in placebo + FOLFIRI) were evaluated for 20 markers at baseline (n = 149) and cycle 1 day 21 (C1D21, n = 81). Predictive and prognostic values of each marker at baseline were analyzed for both PFS and overall survival (OS) using Cox proportional hazard models. On-treatment changes were quantified as fold change [log2(C1D21/baseline)] and differences between arms were evaluated using the Mann-Whitney test. Results: The primary objective of this study was to determine whether any marker was predictive of benefit with Rego for PFS. Although no treatment by marker interactions were significant after adjusting for multiple testing, the top three markers of interest were OPN (unadjusted p-values of 0.02), VCAM-1 (0.02), and PDGF-AA (0.04). VCAM-1 was also predictive for OS benefit in pts treated with Rego (unadjusted p = 0.01). Baseline levels of multiple markers (including HGF, IL-6, PlGF, VEGF-R1, OPN) were prognostic for both PFS and OS. Higher levels of these markers were associated with worse survival. Biomarker changes in response to treatment were explored and compared between arms. Fold change of three markers (PlGF, VEGF-A, VCAM-1) were significantly different between arms (p < 0.0001), all being markedly up-regulated in the Rego arm compared to the placebo after treatment. Conclusions: In this hypothesis generating report, VCAM-1, OPN, and PDGF-AA were the top biomarkers when analyzing the potential predictive association with PFS, where a lower hazard was observed for pts receiving Rego. Candidate prognostic markers were identified, including PlGF and VEGF-R1, key factors in VEGF biology. Biomarker changes observed here may offer insights into potential combinatorial strategies with Rego for future studies.
On-treatment changes of plasma protein biomarkers in CALGB/SWOG 80405 (Alliance).
Authors: Hatch Ace Joseph , Ou Fang-Shu , Zemla Tyler , Starr Mark D. , Brady John C. , Liu Yingmiao , Innocenti Federico , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary , Lenz Heinz-Josef , Hurwitz Herbert , Venook Alan P. , Nixon Andrew B.
Published: January 2019

588

Background: CALGB/SWOG 80405 found no difference in overall survival (OS) or progression-free survival (PFS) in 1137 patients with KRAS wild-type metastatic colorectal cancer (mCRC) treated with either the anti-VEGF agent bevacizumab (Bev) or the anti-EGFR agent cetuximab (Cet) in combination with chemotherapy (FOLFOX or FOLFIRI) as first-line therapy. Additional molecular biomarkers are required for the optimization of treatment choices for patients with mCRC. Methods: Levels of 24 proteins were assayed in EDTA-plasma samples using multiplex ELISA techniques. Plasma samples were collected at baseline and cycle 2 day 1 (C2D1). Analyses of baseline markers have been presented previously. Changes from baseline to C2D1 were expressed as an L-ratio (LR, log2 of C2D1 divided by baseline measure). LRs dichotomized at 0 were analyzed for potential prognostic and predictive effects on OS and PFS using Cox models while adjusting for confounders (post-hoc optimized cutpoints were used for PLGF, TIMP1, VCAM1, and VEGFR3 due to skew in the distributions of these markers). P-values are not corrected for multiple testing. Results: Baseline and matched C2D1 samples from 446 patients (212 Bev/234 Cet) were available for analysis. Thirteen markers were differentially modulated between arms (p < 0.05). Early increases in CD73 (p = 0.001), ICAM1 (p = 0.022), TIMP1 (p = 0.001), TSP2 (p = 0.024), and VEGFR3 (p = 0.006) were prognostic for shorter OS. Increases in ICAM1 (p = 0.008), TIMP1 (p = 0.042), and TGFB1 (p = 0.039) were prognostic for shorter PFS. Changes in VEGFR3 (pint = 0.097) and TGFBR3 (pint = 0.052) were predictive for OS and PFS, respectively. No other markers were predictive for OS or PFS (p < 0.1). Conclusions: Changes in circulating plasma protein biomarkers observed in patients enrolled in CALGB/SWOG 80405 were both prognostic and predictive for OS and PFS and warrant further study. Such changes could provide valuable information and help guide treatment decisions. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180830; ClinicalTrials.gov: NCT00265850. [Table: see text]
Prognostic significance of circulating tumor cells in patients with gastric cancer: Epithelial mesenchymal transition and perioperative kinetics.
Authors: Ishiguro Yui
Published: January 2019

