bluuebunny/crossref_metadata_2025 huggingface dataset:
Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study.
Authors: Yalcin Suayib , Uslu Ruchan , Dane Faysal , Yilmaz Ugur , Zengin Nurullah , Buyukunal Evin , Buyukberber Suleyman , Camci Celalettin , Sencan Orhan , Kilickap Saadettin , Ozdener Fatih , Cevik Duygu
Published: March 2020

3565

Background: Colorectal cancer is one of the most frequent malignancies, second after breast cancer in women and third after lung cancer and prostate cancer in men. The aim of this study was to evaluate and compare the progression-free survival (PFS) between two arms: Arm A is a combination of BEV + XELOX; Arm B is a combination of BEV + XELOX for 6 cycles followed by maintenance BEV + capecitabine as first-line therapy in mCRC. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 pts was required to detect with 80% power an increase of 1.5 months in median PFS between two arms with a standard deviation of 3.9 months and significance level of 0.05 (10% drop-out rate). Results: A total of 123 pts were randomized. Demographic characteristics were balanced between the arms. Median treatment period was 7.5 (range 0.5–13.9) and 8.1 (range 0.1–20.7) months in Arms A and B, respectively. There was a statistically significant difference in median PFS between arms, although there was no significant difference in ORR and OS (see table). Tolerability was acceptable in both arms with the following grade 3/4 adverse events (AEs): Arm A 48.4%; Arm B 34.4% (p=0.116). Grade 3/4 diarrhoea occurred in 9.7% vs. 3.3%, weakness in 8.1% vs. 8.2%, hand-foot syndrome in 3.2% vs. 1.6%, and neuropathy in 4.8% vs. 3.3% of pts in Arms A and B, respectively. Conclusions: These findings suggest that maintenance therapy with BEV + capecitabine following induction with 6 cycles of BEV + XELOX may be superior to continuous BEV + XELOX until progression inpts with previously untreated mCRC. [Table: see text]
Implications of generating genetic test results for colon cancer in the international, population-based colon cancer family registry.
Authors: Keogh Louise A. , Fisher Douglass , Gorin Sherri Sheinfeld , Schully Sheri D , Lowery Jan , Ahnen Dennis J. , Maskiell Judith A , Lindor Noralane M. , Hopper John L. , Burnett Terrilea , Holter Spring , Arnold Julie , Gallinger Steven , Laurino Mercy , Esplen Mary-Jane , Sinicrope Pamela S ,   Colon Cancer Family Registry
Published: March 2020

3567

Background: The ability to genotype large numbers of people rapidly and inexpensively for research purposes highlights the need to develop guidelines for providing medically-relevant research results - including unanticipated findings - to study participants. The Colon Cancer Family Registry (C-CFR) is the oldest and largest international colon cancer population-based registry; its experience managing genetic research findings can offer guidance to clinicians and researchers. The C-CFR has enrolled 10,019 cases with colon cancer and 24,708 family members in six registries in the US, Canada, Australia, and New Zealand. Deleterious (“high risk”) germline mutations have been identified in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and the MutYH gene. The aims of this presentation are to: (1) report the uptake of genetic test results by C-CFR participants; (2) systematically compare disclosure protocols and barriers to uptake by registry; (3) make recommendations to guide clinicians and researchers. Methods: Uptake of genetic test results was calculated from data collected by the C-CFR; key investigators (KIs) from each registry completed a survey about disclosure decision-making; KIs also took part in discussions to generate recommendations. Results: Registry-wide molecular testing has identified deleterious MMR germline mutations for at least one member of 424 families (4%) and 48 biallelic MutYH gene carriers. Uptake of test results ranged from 56-86% (n= 1542) across registries. Barriers to disclosure include: (1) lack of pre-existing notification protocols; (2) logistics of re-consent; (3) limited involvement of genetic counselors at some registries; (4) in the US, the requirement that genetic testing be performed in a CLIA approved laboratory; (5) IRBs declining approval; and (6) budget constraints. Conclusions: Based on our international registry’s findings we recommend that researchers generating genetic information establish plans for disclosure at the outset; obtain subject consent a priori; consider subject knowledge and disclosure preferences; provide guidance and budget for clinical follow-up; and involve genetic counselors.
Molecular and clinicopathologic evidence of heterogeneity in KRAS-mutant colon cancers.
Authors: Popovici Vlad Calin , Budinska Eva , Tejpar Sabine , d'Ario Giovanni , Di Narzo Antonio Fabio , Hodgson John Graeme , Roth Arnaud , Bosman Fred , Delorenzi Mauro
Published: March 2020

