bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl).
Authors: Tabernero Josep , Allegra Carmen Joseph , Rougier Philippe R , Scagliotti Giorgio , Philip Philip Agop , Lakomy Radek , Ramlau Rodryg , Assadourian Sylvie , Chevalier Soazig , Van Cutsem Eric 
Published: March 2020

3579 Background: Three db, pbo-controlled studies were conducted with IV Afl in metastatic cancer patients (pts) (colorectal [CRC], Afl + FOLFIRI [WCGC 2011, abstract O-0024]; lung [LC], Afl + docetaxel [WCLC 2011, abstract 511]; and pancreatic [PC], Afl + gemcitabine [WCGC 2009 abstract O-0006]). Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6 mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AEs) was performed on data from these studies. Methods: A fixed-effect logistic regression model was used, including study, treatment, and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Summary incidences (% of pts) and RR are presented for NCI grade 3-4 events. Results: Safety data from a total of 2662 pts (Afl, 1333; pbo, 1329) were included for analysis. Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant only for hypertension, proteinuria, and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. [Table: see text]
Mechanisms mediating the negative interaction between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in patients (pts) with KRAS mutant (MT) colorectal cancer (CRC).
Authors: Freeman Daniel J. , Ogbagabriel Selam , Xie Jiansong , Juan Gloria , Potter Nicholas , Dekeyser Josh , Radinsky Robert 
Published: March 2020

3580 Background: Phase 3 trials have shown that pts with MT KRAS tumors have shorter progression-free survival and overall survival when an EGFR inhibitor is added to Ox-containing chemotherapy (CT) (Bokemeyer et al 2011, Douillard et al 2010). However, KRAS status alone is not predictive of pt outcomes in this setting. The negative interaction has not been observed in pts with wild-type (WT) KRAS tumors receiving an EGFR inhibitor and platinum-CT or with MT KRAS tumors receiving an EGFR inhibitor with irinotecan (Peeters et al 2010, Van Cutsem et al 2009). Our goal was to understand the pharmacodynamic interaction between EGFR inhibitors and Ox in KRAS MT CRC cells. Methods: Isogenic MT and WT KRAS-expressing HCT116 CRC cells were treated with Ox, SN-38 (the active metabolite of irinotecan), panitumumab, gefitinib, or inhibitors of MEK, PI3K or Src as single agents or in combination. Viability was measured using an ATPlite assay. Cellular distribution of EGFR was visualized by a confocal microscopy. Downstream activation of MAPK and PI3K was detected by Western blotting. Results: Treatment (tx) with gefitinib, but not panitumumab, reversed the anti-proliferative effects of Ox in the MT KRAS-expressing CRC cells vs Ox alone (p<0.0005) despite no differences in the number of platinum-DNA adducts. Neither tx reversed the anti-proliferative effects of Ox observed in the WT KRAS-expressing cells or SN-38 in either the MT or WT KRAS-expressing cells. EGFR was predominantly expressed in the cytoplasm of KRAS MT cells vs on the cell surface in the KRAS WT cells, which may explain the inability of panitumumab to reverse the anti-proliferative effects of Ox in the CRC cells. Combination tx of MT KRAS CRC cells with Ox and gefitinib increased pAKT which was not observed with Ox alone. Tx of the MT KRAS-expressing cells with a MEK, PI3K or Src inhibitor reversed the negative interaction between Ox and gefitinib (p<0.0005). Conclusions: Feedback though AKT may contribute to the increased resistance to Ox in KRAS MT cells. Inhibitors of MEK, PI3K, or Src reversed the negative interaction between the EGFR inhibitors and Ox in a MT-KRAS genetic background.
Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with metastatic colorectal cancer (mCRC): Assessment as prognostic and predictive biomarkers of response to panitumumab (pmab).
Authors: Peeters Marc , Douillard Jean-Yves , Van Cutsem Eric , Siena Salvatore , Zhang Kathy , Williams Richard Thomas , Wiezorek Jeffrey S. 
Published: March 2020

