bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics and characteristics of KRAS mutated circulating tumor DNA in patients with metastatic colorectal cancer during various treatments.
Authors: Takayama Yuji , Suzuki Koichi , Ichida Kosuke , Fukui Taro , Kakizawa Nao , Watanabe Fumiaki , Kikugawa Rina , Hasegawa Fumi , Tsujinaka Shingo , Miyakura Yasuyuki , Konishi Fumio , Rikiyama Toshiki
Published: January 2019

665

Background: KRAS mutated circulating tumor DNA (MctDNA) can be detected in blood of patients with metastatic colorectal cancer (mCRC) but its dynamics and characteristics during anti-EGFR and other treatments are not well known. Methods: Four hundred and fifty-one plasma samples were collected prospectively from 85 patients who underwent chemotherapy due to mCRC in 2014 - 2017. KRAS mutation in codon12/13/61 was explored in tumor tissues and plasma. Results: KRAS assessment in tumor tissues showed 29 patients with KRAS mutation (MT), 56 patients without mutation (WT). Sensitivity and specificity of MctDNA was 86.4% and 100%, respectively. In 29 patients with MT, significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (3.0 months vs.15.0 months; p = 0.005). In 56 patients with WT, 27 patients showed MctDNA during various treatments. Different characteristics in appearance were recognized during several treatments including anti-VEGF, TAS-102 and regorafenib. KRAS mutation in codon12/13 was appeared before and after disease progression. KRAS mutation in codon 61 was, however, frequently detected before disease progression. A spike like appearance of KRAS mutation in codon12/13 was likely seen in response to induction of the sequential treatment. Significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (6.0 months vs. 13.0 months; p = 0.0017), as was observed in patients with MT. Conclusions: Dynamics and characteristics of KRAS status in blood may be involved in the treatment response and outcome in mCRC patients.
Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.
Authors: Murcia Oscar , Juárez Miriam , Hernández-Illán Eva , Rodriguez-Soler Maria , Giner-Calabuig Mar , Alustiza Miren , Egoavil Cecilia , Castillejo Adela , Alenda Cristina , Mangas Carolina , Barberá Victor , Yuste Ana , Bujanda Luís , Clofent Joan , Andreu Montserrat , Castells Antoni , Llor Xavier , Zapater Pedro , Jover Rodrigo
Published: January 2019

668

Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.
Plasma ICAM-1 (pICAM-1) and plasma IL-8 (pIL-8) level as biomarker of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).
Authors: Yamamoto Yoshiyuki , Okamoto Wataru , Makiyama Akitaka , Shitara Kohei , Denda Tadamichi , Ogura Takashi , Nakano Yasuyuki , Nishina Tomohiro , Komoda Masato , Hara Hiroki , Ozaki Yukinori , Kawakami HIsato , Boku Narikazu , Hyodo Ichinosuke , Yamazaki Kentaro , Hironaka Shuichi , Sakai Kazuko , Yamanaka Takeharu , Muro Kei , Nishio Kazuto
Published: January 2019

670

Background: Bevacizumab (BV)-containing chemotherapy has been established as the standard first-line treatment for metastatic colorectal cancer (mCRC). However, no biomarkers have been established to predict the clinical benefit of BV for patients (pts) with mCRC. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). Median values of pICAM-1 and pIL-8 were used as cut-off points to categorize pts into the low and high groups. Progression free survival (PFS) and overall survival (OS) were compared between two groups, using Cox proportional hazards model. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0]. Response rate was 64.6 % [53.3-74.9]. pICAM-1 and pIL-8 were measured in 99 pts and the median values were 190.0 ng/ml [range, 58.0- 1080.1] and 311.5 pg/ml [range, 83.2-4541.4], respectively. The hazard ratios of PFS and OS between the high and low pICAM-1 groups were 2.08 [95%CI, 1.28-3.40, p = 0.003] and 2.04 [0.92-4.50, p = 0.079], respectively. The hazard ratios of PFS and OS between the high and low pIL-8 groups were 1.63 [95%CI, 1.00-2.65, p = 0.048] and 3.42[1.57-7.44, p = 0.002], respectively. Conclusions: High pICAM-1 and pIL-8 were associated with short PFS and OS of mCRC pts treated with BV-containing chemotherapy, suggesting that pICAM-1 and pIL-8 could be predictive markers for prognosis of mCRC treated with BV. Clinical trial information: UMIN000012442.
Somatic mutation landscape of appendiceal cancer.
Authors: Shen John P. , Jacobs Miriam T. , Fuh Ingrid L , Baumgartner Joel Micah , Fanta Paul T. , Lowy Andrew M. , Harismendy Olivier
Published: January 2019

