bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of dacarbazine for metastatic colorectal cancer: Final results with MGMT analysis.
Authors: Amatu Alessio , Sartore Bianchi Andrea , Moutinho Catia , Bencardino Katia , Bonazzina Erica , Pietrogiovanna Lisa , Venturini Filippo , Gambaro Alessandra , Marrapese Giovanna , Belotti Alessandro , Esteller Manel , Siena Salvatore 
Published: March 2020

3581 Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O6-guanine in DNA. Approximately 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O6–guanine site, inducing base pair mismatch, therefore activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild type). Methods: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m2 i.v. qd for 4 consecutive days q21 until PD or intolerable toxicity. We employed a Simon two-stage design to determinate if the ORR would be ≥ 10%. Secondary endpoints included association of response, PFS and disease control rate with MGMT status. Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of 3 cycles of dacarbazine [range 1-12]. Grade 3-4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), anemia (18%). Overall, 2 patients (3%) achieved partial response (PR) and 8 patients (12%) had stable disease (SD). Disease control rate (PR+SD) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Conclusions: Objective clinical responses to dacarbazine in metastatic CRC patients are confined to those tumors harbouring epigenetic inactivation of the DNA repair enzyme MGMT. Clinical trial information: 2011-002080-21.
Impact of nodal metastasis on survival of stage IV colon cancer: Analysis of National Cancer Data Base (NCDB).
Authors: Shaik Mohammed , Korant Alpesh K. , Saha Supriya Kumar , Johnston Gregory , Dhar Vikrom K. , Abadeer Benjamin , Wiese David , Arora Madan L. , Stewart Andrew , Saha Sukamal 
Published: March 2020

3582 Background: Nodal metastasis (mets) is an important prognostic factor in the staging of colon cancer (CCa). However, the significance of nodal mets in stage IV CCa remains undetermined. Therefore, we investigated the impact of nodal mets on 5 year overall survival (5-yr OS) in stage IV CCa. Methods: Patients (pts) from the NCDB who had been diagnosed with histologically confirmed Stage IVCCa from 1998-2010 were divided into two groups: with(+ve) or without(-ve) nodal mets and the 5 yr OS was compared using the Kaplan Meier Curves. Multivariate analysis was performed using CoxProportional regression model. An adjusted hazard ratio(aHR) was calculated for pts with nodal mets compared to those without nodal mets after adjusting for age, grade and tumor size. Results: 70,387 pts from the NCDB with stage IV CCa were included in our analysis. Of these, 12,363(17.5%) had no nodal mets (TN0M1), 23,052(32.7%) had 1-3 nodal mets (TN1M1), and 34,972 (49.69%) had 4 or more nodal mets (TN2M1) involved at the time of diagnosis (Table 1a).The overall nodal positivity was 82.4%. The 5-yrOS of all stage IV pts was 10.7% (Table 1b); 5 yr OS for node -ve pts was 18.4% versus 9.2% for node +ve pts (p<0.0001)(Table1b). The 5 yr OS of N1 and N2 was 12% and 7.2%, respectively. The aHR of pts with nodal mets versus without nodal mets was 1.8 (95% CI of 1.7-1.9), after adjusting other prognostic covariates. Conclusions: Stage IV CCa with nodal mets is associated with an increased risk of death compared to node-negative disease. The number of positive lymph nodes at the time of diagnosis is also an important risk factor. [Table: see text]
Use of tumor size to predict long-term survival in colon cancer patients: Analysis of National Cancer Data Base (NCDB).
Authors: Saha Sukamal , Shaik Mohammed , Saha Supriya Kumar , Korant Alpesh K. , Johnston Gregory , Dhar Vikrom K. , Wiese David , Singh Trevor , Arora Madan L. , Stewart Andrew 
Published: March 2020

