bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT).
Authors: Townsend Amanda Rose , Pirc Louise , Cooper Pamela , Tebbutt Niall C. , Karapetis Christos Stelios , Singhal Nimit , Price Timothy Jay 
Published: March 2020

e14506 Background: The mammalian target of rapamycin (mTOR) is a key downstream protein activated via PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This is a phase Ib study to determine the maximum tolerated dose (MTD) of the PIE combination. Methods: Patients with KRAS WT mCRC following failure of first line fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. Dose finding used a standard 3+3 design with the MTD defined as the dose with dose limiting toxicity (DLT) in ≤1/6 patients. A DLT is any of the following in the first 28 days; febrile neutropenia, G3/G4 neutropenia > 14 days, any G4 thrombocytopenia, any non-haematologic event of G4 or of G3 for >7 days, treatment delays of >14 days. Dose level 1; irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose level 2; irinotecan 200mg/m2, panitumumab 6mg/kg, and everolimus 5mg daily. Results: 15 patients have been enrolled into the study, 2 withdrew prior to receiving any therapy. Five patients were enrolled at dose level 1. Two patients were not evaluable. Of the three evaluable patients there was no DLT. Three patients were then treated at dose level 2. Following one DLT (grade 3 mucositis >7 days), the cohort was expanded to 5 evaluable patients but suspended after a further DLT (grade 3 mucositis > 7 days). Other grade 3 toxicities were anorexia, rash, vomiting, and hypersensitivity. There were no grade 4 toxicities. Dose level 1 was expanded by 3, to a total of 6 evaluable patients. Grade 3 toxicities were mucositis (17%), fatigue (17%), diarrhoea (33%), rash (17%), hypomagnesemia (17%), and neutropenia (17%). There was no DLT. Conclusions: Dose level 2 exceeded the MTD. Dose level 1 appears tolerable and warrants further investigation. The phase II component of the study is ongoing. Clinical trial information: NCT01139138.
Effect of neoadjuvant chemotherapy in patients with resectable colorectal liver metastases.
Authors: Xu Jianmin , Zhu Dexiang , Zhong Yunshi 
Published: March 2020

e14523 Background: Whether patients with resectable colorectal liver metastases (CRLM) receive a survival benefit from neoadjuvant chemotherapy prior to hepatectomy remains controversial. Methods: We retrospectively analyzed 466 consecutive patients with resectable CRLM between 2000 and 2010. Patient and tumor characteristics, surgical procedure and survival data were recorded. Results: The patients were divided into two groups: one group with neoadjuvant chemotherapy (group NC, n=121) and one group without (group WN, n=345). There was no significant difference in the median survival (60.0 m vs. 53.9 m) or 5-year survival (52% vs. 48%) between the two groups. No significant differences were identified between the two groups in terms of 30-day mortality (1.7% vs. 1.2%) or morbidity (33.9% vs. 25.8%). A primary tumor at stage T4, ≥ 4 liver metastases, the largest liver metastasis ≥ 5 cm in diameter, and a serum CEA level ≥ 5 ng/ml were independent prognostic factors for the surgical patients. By assigning one point to each of above factors, all of the patients were divided into a low-risk group (0-2) and a high-risk (3-4). The patients in the low-risk group received no survival benefit from neoadjuvant chemotherapy, whereas those in the high-risk group received a survival benefit (median survival, 38.9 m vs. 28.4 m; 5-year survival, 39% vs. 33%, P=0.028). Conclusions: Preoperative neoadjuvant chemotherapy did not significantly increase mortality or complications. Not all resectable patients (only those with more than 2 independent risk factors) receive a survival benefit from neoadjuvant chemotherapy.
Accuracy of Wif1 methylated gene test and microbial changes identifying colorectal cancer.
Authors: Sobhani Iradj , Mansour Hicham , Furet Jean Pierre , Belkacemi Yazid , Langella Philippe , Aparicio Thomas , Tournigand Christophe , Canoui-Poitrine Florence ,   Val de Marne Oncology Group CCR and CICs
Published: March 2020

