bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of genetic counseling on detection of Lynch syndrome (LS) in colorectal cancer (CRC) patients (pts).
Authors: Haraldsdottir Sigurdis , Hampel Heather , Frankel Wendy , Wu Christina Sing-Ying , Pan Xueliang Jeff , Bekaii-Saab Tanios S. , Goldberg Richard M.
Published: February 2017

419

Background: LS, characterized by germline mutations in MLH1, MSH2, MSH6, or PMS2, leads to defective DNA mismatch repair (dMMR) and causes 2%-3% of CRC cases. Ohio State University (OSU) began immunohistochemistry (IHC) screening on all CRC cases in 2006. In 2006 results were reported in pathology reports without further follow-up. From 2007 to 2010 genetic clinic (GC) counselors contacted pts and recommended further testing. Since 2011, GC counselors met pts at a follow-up appointment. This retrospective study aims to assess if type of follow-up after abnormal IHC, affects rate of conclusive testing. Methods: All CRC pts diagnosed at OSU from 03/06-06/12 had MMR testing per IHC. All pts’ charts were reviewed. Conclusive testing, following the initial MMR IHC, includes either MLH1-hypermethylation testing and/or gene sequencing to identify LS from non-LS pts. Chi-square test was used for categorical parameters and t-test for continuous variables to compare differences between pts with conclusive test vs those without. Results: One-hundred and twenty two tumors of 777 (15.7%) tested had dMMR by IHC. The GC follow-up of abnormal results significantly affected the rate of conclusive testing. The rate of conclusive testing went from 14.3% in 2006 to 38.4% in 2007-2010 and after 2011, 90.5% of the pts had conclusive testing done. Among 51 pts undergoing full testing, 13 pts were diagnosed with LS, 29 pts had MLH1-hypermethylated tumors, and 9 pts were not found to have any mutations on gene sequencing. Conclusions: Conclusive testing rates after abnormal universal screening with IHC improved significantly with GC involvement and was most effective when GC counselors met with the pts during their appointment. [Table: see text]
Development of a metabolite profile for colorectal cancer detection.
Authors: Gu Haiwei , Dai Jin , Carnevale Neto Fausto , Djukovic Danijel , Zhu Jiangjiang , Raftery Daniel
Published: February 2017

422

Background: While carcinogenesis of colorectal cancer (CRC) is a complex process involving genetic abnormalities, metabolomics, which aims to establish metabolic responses of living systems to external or internal perturbations, has great potential to develop a metabolite profile specific to CRC for both early detection and treatment monitoring purposes. In this pilot study, we examined the colon cancer-induced alterations of amino acids and their distribution in the three domains of free amino acids (FAAs), free amino acids and soluble peptide amino acids (FAASPAAs), and proteome amino acids (PAAs). Methods: 56 serum samples were collected from 28 colon cancer patients and 28 healthy controls. FAAs were extracted after protein precipitation. FAASPAAs and PAAs were obtained using traditional acid hydrolysis. We utilized LC-MS/MS to make the amino acid measurements, and performed penalized logistic regression analysis on the amino acid signals in the three domains, both individually and in combination. Results: There were 10, 9, and 14 amino acids with low P-values (<0.05) in FAAs, FAASPAAs, and PAAs, respectively, when comparing the two groups. The penalized logistic regression model based on amino acids from the three domains had a sensitivity of 65% when the specificity was 95%. An area under the receiver operator curve (AUROC) of 0.91 was achieved for the combined statistical model. Significant amino acids in statistical modeling included aspartic acid, glutamic acid, glutamine/lysine, and histidine from FAAs, lysine from FAASPAAs, and arginine, serine, and tyrosine from PAAs. Conclusions: To the best of our knowledge, this is the first study to perform a combined analysis of amino acids in the three domains and derive a multivariate statistical model for detecting colon cancer. It was discovered that amino acid concentrations in all three domains are changed significantly in colon cancer and their relative distributions are also altered. The combined analysis helped improve the statistical model for detecting colon cancer. Since this study aims to investigate amino acids that directly connect the metabolome and proteome, it potentially brings new insights to the diagnosis of and mechanism involved in colon cancer development.
A case series of Lynch syndrome-associated breast cancer.
Authors: Zbuk Kevin M. , Goldberg Mira , Bell Kathleen , Semotiuk Kara , Gallinger Steven , Aronson Melyssa
Published: February 2017