3583 Background: Tumor size (TS) is a known prognostic factor in breast, renal, and lung cancers, however, not in colon cancer (CCa). Tumor (T) depth, nodal status (N), and metastasis (M) are used in the TNM staging. Hence, we studied if TS is an independent risk factor for death in CCa. Methods: Data included TS, grade, T-stage, N, and M-status from the NCDB for 298,021 CCa pts (1998-2010). We divided pts into 4 groups by TS (<2cm;2-4cm;4-6cm;>6cm). Data was analyzed using Spearman’s rho correlation (r) and Kaplan-Meier for overall 5-yr survival (5yrOS). Hazard ratios (HR) were calculated using a Cox model adjusting for age, sex, grade, T, N-status and TNM stage. Results: Proportion of pts with TS 0-2, 2-4, 4-6 and >6cm were 13.25%, 38.95%, 29.54%, and 18.26% respectively. Median TS was 4cm. TS was positively correlated with grade, T, N-status and TNM stage (p=0.0001) and negatively correlated with 5yrOS (65.5%, 52.4%, 45.5%, and 41.2% for four sizes respectively) (Table). Cox modeling demonstrated TS of 4-6cm and >6cm had HRs of 1.23 (95%CI 1.14-1.34) and 1.7 (95%CI 1.5-1.8) respectively. Conclusions: A primary TS of 4-6cm and >6cm is associated with a 23% and 70% increased risk of death, respectively, over 5-yrs in CCa. Prospective studies are needed to evaluate the role of primary TS in CCa prognosis. [Table: see text]
Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.
Authors: Kennecke Hagen F. , Yu Jason , Gill Sharlene , Cheung Winson Y. , Blanke Charles Davic , Cheifetz Rona , Woods Ryan 
Published: March 2020

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]
A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.
Authors: Sym Sun Jin , Hong Junshik , Ahn Hee Kyung , Park Jinny , Cho Eun Kyung , Lee Jae Hoon , Lee Won-Suk , Baek Jeong-Heum , Park Yeon Ho , Shin Dong Bok 
Published: March 2020

3595 Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with fluoropyrimidines-, oxaliplatin- and irinotecan-containing regimens. Methods: 36 pts were enrolled, with the following characteristics: 19 females (53%), median age 57 (28-72), 30 EOGO PS 0-1 (83%). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was 5 (range 1-9), ORR was 16.7% (95% confidence interval [CI] 4.5-28.9%) and disease control rate was 61.1% (95% CI 45.2-77.0%) with 6 partial responses and 16 stable diseases. Median duration of disease control was 5.8 months (95% CI 4.1-7.5 months). Median progression-free survival was 3.7 months (95% CI 2.2-5.2 months) and median overall survival was 10.0 months (95% CI 7.4-12.7 months). Grade 3-4 toxicities were rare (neutropenia 12%, anemia 11%, leucopenia 6%, thrombocytopenia 3% and diarrhea 3%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was a convenient, well tolerated and efficacious for heavily pre-treated pts with mCRC. This regimen warrants further evaluation in pts with good PS but no further treatment options.
Aspirin use and survival outcomes in patients (pts) with PIK3CA mutant colorectal cancer (CRC).
Authors: Tran Ben , Jorissen Robert N , Desai Jayesh , Day Fiona , Lipton Lara Rachel , Wong Hui-Li , Tie Jeanne , Faragher Ian , Jones Ian , Sieber Oliver , Gibbs Peter 
Published: March 2020

3598 Background: Aspirin has an established role in preventing CRC. Recent data suggests aspirin use may also benefit a subset of pts diagnosed with CRC. In one series, the authors identified PIK3CA mutations as a potential predictive biomarker for aspirin use, reporting that PIK3CA mutant CRC pts receiving aspirin had superior cancer specific survival (CSS) compared to those not receiving aspirin (HR 0.18, p<0.001), whereas in pts with wildtype PIK3CA, aspirin had no survival impact. Our study aims to confirm the survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Methods: A cohort of CRC pts with PIK3CA mutations (Sanger sequencing) was identified. Prospectively collected clinicopathological, treatment and outcome data was available. Aspirin use was confirmed by chart review. CSS and overall survival (OS) analyses were conducted using Cox proportional hazards in univariate and multivariate settings. Recurrence free survival (RFS) analyses were limited to early stage CRC pts (Stage A-C). Statistical differences in 5-year CSS (5YS) rates were calculated using Fisher’s exact test. Results: From a cohort of 1,019 CRC pts with known PIK3CA mutation status, 121 (12%) harbored PIK3CA mutations. Of these, 112 (92%) had aspirin usage data available: 27 (24%) pts used aspirin, 85 (76%) did not. In the aspirin group, there were 22 (81%) early stage and 5 (19%) metastatic CRC pts; in the no-aspirin group, there were 59 (69%) early stage and 26 (31%) metastatic CRC pts. In univariate analyses, aspirin use was not associated with superior CSS (HR 0.57, p=0.21), OS (HR 0.83, p=0.57), or RFS (HR 0.72, p=0.57). In multivariate analyses, aspirin use was not associated with improved OS (HR 1.07, p=0.86), CSS (HR 1.04, p=0.94) or RFS (HR 0.54, p=0.34). In 69 (62%) pts with mature follow-up, there was a trend towards superior 5YS for aspirin users (69% v 42%, p=0.09), but this may reflect imbalances in stage at diagnosis. Conclusions: Our study was unable to confirm the recently reported survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Given the small numbers of pts, a modest survival benefit associated with aspirin use cannot be excluded. Analyses in an expanded cohort of early stage pts are underway.
Randomized, phase II study of bevacizumab with mFOLFOX6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: Resectability and safety in OLIVIA.
Authors: Gruenberger Thomas , Bridgewater John A. , Chau Ian , Garcia Alfonso Pilar , Rivoire Michel , Lasserre Susan , Waterkamp Daniel , Adam Rene 
Published: March 2020