59

Background: Circulating tumor cells (CTCs) have been shown to be heterogeneous. This study aimed to identify the prognostic significance of CTCs in patients with gastric cancer, focusing on epithelial mesenchymal transition and perioperative kinetics. Methods: Peripheral blood (7.5 ml) was taken from patients (n = 54) before curative resection, and at 7 days, 1 and 6 months postoperatively. CTCs were enriched using density gradient centrifugation and magnetic-activated cell sorting (negative selection). Cell suspensions were characterized by multi-immunofluorescence staining against cytokeratin (CK) and N-cadherin, and by DAPI staining. CTCs were defined as nucleated cells expressing CK or N-cadherin. Threshold analysis identified 1 CTC/7.5 ml as an optimal cut-off value. The median observation period was 735 days. Results: CTCs were detected in seven patients (24%) with early cancer and 14 patients (56%) with advanced cancer (p < 0.05). Cells were identified as either N-cadherin+/CK−/CD45− or N-cadherin+/CK+/CD45−, but no N-cadherin−/CK+/CD45− cells were observed. The median follow-up period was 24.5 months. After 2 years, postoperative recurrence was detected in nine patients, all of whom had advanced gastric cancer and N-cadherin+/CK−/CD45− CTCs preoperatively. In terms of perioperative kinetics (just before, 7 days and 1 month after surgery), we divided patients with advanced cancer into three risk groups: A, preoperative CTCs ≥1 and increased postoperatively; B, preoperative CTCs ≥1 and decreased postoperatively; C; no preoperative CTCs. The recurrence rates in the above groups were 80% (4/5), 44% (4/9), and 0% (0/11), respectively. Conclusions: Numerous CTCs expressed N-cadherin but not CK. Perioperative measurement of CTCs may be a useful surrogate marker for recurrence risk.
Association of DNA damage response and repair genes (DDR) mutations and microsatellite instability (MSI), PD-L1 expression, tumor mutational burden (TMB) in gastroesophageal cancers.
Authors: Cerniglia Michael , Xiu Joanne , Grothey Axel , Pishvaian Michael J. , Hwang Jimmy J. , Marshall John , Vanderwalde Ari M. , Shields Anthony Frank , Lenz Heinz-Josef , Salem Mohamed E. , Philip Philip Agop , Goldberg Richard M. , Korn W. Michael , Kim Sunnie S.
Published: January 2019

60

Background: DDR mutations are associated with higher neoantigen load and tumor infiltrating lymphocytes, and are a potential biomarker for immunotherapy. We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with MSI, PD-L1, and TMB, known predictors for immune checkpoint inhibitors. Methods: 20 DDR mutations were tested by Next-Generation Sequencing (NGS) with a 592-gene panel on a total of 1935 (709 EC; 831 GC; 355 GEJ) cancers. TMB was assessed by NGS, MSI by NGS or fragment analysis, and PD-L1 by IHC (22c3 for CPS or SP142). Results: GC had the highest DDR mutation rate compared to EC and GEJ (27% vs. 20%, p = 0.0005 and 17%, p = 0.0002, respectively). MSI-High (MSI-H) was significantly more common in the DDR mutated cohort (DDR-M) compared to non-mutated cancers (18% vs. 1%; p < 0.0001). TMB-High (≥ 10 mutations/megabase [mt/MB]) was higher in DDR-M (35% vs. 21%; p < 0.0001); in DDR-M cohort, GC had the highest TMB compared to DDR-M EC and GEJ (mean: 13.8 vs. 9.4 vs. 10 mt/MB, respectively; p < 0.0001). DDR mutations were more frequent in the PD-L1 combined positive score (CPS) ≥ 50 group than CPS 0 (42.9% vs. 24%; p = 0.037) and CPS 1-9 (42.9% vs. 20.6%; p = 0.005). ARID1A, ATRX, BRCA2, and PTEN were the most prevalent DDR mutations in MSI-H (87%, 31%, 25%, 24%, respectively); ARID1A, ATRX, BRCA2, and PTEN in TMB-High (47%, 7.7%, 6.7%, 6.8%) and ARID1A, BRCA2, RAD50, and WRN in PD-L1 high (CPS ≥ 10) (48.5% vs. 5.2% vs. 2.5% vs. 3.4%). Conclusions: MSI-H, TMB-high and high PD-L1 expression were significantly more prevalent in the DDR-M cohort compared to non-DDR-mutated cancers, most pronounced in GC. Alterations in ARID1A, ATRX, BRCA2, and PTEN were correlated with MSI-H and TMB-high while ARID1A, BRCA2, RAD50, and WRN were correlated with increased PD-L1 expression. Our findings may help identify patients for tailored immunotherapy approaches in future clinical trials.
Comprehensive -omic analysis of 152 CRC patients allows greater subclassification than CMS or sidedness alone.
Authors: Szeto Christopher , Kazmierczak Kevin , Chambers Andrew , Kim Yeoun Jin , Nguyen Andrew , Tan Iain B. , Benz Stephen Charles , Vaske Charles Joseph
Published: January 2019

