bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational analysis of clinically relevant cancer related genes in colorectal cancer.
Authors: O'Reilly Aine , Barr Colin , Carr Aoife , Kay Elaine , Kennedy Susan , McDermott Ray , Grogan William , Fennelly David William , Breathnach Oscar S. , Winter Des C , McNamara Deborah A , Kelleher Fergal C , Crown John , Hennessy Bryan , Toomey Sinead
Published: February 2017

615

Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were genotyped for Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations using the Sequenom platform. Results: Tissue from 68 patients was genotyped. 163 mutations were identified in 21 cancer related genes. 45% of patients had stage III CRC & 10% had stage IV CRC at diagnosis. 17 patients developed metastatic CRC. 59 patients had at least 1 mutation. Mutations occurring in at least 5% of patients included KRAS(35%), PIK3R1(34%), TP53(32%), PHLPP2(32%), BRAF(16%), PIK3CA(13%), APC(13%), IDH1(12%), FBXW(7%) & MET(6%). Less frequent mutations (<5%) included GNAS, PTPN, NRAS, STK11, TBX3, and EGFR. KRAS mutations were associated with mucinous histology (P=0.04). TP53 mutations were associated with nodal disease at diagnosis (p=0.03). There was no statistically significant difference in overall survival in patients with KRAS, PIK3, TP53 or BRAF mutations as compared to their wild type (WT) counterparts. No mutation was predictive of disease progression. In patients with mCRC and TP53 mutations, DFS was significantly shorter when mutations in APC, FBXW7, IDH1, MET and NRAS were present (10 months verses 15.5 months p=0.01). Mutations in APC, FBXW7, IDH1, MET and NRAS only occurred in the presence of other mutations. A trend towards reduced DFS was seen in KRAS WT patients with mCRC when mutations in APC, FBXW7, IDH1, MET and NRAS were present (9 months vs. 22 months, p=0.2). A trend towards reduced DFS was seen in patients with mCRC & 3 or more distinct mutations (10 months vs. 18 months p=0.2). Conclusions: These results suggest that mutations in known cancer related signaling pathways occur frequently in patients with CRC. Mutations in APC, FBXW7, IDH1, MET and NRAS conferred a shorter DFS in patients with mCRC &, TP53 mutations, KRAS wild type patients and patients with multiple distinct mutations
Proteomic features of colorectal cancer independently predict relapse-free survival.
Authors: Clarke Callisia , Lee Michael Sangmin , Manyam Ganiraju C. , Jiang Zhi-Qin , Tian Feng , Lu Yiling , Morris Jeffrey , Broom Bradley McIntosh , Menter David , Vilar Sanchez Eduardo , Raghav Kanwal Pratap Singh , Eng Cathy , Chang George J. , Overman Michael J. , Maru Dipen M. , Kopetz Scott
Published: February 2017

616

Background: Proteomic analysis continues to provide major insight into the pathophysiology of colorectal cancer (CRC). Recently, the Cancer Genome Atlas Project and others have utilized reverse-phase protein arrays (RPPAs) to identify critical protein markers and signaling pathways in a variety of tumor types. However, the prognostic relevance of many of these proteins remains unclear. We utilized RPPA to analyze stage 2 and 3 CRC to investigate the prognostic implications of the functional proteome. Methods: Protein extraction was performed on 232 snap frozen stage 2/3 samples from the MD Anderson Cancer Center with a median 5 year follow up. 163 validated proteins and phospho-proteins were analyzed by RPPA (with dichotomization by the median value), and used to identify protein predictors of tumor recurrence. Cox regression was used for univariate analysis with bootstrap validation, followed by inclusion of proteins with corrected p≤ 0.05 into multivariate model with clinical and pathologic variables, including stage, grade, and microsatellite status. Results: 12 proteins were found to be significant predictors of tumor recurrence on univariate analysis after bootstrap validation, which are notable for components of the energy balance/MTOR signaling pathway including AMPK, mTOR, PI3 Kinase p85, FoxO3a. On multivariate analysis, inclusive of known prognostic clinical and pathology variables, phospho-Bad (Ser112), FoxO3a, HER3, and phospho-S6 (Ser240-244) remained significant. Conclusions: Functional proteomic analysis has identified key proteomic features with prognostic importance independent of known clinical/pathological variables. Confirmation studies are ongoing to explore regulators of energy balance and apoptosis in colorectal cancer. [Table: see text]
Prognostic role of serum concentrations of high-sensitivity C-reactive protein in patients with metastatic colon rectal cancer: Results from the ITACa trial.
Authors: Casadei Gardini Andrea , Carloni Silvia , Scarpi Emanuela , Maltoni Paolo , Dorizzi Romolo , Passardi Alessandro , Frassineti Giovanni Luca , Ulivi Paola , Marisi Giorgia , Amadori Dino , Lucchesi Alessandro
Published: February 2017