3581 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR). Significant improvement in progression-free survival (PFS) was demonstrated in pts with wild-type (WT) KRAS mCRC treated with pmab+FOLFOX4 (1st-line; study 20050203), pmab+FOLFIRI (2nd-line; study 20050181), and pmab monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12 and 13 are established biomarkers for lack of clinical benefit to anti-EGFR therapies. We retrospectively examined individual MT KRAS codon 12 and 13 alleles as prognostic and predictive biomarkers of response in three phase 3 studies. Methods: Pts were randomized to receive FOLFOX4, FOLFIRI, or best supportive care +/- pmab 6.0 mg/kg Q2W in trials 20050203, 20050181, and 20020408, respectively. The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results: MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096), 45% (486/1083), and 43% (184/427) of pts in trials 20050203, 20050181, and 20020408, respectively. MT KRAS allele distribution was conserved across studies and balanced between treatment arms. Baseline demographic and clinical features were comparable between all MT KRAS allele subgroups. There was no consistent evidence that any individual MT KRAS allele, compared to the remaining MT KRAS alleles or the entire MT KRAS group, differentially impacted PFS or overall survival (OS) in control arm-treated or pmab-treated pts. Only in the pmab+FOLFOX4 arm of study 20050203 were G13D (unfavorably) and G12V (favorably) significantly associated with OS. Response rates were similar between MT KRAS allele groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a significant negative predictive factor for OS. Conclusions: The lack of consistent results across three lines of therapy indicates pts whose tumors harbor MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab therapy. Currently, only pts with WT KRAS mCRC should be treated with EGFR antibodies.
Examining the effects of metformin on survival outcome in stage II/III colorectal cancer patients with diabetes mellitus.
Authors: Lee Guek Eng , Aung Thinzar , Lim Kiat Hon , Tan Wah Siew , Tai Wai Meng David , Suhaimi Nur-Afidah Binte , Tan Min-Han , Tan Iain B. 
Published: March 2020

3589 Background: Insulin resistance and deregulation of the insulin-like growth factor (IGF) axis is implicated in colonic carcinogenesis. Metformin inhibits hepatic gluconeogenesis and increases insulin sensitivity. It induces AMPK activation, thus inhibiting mTOR and downstream survival and proliferation pathways. We evaluated the effects of metformin on survival outcomes of patients with stage 2 and 3 colorectal cancer (CRC). Methods: Among 1455 patients with stage II or III colorectal cancer, we identified 344 patients with both CRC and diabetes mellitus. 219 diabetic patients received metformin and 125 diabetic patients were not receiving metformin. Patient’s demographics, clinical and histopathologic characteristics, overall survival, time to recurrence and relapse-free survival were evaluated. Molecular analysis for AMPK, and mTOR pathway on archival tissue is ongoing. Results: After a median follow-up of 78 months (6.5 years), there was no difference in survival outcomes between diabetic and non-diabetic patients. Among diabetic patients, there were 99 relapses and 90 deaths. Metformin use was associated with improved overall survival (HR 0.23; 95%CI: 0.15-0.35 p<0.01), time to recurrence (HR 0.63; 95%CI: 0.41-0.96) and relapse-free survival (HR 0.47; 95%CI:0.33-0.67,p<0.01). In multivariate analysis, after adjustment for T stage, N stage and patients' age, metformin use remained associated with improved overall survival (HR 0.18, p<0.01); time to recurrence (HR 0.55; p<0.04) and relapse-free survival (HR 0.44, p<0.01). Results of molecular correlative studies performed on archival tissue will be presented at the meeting. Conclusions: Among patients with diabetes and colorectal cancer, use of metformin is associated with improved survival outcomes in both univariate and multivariate analysis lending support to the hypothesis that it may have anti-cancer activity.
U.S. patients receiving resin 90Y microspheres for unresectable colorectal liver metastases: A multicenter study of 506 patients.
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Rose Steven C. , Nutting Charles W. , Moeslein Fred M , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric 
Published: March 2020