671

Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, which has prevented the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease. Standard treatment generally follows consensus guidelines for colorectal cancer; however, there are currently no standards to guide chemotherapy selection in the adjuvant or metastatic setting. Methods: Somatic mutation profiles covering ~300 frequently mutated genes were obtained for 385 primary appendiceal tumors (Foundation Medicine). A retrospective review was performed to gather clinico-pathologic data. The primary objective was to assess the somatic mutation profile of each subtype of appendiceal cancer and to compare these to colorectal cancer. Colorectal data was obtained from TCGA cohort via cBioPortal. Results: Appendiceal adenocarcinoma (non-mucinous) and mucinous adenocarcinoma had shared somatic mutations albeit with differing frequencies. The most common mutations were KRAS (60.1% and 80.5%, respectively), GNAS (32.4%, 58.5%), TP53 (42.8%, 19.5%), and SMAD4 (14.8%, 14.6%). Tumors with goblet cell (adenocarcinoid) histology had lower prevalence of KRAS (16.0%) and GNAS mutations (8.0%), but similar prevalence of TP53 mutation (24.0%) and a greater prevalence of ARID1A mutation (20.0%). The mutation profiles of all appendiceal histologies differed from colorectal adenocarcinoma with markedly lower prevalence of ATM (7.9% vs. 71.0%). Chemotherapy data was available for 30 metastatic patients; these patients received an average of 1.76 lines of therapy (range 1-4). All 30 were treated with either 5-FU or capecitabine, 11 (36.7%) with oxaliplatin, 23 (76.7%) with irinotecan and 19 (63.3%) with bevacizumab. Analysis of survival data and correlation with molecular and histologic features is ongoing. Conclusions: Despite clear molecular differences between appendiceal and colorectal tumors, appendiceal tumors are primarily treated with colorectal chemotherapy regimens. There remains a pressing need for both pre-clinical and clinical investigation to develop treatment regimens specific to appendix cancer.
Assessment of microsatellite instability (MSI) in cell free DNA (cfDNA) of colorectal cancers (CRC) patients (pts).
Authors: Barzi Afsaneh , Campan Mihaela , Petterson Jonas , Du Lan , Long Tiffany , Dubeau Louis , Lenz Heinz-Josef , Ward Pamela
Published: January 2019

672

Background: While there is accumulating evidence that tumor specific mutations can be accurately detected in cfDNA, the determination of MSI status in cfDNA has not been investigated, perhaps because the complexity of detecting tumor instability embedded within stutter amplification patterns generated from normal cfDNA was considered too challenging to allow the detection of altered microsatellite profiles. We explored the possibility of detecting MSI in cfDNA. Methods: Circulating cfDNA was isolated from Streck tubes from 13 patients with CRC; 6 pts had serial collections. Isolation and testing of cfDNA for MSI was performed using kits purchased from Promega. Microsatellite alterations were scored by comparing the amplicon stutter profiles of 5 mononucleotide markers generated from cfDNA to those present in genomic DNA extracted from buffy coats from the same pts. MSI was diagnosed based on a shift in the size of a predominant stutter peak together with a commensurate shift in the stutter profile resulting in the appearance of at least one new stutter in tumor-derived DNA compared to matched germline DNA. MSI was scored high when 30% or more of the markers showed MSI or low if present in less than 30% of the biomarkers examined. Results: No MSI was detected in 3 pts with microsatellite stable tumors and 2 Lynch syndrome pts with no evidence of disease. Five of six pts with MSI high tumors (sporadic and Lynch syndrome) had a detectable MSI high biomarker profile in cfDNA at baseline. Four pts with positive MSI in cfDNA started immunotherapy and had a decline in the relative amounts of tumor-derived microsatellite alleles in their subsequent specimens. The pt with MSI high in the primary tumor and no MSI in cfDNA had rapid progression on immunotherapy. Two other pts with MSI high who responded deeply to check point inhibitors had no evidence of MSI in cfDNA at the time of their specimen collection. In each case with MSI in cfDNA, the electrophoretic profile matched that in the respective primary tumor. Conclusions: Detection of MSI in cfDNA is feasible and may be reflective of burden of the disease. A prospective study to establish the validity of cfDNA in the diagnosis and follow up care in pts with metastatic CRC is planned.
Intensive first-line triplet chemotherapy plus cetuximab FIr-C/FOx-C in RAS wild-type MCRC: Preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.
Authors: Bruera Gemma , Massacese Silvia , Dal Mas Antonella , Ficorella Corrado , Ciacco Eugenio , Calvisi Giuseppe , Simmaco Maurizio , Ricevuto Enrico
Published: January 2019

673

Background: Intensive first line bevacizumab added to triplet, and cetuximab (CET) to doublet in RAS wild-type MCRC significantly increased outcomes. We investigated safety/activity of FIr-C/FOx-C adding CET to triplet in RAS wild-type. Methods: Phase II study according to Simon two-step design: delta 15% (p070%, p185%), power80%, α5%, β20%; projected ORR I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-TFI 900 mg/m2 days (d) 1-2,8-9,15-16,22-23 associated to weekly alternating irinotecan (CPT-11) 160 mg/m2 d1,15 or oxaliplatin 80 mg/m2 d8,22; CET loading dose, then 250 mg/m2 d1,8,15,22; every 28d. Toxicity, LTS evaluated/compared by chi-square test; activity/efficacy by log-rank. Pharmacogenomic biomarkers of 5-FU/CPT-11, 5-FU degradation rate (5-FUDR), Single Nucleotide Polimorphisms (SNP) ABCB1, CYP3A4, DYPD, UGT1A1, evaluated in individual patients with limiting toxicity syndromes (LTS) and at recommended dose. Results: 29 patients < 75 years, primary/intermediate CIRS. From April 2014, KRAS/NRAS wild-type eligible: median age 59; young-elderly (yE) 7, 24%; liver-limited (L-L) 7, 24%. Recommended CPT-11/5-FU doses 120/750 mg/m2. Activity met primary endpoint: OR 14/18 evaluable as-treated (76%), confirmed in preliminary phase II, 17/23 intent-to-treat (74%). Liver metastasectomies 14%, 57% L-L. At median follow-up 18 months, PFS 12, OS 23 months. At recommended doses, received DI > 80% for each drug; cumulative G3-4 toxicities: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS, consisting of the LT, associated or not to G2 or other LT, in 19 patients (65.5%), 83% yE. LTS prevalently multiple than single site (59 vs 7% p0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, frequently associated, prevalently in patients with gastrointestinal LTS, while not without LTS. Conclusions: Intensive first-line FIr-C/FOx-C at recommended dose is tolerable, highly effective in RAS wild-type. Reduced FUDR, CYP3A4, UGT1A1 SNPs may predict individual LTS to select fit patients. Prospective studies will confirm efficacy and personalization by companion toxicity biomarkers. Clinical trial information: EudraCT 2009-016793-32.
An assessment of KRAS, NRAS, and BRAF testing prior to 1st line of therapy among mCRC patients treated at community cancer centers in the United States.
Authors: Florea Ana , Garawin Tamer , Sangaré Laura , Kelsh Michael Anthony , Lowe Kimberly
Published: January 2019

