bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of RAS and TP53 predictive value for cetuximab (C) benefit: Results of the EXPERT-C trial.
Authors: Sclafani Francesco , Gonzalez David , Cunningham David , Hullki Wilson Sanna , Peckitt Clare , Tabernero Josep , Glimelius Bengt , Cervantes Andres , Wotherspoon Andrew , Dewdney Alice , Brown Gina , Tait Diana M. , Oates Jacqueline Rose , Chau Ian 
Published: February 2017

447 Background: We previously reported that TP53 status may predict C benefit in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy and chemoradiotherapy (CRT) and this effect appeared to be independent of KRAS. Recent studies indicate that NRAS mutations and KRAS mutations beyond exons 2-3 may also preclude benefit from anti-EGFRs. We analyzed whether the predictive value of TP53 in EXPERT-C was independent of RAS. Methods: 164 patients received 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83) and were analyzed for KRAS (exons 2-3) and NRAS (exon 3). TP53 mutations (exons 4-9) were screened for by CE-SSCA. KRAS (exon 4) and NRAS (exons 2 and 4) mutations were screened for by bi-directional Sanger sequencing. Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier methods and log-rank analysis was used to compare the treatment arms. The interaction between treatment and TP53 was adjusted for prognostic variables and RAS in a multivariate model. Results: 75/144 (52%) eligible patients had a TP53 mutation. 81/86 patients with known KRAS (exons 2-3) and NRAS (exon 3) wild-type (WT) status were analyzed for the remaining RAS mutations. Of these, 11 (13%) had tumours with mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 75/144 (52%) patients were RAS WT (CAPOX, n=39; CAPOX-C, n=36). After a median follow-up of 65 months, no difference in PFS (HR 1.21, p=0.59) and OS (HR 0.97, p=0.94) was observed between TP53 mutant patients treated with CAPOX or CAPOX-C. In TP53 WT patients, the addition of C was associated with a statistically significant improvement in PFS (HR 0.23, p=0.02) and OS (HR 0.16, p=0.02). A significant interaction between TP53 status and C effect was found (PFS, p=0.029; OS, p=0.036). In multivariate analyses, this interaction remained significant even after adjusting for RAS status (PFS, p=0.026; OS, p=0.033). Conclusions: In EXPERT-C, the value of TP53 as predictive biomarker for C benefit was independent of RAS. The value of monoallelic vs. biallelic TP53 inactivation will be presented at the meeting.
Efficiency of biomarker screening for enriched metastatic colorectal cancer trials: The ATTACC program experience.
Authors: Morris Van Karlyle , Overman Michael J. , Kee Bryan K. , Fogelman David R. , Eng Cathy , Dasari Arvind , Shroff Rachna T. , Deaton Laurel , Manuel Shanequa , Garrett Chris R. , Vilar Sanchez Eduardo , Pini Tunghi May , Shureiqi Imad , Mills Gordon B. , Hamilton Stanley R. , Wolff Robert A. , Meric-Bernstam Funda , Abbruzzese James L. , Maru Dipen M. , Kopetz Scott 
Published: February 2017

450 Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials for metastatic colorectal cancer (mCRC) has been proposed or initiated by NSABP, EORTC, NCI Colon Task Force, and UK MRC. The feasibility of large scale screening efforts in mCRC has not been previously assessed. Methods: Patients (pts) with 5-FU refractory mCRC at MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion clinical trials with a therapy targeted to an aberration detected in the patient. Results: Between 8/2010 and 8/2013, 400 heavily pretreated mCRC pts were enrolled onto ATTACC for screening and allocation onto 10 separate Phase I or II companion trials based on banked FFPE tumor testing by IHC, gene sequencing, and CpG island methylation phenotype (CIMP) assay. Outside tissue was obtained with a median of 6 calendar days (8% had insufficient tumor). IHC, sequencing, and CIMP results required a median of 11, 12, and 20 days, respectively. In this population, 53% tumors had KRAS mutations, with BRAF, NRAS, and PI3KCA mutations, and complete PTEN loss present in 8.1%, 8.6%, 21%, and 12%, respectively. CIMP-high status (≥2 markers) was noted in 38% of pts. Given molecular results, trial-specific eligibility, and intermittent study openings, fewer than 25% of screened pts were eligible for enrollment onto a companion protocol. Of these eligible patients, approximately half (13%) enrolled onto a companion trial. Within the entire cohort, 19% enrolled in unenriched trials, and 51% received standard-of-care therapies. ATTACC screening, with an expanding biomarker panel, remains ongoing at a rate of 25-30 patients per month. Conclusions: Universal screening programs such as ATTACC represent an optimal strategy for enrolling patients in multiple biomarker enrichment studies. Even in the setting of multiple companion treatment studies, motivated patients/physicians, and a dedicated screening infrastructure, a majority of patients did not ultimately participate on a companion trial, emphasizing the lack of drugs targeting a number of common aberrations.
Molecular subtypes of colorectal cancer in relation to disease survival.
Authors: Phipps Amanda I. , Limburg Paul J. , Baron John A. , Burnett-Hartman Andrea N. , Weisenberger Daniel J , Laird Peter W. , Sinicrope Frank A. , Rosty Christophe , Buchanan Daniel D. , Potter John D. , Newcomb Polly A. 
Published: February 2017