3575

Background: The activation of the MEK/ERK signaling cascade by KRAS or BRAF mutations has a high incidence in colorectal cancer (CRC). While these mutations are mutually exclusive, we have identified a highly conserved gene expression pattern, characteristic to BRAF mutants, that can also be observed in KRAS mutants (AACR 2011, JCO 2012), and which defines a distinct subpopulation. Its characterization is important as it may shed a light on the observed survival and treatment response variability of this group of CRCs. Methods: A set of 257 stage II and III KRAS mutant CRCs from the PETACC3 clinical trial and a subset of 150 CRCs from TCGA project were used for this study. Gene expression data was available for all samples and, additionally, CNV and methylation data was available for some of the samples. Due to the limited number of MSI samples, the analyses were focused on MSS subpopulation. Results: The cluster analysis on the genes from the BRAF signature clearly indicated a major split of the KRAS mutants into two subgroups, that were further compared in terms of clinico-pathological and survival parameters. The BRAF-mutant-like (BML) subgroup was clearly enriched in MSI-H (p<0.001), right-sided (p=0.038) and mucinous histology (p<0.001) tumors. The enrichment in mucinous tumors remained significant also in stratified analysis by MSI status. In MSS, the BML subpopulation of KRAS mutants had the worst prognosis for overall survival (p=0.05, HR=1.6) and survival after relapse (p=0.004, HR=2.1). Analysis of differentially expressed genes between BML and the rest of KRAS mutants identified genes responsible for colon crypt differentiation, Wnt pathway activation and, more intriguingly, 50 other genes, all located on chromosome 20q, that had significantly different activation levels in BML tumors. Among these genes, there are a number of important tumor suppressors, like PLAGL2, TP53RK and POFUT1. No differences in type of KRAS mutation nor in PIK3CA mutations were found between BML and the rest of KRAS mutants. Conclusions: We identified a subgroup of KRAS mutants formed of more aggressive, poorly differentiated tumors. All these results prove that KRAS mutant CRCs form a heterogeneous group tumors.
Prognostic impact of preoperative plasma tissue inhibitor of metalloproteinase 1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled analysis of 1,024 stage II/III pts.
Authors: Brünner Nils , Shi Qian , Christensen Ib Jarle , Nielsen Hans J. , Hendriks T , Glimelius Bengt , Birgisson Helgi , Holten-Andersen Mads , Sargent Daniel J.
Published: March 2020

3576

Background: Identification of a marker with strong prognostic impact on clinical outcomes would aid in the management of pts with primary, curatively resected CRC. We conducted a pooled individual pt data analysis to confirm the prognostic value of pTIMP-1 for overall survival (OS) in stage II and III CRC. Methods: pTIMP-1 was determined in plasma using immunoassays. Samples and clinical data were included from 5 studies with a total of 1,042 stage II/III pts resected between 1991 – 2006 (Holten-Andersen (HA), 2000 [n=378], HA, 2004 [n=226], Waas, 2005 [52], Birgisson, 2010 [225], Nielsen, 2011[n=161]). To provide comparable measures across studies, pTIMP-1 values were rescaled using fractional ranks (FR, based on ranks and sample size). Pts were grouped by the median of the pTIMP-1 FR score. Stratified log-rank tests and multivariate Cox models assessed the association between OS and pTIMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had stage II disease and 50% had colon cancer. The median follow-up was 5.5 years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was significantly associated with OS (p < .0001, HR=1.38 for a 0.3 unit increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs below the median had significantly shorter OS (HR, 1.72; 95% confidence interval[CI], 1.42 to 2.08, p <0.0001), which remained significant after adjusting for age, gender, stage, disease location, and serological CEA (HR, 1.31; 95%CI, 1.07 to 1.60; p = 0.009). Results by stage are shown in the table. No evidence of an interaction between pTIMP-1 and stage or disease location (colon vs. rectal) was observed (all p > 0.6). Conclusions: pTIMP-1 is a strong prognostic marker for predicting OS independent of age, gender, CEA, stage and site of disease in curatively resected stage II and III CRC. [Table: see text]
Is there any significant difference between tumor regression grade systems of rectal cancer?
Authors: Trakarnsanga Atthaphorn , Gonen Mithat , Shia Jinru , Nash Garrett Michael , Temple Larissa K. F. , Guillem Jose G. , Paty Philip , Goodman Karyn A. , Gollub Marc , Saltz Leonard , Weiser Martin R.
Published: March 2020