e14525 Background: Faecal blood test (FOBT) is recommended for CRC screening. However, it had fair sensitivity and specificity (both around 50%). CRC results from genetic and epigenetic alterations involving Wnt pathway. Environmental factors can methylate Wnt inhibitory factor1 (Wif1). Colon microbiota dysbiosis, consequence of environment, is also associated with CRC. The aim was to assess the diagnosis accuracies of dysbiosis, methylated genes and FOBT for identifying CRC versus colonoscopy. Methods: A cross-sectional study included subjects referred (2003 up to 2007) for colonoscopy. Clinical factors (age, gender, personal/familial history of cancer, BMI, diabetes, and treatments) were recorded. Effluents (fresh stools, sera-S and urines-U) were harvested prior to colonoscopy and FOBT was performed. Seven dominant and subdominant bacterial populations in stools and methylation genes’ (Wif1, ALX4, and vimentin) levels in stools, S and U were quantified using qPCR. Gene markers (Kras mutations, Bat25, Bat 26) have been detected in tissues and stools. Calibration was assessed by Hosmer-Lemeshow chisquare and discrimination by Area Under ROC curve (AUC). Results: 247 patients were included (mean age 60.8, 52% men). Colonoscopy and pathology identified 90 pts with CRC (n=66) or large adenomas (>10 cm). Wif1 was the more sensitive gene marker. A multivariate model adjusted for age, gender, previous personal/familial history of polyps/cancer leaded to AUC of 81.5% (95%CI: 75.7-87.4). After supplementary adjustment in different models, for dysbiosis, AUC increased to 83.4% (77.9-88.9) (bacteroides and leptum levels) (p= 0.08), to 84.9% (79.6-90.3) (p=0.02) after adjustment for FOBT, to 90.1% (85.8-94.4) (p<0.001) after adjustment for Wif1 (S or U). When adjusted jointly for clinical parameters, FOBT, dysbiosis and Wif1, FOBT and wif1 remained independently associated with CRC whereas dysbiosis were not. However, the AUC of the full-adjusted multivariate model did not increase significantly (91.7; 87.8-95.6; p=0.075). Conclusions: Wif1 methylated marker in S or U improved diagnosis accuracy for identifying CRC compared to FOBT while microbial changes in dominant or subdominant bacteria populations did not.
Comparison of circulating tumor cells (CTC) and disseminated tumor cells (DTC) in patients with colorectal carcinoma for a predictive marker for tumor recurrence.
Authors: Sakihama Hideyasu , Kobayashi Nozomi , Minagawa Nozomi , Shimokuni Tatsushi , Homma Shigenori , Takahashi Norihiko , Kamiyama Toshiya , Taketomi Akinobu 
Published: March 2020

e14548 Background: Although the presence of CTC or DTC is proposed as a pridictive or a prognostic marker in the management of colorectal carcinoma patients, it is still well unknown what is different of both types of cells. The aim of this study is to compare CTC and DTC as a predictive marker for tumor recurrence by magnetic activated cell sorting system. Methods: Peripheral blood (PB) samples (n=139) and bone marrow (BM) samples (n=41) were preoperatively collected from colorectal carcinoma patients between February 2009 and March 2012. PB samples were obtainable from all patients who provided their BM samples (n=41). Enrichment of CTC was performed by direct immunomagnetic labeling of EpCAM + cells in PB. Enrichment of DTC was done by negative selection of CD45+cells. Subsequently, double immunofluorescences staining for cytokeratin and CD45 was performed to detect CTC or DTC. PB samples from 20 healthy volunteers and BM samples from 3 patients with benign disease were used as controls. Median follow-up time is 28.5 months (range 10-44). Written informed consent was obtained from all enrolled patients. Results: Preoperative positive rates of CTC and DTC were 20.9% (29/139) and 29.3% (12/41), respectively. No CTC or DTC was found in the control groups. In DTC+patients, only 4 patients were positive for CTC (33.3%), whereas 31% of DTC- patients had CTC. We found 13 patients who experienced postoperative recurrence among 139 patients, 7 patients of whom were CTC positive (53.8%). There is a significant higher incidence of recurrence in CTC+patients (risk ratio=4.4, p<0.01). As for DTC, we found 5 patients with recurrence in 41 patients, 4 patients of whom were DTC positive (80%). DTC+ patients have a significant risk of recurrence (risk ratio=9.7, p=0.01). The relationship of CTC / DTC status and the recurrence rates is as follows: 50 % in CTC+/DTC+ patients (2/4); 11.1% in CTC+/DTC- patients (1/9); 25% in CTC-/DTC+ patients (2/8); 0% in CTC-/DTC-patients (0/20). Conclusions: DTC status is more predictive for postoperative recurrence than CTC status. The combination of CTC and DTC analysis might predict recurrence risk more accurately than either of the two analyses.
Safety and efficacy of the addition of simvastatin to panitumumab in KRAS mutant metastatic colorectal cancer patients.
Authors: Guchelaar Henk-jan , Baas Jara M , Krens Lisanne , Bos Monique M.E.M. , Portielje Johanna Elisabeth A. , Batman Erdogan , Gelderblom Hans 
Published: March 2020