617

Background: Serum levels of interleukine-6 and C-reactive protein are significatively higher in patients with neoplastic conditions. Therefore, the determination of high-sensitivity C-reactive protein (hs-PCR) has been widely used as a surrogate marker for chronic elevation of circulating cytokines. Increased hs-CRP concentrations have been reported in many conditions, in particular in patients with cardiovascular diseases, obesity, diabetes, autoimmunity, inflammatory bowel diseases and cancer risk. Some authors, on the basis of these findings, have encouraged further studies to clarify the etiologic and prognostic role of the aforementioned test. Our study has been conducted in patients enrolled in the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa),” in order to assess hs-CRP levels at diagnosis and their significance with respect to overall survival (OS) and progresion free survival. Methods: Peripheral blood samples from 133 consecutive patients were collected into EDTA tubes. The collection was obtained before the beginning of first line chemotherapy. The supernatant was immediately transfer into a cryovial and stored at –80°C. Samples were thawed and hs-CRP has been measured with Cobas c501 analyzer. Results: Levels of hs-CRP >13.1 mg/L were associated with a worse median PFS, 8.9 months (95% CI 6.8-9.6) vs. 12.1 months (95% CI 9.3-14.9) in patients with levels <13.1 mg/L (p<0.0001). Similarly, levels >13.1 mg/L were associated with worse median OS, 14.4 (95% CI 11.5-17.1) vs. 28.8 (95% CI 24.3-36.6) in patients with a concentration <13.1 mg/L (p<0.0001). In multivariate analysis, hs-PCR adjusted for baseline factors including age (<70, ≥70 years), gender, ECOG perfomance status (0,1-2), tumor localization (rectum, colon), stage at diagnosis (I-III, IV), CT regimen (Folfiri, Folfox), KRAS status (wild type, mutant), site of metastases (liver, other metastases), was found to be independently associated with PFS and OS. Conclusions: Our study demonstrates the prognostic value of hs-CRP in patients with metastatic carcinoma of the colon and rectum.
Siginificance of platinum concentration in blood and red blood cell in patients with oxaliplatin-based chemotherapy [UMIN000009128].
Authors: Higashijima Jun , Shimada Mitsuo , Iwata Takashi , Yoshikawa Kozo , Nakao Toshihiro , Nishi Masaaki , Takasu Chie , Eto Shohei
Published: February 2017

620

Background: Oxaliplatin(Ox) based regimen is widely used in colorectal cancer patients.One of the major adverse effects of Ox is a neuropathy. There is no useful biomarker predicting such adverse effect. The aim of this study is to evaluate platinum concentration as a biomarker predicting the adverse effect. Methods: Ten patients who underwent curative colectomy were included in this study. Final stage of all patients was UICC stage III. All patients underwent adjuvant chemotherapy by CapeOX regimen for eight cycles (or six months). Blood samples were collected after fourth cycle and last cycle. Ox concentration was measured in red blood cells (RBC) and serum, and evaluated the kinetics of platinum (PL) in blood. In addition, we investigated relationship between Ox concentration and adverse effects. Results: 1) Kinetics of PL concentration: PL concentration in RBC tended to be correlated with the difference of RBC numbers between pre- and post-chemotherapy (R2=0.358, p=0.068). The PL concentration in RBC siginificantly correlated with the difference of mean corpuscular volume (MCV) between pre- and post-chemotherapy (R2=0.661, p=0.004). After four cycle, the platinum concentration in RBC siginificantly correlated with the hemoglobin and hematocrit (R2=0.447, p=0.004 and R2=0.425, p=0.041). There was no siginificant difference in PL concentration in both RBC and serum between the points after four cycle and last cycle points (RBC: 1380.5±495.2 ng/ml vs. 1107.0±699.2 ng/ml Aserum: 210.1±38.9 ng/ml vs. 221.2±99.2 ng/ml). 2) PL concentration and adverse effects: PL concentration did not elevate depending on cycle number. There was no siginificant correlations between PL concentrations in RBC or serum and the grade of neuropathy. Conclusions: The PL concentration was significantly related with the difference of RBC numbers and MCV between pre- and post-chemotherapy. However, there was no siginificant relationship between Ox concentration in blood and side effects including neuropathy. So Ox concentration in blood could not be a reliable biomarker for predicting the grade of neuropathy. Clinical trial information: 000009128.
Acquired mutations in MAPK signaling pathway following initial pharmacological response in BRAF-mutated metastatic colorectal cancer (mCRC).
Authors: Morris Van Karlyle , James Brian , Tian Feng , Jiang Zhi-Qin , Overman Michael J. , Maru Dipen M. , Menter David , Powis Garth , Kopetz Scott
Published: February 2017

629

Background: BRAF V600 mutations are associated with inferior survival and limited responses to standard therapies. Blockade of BRAF by vemurafenib generates reflexive activation of EGFR, whose activity can be overcome by concomitant addition of cetuximab. Early-phase clinical trials have demonstrated objective responses with the combination of vemurafenib and cetuximab in patients with BRAFmutmCRC. Mechanisms of resistance following initial anti-tumor response have not yet been described. Methods: Patient-derived xenograft (PDX) models of BRAFmut mCRC have been established at our institution by subcutaneous implantation of tumor into NSG female mice. Here, two different models of BRAFmut mCRC, one with innate sensitivity to vemurafenib and another with innate resistance, were selected for further study. Mice were given vemurafenib chow (417 mg/kg) and/or intraperitoneal cetuximab (1 mg/kg twice a week). Tumor dimensions were serially measured. Tumor resistance developed after a median of 35 days. Tumor DNA was extracted, and whole exome sequencing was performed and compared to untreated controls. Results: In one model of BRAFmut mCRC, 8 mice treated with vemurafenib demonstrated an initial complete response but later developed resistance despite continued treatment. Exome sequencing of the resistant tumors from 6 of 8 mice revealed novel mutations in EGFR, KRAS, NRAS, and MEK not detected in untreated controls (Table). All mutations are predicted to be damaging in COSMIC. Expansion of tumors with acquired NRAS G13D mutation into another generation of mice showed cross-resistance with the combination of BRAF and EGFR inhibition in vivo. In contrast, another PDX model with innate resistance to vemurafenib did not acquire additional mutations in MAPK oncogenes. Conclusions: Acquired activating mutations in oncogenes critical to MAPK signaling have not been described in BRAFmut mCRC after initial pharmacological response. Such mutations, if present as low-frequency clones prior to treatment, may generate resistance following treatment with BRAF and EGFR inhibitors. [Table: see text]
Effect of IMP3 on epithelial-to-mesenchymal transition and the function of colon cancer stem cells.
Authors: Wei Ping , Li Dawei , Xu Ye , Cai Sanjun , Du Xiang
Published: February 2017