601

Background: Despite relatively high TMB in CRC, immune checkpoint inhibition (ICI) response is lower than in similarly mutated tissues such as melanoma (ORR 10-20% vs. 20-50%). MSI-status can be used to pre-select likely-responders, however MSI is rare. There is a need to guide ICI candidacy in CRC. Four transcriptomic-based CRC consensus molecular subtypes (CMS) have been described with ad hocclinical associations. We sought to confirm these subtypes in proteomic assays and their clinical associations. Methods: 152 CRC tumors from the National Cancer Centre Singapore were available for analysis. Tumor/normal-paired DNAseq (WGS or WES) and deep RNAseq was performed. Mass-spec based global proteomics was successfully performed on 143/152 samples. Consensus between RNAseq and global proteomics was confirmed by correlation significance analysis. MSI-status was determined by both PCR and WGS/WES profiles. CMS types, checkpoint expression, and immune-infiltration deconvolution were calculated upon RNAseq data. A CMS-like clustering of proteomic data was identified by analyzing homogeneity of candidate clusterings with CMS types. Significant enrichment for MSI, immune status, CMS types, and clinical covariates was analyzed. Results: DNAseq-based MSI and PCR-based MSI were statistically equivalent (adj. p < 1.4E-14). 3075/5135 genes were significantly correlated between RNAseq and global proteomic assays. The most correlated genes within COSMIC cancer-related genes were enriched for MHC binding processes. Clustering of immune-expression deconvolution bifurcated into hot and cold tumors. Significant association was found between CMS1, MSI, transverse sides, and being immune hot. Conversely, CMS2 was found to be significantly MSS, left-sided, and immune cold. A semi-supervised clustering of global proteomic data significantly recapitulated some CMS subtypes, but grouped CMS1 (MSI enriched) and CMS3 (Ras mt enriched) subtypes. Genes driving this association were significantly enriched for ECM organization. Conclusions: CMS1 tumors are the best candidates for ICI therapy. CMS3 co-clusters with CMS1 in ECM genes within proteomic data, warranting further research of CMS3 ICI outcomes.
Characteristics of colorectal cancer (CRC) patients with BRCA1 and BRCA2 mutations.
Authors: Naseem Madiha , Xiu Joanne , Salem Mohamed E. , Goldberg Richard M. , Vanderwalde Ari M. , Grothey Axel , Philip Philip Agop , Seeber Andreas , Puccini Alberto , Tokunaga Ryuma , Battaglin Francesca , Berger Martin D. , Barzi Afsaneh , Hanna Diana L. , Zhang Wu , Hwang Jimmy J. , Shields Anthony Frank , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef
Published: January 2019