e14558 Background: Epithelial growth factor receptor (EGFR) inhibitors are not effective in KRAS mutant colorectal tumors. In these tumors the k-ras protein is activated by post-translational modification by binding farnesyl (C15) and geranylgeranyl (C17) moieties. Both are products of the mevalonate pathway, as is cholesterol. Statins (HMG-CoA-reductase inhibitors) not only inhibit synthesis of cholesterol, but also of C15 and C17 and thus may relevantly inhibit post-translational activation of ras proteins. Therefore, statins may inhibit the expression of the mutant KRAS phenotype and normalize the phenotype into KRAS wild type. In a phase II study we investigated whether simvastatin treatment renders KRAS mutant colorectal tumors sensitive to panitumumab. Methods: Major eligibility criteria were advanced or metastatic colorectal cancer failing prior 5FU, oxaliplatin and irinotecan containing regimens, with a mutation in codon 12, 13 or 61 of KRAS gene on tumor sample. Patients were treated with simvastatin 80mg once daily and panitumumab 6mg/kg every 2 weeks. Primary objective was to investigate the percentage of patients free from progression and alive 11 weeks after the first administration of panitumumab. This phase II study was performed in a Simon two stage design, performing an interim analysis after the enrolment of 15 patients. When at least 6 of these patients (i.e. 40%) were to be alive and free from progression free at 11 weeks after the first administration of panitumumab (similar to the results of the KRAS wild type population of the phase III study), another 31 patients would be included during stage 2. Results: Fifteen evaluable patients were enrolled by 4 study sites. Only one patient was free from progression 11 weeks after start of panitumumab treatment (6.7%). Mean progression free survival was 9.1 weeks (range 5-17 weeks). Most frequent reported side effect was skin toxicity (40%), one patient experienced myositis grade 3. Conclusions: Simvastatin 80mg once daily was not able to inhibit the KRAS mutant phenotype sufficiently to reach sensitivity to panitumumab in colorectal cancer patients with a mutation in the KRAS gene. Clinical trial information: NCT01110785.
Microarray gene expression study of the RESPECT trial for the identification of prognostic and predictive markers.
Authors: Delorenzi Mauro , Gerster Sarah , Tabernero Josep , Köhne Claus-Henning , O'Dwyer Peter J. , Sobrero Alberto F. , van Cutsem Eric , Garcia-Carbonero Rocio , Salazar Ramon , Rivera Fernando , Samuel Leslie M. , Potter Vanessa Alice , Chang Yu-Lin , Lokker Nathalie Andrienne , Tejpar Sabine 
Published: March 2020

e14561 Background: The RESPECT trial (n = 198) tested the addition of Sorafenib to standard mFOLFOX6 treatment in first line metastatic colorectal cancer (mCRC) patients but resulted in no statistical significant improvement in progression free survival, and no evidence for overall benefit. Sorafenib inhibits several Raf kinases (including B-Raf). Samples with high BRAF-mutant-like score were previously shown to identify a subset of colon tumors with a similar biology and outcome to BRAF mutant patients (Popovici et al. J. Clin. Oncol., 30(12):1288–95, 2012). Methods: A subset of 125 patients from the trial was available for gene expression analysis from their primary tumor FFPE samples, using the Colon DSA gene expression arrays from Almac. Mutation status for KRAS and BRAF was previously assessed. The potential prognostic and/or predictive effect of a high BRAF-mutant-like score was assessed. The analyses were performed using Cox proportional hazards regression models and Kaplan-Meier curves. The logrank test was used to compare the survival distributions (significance level: 5%). Results: Molecular profiling was performed on FFPE tissue samples from primary tumors of 125 mCRC patients, 95 samples (47 in the combined arm; 3 BRAF mutants) were successfully processed. Limitations in amount of material available in this retrospective analysis led to failure to reach the required RNA amount for amplification in 30 samples (dropout rate = 24%). The collected gene expression data was of good quality: all 95 array profiles could be used (10 were flagged for slightly inferior quality). The BRAF-mutant-like score was recognized as marker of poor OS in a Cox regression model (HR = 1.55 [95% CI: 1.12 - 2.13], 1 unit = 1 IQR, P = 0.007). The HR difference between the two arms (combined arm: HR = 1.36; reference arm: HR = 1.41) is not significant. Conclusions: The poor survival of metastatic colorectal cancer patients with a BRAF-mutated-like tumor is confirmed, but no predictive effect was found. FFPE tissues are well-suited for this kind of study and allow to accurately test the hypotheses of interest. Further analyses are planned to generate hypotheses about markers of sensitivity to mFOLFOX6 or Sorafenib.
Association of mesenchymal phenotype in circulating tumor cells with poor prognosis in metastatic colorectal cancer.
Authors: Dasari Arvind , Gao Hui , Deaton Laurel , Overman Michael J. , Hauch Siegfried , Kopetz Scott , Reuben James M. 
Published: March 2020