631

Background: EMT could promote the acquisition of stem-like properties in cancer cells and cancer stem cell (CSC) has EMT properties. However, the underlying mechanism of the interaction between EMT and CSC still remain unclear. We previously identified Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) plays a vital role in colon cancer carcinogenesis. Here, we aimed to identify the gene function between EMT and CSC in colon cancer. Methods: The expression of IMP3 was analyzed in human tumor tissues. Colonospheres were isolated from colon cancer cell lines and the biological features of IMP3 were investigated in the process of EMT and colonoshpere cells. Results: Increased IMP3 levels were significantly correlated with higher clinical stage, T classification, LNM, presence of distant metastasis. Patients with IMP3-positive localized tumors had lower 5-year disease-free survival (DFS) and overall survival (OS) than those with IMP3-negative tumors. Multivariate survival analysis showed that IMP3 was an independent prognostic marker for DFS and OS. Expanded colonospheres contained cells that expressed high levels of CD133 and had the ability to promote migration and activate the epithelial-mesenchymal transition. Down regulation of IMP3 in HCT116 cells inhibited the invasion, migration ability and epithelial-mesenchymal transition and the properties of colonospheres. Conclusions: These findings suggest that IMP3 plays an important role in colon cancer tumorigenesis and metastasis through transactivation of colon CSC with EMT property, which is helpful to identify critical marker and therapeutic target.
K-ras mutational status and its clinical implications in Korean colorectal cancer patients.
Authors: An Ho Jung , Gye Bong-Hyeon , Kim Hyung Jin , Jung Ji Han , Lee Jong Hoon , Kim Sung Whan , Cho Hyun Min , Shim Byoungyong
Published: February 2017

641

Background: The incidence of K-ras mutation of exon 2 was reported between 30-40% in colorectal cancer, and it is well known predictive biomarker for EGFR monoclonal antibody. However, its prognostic role has not been defined so far, especially in Eastern country. Methods: From January 2007 to September 2013, patients who were diagnosed as colorectal cancer and examed K-ras exon 2 mutation in Saint Vincent’s hospital were retrospectively reviewed. Results: Among 436 patients, 343 patients with sufficient clinical information were analyzed. The median follow up period was 13.0 (0.2-94.8) months. The incidence of K-ras mutation was 37.9% (codon 12 mutation: 28.6%, codon 13 mutaiton: 9.0%, both: 0.3%). Codon 12 p.G12D was most frequent (52.3%), and codon 13 p.G13D was the next (22.3%). The presence of K-ras mutation was associated with old age (p=0.038), female gender (p=0.034), lesser nodal involvement (p<0.001), but not related to stage, tumor site, and histology. There is no significant clinical differences between codon 12 and 13 mutations. The recurrence free survival in patients who received curative resection was worse in patients with K-ras mutation (p=0.001). The prognostic role of K-ras mutation was more prominent in colon cancer, while it lost its prognostic significance in rectal cancer. Conclusions: The prognostic role of K-ras mutation was different according to primary tumor sites in colorectal cancer.
Improving neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, a nanoparticle-drug conjugate, with a camptothecin payload.
Authors: Wang Andrew , Tian Xi , Nguyen Minh , McRee Autumn Jackson , Sanoff Hanna Kelly , O'Neil Bert H. , Hennessy Meliessa G. , Eliasof Scott , Garmey Edward Graeme , Tepper Joel E.
Published: February 2017

645

Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a camptothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, a dynamically tumor targeted nanoparticle-drug conjugate differentially delivers CPT into cancer cells and appears to durably suppress HIF-1α as well as topoisomerase 1, but with less gastrointestinal toxicities than irinotecan. We therefore hypothesized that the addition of CRLX101 to CRT may further improve the therapeutic index in this setting. Methods: CRLX101 was evaluated using murine flank xenograft models (SW480 and HT29) of colorectal cancer alone or in combination with radiotherapy (XRT) and/or 5-FU and compared to CPT plus CRT. Skin toxicity and hematologic toxicity were also studied. In addition, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT in the neo-adjuvant treatment of rectal cancer is currently underway. A standard 3 + 3 design was used for the phase Ib with a CRLX101 starting dose of 12 mg/m2 in the first cohort escalating to the CRLX101 monotherapy MTD of 15 mg/m2 in the second. The primary phase 2 end-point is the pathological complete response (pCR) rate from treatment. Results: In the HT29 xenografts model, CRLX101+5FU+XRT delayed tumor growth significantly more than the other treatment regimens evaluated. In the SW480 xenografts model, both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens, but there was no statistical advantage to the addition of 5-FU to CRLX101+XRT in this model. The addition of CRLX101 to 5FU+XRT did not increase hematologic or skin toxicities. In the ongoing clinical trial, none of the first 3 patients enrolled (the first dosing cohort) have experienced dose limiting toxicities and 1 out of 3 patients had a pCR. Conclusions: CRLX101 has been shown in preclinical experiments to improve the therapeutic index of CRT for rectal cancer. Preliminary clinical data suggest that CRLX101+5FU+XRT treatment is well tolerated. Clinical trial information: NCT02010567.
Novel mechanism linking noncanonical Wnt ligand induction to suppression of colorectal cancer cell proliferation.
Authors: Braun Donald Peter , Fagla Bani M , Ali Irshad
Published: February 2017

