bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Gain of ALK gene copy number to predict lack of response to anti-EGFR treatment in advanced chemorefractory colorectal cancer (CRC) with KRAS/NRAS/BRAF/PI3KCA wild-type status.
Authors: Pietrantonio Filippo , Tessari Anna , Miceli Rosalba , Biondani Pamela , Perrone Federica , Testi Adele , Tamborini Elena , Pelosi Giuseppe , Mariani Luigi , Fanetti Giuseppe , Gevorgyan Arpine , Bossi Ilaria , Di Bartolomeo Maria , De Braud Filippo G.
Published: March 2020

3641

Background: KRAS, BRAF, NRAS and exon 20 PIK3CA quadruple wild-type CRC is associated with 41.2% response rate to anti-EGFR treatments. Even in molecular characterized patients, there is still a subset of non responders. The identification of additional predictive biomarkers is an unmet clinical need for treatment personalization. Alterations of ALK oncoprotein may interfere with the biological activity of EGFR through cross-talk of downstream signalling pathways. Methods: This retrospective analysis aimed to investigate the correlation between ALK gene copy number (GCN), assessed by fluorescence in situ hybridization (FISH), and clinical outcome in KRAS/NRAS/BRAF/PI3KCA wild-type chemorefractory advanced CRC patients receiving cetuximab or panitumumab. FISH was perfomed with break-apart ALK (2p23) probes and gain of ALK GCN was defined as a mean of 3 to 5 signals in ≥10% of cells and amplification as ≥6 signals. Association of ALK status with RECIST response was performed by Fisher’s exact test. Results: Forty-one patients were identified, of whom 17 (41%) were ALK GCN positive, whereas the remaining 24 cases (59%) were ALK GCN negative. No ALK translocations were detected. Overall response rate was 19/41 (46%). We observed a partial response in 3/17 patients with ALK GCN positive versus 16/24 patients with ALK GCN negative (18% versus 67%, respectively; P=0.0036). Kaplan-meier curves for comparison of median progression-free and overall survival, as well as correlation with ALK expression by immunohistochemistry, will be presented at the Meeting exploring the whole National Cancer Institute data-set. Conclusions: In this study population with KRAS/NRAS/BRAF/PI3KCA wild-type tumors, the response rate greater than 40% is in line with literature data. ALK GCN may be a biomarker for clinical outcome prediction in advanced chemorefractory CRC patients treated with cetuximab or panitumumab.
Bevacizumab before cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin: Analysis of early postoperative complication rate and long term follow-up.
Authors: Eveno Clarisse , Passot Guillaume , Goéré Diane , Soyer Philippe , Gayat Etienne , Glehen Olivier , Elias Dominique , Pocard Marc
Published: March 2020

3642

Background: Patients with stage IV colorectal cancer and peritoneal carcinomatosis are increasingly treated with curative intent and perioperative systemic chemotherapy combined with targeted therapy.The aim of the study was to analyze the potential impact of bevacizumab on early morbidity and survival after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin. Methods: From 2004 to 2010, in three referral centers, 182 patients with colorectal carcinomatosis were treated with complete cytoreduction followed by HIPEC after either preoperative systemic chemotherapy alone or in combination with bevacizumab. Because there was no control on treatment allocation, propensity score methods were used to control this bias. Results: The median time from discontinuation of bevacizumab to HIPEC was 7 weeks (range, 6-10). Major morbidity was greater in the Beva group (34 vs. 19%, p=0.020). Nine patients died postoperatively: 5 (6.2%) in the Beva group (n=80) and 4 (3.9%) in the group treated with chemotherapy alone (n=102) (p=NS). The rate of digestive fistulas was greater in the Beva group, although not significant (18 vs. 10%, p=NS). After matching, the effect of Bevacizumab on major morbidity (including death) was found to be significant (OR = 2.28, 95% CI; 1.05 - 4.95) (p=0.04). No difference in median of overall and disease free survival was found between the two groups (12 and 36 month in Beva group vs. 14.3 and 49 month in the control group, p=NS). Conclusions: Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for colorectal carcinomatosis is associated with 2-fold increased morbidity. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated with prospective randomized study.
Maintenance with the TLR-9 agonist MGN1703 versus placebo in patients with advanced colorectal carcincoma (mCRC): A randomized phase II trial (IMPACT).
Authors: Riera-Knorrenschild Jorge , Schmoll Hans-Joachim , Arnold Dirk , Kroening Hendrik , Mayer Frank , Nitsche Dieter , Ziebermayr Reinhard , Scheithauer Werner , Andel Johannes , Meisel Christian , Schmidt Manuel , Wittig Burghardt
Published: March 2020