678

Background: We sought to determine the proportion of patients with mCRC in the United States who were tested for KRAS, NRAS, and BRAF mutational status before any 1st line of therapy. Patient demographics that may influence testing, and the turnaround time between key events associated with biomarker testing and utilization of biomarker results were also assessed. Methods: The study utilized the Oncology Services Comprehensive Electronic Records (OSCER) 2.0 dataset, provided by Flatiron Health, which includes mCRC patients from community cancer centers across the United States. Biomarker results are recorded in the Flatiron Electronic Health Record when available. The proportion of patients tested or not tested for KRAS, NRAS, and BRAF mutational status before 1st line of therapy between 2013 and 2017 was calculated, as were the differences in the patient demographics. The median number of days between the date of tissue collection, the date the tissue was received by the laboratory, and the date the oncologist received the test results was calculated. Results: Of the 13,437 patients included in the analysis, the proportion of patients who were tested prior to 1st line of therapy was as follows: KRAS, 30.8%,; NRAS, 9.9%; BRAF, 11.5%. Age, insurance type, race, and presence of liver metastases were all statistically significant factors that influenced testing. Specifically, younger, commercially-insured, Caucasian patients, and those who had liver metastases were more likely to be tested. For KRAS testing, the median time between tissue collection and tissue received by the laboratory was 26 days. Receipt of the results by the oncologist took an additional median number of 27 days. Conclusions: This study found that the testing rate for these key mCRC biomarkers was less than 31% and that the median number of days to assess biomarker results was 26. Further studies conducted in various settings, such as academic cancer clinics, are needed to investigate this low proportion of testing and long time to assess results.
Phase II trial of palbociclib in patients with advanced esophageal or gastric cancer.
Authors: Karasic Thomas Benjamin , O'Hara Mark H. , Teitelbaum Ursina R. , Damjanov Nevena , Giantonio Bruce J. , d'Entremont Tracy S. , Gallagher Maryann , Zhang Paul J. , O'Dwyer Peter J.
Published: January 2019

68

Background: Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases 4 and 6 (CDK4/6), which are regulated by cyclins D and E. A positive feedback loop between apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP kinase pathway, and cyclin D1 has been shown to drive cell proliferation in gastric cancer. In addition, amplification of cyclin D loci and/or activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We hypothesized that palbociclib, a potent inhibitor of CDK4/6 would disrupt proliferative signaling, and arrest the growth of gastric cancer. We conducted a phase II trial of palbociclib in gastric and esophageal cancers as an initial test of efficacy. Methods: We screened 38 subjects with gastric, GE junction, or esophageal cancer for RB nuclear expression by immunohistochemistry, and 38/38 (100%) were positive. We enrolled 21 subjects, of whom 5 had gastric adenocarcinoma, 3 had GE junction adenocarcinoma, 8 had esophageal adenocarcinoma, and 5 had esophageal squamous cell carcinoma. Four of 19 subjects tested positive for CCND1 overexpression by FISH. Patients received 125mg daily of palbociclib for days 1-21 of 28-day cycles. Results: Subjects remained on treatment for a median of 1.7 months. By the initial 2-month assessment, 5 of 21 subjects had stable disease, and 16 subjects had progressive disease by imaging and/or clinical progression. No objective responses were seen. The maximum duration of therapy was 5.5 months in two subjects. One of these subjects had progressing HER2-amplified gastric adenocarcinoma, and continued concurrent trastuzumab with palbociclib, while the other had squamous cell carcinoma of the esophagus. Grade 3 or 4 cytopenias occurred in 9 of 21 subjects (43%), with neutropenia in 8 (38%), anemia in 4 (19%), and thrombocytopenia in 1 (5%). One subject discontinued therapy due to grade 4 thrombocytopenia with GI bleed. All other subjects discontinued therapy due to disease progression. Conclusions: Palbociclib has modest single-agent activity in gastroesophageal tumors despite universal RB expression. Clinical trial information: NCT01037790.
Cell cycle checkpoint defects in gastrointestinal malignancies.
Authors: Thota Ramya , Lewis Mark Andrew , Nadauld Lincoln , Haslem Derrick S. , Rhodes Terence Duane , Christensen Bryce , Fulde Gail , Abraham Tyler , Romero Robin , Moulton Bryce , Raghunath Sharanya , Barker Tyler
Published: January 2019