432

Background: Studies suggest breast cancer (BC) might be a feature of Lynch syndrome (LS). Further characterization of this risk is required before recommending increased surveillance for BC in LS families. This study describes the prevalence and characteristics of BC amongst LS families in a large familial cancer registry. Methods: The pedigrees of 325 families carrying an MMR gene mutation (149 MSH2 46%, 113 MLH1 35%, 38 MSH6 12%, 19 PMS2 5%, and 6 EPCAM 2%) within the Familial Gastrointestinal Cancer Registry (FGICR) were screened for a diagnosis of BC. The analysis was limited to known or obligate carriers of a MMR gene mutation. The diagnosis and age of diagnosis of BC was confirmed utilizing clinic records and pathology reports where available. Descriptive and Chi-squared statistics were utilized. Results: 39 female mutation carriers from 33 unrelated families with a diagnosis of BC were identified. The average age of BC diagnosis was 53y. The vast majority of families (25/33, 76%) carried MSH2 mutations. Of the 8 remaining families there were 6 (18%) MLH1 carriers, 1 (2.5%) MSH6 carrier, and 1 PMS2 carrier. The mutation distribution amongst the LS patients with BC was statistically different from those without BC (p = 0.008), reflecting the predominance of MSH2 mutations amongst patients with BC. Twenty-nine of 33 LS families with BC met Amsterdam Criteria (88%), compared with 142 of 292 LS families without BC in a known carrier (48%) (p = 0.03). LS associated BCs tended to be high grade (10 of 19 were grade 3), and 50% were ER/PR/Her2 negative. Additional manifestations in patients with BC included 9 women with colorectal cancer, 4 with multiple (2-4) colorectal cancers, 20 with endometrial cancer, 7 with cutaneous manifestations of LS, and 5 with genitourinary cancers. The mean number of additional LS related manifestations for these patients with BC was 1.5 (range 0-8) per patient. Conclusions: Within the registry utilized in this study, LS associated BC is strongly associated with MSH2 mutation status. Most patients with LS associated BC harbored multiple manifestations of LS, and their families almost always met Amsterdam criteria. LS associated BC was frequently high grade and often hormone receptor negative, suggesting an aggressive histology.
Distribution and histopathology of colorectal polyps in the Asian population in the United States.
Authors: Patel Samarth , Bansal Raghav , Gandhi Divyangkumar , Sidhu Loveleen , Walfish Aron , Rajnish Ishita
Published: February 2017

436

Background: Limited data exists for colorectal polyps in Asian population in U.S. Advanced polyps are considered as a high risk for CRC and require close surveillance. The aim of the study was to evaluate and compare the characteristics of polyps based on patient demographics, anatomic distribution, size, and histopathology in the Asian population living in one of the most heavily populated and diverse communities in U.S. Methods: We conducted a retrospective, single center chart review study of all asymptomatic Asian patients who underwent screening colonoscopy at a New York City hospital from Jan 2006 to Dec 2010. The patients without polyps were excluded from the study. Based on histopathology and size, polyps were divided into 2 groups: advanced and non-advanced. Results: Of the total 1,300 patients, 311 were found to have colon polyps. Mean age of the study population was 60.8 years (range 50-82). There were 173 males and 138 females, with male to female ratio 1.3:1. In gender analysis, 61% of the advanced polyps were found in males, however, the difference was not statistically significant (p = 0.255). 41% of patients had right sided polyps, 49% had left sided polyps, and 10% had bilateral polyps. Analysis showed significant increase in the proportion of patients with advanced polyps on left side (65%, p < 0.05). Large size (≥ 1 cm) of the polyp correlated with advanced nature of the polyp (p < 0.0001). On pathology review of the patients with polyps, 191 had non-advanced tubular adenoma, 38 had advanced tubular adenoma, 33 had hyperplastic polyp, 35 had villous/tubulovillous, and 13 had high grade dysplasia/colorectal cancer. Only 43 out of 86 patients (49%) with advanced polyps had follow-up colonoscopy. Conclusions: Polyps located on the left side were independently associated with advanced nature of polyp. Our results also revealed that large size polyps (≥ 1 cm) were strongly associated with being advanced in nature.Vigilant approach of the left side and large lesions should be exercised during screening colonoscopy in Asian Americans. Failure of the patients to follow up could be secondary to poor access to health care, language barrier, or health care beliefs. Efforts should be made to ensure adequate follow-up for surveillance colonoscopy.
Interaction between visfatin and resistin and the risk of colorectal adenoma.
Authors: Maejima Aiko , Yamada Yasuhide , Yamaji Taiki , Honma Yoshitaka , Okita Natsuko T. , Takashima Atsuo , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro , Tsugane Shoichiro
Published: February 2017

438

Background: Colorectal adenoma is a well-established precursor lesion of colorectal cancer, so the prevention of adenoma may also contribute to the prevention of cancer. Adipocyte secretes hormones, namely adipocytokines, some of which are likely to be associated with malignancies such as colorectal, breast, and prostate gland cancer. Among several adipocytokines, resistin and visfatin have been suggested to be associated with the progression of colon cancer, and they could therefore be good biomarkers for colorectal adenoma and cancer. Methods: Prior to any procedures, healthy volunteers provided their venous blood, from which we obtained the plasma to measure concentrations of adiponectin, visfatin, and resistin. We underwent total colonoscopy, and identified 776 adenoma cases (522 males, 254 females), 734 controls (478 males, 256 females) were selected from those without adenoma. An unconditional logistic regression model was used to estimate odds ratios for colorectal adenoma after adjustment for potential confounders, including body mass index (BMI). Results: We found no positive association between the presence of colorectal adenoma and the levels of either visfatin (P trend: male 0.24, female 0.87), or resistin (P trend: male 0.85, female 0.71). After adjusting for potential confounders, we still saw no association. On the other hand, adiponectin levels showed a correlation with both BMI (P: male <0.0001, female 0.0007) and the volume of fat. Furthermore, adiponectin levels indicated no positive correlation with visfatin (P: male 0.656, female 0.1445) or resistin (P: male 0.2116, female 0.1352). Conclusions: In this study, no association was observed between visfatin/resistin levels and colorectal adenoma, and they showed no positive correlation with BMI or the volume of intra-abdominal fat. However, other confounders may account for these results, so we plan to conduct further differential analyses.
Early detection to neoadjuvant chemotherapy response in locally advanced rectal cancer using 18F-FDG PET.
Authors: Hasegawa Junichi , Nishimura Junichi , Ogawa Yoji , Kim Ho Min , Hitora Toshiki , Murakami Masahiro , Hirota Masaki , Yoshikawa Masato , Ikenaga Masakazu , Shimizu Junzo , Mikata Shoki , Miwa Hideaki
Published: February 2017