451 Background: Classifications for molecular subtypes of colorectal cancer based on microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and somatic mutations in BRAFV600E and KRAS have been proposed to reflect distinct pathways of colorectal tumorigenesis. We assessed the relationship between these subtype classifications and colorectal cancer survival in a population-based study. Methods: Tumor-markers were evaluated in incident colorectal cancer cases diagnosed between 1997-2007 in western Washington State. Cases were classified into pathway-based subtypes according to the following tumor-marker combinations: (1) traditional pathway [microsatellite stable / low MSI (MSS/MSI-L), non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 631]; (2) MSI-high serrated (MSI-high, CIMP-positive, BRAF-mutated, KRAS-wildtype, N=100); (3) MSS/MSI-L serrated (MSS/MSI-L, CIMP-positive, BRAF-mutated, KRAS-wildtype, n = 55); (4) alternate pathway (MSS/MSI-L, non-CIMP, BRAF-wildtype, KRAS-mutated, n = 353); and (5) MSI-high familial (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 50). Multiple-imputation was used to classify tumor-marker status for cases with missing data on one to three markers. Differences in survival across subtypes were assessed through multivariable-adjusted Cox regression. Results: Relative to cases of the predominant traditional pathway subtype, cases with MSS/MSI-L serrated and alternate pathway tumor subtypes experienced statistically significantly worse disease-specific survival [hazard ratio (HR) = 2.25, 95% confidence interval (CI): 1.50-3.36 and HR = 1.39, 95% CI: 1.12-1.71, respectively]; cases with MSI-high familial tumors had the most favorable disease-specific prognosis (HR = 0.28, 95% CI: 0.12-0.64). With respect to overall survival, associations were similar but slightly attenuated. Conclusions: In this large, population-based study, colorectal cancer subtype classifications based on integrated pathways were associated with marked differences in survival, highlighting the significance of molecular heterogeneity in colorectal cancer.
Association of prior treatment with anti-EGFR monoclonal antibodies with downregulation of circulating TRAIL and upregulation of EGFR and VEGF family ligands in metastatic colorectal cancer.
Authors: Lee Michael Sangmin , Lieu Christopher Hanyoung , Overman Michael J. , Eng Cathy , Morris Jeffrey , Jiang Zhi-Qin , Morelli Maria , Heymach John , Tran Hai T. , Kopetz Scott 
Published: February 2017