680

Background: Cyclin Dependent Kinases (CDKs) play a significant role in cell cycle regulation. Aberrations involving the cell cycle pathway genes can lead to uncontrolled cell proliferation and genomic instability. These could potentially be targeted with CDK4/6 inhibitors. The frequency and type of these alterations in GI tumors is largely unknown. Methods: We analyzed the frequency of abnormalities in cell cycle genes in patients with diverse GI malignancies (colorectal, liver, pancreas, gastroesophageal, anal, appendix) that underwent next generation sequencing from January 2013 to August 2017. Results: Aberrations in the cell cycle pathway were identified in 33 of 299 (11%) of cancers. The frequency of aberrations was as follows: CDKN2A/B in 10 (30.3%), CCND1 in 7 patients (pts) (21.2%), CCND2 in 2 pts (6%), CEBPA in 2 pts (6%), CDK6 in 2 pts (6%), CDK8 in 2 pts (6%) and CDK2 in 1 (3%). Alteration involving multiple genes of cell cycle noted in 7 patients (21.2%) with combination of CCND1 and CDKN2A being most common combination. The cell cycle checkpoint defects were most frequently seen in 9 pts with colon (27%), 8 pts with hepatobiliary (27%), 8 pts with pancreatic (24%), 7 pts with esophageal (21%), and less commonly in small bowel (6%) and GIST (6%). Conclusions: The alterations in the cell cycle pathway are most common in certain GI tumors mainly colon, pancreatic, hepatobiliary and esophageal tumors. Future clinical trials exploring the potential role of targeted agents such as CDK4/6 inhibitors alone or in combination with other targeted agents such as MEK inhibitors requires further exploration in these tumors.
Molecular profiling to predict outcomes following Y90 radioembolization for metastatic colorectal cancer.
Authors: Prins Petra , Gradzka Alexandra , Kim Alexander Y. , Marshall John , Unger Keith Robert
Published: January 2019

686

Background: Radioembolizaton with yttrium-90 (Y90) has been shown to decrease progression within the liver in patients with unresectable metastatic colorectal cancer (CRC). Molecular profiling (MP) plays an important role in providing precision based therapy for our patients. The purpose of this study was to evaluate predictive associations between genetic mutations in Y90 treated CRC pts and treatment outcomes. Methods: A retrospective chart review of patients at GUMH was conducted for patients who underwent Y90 radioembolization for metastatic CRC between 2010 and 2017. Inclusion criteria were: Liver metastasis, Y90 treatment and MP. Y90 response of the treated liver lesions was evaluated according to RECIST criteria within 4 months of treatment; non-responders were classified as those with progressive disease (PD) and all others were considered responders. Statistical analysis was performed to reveal any significant associations. Results: Out of 285 CRC records with MP screened, 32 pts adhered to our inclusion criteria. Of these 47% were male and 53% female. The average age at diagnosis was 50.4 yrs. For22 pts (69%) Y90 treatment was combined with chemotherapy. Y90 response data showed response in 50% (n = 16) and PD in 31% (n = 10) of the pts. Six pts did not have Y90 response data. Median OS between groups was not significant but longer for those responders (33 vs 26 m). Next Generation Sequencing revealed pathogenic mutations for APC in 20 pts (63%), KRAS in 12 (38%) and TP53 in 13 pts (41%) none of them showing any significant association with Y90 response data (p > 0.05). OS from date of Y90 was significantly improved in patients with TP53 mutations and KRAS WT. There was no association between differences in MP and OS from date of diagnosis. Conclusions: TP53 and KRAS mutations were predictive of survival but not response following Y90 for metastatic colorectal cancer patients. This hypothesis generating study demonstrates the MP may be helpful in stratifying CRC patients who benefit from radiation therapy. Further study is necessary.
Plasma VEGF-A (pVEGF-A) level in efficacy analysis of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).
Authors: Okamoto Wataru , Makiyama Akitaka , Yamamoto Yoshiyuki , Shitara Kohei , Denda Tadamichi , Izawa Naoki , Nakano Yasuyuki , Nishina Tomohiro , Esaki Taito , Hara Hiroki , Ozaki Yukinori , Okuda Hiroyuki , Boku Narikazu , Hyodo Ichinosuke , Yamazaki Kentaro , Hironaka Shuichi , Sakai Kazuko , Yamanaka Takeharu , Muro Kei , Nishio Kazuto
Published: January 2019

699

Background: Plasma levels of VEGF-A short isoforms (VEGF-A110 and -A121) measured by immunological multiparametric chip technique (IMPACT) were reported to be associated with clinical benefits from bevacizumab (BV) in advanced gastric and pancreatic cancer but not in metastatic colorectal cancer (mCRC). Negative results in mCRC studies might be caused by different sample handling: citrate instead of EDTA and repetition of freeze/thaw. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). A median value of pVEGF-A was used as a cut-off point to categorize patients (pts) into the low and high pVEGF-A groups. Progression free survival (PFS) and overall survival (OS) between the low and high pVEGF-A groups were compared, using Cox proportional hazards model. We hypothesized that BV-containing treatment extend shorter PFS of pts with high pVEGF-A to that with low pVEGF-A, and estimated a threshold hazard ratio (HR) between them as below 1.15. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0] and response rate was 64.6 % [range, 53.3-74.9]. pVEGF-A was measured in 97 pts and the median value was 36.8 pg/ml [range, 6.5- 262.2]. The hazard ratios of PFS and OS between the high and low pVEGF-A groups were 1.23 [95%CI, 0.76-1.97, p = 0.40] and 2.47 [95%CI, 1.14-5.36, p = 0.02], respectively. Conclusions: mCRC pts with high pVEGF-A showed shorter PFS than those with low pVEGF-A beyond the predefined threshold (HR 1.15) in BV-containing chemotherapy, suggesting that pVEGF-A could not be a predictive marker for BV efficacy. Clinical trial information: UMIN000012442.
Plasma ctDNA RAS/RAF mutations analysis for monitoring overall survival (OS) and heterogeneity in metastatic colorectal cancer patients (mCRC).
Authors: Mancuso Andrea Petricca , Varchetta Veronica , Montagnese Fabrizio , Campanella Carla , Brandi Rita , Vitale Marco , Soda Giuseppe
Published: January 2019