648

Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation. A central pathway in the control of proliferation and differentiation is the Wnt pathway. Wnt function is mediated by a canonical pathway (CP) which utilizes β-catenin and stimulates cell proliferation, and a non-canonical pathway (NCP) independent of β-catenin involved with differentiation. Studies suggest that dysfunctional Wnt signaling results from imbalance of CP components. The possibility that modulation of NCP components are involved in this process has not been studied comprehensively. Given their importance in constraining CP signaling and proliferation, the purpose of this study was to determine the capacity of NCP components to suppress human colorectal cancer (CRC) proliferation. Methods: Short term, primary CRC lines were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of the CP, Dkk1, an inhibitor of the CP, and IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion. CRC proliferation and Wnt pathway gene expression were determined by MTS assays and quantitative gene expression respectively. Results: Unexpectedly, CRC proliferation was inhibited significantly (p<0.01) by LiCl and stimulated modestly (ns) by Dkk1. This was associated with a 20 fold increase in gene expression for the NCP ligand, Wnt9A. LiCl treated cells incubated with IWP-2 reversed the unexpected LiCl-mediated suppression of CRC proliferation. Conclusions: The unexpected finding that LiCl suppresses proliferation and Dkk1 has the opposite effect indicate dysregulation of the Wnt pathway in CRC. Further support for this hypothesis is the fact that Wnt 9A, an NCP ligand is increased by LiCl in CRC, an effect that is not expected in non-malignant cells. That IWP-2, a pan Wnt ligand secretion inhibitor reverses these effects is consistent with these observations. This study is the first to demonstrate a correlation between NCP ligand induction and suppression of CRC proliferation and suggests that control of CRC proliferation may be achieved in patients by modalities that activate the NCP Wnt pathway.
Prognostic and predictive values of APC and WNT pathway mutations in MSS colorectal cancers.
Authors: Kothari Nishi , Yue Binglin , Teer Jamie K. , Schell Michael J. , Kim Richard D.
Published: February 2017

652

Background: WNT signaling is abnormal in many inherited and acquired colorectal cancers, through mutations in APC and other components of the pathway including beta catenins and AXINs. Aspirin and other COX-2 inhibitors have been hypothesized to decrease WNT pathway activity in preclinical models, potentially leading to improved survival. We evaluated APC and WNT pathway mutations as potential prognostic and predictive biomarkers for ASA use in a cohort of colorectal cancer patients. Methods: We analyzed tumor samples collected from 468 CRC patients diagnosed between 1998 and 2010 as part of a multi-institutional observational study. We performed targeted exome sequencing using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, so filtering of normal variants was performed using 1000 Genomes. One or 2 mutations in the APC gene were counted as mutant. Additional WNT pathway mutations included AXIN1, AXIN2, CTNNB1, WNT1, and WNT2. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. ASA use data was collected through retrospective chart review. Results: MSI-H tumors were excluded. 356 patients were eligible for analysis. 258 patients had APC mutations and 20 patients had other WNT pathway mutations including CTNNs, WNTs, AXINs, and TCF7L2. 140 patients had metastatic disease. Aspirin users had a median age of 70 compared to non-users at 63. Patients with APC mutations had improved overall survival compared to wild type patients for early stage disease (p = 0.03) with a trend towards improvement in survival for metastatic patients. Additional WNT pathway mutations did not strengthen this relationship. ASA use was not associated with improved OS in the APC or WNT pathway mutant patients. Conclusions: In this population, APC mutations had positive prognostic value, which was more pronounced in early stage disease. There was limited predictive value for ASA use in APC mutant patients. However, aspirin users tended to be older which might have confounded the association.
Correlation of overexpression of ATPase Na+/K+ transporting alpha 1 polypeptide with the diagnosis and clinical staging of esophageal cancer: A translational study.
Authors: Wu I-Chen
Published: February 2017

66

Background: This study aims to identify the novel and potential upregulated genes related to secretionary or membranous proteins for the clinical diagnosis and staging of esophageal squamous cell carcinoma (ESCC). Methods: By combining microarray-based screening, which contained at least 25,000 DNA oligonucleotide probes, of esophageal tumors from both N-nitrosomethylbenzylamine- and arecoline-induced F344 rats and 17 human ESCC specimens, we further confirmed the potential candidate genes by tissue arrays in 243 cancer tissues and 126 normal tissues of esophagus from Taiwan, Korea, and USA and by ELISA in 78 serum specimens of ESCC patients from Taiwan. Results: Four candidate genes, including ATP1A1, SPINT2, CMTM8, and AGR2, were chosen due to their up-regulation in more than half of 17 paired tissues from 17 ESCC patients in the microarray-based screening. The four genes were verified by RT-PCR and immunohistochemical (IHC) staining in ESCC tissue specimens and only ATP1A1 (ATPase Na+/K+ transporting alpha 1 polypeptide) expression was consistent and further studied. Among the 243 cancer tissues and 126 normal tissues of esophagus, we found that the positive expressions of ATP1A1 by IHC staining were 207 (85%) of 243 in cancer tissues and 88 (70%) of 126 in normal tissues. After adjusted for age and sex, ATP1A1 overexpression had a 3.2-time (95% CI = 1.8-5.6) to be likely in cancer tissues than in normal tissues. ATP1A1 expression was also correlated to the tumor stage by IHC staining. Using the median level of 1,465.0 pg/mL of serum ATP1A1 protein expression as the cut-off point, we found that patients with stage III-IV had a 2.91-fold (1.12-7.36) likely to have high serum ATP1A1 levels than those with stage I-II after adjusting for age and sex. Conclusions: ATP1A1 overexpression may serve as a potential noninvasive marker of the clinical diagnosis and staging for ESCC patients.
The clinical utility of a tumour microenvironment-based histopathological score in patients with primary operable colorectal cancer.
Authors: Park James Hugh , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S.D.
Published: February 2017