606

Background: Between 3-5% of CRC patients have BRCA1/2 pathogenic mutations. This study aims to identify associations between BRCA1 and BRCA2 mutations and clinical characteristics in CRC. Methods: A total of 6396 CRC tumor samples were tested with Next-Generation Sequencing (NGS) on a 592-gene panel, pathogenic or presumed pathogenic variants were counted as mutations (mt). Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS. Statistical correlations were investigated using ANOVA, Chi-square and t-test. Results: Among tumors sampled, 53% derived from male patients and median age was 60 years. BRCA1 mt were detected in 1.1% (n = 72) of tumors, while BRCA2 in 2.8% (n = 179). BRCA1 mt were more frequent in women (W;65%) than men (M;35%) (p = 0.0019) while no relationship with sex was seen for BRCA2 mt (42% F vs. 58% M). No significant associations with age were noticed. Majority of pathogenic mt in BRCA1 (52%; n = 34) and BRCA2 (62%; n = 103) occurred in MSI-High (MSI-H) cases. MSI-H pts had more frameshift mt in both BRCA1/2 than MSS pts. MSS cases had lower rates of BRCA1 and 2 pathogenic mt (44% and 37%, respectively). Right-sided tumors were significantly associated with BRCA1 (p = 0.0056) and BRCA2 (p < 0.0001) mt in MSI-H cases only. BRCA1/2 mt were associated with higher TMB in all CRCs, including MSI-H and MSS cases (p < 0.001). POLE mt (n = 31) were associated with higher BRCA1/2 mt rates (9.6%, 55% respectively). Among MSS cases with POLE wild-type status, BRCA1 (p = 0.0269) and BRCA2 (p = 0.0151) mt were associated with high TMB and combining both BRCA1/2 mutations led to an even higher TMB (3.6%; p = 0.001). Conclusions: This is the first study to show that BRCA1/2 mutations are more frequent in MSI-H, and independently associated with higher TMB, pathogenic POLE mutations, and right-sided tumors in MSI-H CRCs. Given their relationship with TMB, the presence of BRCA1/2 mutations may be potential predictive biomarkers for checkpoint or PARP inhibitors in CRC, a finding that should be prospectively evaluated.
A systematic review and network meta-analysis of regorafenib and TAS-102 in refractory metastatic colorectal cancer.
Authors: Sonbol Mohamad Bassam , Benkhadra Raed , Wang Zhen , Firwana Belal , Mody Kabir , Kasi Pashtoon Murtaza , Hubbard Joleen Marie , Murad M. Hassan , Ahn Daniel H. , Bekaii-Saab Tanios S.
Published: January 2019

619

Background: Regorafenib (at a starting dose of 160 mg/day, rego 160), regorafenib (with a weekly dose escalation, rego 80+) and TAS-102, are suggested treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these 3 strategies. Methods: We searched PubMed, Embase, and Cochrane CENTRAL, for randomized controlled trials evaluating TAS 102 or regorafenib in refractory mCRC patients who progressed on/intolerant of previous oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Results: Six trials (3 of regorafenib and 3 of TAS-102) at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to BSC in terms of PFS (Rego 160: HR = 0.4, CI 0.26 to 0.63; TAS-102: HR = 0.46, CI 0.40 to 0.52) and OS (Rego 160: HR = 0.67, CI 0.48 to 0.93; TAS-102: HR = 0.67, CI 0.57 to 0.80). Network analysis showed that there was no difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR = 0.44, CI 0.23 to 0.84) and PFS (HR = 0.37, CI 0.21 to 0.66). There was a numerical advantage for Rego 80+ compared to TAS-102 and Rego 160 (see table). Conclusions: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. [Table: see text]
Left- versus right-side metastatic colorectal cancer: Teasing out clinicopathologic drivers of disparity in survival.
Authors: Mendis Shehara Ramyalini , Lee Belinda , Lee Margaret , Wong Rachel , Kosmider Suzanne , Shapiro Jeremy David , Yip Desmond , Steel Simone Anne , Nott Louise M. , Jennens Ross , Lipton Lara Rachel , Burge Matthew E. , Field Kathryn Maree , Ananda Sumitra , Beck Sophie , Wong Hui-Li , Gibbs Peter
Published: January 2019

623

Background: Patients with metastatic colorectal cancer (mCRC) arising from a right sided colorectal cancer (RC) have an inferior survival versus patients with a left sided colorectal cancer (LC). Previous analyses have suggested that multiple factors contribute. Methods: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry has prospectively captured comprehensive data on consecutive mCRC patients since 2009. For this analysis LC were defined as primary tumors at or distal to the splenic flexure and included rectal cancers. We analysed patient, tumor, treatment and outcome data. Results: Of 2306 patients enrolled from July 2009–March 2018, median age 67 years (range 18–100), 1559 (67.6%) had a LC. Patients with a RC were older (median 71 vs 65 years, p < 0.001), more likely to be female (50.2% vs 36.9%, p < 0.001) and to have a Charlson score ≥ 3 (67.5% vs 54.6%, p < 0.001). More common in RC, where tested, were BRAF mutations (22.3% vs 7.2%, p < 0.001) and deficient mismatch repair (6.4% vs 1.5%, p < 0.001), but not RAS mutations. Peritoneal metastases were more frequent in RC (29.7% vs 14.9%, p < 0.001). RC patients were more likely to have their primary tumor resected (77.9% vs 70.6%, p < 0.001) and to receive less first-line chemotherapy (72.2% vs 78.7%, p = 0.001). Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs 10.8 months, HR 1.38, p < 0.001). Median overall survival (OS) for all RC patients was inferior (19.6 vs 27.5 months, HR 1.44, p < 0.001). Primary side remained a significant factor for OS in multivariate analysis. Conclusions: Our data confirms the poor prognosis associated with RC, contributed to by multiple factors. However, primary side remains significant even when adjusting for these, indicating the existence of further as yet undefined differences. [Table: see text]
Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).
Authors: Palmieri Lola-Jade , Mineur Laurent , Tougeron David , Rousseau Benoit , Granger Victoire , Gornet Jean-Marc , Smith Denis Michel , Lièvre Astrid , Galais Marie-Pierre , Doat Solene , Pernot Simon , Bignon Anne Laure , Metges Jean-Philippe , Baba-Hamed Nabil , Sefrioui David , Obled Stephane , Vitellius Carole , Bouche Olivier , Henriques Julie , Coriat Romain ,   Association des Gastro-Entérologues Oncologues (AGEO)
Published: January 2019