3583

Background: Tumor regression grade (TRG) is a measure of histopathologic response of rectal cancer to preoperative chemoradiation (CRT) and correlates with outcomes. Several TRG systems have been reported including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan Kettering Cancer Center (MSKCC), and American Joint Committee of Cancer (AJCC). The purpose of this study is to compare the different TRG systems and determine which one(s) best predict recurrence and survival. Methods: Review of prospective maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/4 and/or N1) and treated with long-course CRT followed by total mesorectal excision. TRG was determined by measuring proportion of tumor mass replaced by fibrosis. Patients were then classified into the various TRG schemes which were compared by analyzing association with recurrence and survival using concordance index (CI) and reclassification index. CI is a measure that summarizes the predictive strength of a marker. Computing and contrasting CI across several markers is a way of selecting the best prognostic marker. Results: 75% of patients were noted to have clinical stage III disease by endorectal ultrasound or rectal MRI. Following resection with median follow-up of 39.3 months, 2% developed local recurrence and 17% developed distant metastasis. The median interval time between completion of CRT and surgery is 48 days. 20% demonstarted complete pathological response. CI of the 3 tier Mandard, 3 tier Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694, respectively (higher number indicates better prediction). The AJCC was significantly more accurate in predicting recurrence than the 3- tier Mandard (p=0.002), and Dowrak/Rodel (p=0.006). AJCC had a higher CI than MSKCC although it did not reach significance (p=0.068). Comparing the 3 tier systems, MSKCC was most accurate and correctly reclassified 17 % and 23 % of the patients Mandard and Dowrak/Rodel systems, respectively. Conclusions: TRG predicts recurrence and survival following combined modality therapy for rectal cancer. The TRG system that recently was proposed in the 7thAJCC staging is currently the most accurate predictor.
Functional SNPs in vascular endothelial growth factor (VEGF-A) and overall survival (OS) in bevacizumab-treated patients with metastatic colorectal cancer (mCRC).
Authors: Murphy Janet E. , Liebman Hannah M. , Zhou Qian , Bote Josiah T. , Daskalova Anastassia , Hooshmand Susanne M. , Ryan David P. , Kulke Matthew , Christiani David C.
Published: March 2020

3594

Background: Functional SNPs in VEGF-A are prognostic for OS in several malignancies, but not described definitively in mCRC. In bevacizumab-treated patients with advanced breast cancer, VEGF -2578AA and -1154A were predictive of OS—the latter SNP reported in a recent mCRC series as well. We examined the association between five functional VEGF-A SNPs and OS in a large cohort of bevacizumab-treated patients with mCRC. Methods: 403 patients with mCRC treated from 2004-2010 were included in a retrospective analysis. DNA extraction, genotyping, and SNP evaluation were performed according to standard protocols. Survival was calculated from the time of Stage IV diagnosis until death. Data were censored as of 12/31/2010. Results: There were 279 deaths in this group of 403 patients (69%). Median age was 55.7 (24-86 y), and 54% of patients were male. Age, sex, race, tumor grade, chemotherapies, and curative surgery (metastatectomy to negative margins) were considered. Significant clinical predictors of OS in univariate Cox modeling were cetuximab treatment [HR=1.46; 95% CI 1.13-1.88; p=0.0014], irinotecan treatment [HR=2.10; 1.32-3.35; p<0.001], and curative surgery [HR=0.36; 0.25-0.75; p<0.001]. Significant negative interaction was found between both cetuximab and irinotecan and curative surgery, and in modeling that included this interaction, only surgery remained predictive. In multivariate analysis, no association was found between VEGF-A and OS (Table). Conclusions: There was no association between five functional VEGF-A SNPs and OS in this large bevacizumab-treated mCRC cohort. [Table: see text]
Genetic variants of kinases suppressors of ras in KRAS-BRAF wild-type metastatic colorectal cancer patients treated with cetuximab and irinotecan.
Authors: Benhaim Leonor , Loupakis Fotios , Zhang Wu , Gerger Armin , Bohanes Pierre Oliver , Páez David , Cremolini Chiara , Wakatsuki Takeru , Yang Dongyun , Ning Yan , El-Khoueiry Rita , Zhang Hua , Salvatore Lisa , Schirripa Marta , Falcone Alfredo , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef
Published: March 2020