701

Background: The study was designed to estimate the clinical usefulness of genetic analysis for circulating tumor DNA (ctDNA) by digital polymerase chain reaction in patients with mCRC. Methods: We compared B-RAF and K/N/H-RAS mutations detected in surgical or endoscopic ultrasound-guided fine-needle aspiration biopsy tissue DNA and in ctDNA from 63 patients with mCRC. p53 mutational status and PD-L1 expression in the serum and in tissues respectively (positivity H score > 55) were also analyzed with a comparison with survival rates. Results: The frequencies of K-RAS mutations in tissue samples at G12V, G12D, and G12R in codon 12 were 18 of 63 samples (28.57%), 5 of 63 samples (7.93%), and 6 of 63 samples (9.52%), respectively. Conversely, the rates of the mutations in ctDNA were 22 of 63 samples (34.92%), 6 of 63 samples (9.52%), and 9 of 63 samples (14.28%), respectively. No H-RAS or N-RAS mutation were detected. 2 tissue samples harbored a BRAF mutation (3.17%) in a complete discordance with same mutation detected in 6 different serum ctDNA (9.52%). Overall, the K-RAS mutation rates in tissue and ctDNA were 45.72% and 58.72%, respectively, and the concordance rate between them was 29 of 37 samples (78,37%). OS did not appear to differ by the presence of K-RAS mutations in tissue or in the serum DNA, but the OS of patients with B-RAF mutations in ctDNA was significantly shorter than that of patients with tissue K-RAS/B-RAF mutations (11 vs 19 months, p < 0.0001). PD-L1 positivity was significantly associated with p53 mutational status (concordance: 82%) and with a worse outcome for OS. Conclusions: Analysis of ctDNA is a new useful procedure for detecting mutations in mCRC patients. This non invasive method may have great potential to understand tumor heterogeneity and appear a new strategy for the planning therapies as well as for predicting survival.
Prognostic relevance of primary tumor location in stage III and II colon cancer: Experience at University Hospital Ramon y Cajal (HURyC) Madrid.
Authors: Barquín García Arantzazu Martínez , Martinez Saez Olga , Serrano Domingo Juan José , Martín Huertas Roberto , Villamayor Delgado Maria , Saavedra Serrano Cristina , Corral de la Fuente Elena , Reguera Puertas Pablo , LONGO FEDERICO , Pachón Olmos Vanesa , Rodríguez Garrote Mercedes , Guillen Carmen , Carrato Alfredo , Ferreiro REYES
Published: January 2019

703

Background: Primary tumor location of colon cancer (CC) is emerging as an important prognostic factor owing to distinct biological features. However, this factor still does not represent a prognostic parameter when deciding for adyuvant or palliative chemotherapy. In a meta-analysis of 66 studies including patients with all stages of disease, left-sided primary tumor location was associated with a significantly reduced risk of death and this was independent of other prognostic factors. Methods: We retrospectively included patients with stage II and III CC that underwent surgical resection between 2009 and 2014 HURyC. We performed a multivariate Cox model analysis to estimate if tumor location is an independent prognostic factor for overall survival (OS). The model was further adjusted by including the following confounders: ECOG-PS, number of removed nodes ( < 12 or ≥ 12), perforation, grade, use of adyuvant chemotherapy and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied > 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (267 left sided and 297 right sided). The median follow-up of the entire cohort was 49 months. Globally, right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.74, p: 0.128; HR: 0.94, p: 0.75, respectively). By stages, stage II right sided CC seemed to show better DFS (HR: 0.45, p: 0.02), although no significant differences were found in OS (HR: 1.004, p: 0.98). Stage III right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.87, p: 0.585; HR: 0.66, p: 0.19, respectively). Conclusions: The multivariate analysis did not show significant differences in terms of prognostic relevance of primary tumor location in the adyuvant setting.
Correlation of BMAL1 expression in colorectal cancer with resistance to anti-VEGFA therapy with bevacizumab.
Authors: Burgermeister Elke , Eladly Fagr , Wu Wen , Schulte Nadine , Betge Johannes , Hartel Nicolai , Gaiser Timo , Marx Alexander , Weiss Christel , Hofheinz Ralf , Miller Ian S. , Byrne Annette T. , Ebert Matthias Philip
Published: January 2019

