bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the 12-gene colon cancer assay results on treatment recommendations in patients with stage II colon cancer.
Authors: Cartwright Thomas H. , Chao Calvin , Lopatin Margarita , Bentley Tanya G. , Broder Michael S. , Chang Eunice 
Published: March 2020

3626 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in clinical practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (n=346) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: We analyzed survey results from 116 eligible physicians. Physicians were more often in community (86%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 32–85). Most patients (81%) had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 3%, 13% and 84% of the time and 38% had comorbidities. Of the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 (45%) patients, observation in 40 (34%), and there was no recommendation in 24 (21%). For the 92 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 27 patients (29%). Treatment intensity decreased for 18 (67%) and increased for 9 (33%) of 27 changed recommendations. A significant trend of decreasing treatment intensity with lower RS values was observed (p=.0035). Conclusions: These findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results in 29% of patients. Use of the Oncotype DX assay may lead to reductions in treatment intensity, contributing to the assay’s cost effectiveness.
Use of gene set analysis (GSA) for molecular classification of responders and nonresponders to FOLFOX therapy in colorectal cancer (CRC).
Authors: Yip Stephen , Cheang Maggie Chon U. , Kennecke Hagen F. 
Published: March 2020

3628 Background: Folinic acid (FOL) fluorouracil (F) and oxaliplatin (OX) chemotherapy is a commonly used therapy for CRC. Lacking in current literature are clinically relevant classifiers for potential responders. GSA technique is statistical method that detects significance of sets of genes, instead of examining a gene-by-gene basis. The objective of this study was to identify differential functionally annotated gene expression profiles associated with response to FOLFOX therapy in CRC tumors using gene-by-gene and GSA approaches. Methods: Genome wide expression profile data were collected on pre-treatment tumor tissues from patients with unresectable CRC receiving FOLFOX therapy (n = 83, Affymetrix HG U133A, GSE28702, Tsuji et al. BJC 2012). Gene expression was compared between responders (n = 42) and Non-responders (n = 41). GSA was conducted on 3272 curated gene sets from the Molecular Signatures Database (Subramanian, Tamayo et al. 2005, PNAS 102, 15545-15550) annotated by biological pathway, biochemical function and clinical behavior. Significant analysis of Microarray (SAM) and GSA (Tibshirani et al.) was done to identify gene sets associated with FOLFOX response. Results: Differential expressions of 23 genes were significantly associated with response, based on a single gene approach (p-value < 0.05). 13 of these were located on Chromosome 17 (p < 0.001). Among these, the top 5 ranked genes included NPEPPS, MBTD1, CEP44, LTA4H and CPNE4 which are involved in metal ion binding and aminopeptidase activity. GSA revealed only 44 out of 3272 gene sets were significantly associated with response, with a false discovery rate less than 25%. Increased expression of B-lymphocyte differentiation and Ras-signalling-related gene sets was associated with responders while mTOR signaling and hematopoietic stem cell-related genes set were associated with non-responders. Conclusions: Our data showed that differential biological pathways could be identified to predict response to FOLFOX therapy for CRC patients. Analysis may be useful to help define clinically relevant biologic subtypes among patients with metastatic colorectal cancer.
Evaluation of the prognostic utility of miRNA and multiple genetic markers in stage IIA colon cancer.
Authors: Mambo Elizabeth , Sanford Tiffany , Buddavarapu Kalyan , Adai Alex , Lebourgeois Paul A. , Rasmussan Karen , Garmire Lana 
Published: March 2020