3597

Background: Scaffold proteins kinase suppressor of ras (KSRs) have emerged as critical modulators of the EGFR pathway that binds to RAS promoting ERK activation. KSR1 and KSR2 have been shown to be over expressed in various solid tumours including colon cancer. In-vitro, the down-regulation of KSR results in reduction of cells proliferation and tumour growth independently to KRAS status. Moving from this biological rational we investigated the correlation between functional polymorphisms in the KSR genes and clinical outcomes in patients with KRAS and BRAF wild-type mCRC treated with cetuximab and irinotecan. Methods: Germline DNA was obtained from peripheral blood of patients with mCRC KRAS and BRAF wild- type resistant to irinotecan treated with a combination of cetuximab and irinotecan. Seven functionally relevant SNP were selected on the basis of public literature resources and databases, 4 in the KSR1 and 3 in the KSR2 genes and analyzed by PCR followed by direct sequencing. All candidate SNPs were evaluated for association with response rate, PFS and OS. Results: A total of 66 patients were included.After a median follow-up of 13.3 months, median PFS and OS were 4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%) achieved a RECIST response. In univariate analysis, KSR2 rs11068551 any G(AG/GG) genotype was significantly associated with shorter PFS compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR=1.74 [95%CI: 1-3.04] p=0.049, log-rank test). This result remained significant in a multivariate model (HR=2.13 [95%CI: 1.15-3.95], p=0.017, log-rank test). None of the other tested SNPs were significantly associated with outcomes. Conclusions: Beyond KRAS and BRAF, some proteins including KSR are involved in modulating the level of activation of the EGFR pathway. Our results show that the functionally relevant KSR2 rs11068551 could affect PFS in advanced mCRC patients treated with cetuximab and irinotecan. Preclinical studies to confirm and further explain these preliminary findings are ongoing.
Correlation of specific cytokine profiles with high blood neutrophil-to-lymphocyte ratio and outcome in metastatic colorectal cancer.
Authors: Chen Zhi-Yu , Lieu Christopher Hanyoung , Jiang Zhi-Qin , Eng Cathy , Vauthey Jean-Nicolas , Chang George J. , Qiao Wei , Morris Jeffrey , Hong David S. , Hoff Paulo , Tran Hai T. , Heymach John , Overman Michael J. , Kopetz Scott
Published: March 2020

3598

Background: High blood neutrophil-to-lymphocyte ratio (NLR) has been previously identified as a poor prognostic marker in patients with metastatic colorectal cancer (mCRC). However, the underlying pathophysiology associated with this marker is not well defined. We validated this biomarker and investigated the relationship between circulating cytokines and high NLR. Methods: NLRs were calculated retrospectively from the ratio of peripheral blood absolute neutrophil and lymphocyte counts, and segregated based on previously determined cutoff of ≤5 and >5. Four cohorts with a total of 805 CRC pts were evaluated to confirm the prognostic clinical significance of NLR. Plasma cytokine levels were evaluated in exploratory (n=39) and validation cohorts (n=166) of previously untreated mCRC patients using multiplex-bead assays, and correlated with NLR. Results: High NLR is present in 20% of CRC patients and is associated with poor prognosis, independent of known prognostic factors (Table). Expression of 6 cytokines (IL-6, IL-8, IL-2Ra, HGF, M-CSF and VEGF) correlated with NLR>5 in both the exploratory and validation cohort. In the validation cohort, an additional 14 cytokines correlated with NLR>5, including high EREG,AREG, and TGF-α, and low TRAIL. By hierarchial clustering, these 20 cytokines fall into 3 overlapping major clusters: angiogenic cytokines, inflammatory cytokines, and epidermal growth factor ligands. In the validation cohort, pts with a composite cytokine score below the median have longer survival than patients with high scores (40.0 mo vs 20.0 mo, HR = 2.24; 95% CI=1.47–3.41; P<0.001). Conclusions: High peripheral blood neutrophil/lymphocyte ratio (NLR) is associated with poor outcomes independent of other known prognostic features. NLR correlates with discrete sets of cytokines which may reflect important biological features in poor prognosis mCRC. [Table: see text]
Aflibercept versus placebo in combination with FOLFIRI in previously treated metastatic colorectal cancer (mCRC): Mean overall survival (OS) estimation from a phase III trial (VELOUR).
Authors: Joulain Florence , Van Cutsem Eric , Iqbal Sheikh Usman , Hoyle Martin , Allegra Carmen Joseph
Published: March 2020