440

Background: Early detection of treatment response of neoadjuvant chemotherapy (CTx) for locally advanced rectal cancer may spare patients the toxicity of ineffective CTx. We evaluated prospectively tumor response with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the early course of preoperative CTx. Methods: A total of 15 patients with locally advanced rectal cancer (T3 or T4 and N0-N2) received neoadjuvant CTx (XELOX or XELOX+bevacizumab). Patients underwent 18F-FDG PET before CTx, at the end of first cycle of CTx (12-38 days: median 15days), and before surgical resection. Scans were interpreted using SUVmax parameter. Magnetic resonance imaging (MRI) was undergone before CTx, at the end of 2 cycles of CTx (25-54 days: median 38 days), and before resection. The tumor longest diameter was measured by MRI T2-weighted images. After resection, SUVmax and diameter were compared with the Tumor Regression Grade (TRG). Results: Of 15 patients, TRG1 was in 1 patient, TRG2 was in 5 patients, and TRG3 was in 9 patients. We divided into 2 groups, non-responder (NR) group was TRG1 and TRG2, and responder (R) group was TRG3. There was no significant difference as for clinicopathological parameters before CTx including tumor diameter and SUVmax. The tumor size before surgery was significantly smaller in R group than NR group (22.2 mm vs. 35.0 mm; p = 0.017). SUVmax in R group was significantly lower at the end of first cycle of CTx (4.9 vs. 9.3; p = 0.023), and before surgical resection (3.2 vs. 10.3; p = 0.007) than that in NR group. Conclusions: In this study, 18F-FDG PET at the end of first neoadjuvant CTx successfully predict pathological response of locally advanced rectal cancer.
Prolonged bevacizumab exposure accompanied by EGFR activation in colorectal cancer (CRC) models to provide a rational for combinations of bevacizumab and erlotinib in the GERCOR DREAM phase III trial.
Authors: Larsen Annette K. , de Gramont Aimery , André Thierry , Tournigand Christophe , Savina Ariel , Batistella Aude , Poindessous Virginie , Mésange Paul
Published: February 2017

449

Background: Combinations of EGFR and VEGF(R)-targeted agents have consistently shown at least additive activity in preclinical CRC models when the targeted agents were administered alone (Larsen et al., Pharmacol Therap. 131:80, 2011; Poindessous et al., Clin Cancer Res. 17:6522, 2011) paving the way for the GERCOR DREAM-OPTIMOX3 phase III trial in metastatic CRC. Although use of EGFR-directed mAbs are counter-indicated in CRC patients with mutant KRAS, the situation is less clear for EGFR-targeted TKIs like erlotinib. Methods: Three human CRC xenograft models expressing wt KRAS/BRAF, mutant KRAS or mutant BRAF were established in nude mice. Animals were treated with bevacizumab and erlotinib, alone or in combination, and the influence on tumor growth, viability and the presence of phosphorylated ErbB/HER family members was determined. Treatment-related toxicity was estimated by weight loss. Results: Combinations of bevacizumab and erlotinib were significantly more active than either agent alone for all three xenograft models although the advantage of combining the two agents was particularly striking for the KRAS/BRAF wt xenograft model. Unexpectedly, erlotinib alone showed strong antitumor activity in the BRAF mutant HT-29 xenograft model. The bevacizumab plus erlotinib combination was less toxic, as determined by weight loss, compared to erlotinib alone. Interestingly, IHC analysis showed that bevacizumab activates EGFR in all three xenograft models. Conclusions: We here report that bevacizumab and erlotinib combinations are significantly more active than either agent alone in CRC models with different KRAS and BRAF status. We further demonstrate that bevacizumab activates EGFR signaling similar to what has been described for irinotecan and ionizing radiation. Taken together, our findings suggest that mutant KRAS and BRAF have lesser influence on the sensitivity to EGFR-targeted TKIs than is the case for the EGFR directed mAbs and provide a mechanistic basis for the increased activity of the bevacizumab and erlotinib combination.
Integrin genetic variants and risk of thromboembolic events in patients with colorectal cancer.
Authors: Prager Gerald , Schuler Alexandra , Ay Cihan , Pausz Clemens , Lenz Heinz-Josef , Pabinger Ingrid , Zielinski Christoph
Published: February 2017