3630 Background: The variable prognoses of stage II colon cancer subjects have provoked a therapeutic dilemma of who should receive adjuvant therapy. Presently, prognosis is evaluated on often subjective histopathological features. Reliable, objective markers that can accurately predict recurrence risk are needed. Using retrospectively collected tumor samples with known clinical outcome, we evaluated the prognostic utility of miRNA together with clinicopathological features and molecular markers with suggestive prognostic value. Methods: We evaluated the expression of miRNA in 118 stage IIA FFPE tumors (73 non-recurrent, NR; 45 recurrent, R) using the Affymetrix Gene Chip V1.0 microarray, and performed RT-qPCR to verify select miRNAs. We also sequenced KRAS codons 12/13, and BRAF codon 600, and assessed MSI status using a fluorescent PCR-based assay. MMR protein expression was determined by IHC. An empirical approach was applied to screen miRNA using combinatorial criteria of microarray 2-way ANOVA analysis, Kaplan-Meier curve logrank, and single and multivariate Cox-regression. miRNA was the most significant predictor among all histopathological and molecular features (FDR<0.05). A miRNA classifier was built with nested two-layer cross-validation. Results: The top miRNA model was selected based on AUC estimates and Cox-regression p-value. This model included 30 miRNAs; 25 of these were common with the empirical approach, confirming the robustness of candidate selection. The miRNA classifier distinguished R from NR cases with an AUC of ~0.74. Among all histopathological and molecular features evaluated, grade was significantly associated with disease-free survival (logrank p<0.05). Both single variate and multivariate Cox analysis revealed that grade and PMS2 status were strongly associated with recurrence (p<0.05). Lastly, lack of expression of PMS2 and MLH1, BRAF V600E and MSI was highly correlated (Φ coefficient > 0.6), and associated with non-recurrent disease. Conclusions: These data provide strong support for miRNAs as independent prognostic biomarkers for stage IIA colon cancer.Validation work is ongoing to demonstrate the potential utility of these miRNAs in patient stratification.
Adverse prognostic impact of heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma (EAC).
Authors: Yoon Harry H. , Shi Qian , Sukov William R. , Sattler Christopher A. , Wiktor Anne E. , Wu Tsung-Teh , Diasio Robert B. , Jenkins Robert B. , Sinicrope Frank A. 
Published: March 2020

4009 Background: HER2 expression in upper digestive cancer is reported to be heterogeneous, which substantially affects interpretation of HER2 positivity in the clinic. Yet the frequency and prognostic impact of HER2 genetic heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: HER2 amplification (fluorescence in situ hybridization) and protein expression were examined in untreated surgical EAC specimens (N = 661) at Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as amplification (HER2/CEP17 ratio ≥ 2) in 5-50% of cancer cells; poly17 refers to ≥ 3 copies of chromosome 17. Most tumors were T3-4 (68%) or lymph node (LN)-positive (73%). Cox models were used to assess disease-specific (DSS) and overall survival (OS). Results: HER2 amplification was detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 heterogeneity. HER2 heterogeneous tumors had a significantly higher frequency of poly17 and high tumor grade. HER2 heterogeneity by amplification vs expression were correlated. Since heterogeneity was limited to HER2-amplified tumors, survival analysis was stratified by amplification status. In multivariable analysis, only HER2 heterogeneity and metastatic LN number were prognostic (Table). Conclusions: Among HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated with increased poly17 and independently predicts 2-fold higher risk of cancer-specific death. Among HER2-nonamplified cases, poly17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and evaluation of benefit from HER2 targeted therapy. [Table: see text]
Impact of insulin-like growth factor 1 receptor (IGF1R) and amphiregulin (AREG) expressions on survival in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Ichikawa Wataru , Terashima Masanori , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Shinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi , Sasako Mitsuru 
Published: March 2020

4012 Background: Exploratory biomarker analysis was conducted to identify factors related to outcomes of patients enrolled in the ACTS-GC study, a randomized controlled trial comparing adjuvant S-1 administration with surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: Formalin-fixed paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative real-time RT-PCR after TaqMan assay-based pre-amplification. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as reference genes. The expression of each gene was categorized into low and high values at those median. The impacts of gene expression on survival were analyzed using the 5-year survival data of the ACTS-GC. The Benjamini and Hochberg procedure was used to control the false discovery rate (FDR). Results: Among 63 screened genes, IGF1R and AREG most strongly correlated with overall survival (OS), with FDR of 0.0048 and 0.018, respectively. OS was significantly worse in IGF1R high patients than in IGF1R low patients, but better in AREG high patients than in AREG low patients. The hazard ratio (HR) for death in the analysis of OS (S-1 vs. surgery alone) was lower in the high IGF1R group (HR, 0.55; 95%CI, 0.40-0.76) than in the low IGF1R group (HR, 0.72; 95%CI, 0.49-1.06). Likewise, the HR for death in the analysis of OS (S-1 vs. surgery alone) was much smaller in the low AREG group (HR, 0.57; 95%CI, 0.41-0.79) than in the high AREG group (HR, 0.74; 95%CI, 0.51-1.08). Interactions were not statistically significant. Conclusions: IGFR1 gene expression was associated with poor outcomes after curative resection of stage II/III gastric cancer, whereas AREG gene expression was associated with good outcomes. No interaction for survival was evident between S-1 and these gene expressions.
Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.
Authors: Fukutomi Akira , Okusaka Takuji , Sugimori Kazuya , Ueno Hideki , Ioka Tatsuya , Ohkawa Shinichi , Boku Narikazu , Yamao Kenji , Mizumoto Kazuhiro , Furuse Junji , Funakoshi Akihiro , Hatori Takashi , Yamaguchi Taketo , Egawa Shinichi , Sato Atsushi , Ohashi Yasuo , Cheng Ann-Lii , Tanaka Masao 
Published: March 2020