3643

Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA-based immunomodulator, acts as TLR-9 agonist. This trial has been conducted to assess clinical efficacy, safety, and immunogenicity of MGN1703 as maintenance therapy vs placebo. Methods: The IMPACT trial is an international, multicenter, randomized (2:1) double-blind placebo-controlled phase 2 trial in mCRC patients with disease control (CR, PR, SD) after 4.5 to 6 months of 1st-line induction chemotherapy with FOLFOX/XELOX or FOLFIRI +/- bevacizumab. Results: 59 patients have been randomized (43 MGN1703, 16 placebo). Median PFS from start of maintenance was not different with 2.8 vs 2.7 months, however the HR was 0.56 (CI 95%: 0.29-1.08; p=0.069) in favor of MGN1703, due to a small favorable subgroup with long-term PFS (20% vs 0% at 9 months; p=0.006). Total PFS from beginning of induction chemotherapy including maintenance was significantly improved: HR 0.49 (CI 95%: 0.25-0.94), p=0.029. After a median follow-up of 13 months 66% of patients are still alive (67% vs 62%), therefore survival data are still preliminary (HR 0.79; CI 95%: 0.3-2.1) and will be mature at the meeting. Activation of cellular immune function as indicated by significant increase of CD14+CD169+monocytes was observed in all but one of the MGN1703 treated patients, while absent in all placebo patients. Treatment was well tolerated: 46.5% vs 31.3% of patients (MGN1703 vs placebo) had any drug-related adverse events (AE) and 20.9% vs 18.8% had AE with grade 3 or 4 (including hypertension, ileus, sepsis, sensory polyneuropathy, nausea/vomiting for MGN1703 and pain, popular exanthema for placebo). Conclusions: MGN1703 maintenance seems to prolong PFS in a subgroup of patients with disease control after induction chemotherapy vs placebo, and is associated with relative mild toxicity. This in an early signal in a selected and very limited patient population which supports further investigation. Predictive biomarkers are under evaluation to identify a potential subgroup which might have benefit from this TLR-9 MGN1703 maintenance. Clinical trial information: NCT01208194.
Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study.
Authors: Bang Yung-Jue , Im Seock-Ah , Lee Keun-Wook , Cho Jae Yong , Song Eun-Kee , Lee Kyung Hee , Kim Yeul Hong , Park Joon Oh , Chun Hoo Geun , Zang Dae Young , Fielding Anitra , Rowbottom Jacqui , Kim Woo Ho
Published: March 2020