3602

Background: VELOUR evaluated the efficacy and safety of the novel fusion protein aflibercept (VEGF Trap) in combination with FOLFIRI in mCRC patients previously treated with oxaliplatin. Median OS showed significant improvement with 12.06 months in placebo arm vs 13.50 months in aflibercept arm (p=0.0032; HR=0.82 [95.34% CI: 0.71 to 0.94]) [Van Cutsem, 2011]. Since survival data in oncology are usually right skewed, median survival is preferred for regulatory purposes. However, mean survival estimation can render a more meaningful estimate for long term benefit of interventions, and be effectively applied to clinical and economic decision support. Estimating mean OS also allows payers to derive an estimation of total costs and outcomes in the population. The purpose of this study was to estimate the mean OS for VELOUR trial. Methods: During the trial follow-up period, mean OS is not observable and can be estimated by extrapolating the trial Kaplan-Meier curve using a survival function. Several standard parametric distributions were tested: exponential, weibull, lognormal, loglogistic and gompertz. Akaike’s Information Criteria (AIC), Bayesian Information Criteria (BIC) and graphical method were used to evaluate the goodness of fit of the distributions. Models were run by treatment arm separately or combining the two arms and using treatment as covariate to control for variation. Results: Using AIC/BIC and graphical method, loglogistic function best fit the VELOUR data both with and without treatment as covariate. Weibull distribution is used for sensitivity analysis. Conclusions: Using loglogistic function, mean OS benefit for aflibercept in combination with FOLFIRI is at least 2.9 months (versus 1.4 months difference in median survival). The results have important implications for clinical and economic decision support. Study NCT00561470 was funded by sanofi, in partnership with Regeneron. [Table: see text]
Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?
Authors: Foltran Luisa , Aprile Giuseppe , De Maglio Giovanna , Pisa Federica Edith , Casagrande Mariaelena , Ferrari Laura , Lutrino Stefania Eufemia , Mazzer Micol , Masiero Elena , Pella Nicoletta , Giovannoni Mariella , Iaiza Emiliana , Cardellino Giovanni , Ermacora Paola , Durastante Vittorio , Cristin Antonio , Petri Roberto , Pizzolitto Stefano , Fasola Gianpiero
Published: March 2020

3612

Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]
Novel colon cancer tumor suppressor gene, β-defensin 1, to predict recurrence in patients with stage II and III colon cancer.
Authors: Labonte Melissa Janae , Bohanes Pierre Oliver , Yang Dongyun , Loupakis Fotios , Wilson Peter M.D. , Gerger Armin , Ning Yan , Wakatsuki Takeru , Zhang Wu , Benhaim Leonor , Ladner Robert D. , El-Khoueiry Anthony B. , El-Khoueiry Rita , Iqbal Syma , Lenz Heinz-Josef
Published: March 2020

3622

Background: Human β-defensin 1 (hBD-1) encoded by the DEFB1 gene is an antimicrobial peptide involved in the innate immune response and is expressed in epithelial cells, including the colon. hBD-1 has been shown to have tumor suppressor functions in urothelial cancer models. We tested whether 4 germline single nucleotide polymorphisms (SNPs) in DEFB1 could predict time to tumor recurrence (TTR) in stage II and III colon cancer (CC) patients. We then sought to demonstrate if hBD-1 has tumor suppressor functions in CC models. Methods: A total of 234 patients, 105 stage II and 129 stage III, treated with 5-FU-based chemotherapy at the University of Southern California were included. The median follow-up time was 4.4 yrs. SNPs were analyzed from whole blood samples using direct DNA-sequencing. To gain insight into hBD-1’s function, hBD-1 expression in CC cell lines was determined by qRT-PCR and Western blotting. hBD-1 expression was induced ectopically and CC cells and viability, membrane permeability, cell-cycle and apoptosis analyzed. Results: Stage III patients with rs1800972 DEFB1 -44G containing genotypes had longer TTR than patients with C/C genotype (11.3 mo vs 2.7 mo; p=.008). In contrast in stage II, patients with rs1799946 DEFB1 -52A containing genotypes, had significantly longer TTR than patients with G/G genotype (16.8 mo vs 5.9 mo; p=.017). In the multivariate analysis, both DEFB1 -44C/G and DEFB1 -52G/A SNPs remained significant, respectively in stage III (HR=.419; 95%CI .201-.87; p=.020) and in stage II (HR=.360; 95%CI .152-.853; p=.020). Haplotype of all four SNPs was significantly associated with stage-specific TTR (to be presented at the meeting). In CC cell line models, there was a loss of hBD-1 expression, and induction of hBD-1 expression resulted in a loss of cell viability, membrane permeability and the induction of apoptosis. Conclusions: The results demonstrate for the first time evidence of hBD-1’s potential influence on the microenvironment and its role as a tumor suppressor in CC. Further studies need to be conducted to better understand the role of hBD-1 in CC development and progression and evaluate the potential utility of hBD-1 as a therapeutic strategy.
Impact of “poorly differentiated clusters” in primary lesion as a novel prognostic indicator in colorectal liver metastasis.
Authors: Konishi Tsuyoshi , Ueno Hideki , Ishikawa Yuichi , Ueno Masashi , Saiura Akio , Yamamoto Junji , Fukunaga Yosuke , Nagayama Satoshi , Yamamoto Chiriko , Hase Kazuo , Hashiguchi Yojiro , Hatsuse Kazuo , Muto Tetsuichiro , Yamaguchi Toshiharu
Published: March 2020