462

Background: Patients with colorectal cancer are at increased risk of venous thromboembolism (VTE). Integrin beta-3 are involved in tumor biology as well as platelet aggregation, thus, we tested as a primary endpoint whether a comprehensive panel of germline single nucleotide polymorphisms (SNPs) in the integrin beta-3 gene could predict the risk of VTE in colorectal cancer patients. Methods: The study population comprises patients recruited into the Vienna Cancer and Thrombosis Study (CATS) (Ay, C et al; JCO 2011 vol. 29 no. 15), an ongoing prospective observational cohort study initiated in October 2003 at the Medical University of Vienna. In 114 out of 139 patients diagnosed with colon cancer DNA was assessable for integrin beta-3 germline SNPs rs3809865, rs5918, rs4642 characterization. Whole blood samples were analyzed using PCR-RFLP or direct DNA-sequencing. VTE events were statistical analyzed using one-way Anova testing. Results: The patient’s demographics and tumor characteristics were balanced between groups. VTE occurred in 14 patients (12.28%). In colorectal cancer patients with an rs3809865 A/A allele profile a statistical significant (p=0.0015) increased risk of VTE events was observed as 12 (25%) of 48 patients experienced VTE. Only 2 of 52 patients (3.85%) harboring an A/T allele VTE was diagnosed. None (0%) of the T/T subgroup had any VTE. Other SNPs revealed no predictive value for VTE. In multivariable analysis including age, sex, chemotherapy, and anti-VEGF therapy rs3809865 A/A allele profile remained a statistical significant risk factor for VTE. Conclusions: This study identifies germline polymorphisms in integrin genes as independent prognostic markers for VTE in colorectal cancer. These data may help to select subgroups of patients who may benefit from an enforced prophylaxis of venous thromboembolism (VTE).
Changes in expression levels of excision repair cross-complementing group 1 (ERCC1) and dihydropyrimidine dehydrogenase (DPD) after first-line oxaliplatin-based chemotherapy for metastatic colorectal cancer: Results of a multicenter study.
Authors: Baba Hideo , Baba Yoshifumi , Uemoto Shinji , Oki Eiji , Ikeda Yasuharu , Yamamoto Masakazu , Matsuda Hiroyuki , Shimada Mitsuo , Kokudo Norihiro
Published: February 2017

463

Background: Our previous single-center study showed that expression levels of ERCC1 (a nucleotide excision repair pathway gene) and DPD (a pyrimidine catabolic pathway gene) in liver metastases from colorectal cancers (CRCs) were significantly higher in patients given oxaliplatin as first-line chemotherapy than those not given oxaliplatin. We conducted this multicenter study to validate our findings and better define a basic rationale for second-line therapy for metastatic CRC resistant to first-line therapy. Methods: Irinotecan-naive patients with mCRC (n = 190) were enrolled at 17 sites in Japan. Resected liver metastases were available for 91 patients who had received FOLFOX (or FOLFOX plus bevacizumab; FOLFOX group) and 99 who had not received oxaliplatin-based chemotherapy (non-oxaliplatin group). We measured mRNA expression levels of ERCC1 and DPD by real-time RT-PCR. Protein expression levels of ERCC1 and DPD were evaluated immunohistochemically. The methylation level of the long interspersed nucleotide element-1 (LINE-1; a surrogate m arker of global DNA methylation) was determined by pyrosequencing. Results: The median age at liver resection was 64 years (range, 32–89). Baseline features (e.g., sex, histology) were similar in the groups. Expression levels of DPD at the mRNA and protein levels were significantly higher in the FOLFOX group than in the non-oxaliplatin group (p < 0.05). The mRNA expression level of ERCC1 was slightly, but not significantly higher in the FOLFOX group than in the non-oxaliplatin group (p = 0.053). Interestingly, ERCC1 expression levels correlated with DPD expression levels (r = 0.38, p< 0.0001). LINE-1 methylation levels were similar in the groups. Conclusions: This multicenter study confirmed increased expression levels of DPD after first-line oxaliplatin-based chemotherapy, which may affect chemosensitivity to subsequent therapy. ERCC1 expression and epigenetic control by mechanisms such as aberrant promoter methylation of specific genes warrant further investigation.
Regulation of STAT3 activity by DARPP-32 in gastric cancer.
Authors: Chen Zheng , Zhu Shoumin , Soutto Mohammed , Hong Jun , Belkhiri Abbes , Zaika Alexander , El-Rifai Wael
Published: February 2017

47

Background: Dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) and its truncated form (t-DARPP) are overexpressed in two-thirds of gastric adenocarcinomas. STAT3 is a member of STAT family. It mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects. The relationship and interaction between DARPP-32 and STAT3 remain unknown. Methods: DARPP-32 was stable or transient overexpressed in gastric cancer cell lines. STAT3 expression and transcriptional activity were investigated by immunofluorescence and STAT3 luciferase reporter assay. DARPP-32 mRNA level was detected in 63 gastric cancer samples. Results: Using stable and transient expression of DARPP-32 and t-DARPP in AGS gastric cancer cell line, lacking endogenous DARPP-32, led to a significant increase of the phosphorylation of STAT3 as compared to empty vector control. Consistent with these findings, immunofluorescence assay also showed the up-regulation of nuclear p-STAT3 in AGS cells following transient expression of DARPP-32, as compared to empty vector control. Using the STAT3 luciferase reporter assay, AGS cells with stable overexpression of DARPP-32 showed higher luciferase activity than empty vector stable cells with and without IL-6 stimulate (p<0.01). Using qPCR in 63 gastric cancers, we found that DARPP-32 is frequently overexpressed in gastric cancer samples (p=0.018). We have also shown that DARPP-32 has a progressive increase in expression from normal to metaplasia, dysplasia, and adenocarcinoma (p<0.001). The relationship between DARPP-32 and STAT3 in these tissues will be examined. Conclusions: Our results suggest that DARPP-32 overexpression may participate in regulating the STAT3 phosphorylation and activating STAT3 signaling pathway in gastric cancer. The precise signaling mechanisms that mediate this activation and its functional impact on gastric tumorigenesis are under investigation.
BRAF and KRAS mutations in liver-resected metastatic colorectal cancer (mCRC) patients (pts).
Authors: Bergamo Francesca , Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Casagrande Mariaelena , Lonardi Sara , Aprile Giuseppe , Marmorino Federica , Salvatore Lisa , Antoniotti Carlotta , Sensi Elisa , Lupi Cristiana , De Maglio Giovanna , Bertorelle Roberta , Galiano Antonella , Griguolo Gaia , Balistreri Mariangela , Fontanini Gabriella , Zagonel Vittorina , Falcone Alfredo
Published: February 2017