4013

Background: Our multicenter study compared the efficacy of the oral PARP inhibitor olaparib plus paclitaxel (O/P) vs paclitaxel alone (P) as second-line therapy in pts with recurrent/metastatic gastric cancer (GC) (NCT01063517). As initial preclinical data suggested that responsiveness of GC cell lines to olaparib was associated with low ATM protein levels, our study was enriched for pts with low ATM tumors (ATM–) by IHC (50% randomized vs 14% screening prevalence). Methods: Eligible pts were randomized 1:1 (stratified by ATM status) to receiveolaparib 100 mg bid (tablet form) plus paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) or placebo plus paclitaxel until progression or investigator decision. After combination therapy, pts could take olaparib 200 mg bid monotherapy or placebo until progression. Co-primary endpoints: progression-free survival (PFS; RECIST v1.1) in all pts and ATM– pts. Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Results: 123/124 randomized pts were treated (O/P=61; P=62). Baseline characteristics were generally well balanced. Use of post-progression therapy was similar in both arms (O/P=48.4%; P=43.5%) as was median paclitaxel duration (O/P=17 wks; P=16 wks); 18 pts received monotherapy (O/P=11; P=7). More pts in the O/P than P arm had delays (79 vs 63%) and reductions (41 vs 27%) in paclitaxel dosing. The most common grade ≥3 AEs in the O/P and P arms were neutropenia (56 vs 39%) and anemia (11 vs 11%). Conclusions: Olaparib plus paclitaxel was well tolerated and led to a statistically significant improvement in OS, but not PFS, vs paclitaxel alone in both all pts and ATM– pts, with a larger benefit in ATM– pts. Clinical trial information: NCT01063517. [Table: see text]
Association of gene expressions of TOP2A, GGH, and PECAM1 with hematogenous, lymph-node, and peritoneal recurrence in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Terashima Masanori , Ichikawa Wataru , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Sinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi , Sasako Mitsuru ,   ACTS-GC Group
Published: March 2020

4019

Background: Exploratory biomarker analysis was conducted to identify factors related to relapse sites in the ACTS-GC study, a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients (pts) with stage II/III gastric cancer. Methods: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 pts (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative 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 as lower or higher than the median value. The impact of gene expression on relapse site was analyzed using the 5-year relapse-free survival (RFS) data of the ACTS-GC. Results: Among the 829 pts, hematogenous, lymph-node, and peritoneal recurrence developed in 72, 105, and 138 pts, respectively. The hazard ratios (HR) (S-1 vs. surgery alone) were 0.79 (95%CI, 0.54-1.16) for hematogenous, 0.51 (95%CI, 0.31-0.82) for lymph-node, and 0.60 (95%CI, 0.42-0.84) for peritoneal recurrence. Among 63 screened genes, topoisomerase II alpha (TOP2A), gamma-glutamyl hydrolase (GGH), and platelet/endothelial cell adhesion molecule 1 (PECAM1) most strongly correlated with hematogenous, lymph-node, and peritoneal recurrence, respectively. Hematogenous RFS was significantly worse in TOP2A high pts than in low pts (HR, 2.35; 95% CI, 1.55-3.57). Lymph-node RFS was significantly worse in GGH high pts than in low pts (HR, 1.87; 95% CI, 1.13-3.08). Likewise, peritoneal RFS was significantly worse in PECAM1high pts than in low pts (HR, 2.37: 95% CI, 1.65-3.41). These factors were independent and stronger risk factors than tumor histological type on multivariate analysis. Conclusions: Expression levels of the TOP2A, GGH, and PECAM1 genes in primary tumors are respectively linked to high risks of hematogenous, lymph-node, and peritoneal recurrence in pts with stage II/III gastric cancer.
Effectiveness of D2 gastrectomy for lymph node positive and advanced gastric cancer: Survival results of the Italian Gastric Cancer Study Group (IGCSG) randomized surgical trial on D1 versus D2 dissection for gastric carcinoma.
Authors: Degiuli Maurizio ,   Italian Gastric Cancer Srudy Group (IGCSG)
Published: March 2020