3590 Background: Implantation of radioactive microspheres via the hepatic artery with Yttrium-90 (90Y) is termed “radioembolization, (RE)”. Resin microspheres were FDA cleared for use in colorectal liver metastases (mCRC) in 2002. Rapid worldwide acceptance of this therapy has resulted in greater than 30,000 procedures conducted in the past 10 years. This investigator-initiated study focuses on RE treatment outcomes in US-only patients since 2002. Methods: A retrospective multi-institutional study was designed to analyze the outcome of consecutively treated mCRC patients undergoing RE by experienced treatment centers in the USA using resin 90Y microspheres. IRB approval was obtained by each center with independent data collection and analyses. Primary endpoints: CTC 3.0ae toxicity, RECIST response and survival; baseline treatment parameters, prior chemotherapy, and liver directed therapies. Results: 506 patients at 10 institutions (193 M, 313 F) received 770 RE treatments; median age = 60.4 years (20.8 – 91.9 years); median number of RE treatments per patient = 1.0 (1-5 treatments). Active extrahepatic disease was present at first RE in 34.8% of patients. The majority (90%) of patients received prior chemotherapy, with 30.6% also having undergone prior hepatic surgery/ablative procedures. Median follow up after RE = 8.4 mo. (0.4 – 67.6 mo.) with median survival = 10.1 mo. (95% CI 9.1 – 12.0). For first RE treatment, median tumor volume was 146.0 mL (2.8 – 3228.0 mL). Median radiation activity delivered = 1.18 GBq (0.12 – 2.29 GBq), lung shunt median = 4.8 % (.02 – 45%). Total grade 1-3 events were 32% GI, 44% fatigue and 1% liver failure. Only 2.4% of all treatments required an overnight stay post-procedure. Conclusions: The modern USA experience of 90Y therapy for unresectable, heavily pretreated mCRC liver metastases is encouraging with a median survival of 10.1 months after first RE procedure. Toxicity was mild and of short duration in most patients. RECIST response is being analyzed currently as are data of additional patients.
First-line chemotherapy plus cetuximab in patients grouped according to prognostic risk factors: Analysis of the CRYSTAL and OPUS studies.
Authors: Folprecht Gunnar , Van Cutsem Eric , Bokemeyer Carsten , Schlichting Michael , Heeger Steffen , Kohne Claus-Henning 
Published: March 2020

3591 Background: Analysis of randomized trials has shown that mCRC patients (pts) can be divided into prognostic risk groups according to baseline clinical parameters including ECOG performance status, white blood cell count (WBC), alkaline phosphatase (ALP) and number of metastatic (met) sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect of adding cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these groups of KRAS wild-type mCRC pts was investigated in the CRYSTAL and OPUS studies. Methods: Pt risk groups were: low-risk (LRG= ECOG 0/1, 1 met site) intermediate-risk (IRG= ECOG <1, >1 met site, ALP <300 U/L or, ECOG>1, low WBC, 1 met site) and high-risk (HRG= ECOG<1, >1 met site, ALP>300 U/L or ECOG>1, high WBC, or ECOG>1, low WBC and >2 met sites). Exploratory analyses comprised estimates of effects using Cox‘s proportional hazards model for OS on individual pt data and comparison of treatment arms by log-rank test. Results: Data are shown in the table. In the pooled analyses, in both treatment arms OS was longest in LRG pts and shortest in HRG pts. Adding cetuximab to CT led to marked improvements in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157, p=0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p=0.033), while improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p=0.287) were observed only after prolonged follow up. Data were similar in the separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms the concept of prognostic risk groups for OS according to baseline clinical parameters in pts with KRAS wt mCRC. Benefit from the addition of cetuximab to first-line CT in terms of OS appears to be more pronounced in the IRG and HRG. [Table: see text]
Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer.
Authors: Bohanes Pierre Oliver , Yang Dongyun , Loupakis Fotios , Labonte Melissa Janae , Gerger Armin , Ning Yan , Wakatsuki Takeru , Zhang Wu , Benhaim Leonor , Páez David , El-Khoueiry Anthony B. , El-Khoueiry Rita , Lenz Heinz-Josef 
Published: March 2020