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p<0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p<0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.
A phase II multi-institutional study to evaluate gemcitabine and fractionated stereotactic body radiotherapy for unresectable, locally advanced pancreatic adenocarcinoma.
Authors: Herman Joseph M. , Chang Daniel Tandel , Goodman Karyn A. , Wild Aaron Tyler , Laheru Dan , Zheng Lei , Diaz Luis A. , Le Dung Thi , Raman Siva P , Leal Jeffrey P , Chaudhry Muhammad Ali , Sugar Elizabeth , Columbo Laurie Ann , Tom Ashlyn , Limaye Maneesha R , Edil Barish H , Oteiza Katharine , Hacker-Prietz Amy , Wolfgang Christopher Lee , Koong Albert 
Published: March 2020

4045 Background: Phase I/II studies with single-fraction (25 Gy) stereotactic body radiotherapy (SBRT) for pancreatic ductal adenocarcinoma (PDA) have shown local progression free survival (LPFS) rates of >90%, but are limited by late GI toxicity and minimal tumor response. We performed a phase II multi-center trial of gemcitabine (GEM) and fractionated SBRT to determine if a high rate of LPFS with reduced toxicity could be achieved. Methods: After multidisciplinary review, 32 pts with locally advanced PDA received GEM in sequence with SBRT (6.6 Gy in 5 consecutive daily fractions, 33 Gy total). LPFS, metastasis free survival (MFS), and overall survival (OS) were measured from date of tissue diagnosis. Objective tumor response (OTR) was assessed by RECIST/PERCIST. EORTC QLQ-C30/PAN26 questionnaires were used to measure QOL. Results: Median f-up was 12 mos (range, 2-23). Mean age was 69.9 yrs (SD, 9.8) and 62% were male. Pts received a mean of 2.2 (SD, 1.0) GEM doses prior to SBRT and 8.3 (SD, 5.6) doses total. All pts completed SBRT. Median OS was 15.9 months (95% CI, 12.7-18.8). Stratification by CA19-9 > or < 90 at diagnosis yielded a hazard ratio of 6.2 for > 90 (p=0.021). Median LPFS has not been reached and median MFS was 10.2 mos (95% CI, 2.9-17.5). LPFS rate at 1 year was 87%. OTR on CT was seen in 41%, while 41% had stable disease and 18% progressed. Tumor metabolic activity decreased in 17/18 patients with pre/post-SBRT PET available. Mean peak SUV was 4.0 pre-SBRT versus 2.4 post-SBRT (p=0.002). Median CA19-9 was reduced from 124.7 prior to SBRT to 43.9 afterwards. Acute toxicity included: grade 2 anorexia (37%), fatigue (28%), nausea (22%), abd pain (19%), weight loss (9%), diarrhea (3%); gr 3 nausea (9%); and gr 4 nausea (6%). Late gr ≥3 GI toxicity was seen in 9%. Mean QOL score 4 wks post-SBRT was similar to baseline (p=0.38). At 6 mos there was a trend towards improved QOL (p=0.07). Conclusions: Fractionated SBRT with GEM achieves high rates of LPFS and tumor response. Minimal grade ≥3 acute and late toxicity was observed. SBRT is more likely to benefit patients with Ca-19-9 <90. A combination of SBRT with more aggressive chemotherapy may further improve outcomes.
Addition of algenpantucel-L immunotherapy to standard of care (SOC) adjuvant therapy for pancreatic cancer.
Authors: Hardacre Jeffrey M , Mulcahy Mary Frances , Small William , Talamonti Mark S. , Obel Jennifer Carrie , Rocha Lima Caio Max S. , Safran Howard , Lenz Heinz-Josef , Chiorean E. Gabriela , Vahanian Nicholas N. , Link Charles J. 
Published: March 2020