626

Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.
Obesity and its impact on outcomes in stage III colon cancer (CC) patients receiving adjuvant chemotherapy (AC).
Authors: Ding Qirui , McKinnon Geoff , Xu Yuan , Cheung Winson Y.
Published: January 2019

627

Background: Obesity may complicate CC surgery, which can result in potential AC delays. We aimed to determine the effect of body mass index (BMI) and body surface area (BSA) on CC outcomes, accounting for variations in the time interval between surgery and AC. Methods: We analyzed a population-based cohort of patients from Alberta, Canada who were diagnosed with stage III CC from 2011 to 2016 and underwent AC. Patients were grouped based on their baseline BSA (underweight, < 20 kg/m2; normal, 20-24; overweight, 25-29; obese ≥ 30) and BMI (< 2 m2 vs ≥ 2 m2). Logistic regression models were constructed to examine the effect of BMI/BSA on delays between surgery and AC. The Kaplan-Meier method was used to estimate overall (OS) and cancer-specific survival (CSS) and Cox proportional hazards models were developed to evaluate the impact of BMI/BSA on these outcomes, adjusting for confounders. Results: We examined 915 patients: median age was 64 years, 510 (56%) were men and 155 (17%) had a Charlson comorbidity index (CCI) ≥ 2. In this cohort, 126 (14%), 623 (68%) and 166 (18%) were stage IIIA, IIIB and IIIC, respectively. In total, 132 (14%) were underweight, 452 (49%) normal weight, 233 (26%) overweight and 98 (11%) obese. Based on the Mosteller formula, 527 (58%) patients had normal BSA and 368 (42%) had high BSA. Obese patients were more likely to be men (67% vs 56%, p < 0.001) and had worse CCI (28% vs 17% with CCI ≥ 2, p = 0.03) when compared to non-obese patients. Neither BMI (p = 0.14) nor BSA (p = 0.44) correlated with AC delays after surgery. Similar OS and CSS were observed regardless of BMI and BSA (p = 0.76 and 0.80 for OS and p = 0.60 and 0.89 for CSS, respectively). In multivariate Cox models, only worse nodal stage was associated with inferior OS and CSS (HR 4.74, 95%CI 1.96-11.47, p < 0.001 for OS; HR 4.92, 95%CI 1.42-17.00, p = 0.006 for CSS, comparing IIIC vs IIIA), but BMI and BSA were not (see Table). Conclusions: Obesity as measured by BMI and BSA did not correlate with AC delays or worse outcomes in stage III CC patients. [Table: see text]
Health-related quality of life in the early-access phase IIIb study of trifluridine/tipiracil in pretreated metastatic colorectal cancer (mCRC): Results from PRECONNECT study.
Authors: Taieb Julien , Price Timothy Jay , Ciardiello Fortunato , Peeters Marc , Wyrwicz Lucjan , Bachet Jean-Baptiste , Borg Christophe , De La Fouchardiere Christelle , Becquart Martin , Mounedji Nadjat , Vidot Loïck , Sabater Javier , Falcone Alfredo
Published: January 2019