3604 Background: Integrins are key elements in cancer biology regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Recent evidence showing that integrins are critical in cancer dormancy suggests that their differential expression or activity may be responsible for tumor recurrence. Moving from the hypothesis that integrins could have different effects in stage II and III colon cancer, we tested as a primary endpoint whether a comprehensive panel of germline single nucleotide polymorphisms (SNPs) in integrin genes could predict stage-specific time to tumor recurrence (TTR) in stage II and III colon cancer patients. Methods: A total of 234 patients, 105 high-risk stage II and 129 stage III, treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. The median follow-up time was 4.4 years. Whole blood samples were analyzed for 22 germline SNPs in integrin genes using PCR-RFLP or direct DNA-sequencing. Results: In the multivariate analysis,stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (HR=4.027, 95%CI 1.556-10.421, p=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, HR 95%CI 1.194-3.269, p=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases, both ITGB1 rs2298141 (HR=1.909, 95%CI 1.054-3.459, p=0.033) and ITGA4 rs7562325 (HR=0.227, 95%CI 0.064-0.804, p=0.022) were associated with TTR. The latter showed a significant interaction between stages (p=0.048). Conclusions: This study identifies germline polymorphisms in integrin genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data strengthen the role of tumor dormancy in early colon cancer and may help to select subgroups of patients who may benefit from integrin-targeted treatments.
Effect of postoperative complications on adjuvant chemotherapy use in stage III colon cancer.
Authors: Merkow Ryan P , Bentrem David J , Mulcahy Mary Frances , Ko Clifford Y. , Bilimoria Karl Y. 
Published: March 2020

3608 Background: The National Quality Forum has endorsed the use of adjuvant chemotherapy in stage III colon cancer, yet a substantial treatment gap exists in the United States. Our objective was to evaluate the contribution of postoperative complications on the use of adjuvant therapy after colectomy for cancer. Methods: Patients from the National Surgical Quality Improvement Program and the National Cancer Data Base who underwent colon resection for cancer were linked (2006-2008). The association of complications on adjuvant chemotherapy use was assessed using multivariable regression models. Results: From 140 hospitals, 2368 patients underwent resection for stage III colon adenocarcinoma. Overall, 36.8% (871/2,368) patients were not treated with adjuvant therapy, of which 47.8% (416/871) had documented severe comorbidities or advanced age (≥80) as the reason for no adjuvant therapy receipt. Of the remaining 455 patients, 21.3% (97/455) had ≥1 serious complication that could account for adjuvant therapy omission. The remaining 41.1% (358/871) patients did not have a documented reason for not recieving adjuvant therapy. Complications associated with adjuvant therapy omission were abscess/anastomotic leak (OR 1.91, 95% CI 1.02-3.59), renal failure (OR 7.16, 95% CI 1.92-26.79), prolonged ventilation (OR 7.92, 95% CI 2.97-21.13), re-intubation (OR 5.69, 95% CI 2.13-15.18), and pneumonia (OR 4.05, 95% CI 2.07-7.90). Abscess/anastomotic leak was associated with a 28-day delay in time to adjuvant chemotherapy (73 vs. 45 days, p<0.05). Superficial surgical site infection did not decrease adjuvant therapy receipt but delayed the time to its use (57 vs. 44 days, p<0.05). The occurrence of postoperative sepsis was associated with a 15-day delay to adjuvant chemotherapy (60 vs. 45 days, p<0.05). Conclusions: Serious postoperative complications explained nearly one quarter of the adjuvant chemotherapy treatment gap among stage III colon cancer patients. Postoperative complications affect treatment utilization and should be considered when calculating adherence with the Stage III adjuvant therapy for colon cancer measure. Judging provider performance using quality metrics is challenging without clinical data.
Incidence and prognostic impact of KRAS and BRAF mutations in patients undergoing liver surgery for colorectal metastases.
Authors: Karagkounis Georgios , Torbenson Michael S. , Daniel Hubert D , Azad Nilofer Saba , Diaz Luis A. , Donehower Ross C. , Hirose Kenzo , Pawlik Timothy M. , Choti Michael A. 
Published: March 2020