705

Background: Mechanisms underlying failure of colorectal cancer (CRC) patients to respond to anti-vascular endothelial growth factor A (VEGFA) therapy with bevacizumab in combination with chemotherapy are largely unknown, and novel predictive markers required. Methods: Tumours from patients/mice and CRC cell lines were analysed by IHC, PCR, EMSA, ChIP, ELISA and Western blot. Statistics of (pre)clinical data was calculated with SAS and Graphpad Prism. Response outcomes including progression-free survival (PFS) and restaging according to RECIST (PR/SD/PD) were analyzed. Results: Circadian rhythm transcription factor and heme receptor REVERBA and its target gene BMAL1 promoted binding to and activation of the -700kB RORE DNA-element in the VEGFA promoter resulting in increased VEGFA mRNA expression and VEGFA protein secretion from human CRC cell lines. Conversely, REVERBA siRNA and its antagonist (Fe3+) hemin inhibited VEGFA synthesis. In C57BL/6J Apcmin/+ mice treated with murinized VEGFA Ab (n=11 mu_chimeric_B20-4.1 vs. n=42 mock; 10 mg/kg*week; i.p.; 4 weeks), Vegfa mRNA was reduced, as was incidence (*p=0.0411 Fisher Exact Test) and multiplicity (*p=0.0157 Cochran Armitage Trend Test) of vascularized CRCs. However, Bmal1 mRNA was up-regulated, and high BMAL1 protein expression in tumor cells positively correlated with Ki67+ proliferation (n=3 B20 vs. n=3 mock; *p<0.05 t-test) in treated Apcmin/+ CRCs. BMAL1 protein was also induced in xenografts from BALB/c nude mice s.c. implanted with the human CRC cell line HCT116 and treated with humanized VEGFA Ab (n=4 bevacizumab vs. n=4 vehicle; 10 mg/kg*week; i.p.; 3 weeks; *p<0.05 t-test). In CRC patients, high BMAL1 protein expression in tumor cells was associated with clinical non-response to bevacizumab (n=15 SD vs. n=29 PD: BMAL1- vs. BMAL1+, *p=0.0061 Cochran Armitage Trend Test,*p=0.0130 Fisher Exact Test) and reduced PFS (BMAL1- [671 days] vs. BMAL1+ [368 days], *p=0.0030 log rank test, HR=0.4792 [95%CI 0.3103-0.7871], n=74). Conclusions: BMAL1 may represent a predictive marker for bevacizumab non-response. Due to its drugability, the REVERBA-BMAL1-VEGFA axis may be a potential target to prevent resistance to anti-angiogenic therapy in CRC.
KRAS/NRAS/BRAF genotyping in patients with mestastatic colorectal cancer.
Authors: Rodriguez Salas Nuria , Miranda Jesus , Ostios Lorena , Muñoz Mario , Borobia Alberto , Gordo Gema , Tenorio Jair , Tong Hoi , García Morales Maria Teresa , Martinez Avila Jose Carlos
Published: January 2019

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Background: mCRC is the 2º cause of death in the world. Development of targeted therapies has increased the survival. The efficacy of these drugs (such Bevacizumab and monoclonal antibodies against EGFR) depends on the use of genetic biomarkers such as KRAS and NRAS. The BRAF status acts as prognostic factor. The objective of this study was to perform a mutational analysis of KRAS/NRAS/BRAF in a cohort of 326 Spanish patients, and correlate the findings with clinical factors. Methods: We analyzed KRAS by chip-array analysis (Infiniti System, USA), NRAS using pyrosequencing on a Pyromark Q96MD instrument (Qiagen, USA) and BRAF mutations (in 80 of these samples) by means of Infiniti System (AutoGenomics, USA). Results: KRAS mutations 129/326 patients had KRAS mutation (31.2% in codon 12 and 6.7% in codon 13). The median age was 68.9, 55% male, 66.4% had left-sided tumor, 83% histologically grade 2 tumor. The pattern of spread was liver (51.1%), lung (33.3%) and peritoneum (11.6%). There were 6 types of mutation in codon 12 (p.Gly12Asp, p.Gly12Cys, p.Gly12Val, p.Gly12Arg, p.Gly12Ser, p.Gly12Ala) and 1 type in codon 13 (p.Gly13Asp). We apply a logistic model (age&sex corrected) to location, and we found association between KRAS wild type and left location, OR 1.73 [CI:1.03-2.9] p = 0.035 NRAS mutations: 13 patients had NRAS mutation (3.98%), 8 male, 92% had left-sided, 46% liver metastasis and 53.9% lung metastasis. Type of NRAS mutation: 1.6% in exon 2 (1.2% in codon 12 and 0.4% in codon 13) and 1.8% in exon 3 (0.2% in codon 59 and 1.6% in codon 61). In exon 2 we found 2 types of changes, 1 in codon 12 (p.Gly12Asp) and 1 in codon 13 (p.Gly13Arg). In exon 3 we found 5 types of changes, 1 in codon 59 (p.Ala59Thr) and 4 in codon 61 (p.Gln61Glu; p.Gln61Leu; p.Gln61Arg; p.Gln61His). BRAF mutation: 9/80 patients harboured mutations, all of them at the residue V600E. Conclusions: In our cohort 39.5% had mutations in KRAS, 3.98% in NRAS and 11% in BRAF. KRAS mutation is associated to right-sided location.
KEYNOTE-059 cohort 1: Pembrolizumab (Pembro) monotherapy in previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer in patients (Pts) with PD-L1+ tumors—Asian subgroup analysis.
Authors: Muro Kei , Fuchs Charles S. , Jang Raymond Woo-Jun , Satoh Taroh , Machado Manuela , Sun Weijing , Jalal Shadia Ibrahim , Shah Manish A. , Metges Jean-Philippe , Garrido Marcelo , Golan Talia , Mandala Mario , Wainberg Zev A. , Catenacci Daniel V.T. , Bang Yung-Jue , Lin Jianxin , Lu Jia , Yoon Harry H. , Doi Toshihiko
Published: January 2019