638

Background: Pivotal RECOURSE trial assessed efficacy and safety of trifluridine/tipiracil (FTD/TPI) in mCRC patients (pts) without collecting QoL data. Here we describe a preliminary analysis of QoL in mCRC pts treated with FTD/TPI in the ongoing phase 3b PRECONNECT study (NCT03306394). Methods: Eligible pts had histologically mCRC previously treated with available therapies and an ECOG-PS of 0/1. Pts received FTD/TPI (35 mg/m2 twice daily) orally on days 1–5 and 8–12 of each 28-day cycle. ECOG-PS and QoL were assessed at baseline, every 4 weeks on FTD/TPI and at discontinuation. QoL was measured with EORTC QLQ-C30, EQ-5D index and VAS questionnaires. Utility score was based on EQ-5D index and values from Germany, UK and Spain. For QLQ-C30, clinical relevance was assessed using a 10 point threshold. Changes in utility score and VAS were deemed clinically relevant if ≥ 9 and ≥ 7, respectively. Only results where ≥ 10% of the initial cohort completed the questionnaires were assessed, corresponding to 7 cycles of treatment. Results: 464 pts were included at cutoff (1 November 2017). Median FTD/TPI treatment duration was 2.96 months (range 0.4–14.7). Median time to ECOG-PS ≥ 2 was 8.7 months with 74.3% of pts remaining at ECOG-PS 0/1 at discontinuation. At baseline mean QLQ-C30 global health status was 62.75 (SD = 20.50; median 66.67) with values for all scales in line with EuroQoL reference for mCRC (variation < 10 points on function and < 5 on symptom scales). Baseline EQ-5D VAS was 65.55 (SD = 20.11; median 70.00) and utility score 73.11 (SD = 20.71; median 75.27). There was no clinically relevant difference in mean change from baseline at any time point on global health status score nor any of functional or symptom scales. Similar results were obtained for utility score and VAS. QoL was maintained on FTD/TPI in all subgroups based on age and ECOG-PS for all scales except for appetite loss increase at cycle 5 in pts ≥ 65 and in ECOG-PS 0 in whom the score increased by 12.2 and 10.4, respectively. Conclusions: The first prospective data on QoL suggest that mCRC pts can maintain their QoL while on FTD/TPI treatment. Clinical trial information: NCT03306394.
A phase I/II study of pexa-vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer: Safety report.
Authors: Morelli Maria Pia , Xie Changqing , Brar Gagan , Floudas Charalampos S. , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Greten Tim F.
Published: January 2019

646

Background: The efficacy of immune checkpoint inhibitor has been limited to small portion of colorectal cancer (CRC) patients whose tumors with mismatch repair (MMR) gene abnormalities. There is an urgent need for patients with MMR proficient (pMMR) tumors. Oncolytic immunotherapy represents a novel therapeutic platform for the treatment of cancer with unique activity compared to conventional chemotherapy. The trial is to evaluate if the combination of Pexa-Vec oncolytic virus (PV) with immune checkpoint inhibition enhance antitumor immunity. Methods: Patients with microsatellite-stable and MSI-H mCRC refractory to PD-1 monotherapy were enrolled. Patients received either Arm A treated with PV + Durvalumab or Arm B with PV + Durvalumab and Tremelimumab. Each arm had two dose levels (DL) of PV, 3 x 108 pfu in DL1 and at 109 pfu in DL2, every 2 weeks for total 4 doses. The first dose of PV was administered on Day -12, followed by three more dose administration on Days 2, 16 and 30 in combination with the immune checkpoint inhibition. The primary endpoint is response rate, safety, tolerability and feasibility of these combination therapy in refractory metastatic CRC. Results: Here we report the safety data of Arm A.A total of 9 patients was enrolled so far. The longest follow-up time is 8 months. Four patients received DL1 PV and subsequent five patients received DL2 PV. No DLT was observed at the time of this abstract. No grade 4-5 adverse event (AE) were observed. All patients experienced lymphopenia. All patients with DL2 developed fever, hypotension and papulopastular rashes and were successfully managed with antipyretics, fluid support and skin protection, respectively. The most frequent treatment-related AEs were lymphopenia (8 [100%], fever (7 [87.5%]), chills (6 [75.0%]), hypotension (5 [62.5%]), papulopastular rashes (5 [62.5%], flu-like symptoms (2 [12.5%]), Nausea/vomiting (2 [12.5%]). Conclusions: Pexa-Vec in combination with Durvalumab showed a favorable safety profile. Clinical trial information: NCT03206073.
Clinical implications of microsatellite instability in mucinous colorectal cancer.
Authors: Keane Fergus , Martin Darrell , Leonard Gregory D. , Hynes Sean , Sheehan Margaret
Published: January 2019