476

Background: Up today there are no molecular markers to identify mCRC pts candidate to curative liver surgery at high risk of relapse. There are conflicting results about the prognostic role of KRAS mutation in mCRC pts, while BRAF mutation is a well-known negative prognostic factor characterizing a subgroup of mCRCs with a distinct metastatic spread. We analyzed the impact of BRAF and KRAS mutations on relapse free-survival (RFS) and overall survival (OS) in pts undergoing liver resection with curative intent. Methods: Medical records of pts referred to 3 Italian institutions between 1995 and 2012 were reviewed. 3024 mCRC pts were identified. 401 pts (13.3%) underwent liver resection with curative intent and had adequate follow-up. Mutational status was assessable on 360 samples from primary tumors (n=63), metastases (mts) (n=59) or both (n=238). Primary objective was to evaluate the impact of BRAF mutation on RFS in mCRC pts candidate to liver resection. Secondary objectives were to evaluate the prognostic role of BRAF status on OS, and of KRAS status on RFS and OS in this population. Results: BRAF and KRAS were mutated in 11 (3%) and 116 (32%) out of 360 cases respectively. In 238 cases in which paired samples from primary and metastases were available, no discordance was found in BRAF status while 18 cases (7.6%) showed a discrepancy in KRAS status and were thus excluded from analysis. Pts with BRAF mutation had significantly shorter median RFS compared to pts with BRAF wt tumor (5.7 mos vs 11.7 mos, HR=4.25; 95%CI: 1.52-11.88, p=0.005). OS was significantly reduced in pts with BRAF mutated tumors vs wt (HR=5.39; 95%CI: 1.59-18.27, p=0.007). Mutated KRAS was not prognostic for RFS (HR=1.14; 95%CI: 0.87-1.49, p=0.34), while demonstrated a weak prognostic impact on OS (HR=1.52; 95%CI: 1.05-2.21, p=0.03). In this cohort high-risk Fong score were significantly associated with shorter RFS (p<0.0001) and OS (p<0.0001). Conclusions: BRAF mutation is associated with higher probability of relapse and worse outcome in liver resected mCRC. KRAS mutation was not associated with RFS after liver resection. BRAF mutational status may become a new prognostic marker when planning liver resection in mCRC pts.
Safety and antitumor activity of selinexor (KPT-330), a first-in-class, oral XPO1 selective inhibitor of nuclear export: A phase I study expanded with colon cancer cohort.
Authors: Mau-Soerensen Morten , Razak Albiruni R. A. , Mahipal Amit , Mahaseth Hemchandra , Gerecitano John F. , Shacham Sharon , Yau Cindy Y. F. , Lassen Ulrik , Shields Anthony Frank , McCauley Dilara , Cooksey Jennifer , Tan David Shao Peng , Rashal Tami , Shacham Eran , Landesman Yosef , Pond Gregory , Oza Amit M. , Kauffman Michael , Siu Lillian , Mirza Mansoor Raza
Published: February 2017

482

Background: Tumor suppressor proteins (TSPs) are inactivated by their export from the nucleus by Exportin1 (XPO1/CRM1). The oral selective inhibitor of nuclear export selinexor (KPT-330)restores the nuclear localization and function of TSPs and shows a broad anti-tumor activity in animal models. Here we report on the treatment of a subset of patients (pts) with metastatic colorectal cancer (CRC) in a phase I trial of selinexor. Methods: Objectives were to determine the recommended phase 2 dose, evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response (RECIST 1.1) of selinexor administered in two different schedules with 8 or 10 doses in a 28-day cycle. An expansion cohort of 15 pts with CRC was planned. Results: Twenty-seven pts with CRC were treated across eight doses (3-40 mg/m2) including 15 pts in the expansion cohort (30-35 mg/m2). Median age was 61 yrs and median number of prior regimens was 4. MTD of the 10-dose schedule was 30 mg/m2. MTD for the 8-dose schedule has not been reached. Thirteen pts experienced drug related gr 3-4 adverse events (AEs) including fatigue (n = 6), hyponatremia (n = 5), thrombocytopenia (n = 3), anorexia (n = 3), dehydration (n = 2), anemia (n = 2), hyperglycemia (n = 1), pulmonary embolism (n = 1), and hypotension (n = 1). The most common gr 1-2 drug related AEs were nausea (74 %), anorexia (67 %), fatigue (67 %), vomiting (59 %), dysgeusia (52 %), and weight loss (48 %). Cmax increased with dose to ≈ 1.4 µM with T½ of 4.0 – 7.4 hrs. Significant increases (2-20x) in PD marker XPO1 mRNA in circulating leukocytes were observed at all doses. Analysis of tumor biopsies confirmed nuclear localization of TSPs and induction of apoptosis following selinexor. CEA decreased in 4 of 12 pts. One pt had a partial response at 23 mg/m2, 6 patients had stable disease ≥8 weeks, and 3 patients had stable disease ≥24 weeks in 25 evaluable pts Conclusions: Preliminary signals of antitumor activity in CRC pts were observed. Selinexor is generally well tolerated and prolonged drug exposure is feasible. Selinexor induces Exportin in leucocytes and apoptosis in tumor biopsies with restoration of the nuclear location of TSPs. Clinical trial information: NCT01607905.
Effect of nintedanib, a triple angiokinase inhibitor, on EGFR and HER2 in colorectal cancer (CRC) models, and rational for its combinations with the ErbB family blocker afatinib.
Authors: Larsen Annette K. , de Gramont Aimery , Batistella Aude , Afchain Arnaud , Mésange Paul , Poindessous Virginie
Published: February 2017