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Background: The US FDA approved pembro for treating pts with 1) recurrent locally advanced or metastatic G/GEJ adenocarcinoma, whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score [CPS] ≥1), and 2) unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors that have progressed after prior therapy and who have no fitting options. We report Asian subgroup analyses from cohort 1 of KEYNOTE-059 (NCT02335411), a global, phase 2 study in advanced G/GEJ cancer. Methods: Eligible pts had measurable recurrent or metastatic G/GEJ adenocarcinoma whose disease has progressed on ≥2 prior chemotherapy regimens. Pts received pembro 200 mg Q3W up to 2 y. PD-L1+ tumors had a CPS ≥1. Primary end points were ORR (RECIST 1.1, by central review) and safety. Results: Cohort 1 enrolled 259 pts; 57% had PD-L1+ tumors. MSI status was evaluable in 174 tumor samples; of these, 7 were MSI-H. At data cutoff (4/21/2017), median (range) follow-up was 6 mo (1-25). Overall ORR was 12% (95% CI, 8-17) and median (range) DOR was 14 mo (2-19+). PFS6-mo rate was 15% and OS6-mo rate was 46%. In pts with PD-L1+ tumors, ORR was 16% (95% CI, 11-23) and median (range) DOR was 14 mo (3+-19+). In pts with PD-L1+ tumors, PFS6-mo rate was 20% and OS6-mo rate was 50%. In pts with MSI-H tumors, ORR was 57% (95% CI, 18-90) and median (range) DOR was not reached (5-14+ mo). In cohort 1, 41 pts were Asian and 218 pts were non-Asian. PD-L1+ tumors occurred in 42% of Asian pts and 60% of non-Asian pts. ORR was 12% (95% CI, 2-36) in Asian pts with PD-L1+ tumors and 17% (95% CI, 11-24) in non-Asian pts with PD-L1+ tumors. One of 7 pts with MSI-H tumors was Asian; this pt had CR. Grade 3-5 treatment-related AEs occurred in 17% and 18% of Asian and non-Asian pts, similar to the overall cohort. Conclusions: Pembro showed durable clinical benefit in previously treated pts with advanced G/GEJ cancer, especially those with PD-L1+ or MSI-H tumors. Safety and efficacy were similar in Asian and non-Asian pts. These findings highlight pembro as a standard treatment option in Asian and non-Asian pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.
Totally neoadjuvant chemoradiation therapy with mFOLFOX6 in locally advanced rectal cancer: A single-arm phase II study (FOTAC).
Authors: Deng Yanhong , Zhang Jianwei , Cai Yue , Hu Huabin , Xiao Jian
Published: January 2019

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Background: In our previous FOWARC study, in the group of preoperative systemic chemotherapy with mFOLFOX6 combined with radiation, the pCR rate was up to 27.5%. In another study, adding mFOLFOX6 after neoadjuvant chemo radiation in locally advanced rectal cancer improve the pCR rate to 38%. This phase II study aimed to explore whether totally neoadjuvant chemoradiation therapy with mFOLFOX6 could further improve the pCR rate in locally advanced rectal cancer. Methods: Patients with fixed cT3 or cT4 rectal cancer evaluated by pelvic MRI participated in this trial. All candidates were to receive long term radiation for 25 times and 50Gy before surgery. Four cycles of mFOLFOX6 would be performed every 2 weeks during radiotherapy, and another 4-6 cycles would be added after radiotherapy and before TME. Totally, the patients will receive 6-8 cycles of chemotherapy before surgery. The primary endpoint is the pathologic complete response rate (pCR).The secondary endpoint included 3-year disease free survival rate, 3-year local recurrence rate, and safety. Results: Between April 2016 and May 2017, 81 patients were enrolled and 79 participants had received TME. Two patients required watch and wait, because the tumor location is too low to perform sphincter-preserving operation. Of 79 patients completing chemoradiotherapy and adding chemotherapy before surgery, 32.9% (26/79) of patients achieving pCR, and 54.4% (43/79) of patients had tumor downstaging to ypstage 0-I. Among patients who received 8 cycles of chemotherapy before surgery and the interval was more than 10 weeks between radiotherapy and operation, the pCR was 45.2%. Conclusions: Totally neoadjuvant chemoradiotherapy greatly improve the pCR rate and tumor downstaging rate. Clinical trial information: NCT02887313.
A pilot feasibility study of definitive concurrent chemoradiation with pencil beam scanning proton beam in combination with 5-fluorouracil and mitomycin-c for carcinoma of the anal canal.
Authors: Wo Jennifer Yon-Li , Yeap Beow Y. , DeLaney Thomas F. , Ryan David P. , Parikh Aparna Raj , Clark Jeffrey W. , Allen Jill N. , Ben-Josef Edgar , Plastaras John Peter , Metz James M. , Drapek Lorraine C. , Hong Theodore S.
Published: January 2019