657

Background: Colorectal Cancer(CRC) is becoming increasingly recognised as a heterogeneous tumor type. Mucinous histological subtype is identified in 10-15% of CRCs, most commonly those with microsatellite instability (MSI), and has traditionally been associated with unfavorable outcomes and poor response to chemotherapy. In contrast, MSI is associated with relatively favourable pathological features and better outcomes, compared with CRCs with microsatellite stability (MSS), such that under the 2010 WHO classification, MSI mucinous CRC is considered low grade, while MSS mucinous CRC is classified as high grade. The aim of this study is to establish the significance of microsatellite stability status in non-metastatic mucinous colorectal cancer. Methods: Between 2010 and 2017, 69 patients with stage II or stage III mucinous colorectal cancer were identified. Microsatellite status was tested in all patients (MSS or MSI), and histological and clinical data, as well as recurrence rates, were assessed in both groups. MSI status was established using polymerase chain reaction(PCR) technique. Results: Sixty-nine patients with mucinous CRC were identified. The median age for the entire group was 73 years (range 32-87), no difference in gender was identified. 63%(n=43) and 37%(n=26) were stage II and stage III respectively at diagnosis. The majority of mucinous CRCs were right-sided (72%). 33% (n=23) were identified as microsatellite unstable (MSI). MSI status was associated with right sided tumours (78% right-sided vs 22% left-sided, p<0.05), older age at diagnosis (mean 76 years vs 68 years, p=0.01), and lower TNM staging at diagnosis (83% vs 52% diagnosed stage 2, p=0.007) compared with the MSS group. A lower disease recurrence rate was identified in the MSI group (4.3% vs 13% in MSS group) at median follow-up time of 33 months (range 8-93 months). Conclusions: In patients with mucinous colorectal cancer, MSI status is a useful marker of favourable histological and clinical features, and is associated with better outcomes. Our study supports the current 2010 WHO classification, and highlights the clinical and prognostic significance of MSI status in this patient cohort.
Genomic alterations in appendiceal carcinoma using circulating DNA.
Authors: Shaib Walid Labib , Roberts Ali , Akce Mehmet , Wu Christina , Alese Olatunji B. , El-Rayes Bassel F.
Published: January 2019

658

Background: Appendiceal cancers (AC) comprise around 0.5% of all gastrointestinal neoplasia. The genomic landscape of AC has not been well studied. The yield of circulating tumor DNA (ctDNA) from the plasma of patients with AC has not been reported. The aim of this study is to confirm the feasibility of NGS using ctDNA and characterize common alternations in the genomic profile of AC. Methods: The molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant 360) across multiple institutions, was evaluated. The test detects single nucleotide variants in 54 -73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 303 AC patients were evaluated; 169 female (56%). Median age was 56.8 (range: 25-83). ctDNA NGS testing was done on 372 plasma samples; 48 patients had testing performed twice, 9 three times, and 1 was tested four times. Genomic alterations were defined in 207 (55.6%) samples with a total of 288 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. TP53 associated genes were most commonly altered (n = 96, 33.3%), followed by KRAS (n = 41, 14.2%), APC (n = 19, 6.6%), EGFR (n = 15, 5.2%), BRAF (n = 13, 4.5%), NF1 (n = 13, 4.5%), MYC (n = 9, 3.1%), GNAS (n = 8, 2.7%), PI3CA (n = 7, 2.4%), MET (n = 6, 2.08%), ATM in 6 (1.6%). Other genomic alterations of low frequency, but clinically relevant: AR (n = 4, 1.39%), TERT (n = 4, 1.39%), ERBB2 (n = 4, 1.39%), SMAD4 (n = 3, 1.04%), CDK4 (n = 2, 0.69%), NRAS (n = 2, 0.69%), FGFR1 (n = 2, 0.69%), FGFR2 (n = 2, 0.69%), PTEN (n = 2, 0.69%), RB1 (n = 2, 0.69%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA were all reported once. Conclusions: Evaluation of ctDNA was feasible among individuals with AC. The frequency of genomic alterations in ctDNA testing is similar to those previously reported in tissue NGS. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in patients with AC.
MSI-GC-01: Individual patient data (IPD) meta-analysis of microsatellite instability (MSI) and gastric cancer (GC) from four randomized clinical trials (RCTs).
Authors: Pietrantonio Filippo , Raimondi Alessandra , Choi Yoon Young , Kang WonKi , Langley Ruth E. , Kim Young Woo , Kim Kyoung-Mee , Nankivell Matthew Guy , Perrone Federica , Kook Myeong-Cherl , An Ji Yeong , Grabsch Heike I. , Morano Federica , Cheong Jae-Ho , Noh Sung Hoon , Lee Jeeyun , Cunningham David , Di Bartolomeo Maria , Fucà Giovanni , Smyth Elizabeth Catherine
Published: January 2019