3619^ Background: Patients (pts) with unresectable colorectal cancer liver-only metastases (CLMs) may become resectable after downsizing by chemotherapy (CT) and biologic therapy. Although biologics are thought to improve overall response rate (ORR), the optimal combination of a biologic and CT for resectability remains uncertain. Methods: This open-label, multinational study randomized pts with unresectable CLMs to bevacizumab (BEV) plus mFOLFOX6 or FOLFOXIRI q2w. Resectability was assessed by interdisciplinary review. Unresectability was defined as ≥1 of the following: no possibility of upfront R0/R1 resection of all hepatic lesions, <30% estimated residual liver after resection, or disease in contact with major vessels of the remnant liver. The primary end point was overall resection rate (R0/R1/R2). Results: From 10/2008 to 12/2011, 80 pts were randomized to mFOLFOX6-BEV (n=39) or FOLFOXIRI-BEV (n=41). Pt characteristics were male (46% vs 71%), aged ≥60 y (36% vs 63%), ECOG PS of 1 (23% vs 37%), and ≥5 target CLMs (49% vs 49%) in the mFOLFOX6-BEV and FOLFOXIRI-BEV arms, respectively. Resection rate, ORR, and progression-free survival (PFS) data are shown (Table). Grade ≥3 adverse events (AEs) occurred in 84% and 95% of pts receiving mFOLFOX6-BEV and FOLFOXIRI-BEV, respectively, and included neutropenia (35% vs 48%; febrile, 8% vs 13%) and diarrhea (14% vs 28%). Conclusions: The results suggest that FOLFOXIRI-BEV improves resection rates, ORR, and long-term outcomes vs mFOLFOX6-BEV in pts with initially unresectable CLMs. CT- and BEV-related AEs occurred with the expected incidence and were manageable. FOLFOXIRI-BEV should be evaluated further as an effective regimen to downsize CLMs. Clinical trial information: NCT00778102. [Table: see text]
Cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase (DPD) deficiency in patients with colorectal cancer.
Authors: Ahmed Gul , O' Keeffe Jo , O Mullane Denise , Bransfield Alison , Kenny Andrew , Nor Aiman Mohd , Hashim Nurul Asykin , O Sullivan Roisin , Murphy Kate , Galiauskas Raimundas , Bird Brian Richard , Murphy Conleth G. 
Published: March 2020