664

Background: The tumor microenvironment is increasingly recognized as an important determinant of disease progression and outcome in colorectal cancer (CRC). The aim of the present study was to examine the clinical utility of a novel histopathological prognostic score based on both the tumor inflammatory cell infiltrate and the tumor stroma percentage, termed the Glasgow Microenvironment Score (GMS), in patients with primary operable CRC. Methods: Using routine H&E pathological sections, Klintrup-Mäkinen (KM) grade was graded as strong or weak, and tumor stroma percentage (TSP) was assessed as high (>50%) or low (≤50%) retrospectively in 319 patients undergoing resection of stage II-III CRC. The relationship between a cumulative score based on these factors and cancer-specific survival (CSS) was examined. Results: Median survival of survivors was 122 months with 106 cancer deaths. 63% of patients had stage II CRC. 5-year CSS of patients with stage II and stage III CRC was 82% and 58% respectively (p<0.001). 33% of patients were GMS=0 (strong KM/high or low TSP), 47% were GMS=1 (weak KM/low TSP), and 20% GMS=2 (weak KM/high TSP), with 5-year CSS of 86%, 74%, and 48% (p<0.001) respectively. On multivariate analysis, GMS was associated with CSS (HR 1.77, p<0.001), independent of age, emergency presentation, TNM stage and venous invasion (all p<0.01), and peritoneal involvement (p<0.05). The combination of TNM and GMS stratified 5-year CSS from 92% (stage II, GMS=0) to 35% (stage III, GMS=2) (Table). Conclusions: The present study shows the clinical utility of a novel, routinely available assessment of the tumor microenvironment in patients undergoing curative resection of CRC. [Table: see text]
Improving safety in first-line metastatic colorectal cancer (MCRC) therapy with bevacizumab: Modified FOLFOX7 versus XELOX2—Results of the induction phase of the GERCOR DREAM randomized phase III study.
Authors: Tournigand Christophe , Chibaudel Benoist , Samson Benoit , Scheithauer Werner , Lledo Gérard , Artru Pascal , Viret Frédéric , RAMEE Jean-Francois , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Bonnetain Franck , Louvet Christophe , Larsen Annette K. , André Thierry , De Gramont Aimery ,   GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie
Published: February 2017

670

Background: FOLFOX7 is an oxaliplatin FOLFOX regimen without 5FU bolus, first used in the OPTIMOX1 MCRC study (Tournigand, JCO 2006). Modified (m) FOLFOX7 has a reduced dose of oxaliplatin (100 mg/m²) and has been used in the OPTIMOX2 trial (Chibaudel, JCO 2009). XELOX2 derived from the bi-weekly XELOX regimen with oxaliplatin 85 mg/m² (Scheithauer, JCO 2003). Methods: First-line induction therapy (IT) allocation was randomized in unresectable MCRC patients with performance status (PS) 0-1 between 6 cycles of mFOLFOX7 with bevacizumab (B) or 6 cycles of XELOX2 with B. Stratification criteria were: center, age, ECOG PS, number of metastatic sites and LDH level. After 3-month IT, a second randomization for maintenance therapy allocation was done in non-progressive patients between B or B-erlotinib. mFOLFOX7-B consisted in B 5 mg/kg followed by folinic acid (FA) 400 mg/m² and oxaliplatin 100 mg/m² followed by 5-flurouracil (5FU) 2,400 mg/m² 46h-infusion. XELOX2-B consisted in B 5 mg/kg followed by oxaliplatin 100 mg/m² followed by capecitabine 1,250 mg/m² twice daily for seven days. Cycles were repeated every two weeks. The objective was to compare the safety and efficacy of XELOX2-B to mFOLFOX7-B (secondary objective of the study). Results: 156 patients were randomized to mFOLFOX7-B and 154 to XELOX2-B. Medians (mFOLFOX7/XELOX2) were: PFS 7.9/8.7 months (HR 0.98, CI 0.74-1.31; p=0.918), OS 26.6/23.4 months (HR 1.24, CI 0.98-1.59; p=0.075). RR (mFOLFOX7/XELOX2) was 50.0%/49.3%. Main grade 3/4 toxicities (mFOLFOX7/XELOX2) were neutropenia 9.2%/2.6% (p=0.018), diarrhea 5.2%/18.3% (p<0.001), asthenia 2.6%/11.8% (p=0.003), all 27.5%/37.6% (p=0.068). Conclusions: Both regimens have the same activity as the parent regimens with a reduced toxicity, especially mFOLFOX7-B. These regimens could be good backbones for future combinations with other agents and are well suited for frail and elderly patients. Clinical trial information: NCT00265824.
Observational study of first-line therapy, including cetuximab in cases of nonresectable colorectal cancer: CORAL (interim report).
Authors: Hashida Hiroki , Muro Kei , Itabashi Michio , Ohashi Yasuo , Sugihara Kenichi
Published: February 2017