452 Background: Inhibition of growth factor receptor signaling leads to unintended compensatory pathway activation in preclinical models, which may impact the success of subsequent therapies. We hypothesized that increased circulating levels of receptor ligands after anti-EGFR monoclonal antibody (mAb) therapy, including VEGF ligands or EGFR family ligands, may provide insights into clinically relevant feedback mechanisms. Methods: Plasma was obtained from 96 metastatic colorectal cancer (mCRC) patients: 48 previously treated with anti-EGFR mAbs and 48 mCRC patients previously treated without prior anti-EGFR therapy who were matched for total months of prior chemotherapy and interval since last chemotherapy treatment. Plasma levels of circulating cytokines with emphasis on EGFR and VEGF ligands were determined using suspension bead multiplex assay (BioRad). Comparisons were done by the two-sided nonparametric Wilcoxon signed rank test. Multivariate linear regression analysis was done with forward selection at p<0.1. Results: By Wilcoxon signed rank test, prior anti-EGFR mAb treatment was associated with differences in EGF (3.5-fold increase, p=0.0001), epiregulin (1.6-fold increase, p=0.02), and TGF-alpha (1.4-fold increase, p=0.04). There was no significant association with amphiregulin, betacellulin, or HB-EGF. Prior anti-EGFR mAb treatment was also associated with differences in TRAIL (1.4-fold decrease, p=0.001) and with differences in VEGF-C (1.4-fold increase, p=0.01), and FGF-basic (1.8-fold increase, p=0.02). After multivariate analysis, prior anti-EGFR mAb treatment remained significantly associated with differences in EGF (p=0.003), TRAIL (p=0.045), VEGF-C (p=0.02), and FGF-basic (p=0.02). Conclusions: Prior treatment with anti-EGFR mAbs is associated with an apparent compensatory increase in EGFR ligands and pro-angiogenic factors, and lower levels of the pro-apoptotic cytokine TRAIL. These differences in circulating growth factor receptor ligands may provide insights on resistance mechanisms and optimal treatment sequencing.
A new prognostic staging system for pulmonary metastases from colorectal cancer.
Authors: Hirosawa Tomoichiro , Itabashi Michio , Bamba Yoshiko , Ogawa Shimpei , Sugihara Kenichi , Kameoka Shingo 
Published: February 2017

454 Background: A number of studies have examined the prognostic factors associated with pulmonary metastases of colorectal carcinoma (CRC). However, it has not yet been clarified which factor to emphasize taking the treatment strategy into consideration. Methods: The baseline characteristics and outcomes on 352 CRC patients undergoing complete pulmonary resection were collected from 19 institutions by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Study Group (Group A). The clinical and pathological factors were entered into a multivariate analysis to identify independent variables that were helpful for accurately predicting the long-term prognoses after pulmonary resection. Using the prognostic factors of Group A and the following processes (1) to (3), we developed and examined a new prognostic staging system (PSS): (1) Pulmonary (PUL) staging was performed using only pulmonary metastases-related factors in order to further clarify the prognosis. (2) The PSS was created using the PUL staging, primary cancer-related factors and hepatic metastases-related factors. (3) The new PSS was examined in a validation study in a series of 944 patients from 110 institutions of the JSCCR by the 78th society of the JSCCR (Group B). Results: (1) PUL1a: No. of metastases (No.) = 1 and DFI > 2 years;(The 5-year OS: 66.7%, RFS rates: 52.8%). PUL1b: No. = 1 and DFI ≤ 2 years or No. = 2 or No. ≥ 3 and a unilateral distribution; (47.4%, 30.7%). PUL2:No. ≥ 3 and a bilateral distribution or the presence of lymph node metastases or pleural dissemination; (17.4%, 11.1%), (p<0.01). (2) Grade A: PUL1a and lymph node metastases of N0, N1 or N2, or PUL1b and N0; (75.4%, 55.1%). Grade B: PUL1a and N3 or hepatic metastases cases or PUL1b and N1 or N2; (52.0%, 30.8%). Grade C: PUL1b and N3 or hepatic metastases cases or PUL2; (18.2%, 9.0%), (p<0.01). (3) Grade A (n=324): 75.3%, 53.7%; Grade B (n=359): 60.8%, 41.5% and Grade C (n=261): 48.2%, 21.9%. (p<0.01). Conclusions: Our new PSS was useful for the selection of patients suitable for pulmonary resection.
Prognostic and predictive value of tumor-infiltrating immune cells in Japanese patients with stage II/III gastric cancer.
Authors: Earle Sophie , Aoyama Toru , Wright Alexander I. , Treanor Darren , Miyagi Yohei , Ward Lindsay C. , Arai Tomio , Hayden Jeremy D. , Yoshikawa Takaki , Thygesen Helene H. , Grabsch Heike I. 
Published: February 2017