3627 Background: DPD is an enzyme encoded by the DPYD gene involved in the metabolism of the chemotherapy drug 5-fluorouracil (5FU) and the oral 5FU prodrug capecitabine. Patients (pts) with DPYD mutations are at risk of severe toxicities from standard dose 5FU, although they may safely receive lower dose therapy with careful monitoring and dose escalation. Methods: In this retrospective study we identified all pts starting 5FU-based chemotherapy for colorectal cancer (CRC) at our institution between Jan 1 2010 and Dec 31 2012. During this time DPD testing was usually performed in a reactive manner, typically for pts experiencing severe toxicities. We reviewed the charts of pts who tested positive for DPYD mutations and assessed the financial implications of their hospitalizations with toxicity. These costs were compared to the costs which would have incurred if all pts starting such therapy had been proactively tested. Results: A total of 134 pts started first-line 5FU-based chemotherapy for CRC over the study period, 66 in the adjuvant setting and 68 for metastatic disease. 31 pts had DPYD mutation testing performed. 6 tests (19% of those tested, 4.5% of the total population) revealed heterozygote DPYD mutations. 5 pts had already experienced severe treatment-related toxicity resulting in cessation of therapy, while one was tested prospectively and received chemotherapy with dose reduction ab initio. The total cost related to hospitalization with toxicity for these 5 pts was €155,083. At €177 per test, the cost to prospectively test all pts starting first-line 5FU-based therapy over the time period would have been €23,718 representing a saving of €131,365 through avoiding these admissions alone. 4 pts who tested positive for DPYD mutations were receiving adjuvant therapy and none restarted therapy following severe toxicity early in their therapy. 2 pts subsequently relapsed with metastatic disease. Conclusions: Prospective testing for DPYD mutations in pts with CRC starting 5FU-based therapy for the first time represents a considerable cost-saving opportunity, in addition to potentially avoiding prolonged hospitalization and morbidity for a sizeable minority of pts.
TFAP2E methylation status and prognosis of patients with radically resected colorectal cancer.
Authors: Park Seong Joon , Kim Seung-mi , Hong Yong Sang , Lee Jae-Lyun , Kim Jeong-Eun , Kim Kyu-Pyo , Jin Dong-Hoon , Kim Chan Wook , Yoon Yong Sik , Park In Ja , Lim Seok-Byung , Yu Chang Sik , Kim Jin Cheon , Kim Tae Won 
Published: March 2020

3628 Background: Transcription factor AP-2ε, a member of the AP-2 family has extensively studied in many cancers. Recently, it has been suggested that the gene encoding AP-2ε (TFAP2E) is involved in the development of colorectal cancer (CRC) and is also associated with clinical outcomes of the patients with CRCs. Therefore, we have investigated the clinical significance of TFAP2E in CRC patients who underwent curative resections. Methods: A single-institution cohort of 248 patients with curatively resected, stage I/II/III CRCs between March and December, 2004 were included, and the analyses were performed in 193 patients whose tumors were available for TFAP2E methylation status Results: One hundred twelve patients (58%) showed TFAP2E hypermethylation, which was significantly more common in CRCs with distal location, low pathologic T stage (T1/T2) and stage I. After a median follow-up duration of 86.3 months, the patients with TFAP2E hypermethylation had a trend for better survival outcome in terms of relapse-free survival (RFS) and overall survival (OS) (TFAP2E hypermethylation vs. hypomethylation; 5-year RFS rate 90% vs. 80%, p=0.063; 6-year OS rate 88% vs. 80%, p=0.083). Multivariate analysis showed pathologic nodal stage and TFAP2E methylation status were independent prognostic factors affecting both RFS and OS, which also remained significant factors in the subgroup analysis including 154 patients with stage II/III CRCs who had received adjuvant chemotherapy. Conclusions: TFAP2E hypermethylation was associated with better clinical outcome and may be considered as an independent prognostic factor in the patients with curatively resected CRC.
Clinicopathologic features of KRAS-mutated colorectal tumors vary by site of mutation.
Authors: Morris Van Karlyle , Overman Michael J. , Eng Cathy , Vilar Sanchez Eduardo , Morelli Maria , Jiang Zhiqin , Luthra Rajyalakshmi , Maru Dipen M. , Meric-Bernstam Funda , Kopetz Scott 
Published: March 2020