681

Background: Cetuximab (Cmab) + chemotherapy is now indicated in various treatment guidelines as a first-line therapy for non-resectable metastatic colorectal cancer (mCRC). The efficacy of Cmab + FOLFIRI has been demonstrated in CRYSTAL, but its efficacy and safety in combination with other regimens is unclear. There are few reports on Cmab combination therapy as first-line chemotherapy in Japan, and there are no reports of treatment results in the ESMO guideline groups 1, 2, and 3. Therefore an observational study was planned to evaluate the efficacy and safety of first-line therapy including Cmab, and to clarify the treatment results by group. This study received support from the Public Health Research Foundation’s Comprehensive Support Project for Oncology Research (CSPOR). Methods: The subjects were mCRC patients who received Cmab as first-line therapy either as combination therapy or monotherapy. Endpoints were response rate, PFS, and reason for discontinuation of first-line treatment (curative resection, PD, adverse events). To evaluate safety, skin conditions (incidence, degree, previous history) and other adverse events were investigated. Results: Among 579 patients enrolled at 158 institutes from January 2012 until June 2013, 575 were subjected to analysis. Background factors were PS 0/1/2 at 406/143/26, males females at 368/207, median age of 65 (31-88), groups 1/2/3 at 172/229/174, and concomitant drugs were oxaliplatin/irinotecan/others at 377/173/25. Response rate in the evaluable cases was 57%, and in groups 1/2/3 was 65%/54%/53%. The 1-year survival rate in groups 1/2/3 was 93%/61%/78%. In adverse events, the incidence of skin conditions (rash acneform) at 8 weeks/16 weeks was 69%/60% in patients with no history of acne vulgaris (2%/8% at G3 or higher) and 83%/81% in those with a previous history (13%/14% at G3 or higher). Conclusions: We reported treatment results according to ESMO guideline groups on the efficacy and safety of Cmab as first-line therapy in mCRC patients. Response rate and survival were higher in group 1. Survival outcomes after 1 year will be followed up. Clinical trial information: UMIN000007275.
Impact of duration of neoadjuvant radiation on rectal cancer survival.
Authors: Kumar Aalok , Peixoto Renata D'Alpino , Kennecke Hagen F. , Speers Caroline , Cheung Winson Y.
Published: February 2017

682

Background: The utility of neoadjuvant radiation (XRT) for the treatment of stages II-III rectal cancer has been demonstrated previously. However, the optimal amount and duration XRT in this setting remains unknown. Using a population-based cohort of stage II and II rectal cancer (RC) patients treated with curative intent including XRT, our aims were to 1) examine the patterns in XRT use and 2) explore the relationship between XRT course and survival. Methods: We analyzed patients diagnosed with clinical stage II-III RC from 2006 to 2010 and treated with long course 45-50.4 Gray (LC) or short course 25 Gray (SC) XRT at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the factors associated with the course of XRT given, LC vs. SC. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between XRT course and disease-free (DFS), overall survival (OS), local recurrence free survival (LRFS) and distant recurrence free survival (DRFS). Results: 427 patients were identified: median age 65 years (range 31 to 94), 67% men, 87% T3/4 tumors, and 74% with N1 or N2 disease. Among them, 240 (56%) received SC and 187 (44%) received LC. Adjusting for confounders, patients with N1 or N2 disease were more likely to receive LC (OR for LC 5.08, 95% CI, 2.51-11.22, p<0.0001 and 8.35, 95% CI, 3.35-22.39, p<0.0001, respectively), while older age patients were less likely to receive LC (OR 0.95, 95% CI, 0.94-0.98, p<0.0001). On univariate analysis, there was no significant difference seen in DFS, OS, LRFS, and DRFS between LC and SC. Similarly, in multivariate analyses comparing LC vs. SC, the course of XRT was not associated with differences in DFS (HR 1.06, 95% CI, 0.68-1.64, p=0.80), OS (HR 0.91, 95% CI, 0.61-1.37, p=0.66), LRFS (HR 0.79, 95% CI, 0.39-1.57, p=0.50) and DRFS (HR 0.99, 95% CI, 0.60-1.61, p=0.95). Additional baseline clinical and tumor characteristics did not influence outcomes (all p>0.05). Conclusions: Appropriate pre-operative selection of SC vs. LC neoadjuvant XRT for early stage RC based on patient and tumor characteristics was not associated with differences in survival outcomes.
An investigation of the role of irinotecan and oxaliplatin in liver toxicity during first-line neoadjuvant chemotherapy.
Authors: Desjardin Marie , Bonhomme Benjamin , Soubeyran Isabelle , Vara Jeremy , Fonck Marianne , Becouarn Yves , Desolneux Gregoire , Brouste Veronique , Evrard Serge , Bechade Dominique
Published: February 2017

689

Background: Neoadjuvant chemotherapy (CT) have been associated with an increased risk of surgery for colorectal liver metastases (CRLM). Irinotecan (IRI) is claimed to induce CT-associated steatohepatitis (CASH) and oxaliplatin (OX) to induce sinusoidal obstruction (SOS). Imputability is sometimes difficult to establish and the impact on postoperative complications is unclear. The objective of this study is to investigate the impact of IRI and OX on induced liver toxicity, and to study the effects of toxicity on surgical outcomes. Methods: Patients (Pts) who received only one line of CT before resection of CRLM were retrospectively included. CASH and SOS were described according to Kleiner and Rubbia-Brandt classifications respectively. Associations were sought between CASH or SOS and various patient and treatment factors, and between patient and treatment factors and the occurrence of post-operative complications grade 3 or over. Results: Among 379 pts operated on for CRLM from 2003 to 2013, 223 were eligible for inclusion; 57 were excluded as there was no healthy hepatic parenchyma to be analyzed. Median age was 64 y [34-88], BMI ≥25 kg/m² for 52%, 8% had diabetes, and 28% had a dyslipidemia. CRLM were synchronous in 76.5%. 65 (39.2%) received Folfox, 95 (57.2%) Folfiri and 6 (3.6%) Folfirinox. Bevacizumab, cetuximab and panitumumab were given in 71 (42.8%), 30 (17.5%), 4 (2.4%) respectively. Extra-hepatic resections were performed in 78 pts (47%). 90-day mortality was 1.8% and 31 pts encountered complications more severe than 3A. Histological hepatoxicity was established for 82 pts (49%) including 33 (19.9%) with grade 2 or 3 SOS and 22 (13%) with CASH. No significant associations were identified between SOS and OX, nor CASH and IRI. BMI ≥ 25 kg/m² was correlated with an increased risk of CASH. Only septic extra-hepatic surgeries were correlated with the prediction of postoperative complications. Conclusions: In this selected series, preoperative CT was not associated to liver toxicity. The presence of histological lesions did not worsen post-operative outcomes. BMI and extra-hepatic surgery were the only co-factors correlated with CASH and post-operative complications respectively.
Lower rates of acute gastrointestinal toxicity with pencil beam proton therapy relative to IMRT in neoadjuvant chemoradiation for rectal cancer.
Authors: Batra Sonny , Comisar Lauren , Lukens John Nicholas , Kirk Maura , Both Stefan , McDonough James , Mahmoud Najjia N. , Giantonio Bruce J. , Ben-Josef Edgar , Metz James M. , Plastaras John Peter
Published: February 2017