3625

Background: Preoperative predictors for survival are needed in colorectal liver metastasis in order to select poor-risk group that truly requires perioperative chemotherapy. This study aimed to elucidate survival predictors in patients undergoing curative hepatectomy for colorectal liver metastasis, particularly focusing on the impact of poorly differentiated clusters (PDC); a novel histologic grading system in primary lesion. Methods: A total of 424 consecutive patients undergoing curative resection of both primary colorectal cancers and metastatic liver lesions at two referral centers were enrolled in the study. Determinants of overall survival (OS) and recurrence free survival (RFS) after hepatectomy were investigated by univariate and multivariate analysis, using detailed clinicopathological parameters in primary and metastatic lesions. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a x20 objective lens in a field containing the highest number of clusters at invasive front of primary lesions, and tumors with <5, 5 to 9, and ≥10 clusters were classified as PDC grade (G)1, G2 and G3, respectively (n=65, 132, and 227 tumors, respectively). Results: OS and RFS at 3 years were 59% and 27%, respectively, with average follow up period of 43 months. PDC grade in primary lesion was strongly associated with both 3-year-OS (83%, 62%, and 51%, respectively, p<0.0001) and 3-year-RFS (55%, 30%, and 17%, respectively, p<0.0001). Multivariate analysis revealed that PDC grade in primary lesion was the most potent prognostic factor after hepatectomy independent of T and N of primary lesion and size of liver metastasis. Conclusions: PDC grade in primary lesion is a novel potent prognostic indicator in colorectal liver metastasis, which is independent of T and N. It is noteworthy that PDC grade can bias the survival in clinical studies targeting perioperative chemotherapy in colorectal liver metastasis.
Effect of BSA dosing on 5-FU exposure among colorectal cancer patients depending on their gender and age.
Authors: Haregewoin Abebe , Hamilton Stephanie A. , Grier Charles E. , Kaldate Rajesh R.
Published: March 2020

3627

Background: 5-fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg · h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg · h/L has been proposed. Methods: Plasma samples from the initial treatment cycle of 927 CRC patients who received 2,400 mg/m2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects. Results: There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). See table. These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg · h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive suboptimal doses than older patients. Conclusions: BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimizedby 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings. [Table: see text]
Surgical resection and peri-operative chemotherapy for colorectal cancer (CRC) liver metastases in routine clinical practice: A population-based outcomes study.
Authors: Booth Christopher M. , Li Gavin , Biagi James Joseph , Krzyzanowska Monika K. , Mackillop William J. , Nanji Sulaiman
Published: March 2020

3632

Background: Resection of liver metastases combined with peri-operative chemotherapy is an important treatment option for patients with advanced CRC. Most of the literature describes outcomes achieved in highly selected patients treated at a few high volume institutions. Here we report the results of a population-based study of the management and outcome of all patients who underwent resection of CRC liver metastases in Ontario, Canada. Methods: All cases of CRC in Ontario who underwent surgical resection of liver metastases in 1994-2009 were identified using the population-based Ontario Cancer Registry (OCR). The OCR captures diagnostic and demographic information on ~98% of all incident cancer cases in Ontario. We linked electronic records of treatment to the OCR to identify surgery, neoadjuvant (NACT) and adjuvant chemotherapy (ACT). We describe time trends in treatment and survival using 3 study periods: 1994-1999, 2000-2004, 2005-2009. Results: During 1994-2009, 2717 patients underwent resection of CRC liver metastases in Ontario; mean age was 65 years and 61% were male. From 1994-2009 there was a 103% increase in the number of patients undergoing resection of liver metastases (117/year to 237/year) while incident cases of CRC during this time increased by 31% (5285/year to 6956/year). Use of NACT increased over the study period: 94-99, 11% (78/700); 00-04, 15% (124/830); 05-09, 36%; (424/1187), (p<0.001). Use of ACT also increased: 94-99, 38% (263/700); 00-04, 40% (335/830); 05-09, 45% (532/1187), (p=0.006). In 2005-2009 there was substantial variation across geographic regions in use of NACT (range 19% to 46%, p=0.029) and ACT (range 31% to 56%, p=0.015). Five year overall survival during the 3 study periods was 36% (95%CI 32-39%), 40% (95%CI 36-43%), and 47% (95%CI 43-51%) (p<0.001). Conclusions: Resection of CRC liver metastases in routine practice in the general population of Ontario is associated with survival outcomes that are comparable to those reported in case series from leading comprehensive cancer centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection.
Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II.
Authors: Glynne-Jones Robert , James Roger , Meadows Helen , Begum Rubina , Cunningham David , Northover John , Ledermann Jonathan A. , Beare Sandra , Kadalayil Latha , Sebag-Montefiore David ,   ACT II Study Group
Published: March 2020