3616 Background: Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer metastases, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the prevalence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM). Methods: KRAS and BRAF analysis was performed on 202 patients undergoing curative intent surgical therapy of CRLM between 2003 and 2008. Tumor samples were analyzed for somatic mutations using sequencing analysis (KRAS: codon 12/13, BRAF: V600E). The frequency of mutations was ascertained and their impact on outcome determined relative to other clinicopathologic factors. Results: KRAS gene mutations were detected in 58/202 patients (29%) undergoing surgery for CRLM, comparable to that reported in non-surgical patient series. In contrast, mutation in the BRAF gene was identified in very low frequency in this surgical cohort, found in only 4/202 (2%) patients. KRAS mutations were associated with worse long-term survival (HR=2.13, CI=1.25-3.65), as well as risk of recurrence (HR=1.89, CI=1.12-3.19). ). In addition, KRAS mutation was also associated with risk of recurrence following surgical therapy (HR=1.89, CI=1.12-3.19).While other clinicopathologic features, including tumor number, CEA and primary stage were also associated with survival, KRAS status remained independently predictive of outcome. The low incidence of BRAF mutation limited the ability to determine its prognostic impact. Conclusions: While KRAS mutations were found in approximately one third of patients, BRAF mutations were found in only 2% of patients undergoing surgery for CRLM. KRAS status was an independent predictor of overall and disease-free survival. Molecular biomarkers such as KRAS may help to refine our prognostic assessment of patients undergoing surgical therapy for CRLM.
Relationship between genetic markers and quality of life (QOL) in stage III colon cancer (CC) patients (pts) prior to adjuvant treatment (N0147).
Authors: Sloan Jeff A. , Shi Qian , Lee Adam , Diasio Robert B. , Pavey Emily S , Sargent Daniel J. , Goldberg Richard M. , Sinicrope Frank A. , Mahoney Michelle R. , Alberts Steven R. 
Published: March 2020

3617 Background: In metastatic colorectal cancer (CRC), previous studies suggested potential relationships between certain drug metabolizing (DM) genes (DPYD, ERCC2, GSTP1 and TYMS) and QOL prior to receipt of chemotherapy (Sloan, Plenary Session ASCO 2004). The current study is the first to examine relationships between similar DM genes and QOL in stage III CC pts. Methods: 1,583 CC pts on a randomized adjuvant stage III, phase III trial received FOLFOX, FOLFIRI, or either +/- Cetuximab. Genomic DNA and baseline QOL data via linear analogue self assessment (LASA) scales with 4 QOL variables were obtained. 53 DM SNPs were selected for known functional effect within potential regulatory sites. Two-sample t-tests assessed differences in QOL between pts with variants and wild-type status. Differences of at least 10 points on a 0-100 point QOL score were considered clinically significant. Results: 14 relationships between DM genes and QOL were detected at the nominal p < 0.05 level; six of these were related to DPYD, ERCC2, GSTP1 and TYMS. Relationships were also observed at the 0.05 level with polymorphisms of genes DPYS, ERCC1, MGMT, MTHFR, OPRT and UGT1A1 based on unadjusted and adjusted association tests. GSTP1 I105V and OPRT 5’UTR 28 A>G markers differed on fatigue scores (p=0.04, 0.005, respectively). Variants on MTHFR R594Q were associated with higher mental acuity scores (p=0.02). These relationships remained after adjusting for age, gender, race, T stage, PS, disease site, lymph nodes involved, and grade. The robustness of the observed associations varied with the multiple comparison adjustment method. Conclusions: Similar to the earlier study of stage IV CRC, we observed a possible relationship in pts with Stage III CC with regard to DM genes and QOL, although these relationships were more modest than observed in Stage IV pts. These DM genes may be in linkage disequilibrium with other genetic variants that more directly affect behavior and QOL. Further genome wide association studies are needed to clarify these relationships.