696

Background: Preoperative chemoradiotherapy (CRT) is standard treatment for locally advanced rectal cancer (LARC). GI toxicity leading to ED visits, hospitalization, and need for IV hydration remains a management challenge. Previous studies have established volume of bowel receiving low dose radiation (V15) as the strongest predictor of GI toxicity. We have previously shown pencil beam scanned proton therapy (PBSPT) is dosimetrically superior to IMRT in LARC with respect to low dose to the bowel. This studycompares the toxicity of patients treated with PBSPT and IMRT in neoadjuvant treatment of LARC. Methods: A retrospective review was conducted of patients treated at the University of Pennsylvania with neoadjuvant 5-FU or capecitabine CRT. Patient and tumor characteristics, treatment, and toxicity data were collected. PBSPT (50.4 Gy RBE to standard volumes) was delivered using either two opposed lateral fields or posterior oblique fields with a patient supine or prone. These patients were registered on a prospective registry study. IMRT plans were delivered with 7-9 field IMRT or volumetric arc therapy in the supine or prone position. Statistical analysis was performed using STATA v12.0. Results: Between 3/2009 and 6/2014, 39 patients treated with IMRT and 26 patients treated with PBSPT were studied. Continuous-infusion 5-FU was administered in 31 (79%) IMRT patients and 16 (62%) PBSPT patients (p = 0.162); the remainder received capecitabine. PBSPT patients had significantly lower rates of acute Grade ≥ 2 diarrhea, 12% versus 39% with IMRT (p = 0.022). On multivariable analysis incorporating the type of chemotherapy, use of PBSPT remained a significant predictor of lower rate of Grade ≥ 2 diarrhea (OR = 0.20, 95% CI 0.05 - 0.82, p = 0.025). There was also a borderline significant reduction in Grade ≥ 2 fatigue with the use of PBSPT, occurring in 8% versus 29% of IMRT patients, p = 0.057. Conclusions: These preliminary results indicate PBSPT is associated with significant reduction in acute Grade ≥ 2 diarrhea compared to IMRT. PBSPT may play an important role in the treatment of LARC, a disease with high cure rate where radiation toxicity should be minimized.
The significance of EGFR pathway mutations for the efficacy of first line treatment with bevacizumab in metastatic colonrectal cancer.
Authors: Nakayama Izuma , Shinozaki Eiji , Wakatsuki Takeru , Kumekawa Yosuke , Ogura Mariko , Ichimura Takashi , Takahari Daisuke , Ozaka Masato , Suenaga Mitsukuni , Chin Keisho , Mizunuma Nobuyuki , Yamaguchi Toshiharu
Published: February 2017

699

Background: After analysis of minor RAS mutations (KRAS exon3, 4/NRAS) in FIRE-3 or PRIME study, so called all RAS mutation would be being regarded as a biomarker for anti-EGFR antibodies. BRAF and PIK3CA mutation would be a candidate of biomarkers for anti EGFR targeted therapies. However it remains unknown whether EGFR pathway mutations affect the efficacy of bevacizumab in Stage.‡W CRC. Methods: Of the 1,001 consecutive patients of CRC in our institute between Nov 2006 and Dec 2013, we examined RAS, PIK3CA and BRAF mutational status, 141 patients received systemic chemotherapy for the first line treatment of Stage.‡W. Among them, 96 patients were administered chemotherapy with bevacizumab. Overall survival (OS), Time to Treatment Failure (TTF) and Objective Response Rate (ORR) were evaluated by mutational status. Results: Baseline characteristics were as follows (n=141): median age, 63; male/female, 80/61; ECOG PS 0-1/2, 135/4; chemotherapy with bevacizumab/chemotherapy with anti-EGFR antibodies/cytotoxic agent alone, 96/22/23;KRAS (codon 12,13) wild-type (WT)/RAS wild-type(WT), 89/80; PIK3CA mutation (exon 9/exon 20)/BRAF mutation, 11(5/6)/13. Median OS and TTF were 32.1 and 8.0 months respectively. In chemotherapy with bevacizumab, ORRs were 46.3% (all cases), 55.3% (KRAS WT), 54.5% (RAS WT) and 60.6% (all WT) respectively. ORR was gradually improved by focusing therapeutic target on all wild population. However, there were no significant differences in TTF and OS among them. PIK3CA mutation had a trend toward shorter TTF of bevacizumab (p=0.056). This trend was observed in PIK3CA mutation on exon 20 but not observed exon 9. BRAF mutation had significantly associated with poor OS not only for bevacizumab cases but also all therapies. Conclusions: In our study, profiling of EGFR pathway mutations may not contribute to enrich patients with benefit from chemotherapy with bevacizumab.
Safety analysis of FOLFOX as adjuvant chemotherapy for stage III colon cancer in phase II study (NORTH/HGCSG1003): Detailed analysis of peripheral sensory neuropathy.
Authors: Sogabe Susumu , Yuki Satoshi , Fukushima Hiraku , Takahashi Norihiko , Shichinohe Toshiaki , Kusumi Takaya , Nakamura Fumitaka , Iwanaga Ichiro , Hatanaka Kazuteru , Miyashita Kencho , Konno Jun , Uemura Kazuhito , Nenohi Masaaki , Kina Masaya , Sakamoto Naoya , Taketomi Akinobu , Hirano Satoshi , Amano Toraji , Ito Yoichi M , Komatsu Yoshito
Published: February 2017