4004

Background: In the ACT I trial, relapse-free survival was improved with CRT compared to RT alone, but the CR rate at 6 weeks was similar (39% CRT, 30% RT alone; p=0.08). Most studies assessed CR between 6 and 12 weeks following completion of CRT. We investigated the association between observation of CR at 3 different time-points and progression-free and overall survival (PFS, OS), to determine the optimal time to assess this early endpoint. Methods: ACT II recruited 940 pts between 2001 and 2008. It compared, in a factorial design, CisP versus MMC when combined with 5-FU CRT, and two cycles of maintenance chemotherapy versus no maintenance. CR (complete absence of tumour and node negative) was assessed by rectal exam or imaging at 11, 18 and mandated CT at 26 weeks after the start of CRT. Median follow-up was 5 years. Pts were excluded from analysis if assessment was not done/ missing at one or more time points (n=245). Data from 695 pts were analysed. Results: Pt characteristics (all 940) median age 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). CisP did not improve OS (HR: 0.96, p=0.89) or PFS (HR: 0.85, p=0.43) compared to MMC. This is consistent with the lack of an absolute difference at 18 and 26 weeks, but not at 11 weeks (where a difference was found). CR patients (compared to not-CR) had a significantly lower risk of progression/death. The association between these outcomes and response was strongest at 26 weeks. 202/695 (29%) pts not in CR at 11 weeks were CR at 26 weeks. Conclusions: 29% of pts not in CR at 11 weeks achieved CR at 26 weeks. Early surgical salvage would not have been appropriate for these pts. We recommend assessment at 26 weeks in future trials. [Table: see text]
A pooled analysis of phase II trials of gemcitabine (GEM)-containing doublets plus bevacizumab (BEV): Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer (APC)?
Authors: Van Loon Katherine , Kim George P. , Espinoza Anne Marie , Fogelman David R. , Iyer Renuka V. , Picozzi Vincent J. , Wolff Robert A. , Javle Milind M. , Ko Andrew H.
Published: March 2020

4038

Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p<0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p<0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]
Evaluation of predictive factors for thromboembolic events in patients with advanced pancreatic cancer: Evaluation of the CONKO-004 (PROSPECT) study cohort.
Authors: Pelzer Uwe , Bischoff Sven , Stieler Jens , Sinn Marianne , Oettle Helmut , Dörken Bernd , Riess Hanno
Published: March 2020

4044

Background: Patients (pts) with advanced pancreatic cancer (APC) often suffer from symptomatic thromboembolic events (sVTE). The CONKO-004 trial showed that the low molecular weight heparin (LMWH) enoxaparin reduces sVTE (p<0.05, number needed to treat: 12) without increasing the rate of major bleeding when prophylactically applied. Our goal was to identify predictive factors for sVTE in pts with APC undergoing first-line chemotherapy. Methods: We analyzed the 152 (out of 312) pts randomized in the observation group.SVTE incidence was 9.9%. To identify foremost risk factors we used clinical parameters like performance status, stage, grading, primary or recurrent, gender, age, body mass index, erythropoietin stimulating agents (darbepoetin), as well as baseline laboraty parameters such as creatinine, hemoglobin, WBC, platelets, INR, ptt, CEA, carboanhydrat 19-9, AST, ALT, AP and GGT. The multivariate logistic regression model with forward stepwise selection process was used for this estimation. With reference to a previously proposed scoring system (Khorana et al; Blood 2008) we evaluated the score as well. Results: No single parameter could be isolated demonstrating significant influence on the incidence of sVTE in pts with APC. We verified the Kohrana scoring model with our 152/312 pts. Applying the score to our pts we didn’t discriminate pts between the two high risks groups (Table). Conclusions: Predictive models may help to identify cancer pts at high risk for sVTE to consider preventive anticoagulation. Within a cancer entity at high risk for sVTE such as pts with APC we did not succeed in the identification of single predictive parameters.For pts with APC undergoing first line chemotherapy primary prevention with LMWH should therefore be considered for the whole group of pts for at least three months. [Table: see text]
Phase II trial of bevacizumab, irinotecan, cisplatin, and radiation as preoperative therapy in esophageal adenocarcinoma.
Authors: Ilson David , Goodman Karyn A. , Janjigian Yelena Yuriy , Shah Manish A. , Kelsen David Paul , Rizk Nabil P. , Rusch Valerie W. , Wu Abraham Jing-Ching , Campbell Jenny , Capanu Marinela , Bains Manjit S.
Published: March 2020