485

Background: We have recently shown that combinations of afatinib, a pan-HER/ErbB blocker, and nintedanib, a triple angiokinase (VEGFR, FGFR, PDGFR) inhibitor show synergistic activity in CRC models (Poindessous et al., Clin Cancer Res. 17:6522, 2011). However, the mechanistic basis for the synergistic effects of the combination is incompletely understood. EGFR is activated following exposure to a wide variety of therapeutic modalities including ionizing irradiation and irinotecan. We speculated that nintedanib exposure could also activate EGFR signaling which might explain the synergistic activity of the combination. Methods: Mice with human CRC xenografts were treated with nintedanib and afatinib alone or in combination and the influence on tumor growth, viability and the presence of phosphorylated HER family members was determined. Different scheduling regimens were explored to identify an administration schedule which combined optimal antitumor activity with minimal toxic side effects. Results: We here show that nintedanib treatment results in activation of EGFR and HER2 in multiple CRC xenograft models in a dose-dependent manner. Among the different regimens tested, continuous nintedanib with administration of afatinib every second week proved almost as efficient as continuous administration of the two agents together and was less toxic. Finally, nintedanib plus afatinib was superior to nintedanib alone in three different tumor xenografts with mutant KRAS. Conclusions: We here report that prolonged exposure to nintedanib, a small molecule angiogenesis inhibitor, is accompanied by activation of EGFR and HER2. Accordingly, afatinib, an ErbB family blocker, was synergistic with nintedanib. We subsequently identified a novel regimen for optimizing the antitumor effects of the combination with limited toxic side effects and showed that this regimen is active in four different CRC tumor models including three with mutant KRAS. These findings provide a rationale for clinical trials of the two small molecules, even in patients with mutant KRAS.
RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).
Authors: Sclafani Francesco , Gonzalez David , Cunningham David , Hullki Wilson Sanna , Peckitt Clare , Tabernero Josep , Glimelius Bengt , Cervantes Andres , Wotherspoon Andrew , Brown Gina , Tait Diana M. , Oates Jacqueline Rose , Chau Ian
Published: February 2017

489

Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.
Quantitative analysis of the impact of deepness of response on survival time following patients with metastatic colorectal cancer treated by chemotherapy and anti-EGFR monoclonal antibodies.
Authors: Osumi Hiroki , Matsusaka Satoshi , Suenaga Mitsukuni , Wakatsuki Takeru , Ogura Mariko , Ozaka Masato , Shinozaki Eiji , Chin Keisho , Mizunuma Nobuyuki
Published: February 2017

493

Background: "Deepness of response" (DpR) is a new efficacy outcome measure that could explain the impact of tumor shrinkage on long-term survival outcome. In FIRE-3 trial, OS was significantly longer in patients (pts) treated with FOLFIR plus cetuximab compared with pts who received FOLFIRI plus bevacizumab. One reason was that first-line treatment with Cetximab have a DpR, so it takes a lot of time to grow tumors. The aim of the present analysis was to evaluate OS, PFS, pathological grade and DpR for pts with mCRC treated with anti EGFR antibody+FOLFOX or FOLFIRI. Methods: A total of 100 pts with histopathologically confirmed mCRC treated with first-line chemotherapy in combination with anti-EGFR antibody and second-line chemotherapy with cetximab were enrolled between October 2008 and June 2013. First, we compare DpR for pts with first-line chemotherapy+anti EGFR antibody and second-line chemotherapy+cetximab. Second, we analyzed DpR and pathological grade for 32 pts performed conversion surgery. Third, we compare OS, PFS and DpR for 43 pts treaded with second-line chemotherapy+Cetximab. Results: The 38 (26) pts treated with FOLFOX+cetximab (panitumumab) had a mean DpR of 44.9 (51.4)% (Interquartile range [IR]:36.6 (39.8)%, 60.97 (64.65)%), minimum DpR -45.2 (0)%. The 43 pts treated with second-line FOLFIRI + Cetximab had a mean DpR of 10% (IR:-7.8%, 30.9%) and a minimum DpR of -158%. The DpR wans’t different between first-line FOLFOX+cetximab and panitumumab. But the DpR was significantly different between first-line FOLFOX+cetximab and second-line FOLFIRI+cetximab. Tumor regression grades 0 after preoperative. FOLFOX+cetximab (panitumumab) had a mean DpR of 61.3 (0)%, grade 1 had a mean DpR of 50.83 (56.14)%, grade 2 had a mean DpR of 54.91 (40.5)% and grade 3 had a mean DpR of 58.5 (76)%. Individual DpR of the pts treated with FOLFIRI+cetximab is a significant prognostic factor for survival time (OS and PFS) in the Longest diameter-based models (PFS:p=0.006 OS:p=0.01). Conclusions: Our results emphasize the value of the variable DpR as a new efficacy outcome measure and the DpR was shown to be associated with its ability to prolong OS and PFS.
MSI versus MSS sporadic colorectal cancers: Morphology, inflammation, and angiogenesis revisited.
Authors: Sagaert Xavier , Van Cutsem Eric , Tejpar Sabine , Prenen Hans , De Hertogh Gert
Published: February 2017