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Background: Definitive chemoradiation (CRT) with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) for anal cancer yields high rates of long term survival. However, CRT has significant acute and long term toxicity. Pencil beam scanning proton beam (PBS-PT) may potentially reduce this toxicity. This is a pilot study evaluating the feasibility of definitive concurrent CRT with PBS-PT with 5-FU/MMC for anal cancer. Methods: Pts were enrolled on an NCI sponsored, prospective, multi-institutional, pilot study (NCT 01858025). Key eligibility were ECOG 0-2, age 18+, invasive SCC of the anal canal, clinically staged T1-4, N0-3. Pts were treated per RTOG 0529 RT schema; for T1-2, N0: 50.4 Gy to primary CTV, 42 Gy to elective LNs; for T3+ or N+: 54 Gy to primary CTV, 50.4-54 Gy to involved LN, and 45 Gy to elective LNs. Pts received 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with 5-FU/MMC, determined if grade 3+ dermatologic toxicity is < 48% (grade 3+ dermatologic toxicity from RTOG 98-11). The secondary endpoint was rates of overall grade 3+ toxicities, clinical complete response (cCR) rate and patterns of local regional tumor recurrence. Results: Between February 2014 to April 2017, we enrolled 25 patients into our study, all of whom were analyzed. 23 pts (92%) completed treatment per protocol, 2 pts died on treatment due to underlying comorbidities. Median time to completion of treatment was 42 days (range 38-49). The Grade 3+ radiation dermatitis was 24% (Table 1). With a median follow-up of 17.6 months (range 7.7-42.0) among the 21 patients still alive, the 1 year local control, progression-free survival, and overall survival are 100%, 83% and 87%, respectively. Conclusions: In our prospective, pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. While felt to be unrelated to the study, the two Grade 5 adverse events on this small study highlights potentially treatment related risks of this effective yet toxic regimen. Clinical trial information: NCT01858025. [Table: see text]
The impact of research presented at annual gastrointestinal cancers symposium.
Authors: Sehdev Amikar , Dadi Neelakanta , Haggstrom David Andrew , Koniaris Leonidas George , O'Neil Bert H.
Published: January 2019

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Background: The Gastrointestinal (GI) Cancers Symposium provides a multidisciplinary forum to both present research and gain expertise in the management of GI cancers. We conducted a study to understand the research trends, publication rate and the overall impact of research presented. Methods: A bibliometric review of the conference proceedings of the Symposium from 2013-2015 was undertaken. Data collected on each abstract included author number, demographic information of the presenting author, presentation type, cancer type, research focus (multidisciplinary treatment; prevention, diagnosis and screening; translational research) and research design. A PubMed search was used to determine overall and specific publication data. Descriptive statistics were compiled. Chi-square was used to compare groups. Results: The number of abstracts presented has increased (584 in 2013, 652 in 2014 and 794 in 2015). Fraction of oral presentations by year were similar (2.0%, 2.1% and 1.8%). Median number of authors per abstract was 9 (range 1-20). The subject area in all three years was dominated by multidisciplinary treatment (mean 58.6%), followed by translational research (mean 25.5%) and lastly Prevention, Diagnosis and Screening (mean 15.8%). The most common study design was observational (mean 43.5%), followed by case series (mean 27%), clinical trial (mean 19.8%) and other (mean 9.2%). Overall, 51.5%, 46.9% and 40.4% of the abstracts presented in 2013, 2014 and 2015 were published. The median time to publication was 14.5 months (range 0-49 months). The majority of published abstracts were published in journals with impact factor (IF) < 5 (mean 66.5%) and a small percentage (mean 8.4%) of abstracts were published in high impact journals (IF > 10). Abstracts selected for oral presentation were associated with publication in a journal with high IF (p < 0.001). The presenting author was more commonly male (70%) and a medical oncologist (61.5%). Conclusions: Overall participation is increasing in the Symposium. Selection for oral presentation appeared to be a good marker for both publication and higher impact. Prevention, diagnosis, and screening studies were under-represented and clinical trials were also relatively uncommon.
The fine line between regional and metastatic pelvic lymph nodes in rectal cancer: Patterns of care among U.S. radiation oncologists.
Authors: Yahya Jehan , Herzig Daniel , Farrell Matthew , Degnin Catherine , Chen Yiyi , Holland John M. , Brown Simon , Jaboin Jerry Jeff , Tsikitis Vassiliki Liana , Lu Kim , Thomas Charles R. , Mitin Timur
Published: January 2019

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Background: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis – the stage we refer institutionally to as Stage 3.5 – is controversial. Asian investigators consider internal, external and common iliac lymph nodes (LNs) as regional disease and treat these patients (pts) with curative intent, which often includes LPLN dissection. Conversely, AJCC 7thedition classifies internal iliac LNs as regional, whereas both external and common iliac LNs as metastatic. NCCN guidelines recommend definitive trimodality therapy for Stage III rectal cancer, and palliative chemotherapy for Stage IV disease. Radiation oncologists (ROs) in the U.S. irradiate iliac LNs in the setting of other pelvic malignancies, but it is unknown how they approach newly diagnosed rectal cancer pts with LPLN involvement. Methods: We conducted an anonymous IRB-approved online survey of practicing U.S. ROs, probing their approach to management of rectal cancer pts with clinically involved LPLNs. Results: We received 220 responses. Among the responders, 85 are academically affiliated and the majority self-declared a specialization in treating GI malignancies, with 98 seeing more than 10 rectal cancer pts annually. Among respondents, 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders – 98.6% and 94.5% – treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). Conclusions: Our analysis reveals that the vast majority of surveyed U.S. ROs approach pts with involved LPLNs, both regional (internal iliac) and metastatic (i.e. common iliac) with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of pts with Stage 3.5 rectal cancer.