3632 Background: KRAS mutations in codons 12 and 13 are present in approximately 40% of all colon cancers and predict a lack of response to monoclonal antibodies to the EGFR among patients with metastatic disease. Activating mutations in codons 61 and 146 occur less frequently, and the clinicopathologic features of this subpopulation of KRAS-mutant colorectal tumors have not been clearly defined. Methods: Records of patients treated at MD Anderson Cancer Center between December 2000 and August 2012 for metastatic colorectal cancer whose tumors underwent testing for a KRAS mutation were reviewed for clinical characteristics, concurrent mutations, and survival outcomes. Associations between mutation status and clinic features were measured by calculation of odds ratios, and survival was estimated according to the Kaplan-Meier method. Results: Among the 487 records reviewed, 225 KRAS 12/13 mutations (47.2%) and 14 KRAS 61/146 mutations (2.9%) were detected. Liver metastases were less common for patients with KRAS 61/146 mutations than for patients with KRAS 12/13 mutations (OR 0.26, p-value=0.02). No difference in lung metastases was identified for KRAS 61/146 mutated patients when compared to those with KRAS wild-type tumors (OR=2.1, p-value=0.26), even though lung metastases were more common for patients with KRAS 12/13 mutations (OR 2.86, p-value=0.001). There was no association between the presence of a KRAS 61/146 mutation and gender, stage at presentation, site of primary tumor, body mass index, tobacco history, or concurrent PIK3CA mutation. Whereas a worse survival difference from the time of metastasis detection was noted for KRAS 12/13 patients when compared to those with KRAS wild-type tumors (HR 1.74, p-value= 0.002), patients with KRAS 61/146 mutations demonstrated no change in survival outcome (HR 1.10, p-value=0.87). Conclusions: Patients with KRAS 61/146 mutations have different patterns of metastases compared to KRAS 12/13, but do not appear to share the poor prognosis associated with the more common KRAS 12/13. These results suggest that clinical phenotypes for patients afflicted with colorectal cancer may differ based on the specific codon mutated within the KRAS oncogene.
Ultra-deep amplicon sequencing to identify actionable mutations in matched plasma/tumor specimens from 44 patients with colorectal cancer of UICC stage III and IV.
Authors: Pechanska Paulina , Pross Matthias , Radke Cornelia , Marusch Frank , Lobeck Hartmut , Bunse Joerg , Niedobitek Gerald , Mantke Rene , Pauli Roland , Pertschy Jörg , Kosmehl Hartwig , Weise Steffen , Tennstedt-Schenk Cornelia , Hinzmann Bernd , Adams Hans-Peter , Rosenthal Andre 
Published: March 2020

3634 Background: Circulating cell-free DNA (cf-DNA) isolated from plasma samples of cancer patients (pts) is a promising source for noninvasive examination of tumor-specific mutation patterns. We examined the efficiency of ultra-deep amplicon sequencing (UDAS) of cf-DNA isolated from plasma and tumor DNA isolated from matched primary tumor tissue of pts with colorectal cancer (CRC). Methods: Blood was drawn prior to surgery from 44 pts: 20 male, 24 female; 44-79 years of age (median: 67.5); 11 stage III, 33 stage IV; 36 colon, 8 rectum tumors; no neo-adjuvant therapy. Cf-DNA was isolated from 2 ml of EDTA plasma. UDAS was applied to 72 DNA samples (44 plasma, 28 matched snap-frozen primary tumors) using the MiSeq platform (Illumina). A panel of 49 highly multiplexed amplicons was designed (Life Technologies) representing 9 cancer genes frequently mutated in CRC. For 16 primary tumors the mutation profile was determined using the TruSeq Amplicon Cancer Panel (Illumina). Results: Median cf-DNA yield was 310 ng / 2 ml plasma (1ng – 6.600 ng). There was no significant relation between cf-DNA yield and any clinical characteristic. Median amplicon coverage was 20.162 reads per bp (2.913 - 115.782). 33/49 amplicons (67%) had a coverage of > 10.000 reads. Altogether 61 high quality COSMIC-cited mutations were confirmed in plasma of 29/44 (66%) pts: 24/33 (73%) pts in stage IV, 5/11 (45%) pts in stage III. Confirmed mutations are: APC-17; BRAF-2, FBXW7-1, KRAS-15, NRAS-1, PIK3CA-4, SMAD4-2, and TP53-19 mutations. No high quality mutations were found in CTNNB1 and HRAS. Moreover two pts exhibited four high quality plasma mutations which were not detected in the matched primary tumor: APC (R216X), KRAS (Q61K), and SMAD4 (D355E); PIK3CA (E545K). Conclusions: Ultra deep amplicon sequencing is suitable to detect mutations in plasma samples of CRC pts with a high concordance to matched primary tumors. The concordance rate can be further increased by extending the spectrum of analyzed mutations or by the enrichment of cf-DNA tumor copies. This method could be applied to detect and monitor metastasis thus opening a new paradigm for the selection of pts for targeted therapies.