66

Background: In CLASSIC and MAGIC, MSI was a good prognostic factor, and adjuvant/perioperative chemotherapy had null/detrimental effect. Given the low prevalence of MSI in GCs and its association with other good prognostic variables, larger datasets are needed to draw more robust evidences on its specific prognostic/predictive impact. Methods: This was a multinational IPD meta-analysis of resectable GC pts enrolled in MAGIC, CLASSIC, ARTIST, ITACA-S. Data on pts’ demographics (age, sex, and race), primary site (stomach versus junctional), histotype (intestinal vs. other), T/N stage (7th TNM), treatment received (multimodal therapy vs. surgery alone) and MSI were pooled. Univariable and multivariable associations with disease-free survival (DFS)/overall survival (OS) were assessed. The predictive role of MSI according to treatment received was assessed overall and in the 2 RCTs with a surgery alone arm (MAGIC+CLASSIC). Results: We pooled 1,552 pts with available MSI status: 121 (7,8%) were MSI, 572 Caucasian/980 Asian. In MSI versus MSS subgroups, 5-y DFS was 71.8% (95% CI: 63.8-80.7%) versus 52.3% (49.6-55.0%) (HR = 0.50, 95% CI 0.35-0.72; p < 0.001); 5-y OS 77.4% (69.9-85.8%) versus 59.2% (56.6-62.0%) (HR = 0.50, 95% CI 0.34-0-74; p < 0.001). In multivariable analyses, MSI was independently associated with DFS (HR = 0.48 [0.33-0.70]; p < 0.001) and OS (HR = 0.48 [0.29-0.81]; p = 0.005), as T/N/race/treatment. Conclusions: In resectable primary GC, MSI is an independent good prognostic marker that should be adopted as stratification factor in future RCTs. Chemotherapy omission and/or immune checkpoint blockade should be prospectively investigated in MSI-high GCs according to the clinically-defined risk of relapse. [Table: see text]
Identifying the importance of integrating routine pharmacogenomic testing for UGT1A1 and DPYD/tyms genetic variants in patients receiving irinotecan and/or 5-fluorouracil chemotherapy.
Authors: Baldeo Candice , Hughes Caren , Shahjehan Faisal , Kamatham Saivaishnavi , Kasi Pashtoon Murtaza
Published: January 2019

660

Background: Adverse toxicities to chemotherapy remain a limiting factor for patients receiving treatment for malignancies. In gastrointestinal cancers, particularly metastatic colorectal cancer, the majority of front line treatment remains chemotherapy containing 5-fluorouracil and/or irinotecan. One particular cause that can predispose a patient to increased toxicity from 5-fluorouracil is genetic variation in the DPYD gene, as well as TYMS gene. Similarly, genetic variation in the UGT1A1 gene can increase the risk of irinotecan toxicity. These gene variations may have major implications when deciding on treatment regimens for these types of patients; however, they are not routinely checked. Methods: In Mayo Clinic Florida, patients with metastatic colorectal cancer receiving 5-fluorouracil and/or irinotecan chemotherapy during the period of July 2017-July 2018 were tested for genetic variants in DPYD/TYMS and UGT1A1. This testing was done during routine clinic visit either by buccal swab or blood test. The DPYD/TYMS and UGT1A1 variant results were evaluated together with a pharmacist for recommendations regarding dose reductions on 5-fluorouracil and irinotecan respectively. Results: A total of 292 patients were tested. Total number of patients who had a variation in the DPYD/ TYMS and/or UGT1A1 gene was 169 (57.9%). The UGT1A1 variation was the most prevalent with 154 (52.7%) patients having a variant (115 heterozygous variant, 34 homozygous variant and 5 double heterozygous variant). Specifically there were 3 patients with both UGT1A1 and DPYD variants and 3 patients with both UGT1A1 and TYMS variants. One patient had both DPYD and TYMS variations. Conclusions: Routine pharmacogenomic testing for UGT1A1 and DPYD/TYMS genetic variants should be done in all patients receiving irinotecan and 5-fluorouracil chemotherapy respectively. Avoiding or preemptively dose reducing these agents in patients with gene variations may help prevent toxic adverse events and make treatment more tolerable.