4027

Background: It is still unclear whether D2 lymphadenectomy can significantly improve survival of gastric cancer and therefore should be applied routinely or performed in selected cases. We conducted a multicenter randomized trial to compare the efficacy of D2 and D1 lymphadenectomy for gastric cancer. Primary outcome was overall survival; secondary endpoints were disease specific survival, morbidity and in-hospital mortality. Methods: Between June 1998 and December 2006 patients with gastric adenocarcinoma were randomly assigned to either D1 or D2 lymphadenectomy. Intraoperative randomization was implemented centrally by telephone. Results: A total of 267 eligible patients were allocated to either D1 (133) or D2 group (134). Morbidity (12·0% vs 17·9%, p=0·18) and mortality (3·0% vs 2·3%; p=0·72) were similar. There was no difference in the overall 5-year survival (66·5% vs 64·2%, p = 0.70). Subgroups analyses showed a 5-years disease specific survival benefit for pT1 cases treated with D1 dissection (98.0% vs 82.9%, p = 0.01) and of pT>1 LN+ patients treated with D2 resection (38·4% vs 59·5%, p = 0.05 at five years). Conclusions: In intention to treat analysis we observed no overall 5-year survival benefit from D2 resection. The trial showed a survival benefit of D1 procedure in early stages. On the opposite, despite evidence of contamination in the D1 arm, a survival advantage was documented in patients with advanced disease and lymph node metastases submitted to D2 procedure. Clinical trial information: ISRCTN11154654. [Table: see text]
A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-related symptoms inadequately controlled by somatostatin analogs.
Authors: Wolin Edward M. , Jarzab Barbara , Eriksson Barbro , Walter Thomas , Toumpanakis Christos , Morse Michael , Tomassetti Paola , Weber Matthias , Fogelman David R. , Ramage John , Poon Donald , Huang Jerry M. , Hudson Michelle , Zhi Xin , Pasieka Janice L. , Mahamat Abakar , Swahn Fredrik , Newell-Price John , Mansoor Wasat , Oberg Kjell E.
Published: March 2020

4031

Background: The novel somatostatin analog (SSA) pasireotide has a broader binding profile than currently available SSA (octreotide and lanreotide). Results from a phase III study (NCT00690430) of pasireotide LAR (P) vs octreotide LAR (O) in patients (pts) with NET and disease-related symptoms uncontrolled by the maximum approved dose of available SSA are shown. Methods: Pts (N=110) were randomized and stratified by predominant symptom at baseline (diarrhea [D], flushing [F], or D+F) 1:1 to P (60 mg IM) or O (40 mg IM) q28d. Primary objective was symptom response at month (M) 6. Secondary objectives included tumor response and safety. Progression-free survival (PFS) was an exploratory analysis. Results: 53 and 57 pts were enrolled in the P and O arms when the study was halted due to an interim analysis suggesting futility for symptom response. Baseline characteristics were similar between arms. Majority of primary tumor locations were small intestine (72% and 81% in the P and O arms). Symptom response at M6 was 9/43 (21%) and 12/45 (27%) in the P and O arms, odds ratio 0.73 (95% CI, 0.27-1.97; p=0.53). Median numbers of D/day and F/2 weeks and change in symptom from baseline to M6 are in Table. Hyperglycemia (11% vs 0%), diarrhea (9% vs 7%), and abdominal pain (2% vs 9%) were the most common grade 3/4 AEs in the P vs O arms in the core phase, and 7 (13%) and 4 (7%) pts discontinued due to AEs. Median investigator-assessed PFS was 11.8 months and 6.8 months in the P and O arms (HR=0.46; p=0.045). Conclusions: P and O showed a similar safety profile except for the higher frequency of hyperglycemia in P. Pts on P had PFS 5 months longer than pts on O (investigator assessment), despite no differences in symptom response rates. These results warrant a large phase III trial to clarify the role of P as a therapy for NET. Clinical trial information: NCT00690430. [Table: see text]
Hemoglobin-A1c level to predict for clinical outcomes in patients with pancreatic cancer.
Authors: Fan Katherine Y. , Dholakia Avani Satish , Wild Aaron Tyler , Su Zheng , Hacker-Prietz Amy , Kumar Rachit , Hodgin Mary , Hsu Charles C. , Le Dung T. , De Jesus-Acosta Ana , Diaz Luis A. , Laheru Daniel A. , Hruban Ralph H. , Fishman Elliot K. , Brown Todd D. , Pawlik Timothy M. , Wolfgang Christopher Lee , Tran Phuoc T. , Herman Joseph M.
Published: March 2020