46 Background: Since the ACTS-GC trial, Japanese patients with stage II/III gastric cancer (GC) receive adjuvant S1 chemotherapy. However, selection of patients (pts) by TNM stage does not predict benefit from adjuvant S1 with certainty. Thus, there is an urgent clinical need to identify predictive biomarkers. Increasing evidence suggests tumor immune cell infiltration may be related to GC pts prognosis. We tested the hypothesis that extent and type of immune cell infiltration in GC is related to benefit from adjuvant chemotherapy. Methods: Tissue microarrays from 252 GC resections (109 pts treated by surgery alone (S), 143 pts treated by surgery and adjuvant S1 chemotherapy (SC)) from the Kanagawa Cancer Center Hospital (Yokohama, Japan) were investigated by immunohistochemistry for common leucocytes antigen (CD45), neutrophils (CD66b), macrophages (CD68 and CD163), T-cell subtypes (CD45R0, CD8, CD3), B-cells (CD20) and Treg cells (FOXP3). Staining was quantified as percentage immunoreactivity/area by automated image analysis. Relationship with overall survival was analyzed. A Cox regression model was used to identify independent prognostic markers and treatment interaction effect. Results: The hazard ratio of S1 was 0.694 in this GC cohort which is similar to the results of the ACTS-GC trial. CD45 and CD45R0 were independent prognostic markers in the S group only (CD45 p=0.032, CD45R0 p=0.003). A treatment interaction effect was seen for CD45, CD45R0, and CD68 (p value for test of interaction: CD45 p=0.062, CD45R0 p=0.082, CD68 p=0.057). Survival in the SC group was significantly poorer compared to the S group for CD45>56% or CD68>7% (p<0.05). Conclusions: This is the first study to investigate the relationship between tumor immune cell infiltration at time of surgery and benefit from adjuvant chemotherapy. Our results indicate that GC patients with high intratumoral levels of CD68, CD45, or CD45R0 positive immune cells might not benefit from adjuvant S1 chemotherapy. These findings require validation in a second independent dataset before conducting a prospective study stratifying patients with stage II/III GC based upon extent of CD45, CD45R0, or CD68 immune cell infiltration for adjuvant treatment.
Final results of the UGT1A1-based dose modification of irinotecan and its impact on rates of severe neutropenia and hospitalization.
Authors: Tan Benjamin R. , Wu Ningying , Wang-Gillam Andrea , Suresh Rama , Picus Joel , Baranda Joaquina Celebre , Lockhart Albert C. , McLeod Howard L. 
Published: February 2017

461 Background: UGT1A1 7/7 genotype has been associated with a 3-fold increase in severe neutropenia for patients treated with irinotecan (IRI) (Mcleod 2010, Liu 2013). UGT1A1 determination may tailor IRI therapy and reduce toxicities. However, the impact of the FDA-recommended IRI dose modification on outcomes is unclear. Methods: UGT1A1 genotyping was done for patients with various cancers wherein IRI therapy was planned and who consented to 1 of 3 IRB-approved registries. For patients with UGT1A1 7/7, a reduction in IRI doses was recommended per FDA and toxicities monitored during the first 2 doses. Results: 323/341 patients registered had UGT1A1 determined, of which 13% (42/323) had the 7/7 or 7/8 genotypes. Notably, a significantly higher proportion of African-Americans (AA) harbor these genotypes compared to Caucasians (C) (26.32% vs 10.08%, p=0.001). Among the 251 evaluable for toxicities, the incidence of grade 3-5 ANC for patients with 7/7 was not significantly different than those with 6/6 or 6/7 (Kendall's Tau-b coefficient p=0.494) (see Table). Among the 7/7 patients, 23/33 were treated at IRI doses of 150 mg/m2 or higher. 30% of patients treated at the higher dosages still developed grade 3-5 neutropenia compared to 17-21% for those with other genotypes. 38 of 251 patients were hospitalized during their first 2 cycles of therapy. The proportion of hospitalized patients with 7/7 genotype was not significantly different than those with 6/6 or 6/7 (15% vs 17% vs 12.6%). Conclusions: UGT1A1 can be used to tailor IRI therapy and reduce toxicities. The incidence of severe neutropenia and rate of hospitalization is comparable among patients with all UGT1A1 genotypes when IRI dose is adjusted for those with UGT1A1 7/7. There is a higher incidence of UGT1A1 7/7 genotype among African-Americans comnpared to Caucasians, which warrants further evaluation. [Table: see text]
Results of the MARS study on the management of antiangiogenics’ renovascular safety in colorectal cancer.
Authors: Ray-Coquard Isabelle , Janus Nicolas , Spano Jean-Philippe , Thery Jean Christophe , Goldwasser Francois , Mir Olivier , Beuzeboc Philippe , Daniel Catherine , Morere Jean Francois , Rey Jean-Baptiste , Jouannaud Christelle , Oudard Stephane , Scotte Florian , Azizi Michel , Dorent Richard , Deray Gilbert , Launay-Vacher Vincent 
Published: February 2017