701

Background: Oxaliplatin-containing regimen is a standard adjuvant chemotherapy for resected stage III colon cancer. Oxaliplatin-containing regimens were investigated for their efficacy in patients with resected stage III colon cancer in MOSAIC and XELOXA studies. Since these two international randomized studies were performed outside of Japan, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy in Japanese patients (pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods: This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 biweekly cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was DFS. Secondary endpoints included overall survival (OS) and safety. Results: From September 2010 to March 2013, 273 pts were enrolled at 28 institutions. Safety analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age, 65 (33-84); male/female: 131/134; PS 0/1:258/7; stage IIIA/IIIB/IIIC: 37/197/31; colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), platelet count decreased (2.3%), and allergic reaction (1.5%). The incidence of peripheral sensory neuropathy (PSN) was 41.9% (grade 1), 38.1% (grade 2), and 6.4% (grade 3). PSN tended to be serious depending on the cumulative dose of oxaliplatin (table 1). Median cumulative dose of oxaliplatin at which PSN occurred were as follows: grade 1; 170 mg/m2, ≥ grade 2; 850 mg/m2, ≥ grade 3; (-). The median number of cycles of chemotherapy was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. Conclusions: In Japanese patients with stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. Clinical trial information: 000004590. [Table: see text]
Characteristics of long- versus short-surviving patients (Pts): An analysis of the ARIES Observational Cohort Study (OCS) of bevacizumab (BV)-treated pts with metastatic colorectal cancer (mCRC).
Authors: Kozloff Mark , Grothey Axel , Bendell Johanna C. , Cohn Allen Lee , Bekaii-Saab Tanios S. , Roach Nancy , Flick Elizabeth Dawn , Mun Yong , Fish Susan Meredith , Laeufle Rita , Sommer Nicolas , Hurwitz Herbert
Published: February 2017

702

Background: Median overall survival (OS) in mCRC has significantly improved over the past 20 yrs, but the observed range of OS in pts remains wide; a large percentage of pts have OS <1 yr or >4 yrs. ARIES was a prospective OCS conducted from 2006–2012 that evaluated outcomes in pts receiving BV + chemotherapy (CT) for mCRC in general clinical practice. The objective of this analysis is to examine clinical characteristics of pts with long vs short OS. Methods: This analysis included 1,417/1,550 first-line (1L) BV-treated mCRC pts who died or had complete follow-up on study. Long OS was defined as OS within the upper quartile of the analysis population (range 42–67 mos); short OS was defined as OS within the lower quartile (range 0.3–12 mos). Progression-free survival (PFS) was estimated using Kaplan-Meier methods. Pt and disease characteristics and treatment patterns were described using summary statistics. Results: Pt and disease characteristics are shown in the Table. Median PFS was 22.3 mos (95% CI, 19.9–23.3) vs. 4.9 mos (95% CI, 4.6–5.4), in the long-OS vs. short-OS groups. More pts with long OS received any second-line (2L) therapy (71% vs. 46%), and were exposed to 5-fluorouracil, oxaliplatin, and irinotecan throughout the course of their disease (53% vs. 32%) compared with pts with short OS. KRAS/BRAF mutation status was not collected. Conclusions: Pts with long OS had better baseline performance status, primary tumors more likely to have been resected, and were more likely to have received 2L CT. Additional analyses of detailed treatment patterns and safety are ongoing. Clinical trial information: NCT00388206. [Table: see text]
Randomized phase III study of panitumumab (pmab) vs. cetuximab (cmab) in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC): Outcomes by hypomagnesemia (hypomag) in ASPECCT.
Authors: Price Timothy Jay , Peeters Marc , Kim Tae Won , Li Jin , Cascinu Stefano , Ruff Paul , Suresh Attili Venkatasatya , Thomas Anne , Tjulandin Sergei , Zhang Kathy , Sidhu Roger , Murugappan Swaminathan
Published: February 2017

705

Background: ASPECCT met its primary endpoint of non-inferiority of overall survival (OS) of pmab vs. cmab. We evaluate outcomes by hypomag, an on-treatment, anti-EGFR related adverse event that develops due to the inhibition of EGFR function. Conflicting reports have suggested hypomag is associated with survival. Methods: Patients with previously treated WT KRAS exon 2 mCRC were randomized 1:1 to receive pmab or cmab. The primary endpoint was non-inferiority of OS. Progression-free survival (PFS) and objective response rate (ORR) were secondary endpoints. Patients were categorized ± any grade hypomag during the study and data analyzed by treatment arm. Analysis of Mg supplementation during hypomag was not conducted. Results: 999 patients were randomized and treated: 499 pmab, 500 cmab. Any grade hypomag was 28.8% and grade ≥3 was 7.3% in the pmab arm vs. 18.9% and 2.6% in the cmab arm, respectively. Median time to first hypomag onset was 82 days in the pmab arm and 57 days in the cmab arm. In the pmab arm, 1.0% of patients discontinued treatment and 5% of patients had dose modifications due to hypomag vs. <0.5% and 3% in the cmab arm, respectively. Results are shown (Table). Conclusions: In ASPECCT, rates of hypomag were higher in the pmab vs. the cmab arm. Patients who developed any grade hypomag with pmab or cmab had higher ORR, PFS, and OS compared with those patients who did not. Clinical trial information: NCT00788957. [Table: see text]