4039

Background: An association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDA) has long been recognized. While long-standing DM may be a risk factor for developing PDA, new-onset DM may be a manifestation of the cancer. Here we assess the role of an objective and quantifiable measure of glucose intolerance, hemoglobin-A1c (HbA1c), in predicting clinical outcomes in PDA. Methods: HbA1c values were prospectively collected on 656 consecutive patients presenting to the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic from 2009-2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Patients with prior treatment for PDA or a history of DM greater than a 1-year were excluded. Univariate Cox regression analyses and multivariable proportional hazards models were used to identify poor prognostic factors for overall survival. Results: Of 284 patients included, 44 had benign disease, 62 R-PDA, 115 BL-PDA, and 63 M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had higher HbA1c values on average at presentation than patients with BPD (6.1% vs. 5.6%, p<0.001). There was a trend towards higher HbA1c at presentation in patients with advanced PDA (BL and M) compared to patients with R-PDA (6.2% vs. 5.9%, p=0.100); moreover, the proportion of patients with HbA1c levels in the diabetic range (>6.4%) increased with more advanced stage of disease. Among patients with PDA (n=240), univariate analyses showed HbA1c≥6.5, age≥65, ECOG≥1, CA19-9>90, tumor size >3cm, and advanced stage to be significantly associated with inferior survival (all HR>1, p<0.05). After multivariate analysis with backward elimination, all of the above factors except for tumor size >3cm remained in the model for inferior survival. Conclusions: HbA1c level at presentation appears to correlate with disease stage and, moreover, to predict for survival among all stages of PDA. Patients with PDA have significantly higher HbA1c levels at presentation than patients with BPD. This study highlights the potential utility of HbA1c as a screening tool and prognostic factor.
Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487).
Authors: Heymach John , Tran Hai T. , Nixon Andrew B. , Hurwitz Herbert , Infante Jeffrey R. , Gagnon Robert C. , Steplewski Klaudia , Le Ngocdiep T. , Liu Yuan
Published: March 2020

4042

Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n = 144 baseline [BL]; n = 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P < .01 for significance) and between arms (treatment arm by CAF level interaction, P < .05 for significance). Results: Lower levels (< median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T+G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T+G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T+G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T+G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T+G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.
Assessment of the association of the VeriStrat test with outcomes in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (G) with or without erlotinib (E) in the NCIC CTG PA.3 phase III trial.
Authors: Renouf Daniel John , Parulekar Wendy , Grigorieva Julia , Tu Dongsheng , Moore Malcolm J.
Published: March 2020