4049 Background: Resected pancreatic cancer carries a one year survival rate of ~65%. Algenpantucel (HyperAcute-Pancreas, HAPa) exploits the hyperacute rejection mechanism of xenotransplantation by administering genetically modified, irradiated, allogeneic tumor cells expressing aGal moieties on their surface. We propose that addition of algenpantucel-L to SOC adjuvant therapy may improve survival for patients with resected pancreatic cancer. Methods: Open-label, dose-finding, Phase 2 study (16 sites) evaluating HAPa (100/300 M cells / dose) + SOC (RTOG-9704: Gemcitabine + 5-FU-XRT) for resected pancreatic cancer patients. Primary endpoint: 1-year disease-free survival (DFS). Secondary Endpoints: overall survival (OS), toxicity and immunologic analysis. Results: : 70 patients, median age 62 years, 47% female, 81% lymph node positive, median tumor size 3.2 cm, and 17% post-operative CA 19-9 ≥ 180 received SOC + HAPa. 1-year DFS of 63% and OS of 86% compares favorably to historical controls (~45%% and 65%, respectively) for this high risk population. Subgroup analysis of patients receiving 300M cells /dose shows a higher 12-month DFS compared to 100M cells/dose, 81% vs. 52% (p = 0.02). Likewise, patients receiving 300M cells/dose tended to better 1-year survival compared to a 100M cells/dose, 96% vs. 80% (p = 0.053). Forty-four (63%) developed strong (G1-G3) skin reactions at the injection sites including many long term survival patients with periodic skin flares at injection sites far beyond their last vaccination. In 13/45 (29%) tested patients, an increase of >30% in anti-mesothelin Ab titer was seen after immunization. Thirty-nine (56%) presented with eosinophilia (range: 5- 45%), including one patient with persistent eosinophilia and stable lung metastasis for over 2 years. Conclusions: Addition of HAPa to standard adjuvant therapy for resected pancreatic cancer shows promising immunological activation and may improve survival. A multi-institutional, phase 3 study is currently underway.
Tumor IGF-1 expression as a predictive biomarker for IGF1R-directed therapy in advanced pancreatic cancer (APC).
Authors: Javle Milind M. , Shroff Rachna T. , Varadhachary Gauri R. , Wolff Robert A. , Fogelman David R. , Bhosale Priya , Wang Xuemei , Kar Siddhartha P. , Overman Michael J. , Sathyanarayanan Sriram , Ayers Mark , Mauro David J. , Abbruzzese James L. 
Published: March 2020

4054 Background: IGF-1 up-regulates PC proliferation and invasiveness through activation of PI3K/Akt signaling pathway and down-regulates PTEN. We investigated IGF-1 expression in tissue and blood as potential predictive markers in phase II study of IGF1R-directed monoclonal antibody, MK-0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods: Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1, adequate hematologic and organ function were enrolled. Arm A: G 1,000 mg/m2 over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000 mg/m2 and MK-0646 + E 100 mg daily. Arm C (control) was G 1,000 mg/m2 + E 100 mg. Cycles were repeated every 4 weeks. Pts were equally randomized in the 3 arms. Primary study objective was progression-free survival (PFS). Pre-treatment peripheral blood samples were measured for IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA expression. RNA extraction from FFPE samples used Roche Transcriptor First Strand cDNA Synthesis Kit. TaqMan PreAmp technique was used to amplify target cDNA prior to TaqMan RT-PCR analysis. Cox proportional hazards model for PFS analyzed the interaction between tissue IGF-1 expression and treatment. Results: 50 pts were enrolled (A=15, B=16,C=16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5 months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0 months (95% CI: 1.8 – NA), respectively (log-rank test; p = 0.17). Median OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 – NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p = 0.44). 35 archival core biopsies were analyzed, 21 had adequate tissue for analysis. Using a Multivariable Cox proportional hazards model for PFS, where IGF-1 was dichotomized at the median, there was a 76% reduction in the risk of disease progression or death in arm A as compared with the control (arm C) at high IGF-1 level (p = 0.16). When IGF-1 was fitted as a continuous variable, this reduction was 96% (p = 0.08). There was no correlation between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1 level may represent a promising predictive biomarker for IGF1R-directed therapy in APC.