4061

Background: Preop chemo and radiotherapy (RT) with weekly irinotecan (I), cisplatin (C) and 5040 cGy is tolerable and active [Cancer, in press]. Bevacizumab (B) + weekly I/C in advanced esophagogastric cancer increased response rate and PFS without an increase in toxicity [JCO 24: 5201; 2006]. In a phase II trial in esophageal adenocarcinoma (EA) we combed B + I/C with RT as preop therapy. A toxicity analysis after 10 patients (pts) undergoing surgery indicated no unexpected toxicity with B [JCO 27: Abstract 4573; 2009], and we completed a planned accrual of 33 pts. Methods: Pts had resectable distal esophageal or Siewert’s I or II EA, T2-3 or N1 staged by EUS, PET, and CT scan. Induction chemo: I: 50-65 mg/m2 + C: 30 mg/m2 weeks 1,2,4,5, B: 7.5 mg/kg weeks 1 and 4; Chemort: 180 cGy daily fractions to 5040 cGy, I/C weeks 7,8,10,11+ B weeks 7,10. Esophagectomy was planned 6-8 weeks after RT. Postop: B: 7.5 mg/kg every 3 weeks for 8 cycles. Results: 33 pts were enrolled. 26 male: 7 female; distal esophagus 11 (33%), GEJ 22 (67%); 21 T3N1 (64%); 10 T3N0 (30%); 2 T2N0-1 (6%). 25/33 pts went to surgery (76%), 24 had R0 resection (73%). Pathologic CR 5 pts (15%). 8 pts did not going to surgery: 2 for adverse events (9%, 1 CVA due to patent foramen ovale, 1 esophageal perforation due to endoscopic biopsy), 6 for progressive disease (18%). 21/24 pts (88%) received adjuvant B, 20 (95%) completed all cycles. Grade 3/4 toxicity in 30 evaluable pts during chemort: 24% neutropenia, 3% neutropenic fever, 23% esophagitis, 13% dehydration, 13% thrombocytopenia, 7% pulmonary embolism, 3% nausea/vomiting. Surgical complications: 3 anastomotic leaks (12%), 4 respiratory failure (16%), 1 pulmonary embolism (4%), 2 post op deaths (8%). At a median follow up of 20 months, PFS was 14 months and OS was 30 months. Conclusions: The addition of B to preop chemoRT in EA was tolerable without increase in treatment toxicity or surgical complications. There was no suggestion of improved pathologic CR, PFS, or OS with the addition of B to I/C/RT. Evaluation of B in phase III trials of chemort does not appear warranted. Supported by a grant from Genentech.
Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).
Authors: Lee Soonil , Kang Jung Hun , Lim Do Hyoung , Park Keon-Woo , Oh Sung Yong , Hwang In Gyu , Lee Jeeyun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Park Se Hoon
Published: March 2020

4064

Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p<0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p<0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.
Assessment of the 7th edition of the AJCC classification and a proposal of a new classification in patients with gastric cancer undergoing D2 gastrectomy.
Authors: Catalano Vincenzo , Sisti Valerio , Spada Daniele , Graziano Francesco , Cicetti Moreno , Giordani Paolo , Alessandroni Paolo , Baldelli Anna Maria , Casadei Virginia , Luzi Fedeli Stefano , Rossi David , D'Emidio Silvia , De Nictolis Michele , Testa Enrica , Fiorentini Giammaria , Zingaretti Costantino
Published: March 2020

4084

Background: Studies on Asian, US, and German patients have moved some criticisms on the validity of the 7th edition of the AJCC classification to discriminate outcome of gastric cancer stages. We investigated the effect of this AJCC classification in a high-quality surgical populations of patients receiving D2 lymphadenectomy. Methods: From the prospective database at San Salvatore Hospital, Pesaro, we identified 515 patientswith gastroesophageal junction (Siewert II and III) or stomach adenocarcinoma who underwent gastrectomy with curative intent from 1998 to 2010. Lymphadenectomy extended to the 3rd level 12p/b nodes (D2/D3) was performed in all patients. Overall survival (OS) probabilities, calculated from the date of surgery to the date of death, from any cause, were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 58% of patients were male,median age was 73 years (range 36-96). Median number of examined lymph nodes was 32 (range, 1-89), and only 8.9% of patients had less than 15 examined lymph nodes; 96 patients received adjuvant chemo- or chemoradiotherapy. As shown in the table, we proposed a revised staging system (Pesaro Staging System, PSS), which performs better than the 7th edition of AJCC classification in terms of survival differences between stages. Conclusions: This study confirms once again that the 7th edition of the AJCC classification does not discriminate adequately the outcome from stage to stage. In a European population of patients undergoing gastrectomy plus at least D2 lymphadenectomy, the revised staging system, PSS, better defines patient prognosis. [Table: see text]