4061

Background: VeriStrat is a mass spectrometry based assay performed on serum or plasma that has been shown to be prognostic in several tumor types, and may predict differential drug benefit in several settings. We investigated the association of VeriStrat with outcomes in the NCIC CTG PA.3 randomized phase III trial of G and E vs. G and placebo (P) in pts with advanced PC. Methods: Pre-treatment plasma samples were available for 499/569 (87.7%) enrolled pts. VeriStrat testing was performed in a CLIA-certified laboratory; pts were classified as either Good, Poor, or indeterminate. The relationship between VeriStrat results and overall survival (OS) and progression free survival (PFS) was assessed by Kaplan-Meier curves and log-rank test in univariate analysis and Cox model adjusting for gender, age [>60 vs. ≤60], race [Caucasian vs. other], ECOG [0-1 vs. 2], and pain intensity at baseline [≤20 vs. >20] in multivariate analysis. The predictive effect was assessed by interaction test. All statistical analyses were performed by the NCIC CTG. Results: Of the 499 samples, 11 were hemolyzed and 4 had acquisition failures. VeriStrat was performed on 484 samples, 9 failed quality control, 22 had indeterminate results. Of the remaining 452, 353 (78%) were classified as Good and 99 (22%) as Poor. In the G and P arm, median OS was 7.16 months (ms) for VeriStrat Good vs. 3.78ms for VeriStrat Poor (p<0.0001); Adjusted Hazard Ratio (AHR) 0.59 (0.43-0.82), p=0.002. In the G and E arm, median OS was 7.33ms for VeriStrat Good vs. 4.50ms for VeriStrat Poor p<0.0001; AHR 0.47 (0.32-0.70), p=0.001. A similar relationship was seen for PFS (G and P arm: median PFS 3.91 vs. 2.07ms (p=0.001); AHR 0.67 [0.49-0.92], p=0.01); G and E arm: median PFS 4.24 vs. 2.86ms (p=0.0004); AHR 0.54 [0.37-0.80], p=0.002). Tests of interaction of VeriStrat status and treatment for OS and PFS were not significant: AHR 0.78 (0.48-1.25), p=0.30 and AHR 0.80 (0.50-1.30), p=0.37 respectively. Conclusions: VeriStrat results were significantly associated with OS and PFS for both regimens in this study. VeriStrat was not predictive of benefit from the addition of E to G.
Phase II study of neoadjuvant chemotherapy with modified FOLFOXIRI in borderline resectable or unresectable stage III pancreatic cancer.
Authors: Vasile Enrico , De Lio Nelide , Cappelli Carla , Pollina Luca , Funel Niccola , Sainato Aldo , Ginocchi Laura , Lucchesi Maurizio , Caparello Chiara , Caponi Sara , Perrone Vittorio , Pasqualetti Francesco , Caniglia Fabio , Signori Stefano , Mazzeo Salvatore , Greco Carlo , Falcone Alfredo , Campani Daniela , Mosca Franco , Boggi Ugo
Published: March 2020

4062

Background: FOLFIRINOX has shown high activity in metastatic pancreatic cancer (PC) patients and could be an interesting regimen also for patients with inoperable locally advanced disease. Our group had developed a similar schedule in metastatic colorectal cancer named FOLFOXIRI with good tolerance and activity. Therefore, we have decided to perform a phase II trial to prospectively evaluate the activity of modified FOLFOXIRI in borderline resectable or unresectable PC. Methods: Modified FOLFOXIRI consisted of a lower dose of irinotecan (150 mg/sqm) and of infusional 5-fluorouracil (2800 mg/sqm as a 48-hour continuous infusion on days 1 to 3) with no bolus 5-fluorouracil. Folinic acid and oxaliplatin (85 mg/sqm) remained unchanged. The study enrolled patients with diagnosis of pancreatic adenocarcinoma, stage III borderline resectable or unresectable disease (cT4,cN0-1,cM0), ECOG PS 0-1, age 18-75. The primary end-point of the study was the percent of patients who undergo radical surgical resection after chemotherapy. Results: Thirty-two patients have been enrolled; M/F=12/20; PS 0/1=16/16. Median age was 60 years (range 44-75). Median number of FOLFOXIRI cycles was 6 (range 2-14). Grade 3-4 toxicities was experienced by 20 patients during chemotherapy. Twelve partial responses (37%) and 14 stable diseases (45%) have been observed; 2 patients had progressive diseases (6%). The remaining 4 patients (12%) have not been yet evaluated because are still in the first months of treatment. A local treatment was received after chemotherapy by 18 patients until now: 13 (41%) received radical surgical resection and 5 received concomitant chemo-radiotherapy. Three explorative laparotomy showed occult metastases. In other 7 cases surgery is planned while 2 patients refused surgery. Median progression-free survival is 14.0 months and median overall survival is 24.2 months with a two-year survival rate of 54%. Conclusions: Chemotherapy with FOLFOXIRI seems active in locally advanced PC and may allow to obtain a downstaging of disease leading to achieve a curative surgical resection in some cases. Longer follow up is needed to better evaluate long-term outcome of this strategy.