495

Background: MSI is a well-documented pathway in the pathogenesis of colorectal cancer. A specific cphenotype has been associated with MSI tumors, as they tend to be more right-sided, have a better prognosis, mostly display a poor histologic differentiation and are marked by extensive inflammation. However, the biological basis and of all these features is still largely unknown. We hypothesize that MSI results in an accumulation of intratumoral mutations. Consequencely, lots of aberrant proteins are formed, probably resulting in a poor histologic differentiation but also evoking a strong immune response that may have the ability to limit tumor expansion (hence explaining a better prognosis) and to stimulate angiogenesis. Methods: To sustain this hypothesis we compared 35 MSI and 35 MSS tumors (matching for TNM staging) with respect to their morphology, inflammation and vessel density. Morphology was analyzed on HE stains. Immunohistochemical stainings for CD 3, CD4, CD8, CD20 and CD68 were performed to document the number of T-lymphocytes, B-lymphocytes and macrophages in relation to tumor location (intraepithelial, intratumoral, peritumoral). CD 31 staining was performed to highlight vessel density in the tumor and assess angiogenesis. Conclusions: (1) In accordance with literature, MSI tumors occured at younger age, with preponderance of the right colon and with a smaller likelihood of metastasis. (2) The most striking observation was the higher number of intra-epithelial T-lymphocytes in MSI tumors (not present in their microsatellite stable counterparts). No difference was found between MSI and MSS tumors in terms of intra/peritumoral B-cells, macrophages, and/or T-cells. (3) Half of the MSI tumors and none of the MSS tumors displayed different histological subtypes/patterns within one tumor. As such, we suggest that in daily routine practice, presence of morphologic tumor heterogeneity should initiate analysis for microsatellite instability. (4) MSI tumors had a statistically much higher (micro)vessel density as compared to their MSS counterparts, hence hinting at a potential application of anti-VEGF therapy in this subgroup of colorectal cancers.
Molecular and clinical prognostic factors in metastatic colorectal cancer (CRC) patients (pts): A retrospective study.
Authors: Foltran Luisa , Ermacora Paola , Pella Nicoletta , Aprile Giuseppe , De Maglio Giovanna , Masiero Elena , Giangreco Manuela , Lutrino Stefania Eufemia , Ferrari Laura , Casagrande Mariaelena , Pizzolitto Stefano , Fasola Gianpiero
Published: February 2017

511

Background: Strong evidence is emerging about the usefulness of mutational profiling for CRC pts. This study aimed to evaluate the overall survival in three molecular groups, taking as reference the all-wild type category: (1) BRAF mutated; (2) KRAS mutated codons 12-13 only; (3) any of KRAS codons 61-146, PIK3CA exon 9-20 or NRAS cod 12-13-61 mutations. Also clinical variables were investigated as potential prognostic factors. Methods: Data of 194 consecutive pts treated for metastatic colorectal cancer (mCRC) at our University Hospital in Udine, Italy, between Jan 2004 and Jan 2013 were reviewed. Point mutations were detected by pyrosequencing platform PyroMark Q96 ID instrument for KRAS/NRAS codons 12, 13, 61, and 146, BRAF exon 15, and PIK3CA exons 9 and 20. Clinical and molecular prognostic factors were identified using the Cox proportional hazards model. Results: The all wild-type population consisted of 76 pts (39%). 62 cases (32%) harboured mutations in KRAS codons 12-13. BRAF V600E mutation was found in 10 (5.2%) samples. Mutations in KRAS 61-146, PIK3CA and NRAS codons were detected in 9 (4.6%), 32 (16.5%) and 6 (3.1%) pts, respectively. All factors significant in univariate analysis were subjected to multivariate analysis (see Table). The all-wild type category had the longest survival (27.7 months). Patients carrying BRAF mutations reported an overall survival of 7.6 months and those with KRAS 12-13 mutation 16.7 months. Conclusions: This study reinforces the prognostic value of a full mutational molecular profile and points out some prognostic clinical factors in CRC. The influence of clinical variables such as right colon cancer, primary tumour not resected, exposure to bevacizumab and lines of chemotherapy need further investigation. [Table: see text]
Serum levels of vascular endothelial growth factor in patients with gastrointestinal cancers and correlation with malnutrition, immunosuppression involving MDSC, and systemic inflammation.
Authors: Gonda Kenji , Shibata Masahiko , Suzuki Satoshi , Nakamura Izumi , Kumamoto Kensuke , Shimura Tatsuo , Takenoshita Seiichi
Published: February 2017