466 Background: MARS is a prospective multicentric study conducted to assess the renovascular tolerance of anti-VEGF drugs (AVD) in the clinical setting in France, in a number of different tumor types. Methods: Patients (pts) from 8 centers were included when they were 1) naive of any AVD and 2) about to start treatment with an AVD, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit during f/u. This subgroup analysis presents the results for colorectal cancer (CRC) pts receiving bevacizumab (BVZ). Results: 1,124 pts were included. 200 had CRC and all but 5 received BVZ. Median age: 63.2 years. Visceral, bone, and cerebral metastasis frequencies were 91.3, 10.8, and 0.5%, respectively. All pts presented metastasis. At inclusion, HTN prevalence was 26.2%. Baseline renal assessment retrieved: Pu 30.6%, Hu 10.1%, mean aMDRD 91.1 ml/min/1.73m2. The incidence of de novo Pu and HTN during f/u was 78.2 and 16.1% (Table). 75.6% of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 60.8% afterward improved/normalized. No grade 4 Pu has been reported (at inclusion or during f/u). Renal function decreased with a mean aMDRD of 90.3 at the end of f/u. 5.9% had grade 2 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of BVZ in CC patients showed that 1) TMA is rare, 2) Pu develops in 78.2% of the pts (no grade 4), 3) 16.1% developed HTN. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Overall and abdominal adiposity in a prospective colorectal cancer patient cohort: The COPE study.
Authors: Siegel Erin M. , Maddox Kristen , Riggs Bridget , Townsend Ione G. , Calzada Jazmin , Coppola Domenico , Shibata David 
Published: February 2017

467 Background: Obesity is an important risk factor for colorectal cancer (CRC); however, the exact role of adiposity on CRC remains unknown. Our overarching hypothesis is that abdominal fat, specifically visceral fat, through alterations in pro-inflammatory and tumor-promoting factors (e.g., IGF-1 or insulin) promotes aggressive tumor behavior and proliferation. To address this hypothesis, we have established an ongoing cohort of CRC patients [Colorectal Outcomes, Prognosis and Epidemiology (COPE) Study] with repeated adiposity and blood measures during the first year post-diagnosis. The objective of this study is to begin examining differences in diagnostic overall and abdominal adiposity by clinicopathological factors. Methods: Newly diagnosed patients with invasive adenocarcinoma of the colon or rectum were enrolled from 2010 to 2013 (N=213). Baseline overall adiposity by body mass index (BMI) and abdominal adiposity by waist circumference (WC) were collected. In a pilot study in 30 cases, baseline levels of IGF, IGFBP3, insulin and glucose to examine if serum markers were associated with obesity among CRC patients. The differences were evaluated by gender and clinical factors using ANOVA. Results: This study included 126 male and 87 female CRC patients with a median age of 64 years (range: 29-93). A majority of the patients were Caucasian (94%), married (68%), and never smokers (59%). The mean BMI and WC were 27.6±5.2 kg/m2and 96.5±15.8 cm, respectively. WC, but not BMI, was significantly higher among men (p=0.02), among patients with colon cancer (p=0.01), with higher stage (stage I/II vs. III/IV; p=0.02) and in high grade tumors (p=0.03). Serum IGFBP3 was significantly elevated in patients with abdominal adiposity (p=0.004) and colon cancer (p=0.004). Conclusions: Excess abdominal adiposity (WC) was related to advanced stage and high grade, whereas overall adiposity (BMI) was not. This study highlights the prevalence of abdominal adiposity and its potential biological importance among CRC patients. The development of more refined techniques (e.g. CT-based) of further defining the visceral and subcutaneous components of abdominal adiposity in cancer patients may prove to be informative.