514

Background: Vascular endothelial growth factor (VEGF) reportedly plays an important role in the progression of malignant neoplasms, and have been reported to induce myeloid-derived suppressor cells (MDSC) that appears in cancer and inflammation. Methods: Blood samples were collected from 57 patients, including 8 with esophageal cancer, 20 with gastric cancer, 29 with colorectal cancer, and from 18 healthy volunteers. We measured serum concentrations of VEGF and analyzed correlations with nutritional damage, immune suppression and systemic inflammation. As markers of immune function, IL-12 production of PBMC and MDSC (CD 11b+, CD14-, CD33+) were measured. Serum concentrations of albumin and rapid turnover protein were measured as a marker of nutritional status. Results: A significant increase in serum levels was seen in patients with esophageal, gastric, and colorectal cancers compared to healthy volunteers. Levels of VEGF were inversely correlated with serum concentrations of albumin, prealbumin and retinol-binding protein. Serum concentrations of VEGF were inversely correlated with the production of interleukin (IL)-12 and correlated with MDSC. VEGF levels also correlated with neutrophil count and neutrophil/lymphocyte count, and correlated inversely with lymphocyte count. Serum VEGF levels were then divided about a cutoff of 500 pg/ml, with levels of prealbumin and retinol-binding protein significantly decreased in patients with higher VEGF levels. Stimulation index and IL-12 production were significantly decreased in the group with higher VEGF levels, and MDSC counts tended to be higher in this group. Conclusions: These results demonstrated that increased production of VEGF correlated with systemic inflammation, nutritional impairment and inhibition of cell-mediated immunity involving MDSCs. An inactivation of dendritic cells may be occurring by the activation of MDSC. Anti-VEGF therapy may be of importance in treating digestive system cancers.
TFAP2E methylation status in patients with metastatic colorectal cancer treated with FOLFIRI.
Authors: Park Seong Joon , Kim Seung-mi , Hong Yong Sang , Lee Jae-Lyun , Kim Jeong-Eun , Kim Kyu-Pyo , Jin Dong-Hoon , Kim Tae Won
Published: February 2017

515

Background: Transcription factor AP-2ε, a member of the AP-2 family has been extensively studied in many cancers. Recently, it has been suggested that the gene encoding AP-2ε (TFAP2E) is involved in the development of colorectal cancer (CRC) and is also associated with clinical non-responsiveness to chemotherapy in CRCs. Therefore, we have investigated the clinical significance of TFAP2E methylation status in patients with metastatic CRCs who have received combination chemotherapy with fluoropyrimidine, leucovorin, and irinotecan (FOLFIRI) as first-line treatment. Methods: Eligible patients were those with metastatic CRC treated at Asan Medical center from Jan 2009 to June 2012, and treated with first-line FOLFIRI chemotherapy. The patients without available surgical tissue were excluded. A total of 94 patients were finally included in the study. Results: Forty patients (43%) showed TFAP2E hypermethylation (HM group), and 54 patients (57%) showed TFAP2E hypomethylation (LM group). There were no statistically significant differences in the baseline characteristics according to TFAF2E methylation status. Response rate to chemotherapy was not significantly different between 2 groups (response rate, 50% in HM vs. 36% in LM group, p=0.200; disease control rate, 87% in HM vs. 85% in LM group, p=0.819). After a median follow-up duration of 39.9 months, both progression-free survival (PFS) and overall survival (OS) were not significantly different between 2 groups (HM group vs. LM group; PFS, 5.93 months vs. 5.90 months, p=0.893; OS, 20.9 months vs. 19.8 months, p=0.966). Multivariate analysis showed that there was no significant factor associated with PFS. The patients with well or moderately differentiated tumors showed better OS compared to those with poorly differentiated or mucinous tumors (hazard ratio 0.27, 95% confidence interval 0.13-0.55, p<0.001). However, TFAP2E methylation status was not an independent factor affecting neither PFS nor OS. Conclusions: TFAP2E methylation status may not be a useful biomarker in predicting the clinical outcomes in patients with metastatic colorectal cancers who have received first-line FOLFIRI chemotherapy.
UGT1A1*28 polymorphism in advanced colorectal cancer: The story is not yet ended.
Authors: El Bastawisy Ahmed El Saied , El-Zeiny Amany , Farid Samar , Bahnasy Abeer
Published: February 2017

516

Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, this study tried to investigate correlation with other toxicities like vomiting. Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, group 1—patients with no mutation, group 2—patients with homo or hetero mutation. All patients received standard IFL regimen. Primary endpoints were (1) comparison between the 2 groups as regard vomiting (2) assessement of the incidence of UGT1A1*28 polymorphism. Secondary endpoints were comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS), and overall survival (OS). Results: 46 cases of advanced colorectal cancer presenting to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%) of them 15% are homozygous. Grade (2-4) vomiting was found in 8.3 % of group 1 versus 52.5 % of group 2. (p = 0.01). Grade (2-4) neutropenia were found in 20.8 % of group 1 versus 64.7 % of group2. (p = 0.03). Grade (2-4) diarrhea was found in 37.5 % of patients of group 1 and 27.5% of patients with group 2. (p = 0.75). Treatment delay occurred in 29.16 % of group 1 versus 72.4 % of group 2. (p = 0.02). 25% of group 1 showed PD versus 25 % of group 2. (p = 0.8). 1 year PFS was 19% in group 1 versus 23 % in group 2. (p = 0.8) while there was a trend towards better OS in group 1 (47 % versus % 35). (p = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.