e14567 Background: Although the prognostic relevance of circulating tumor cells (CTCs) is well established in metastatic colorectal cancer (mCRC), their clinical use is currently constrained by the phenotypic definition of such cells that is largely limited to epithelial markers. Our objective in this study is to characterize the prognostic significance of a larger group of CTCs including those with characteristics of epithelial-mesenchymal transition (EMT) or cancer stem cells (CSCs) in a cohort of pre-treated mCRC patients (pts). Methods: Peripheral blood was collected in AdnaCollect preservation tubes from pts for immunomagnetic tumor cell enrichment using the AdnaTest ColonCancer Select kit and multiplex qRT-PCR analyses of tumor-associated epithelial (CEA, EPCAM, EGFR), cancer stem cell (ALDH1) and mesenchymal (TWIST1, AKT2, PIK3CA) transcripts. Results: In the initial phase, 41 previously treated mCRC pts (median prior therapies 3) were enrolled over a 4 month period and were followed prospectively. In this cohort, there was a low rate of CEA, EPCAM, and EGFR expression in the CTCs (12%, 2%, and 0%, respectively), consistent with loss of epithelial markers. Conversely, ALDH1, an established CSC marker was expressed in 30% of pts, with only one pt’s CTCs expressing both ALDH1 and CEA expression. ALDH1 expression was associated with very poor prognosis (HR 24.6, p=0.037) and 57% 60-day mortality, compared to 0% 60-day mortality for pts with no detectable ALDH1 expression. The mesenchymal markers of TWIST1, AKT2, and PIK3CA were strongly correlated with ALDH1 expression (Spearman r=0.55, 0.59, 0.63, respectively, p < 0.01 for each). Conclusions: The majority of CTCs detected in refractory mCRC pts have lost epithelial markers. Acquisition of markers associated with EMT or CSCs appear to be associated with poor prognosis, and may provide important insights into better prognostication and also biology of refractory colorectal cancer. Further enrolment into this study is ongoing and updated results will be presented.
Survival outcomes in U.S. patients with metastatic colorectal cancer: A retrospective database analysis.
Authors: Knopf Kevin B. , Iqbal Sheikh Usman , Thompson Stephen F. , Malangone Elisabetta , Gorritz-Kindu Magdaliz , Stern Lee , Sherman Steven A. , Naoshy Sarah , Wooten Michael , Andria Michael L. 
Published: March 2020

e14576 Background: An increase in survival seen in recent years in patients with metastatic colorectal cancer (mCRC) has been attributed to improvements in treatments, including introduction of targeted biologic agents. Objectives of this retrospective, observational study are to investigate recent treatment patterns in US mCRC patients and examine real-world survival outcomes. Methods: Data were obtained from a large US database (SDI/IMS Health) of mCRC patients diagnosed between January 1, 2004, and June 30, 2011, ≥18 years of age at diagnosis, who received chemotherapy and/or biologic treatment. Complete follow-up was defined as those who died before June 2011 or had at least 1 claim within 30 days of June 30, 2011. Kaplan-Meier curves were generated to determine overall survival (OS) from the date of diagnosis. Results: 1,066 stage IV mCRC patients with complete follow-up were identified (57.5% male; mean age 61.6 years). Approximately 80% were diagnosed after 2006; 51.7% had liver metastases. The most common 1L, 2L, and 3L regimens were FOLFOX plus bevacizumab (34.52%), FOLFIRI plus bevacizumab (21.83%), and irinotecan plus cetuximab (15.83%), respectively. 445 patients died during the study period, yielding a mortality rate of 41.74%. Mean time from diagnosis to first treatment was 3.31 months (SD=7.13). All patients received 1L therapy; OS from diagnosis was 35.77 months (95% CI, 32.57-38.10); 5-year survival was ~28%. After 1L, 591 patients received 2L therapy. For patients who received 2L, median survival from diagnosis was 37.13 months (95% CI, 34.07-40.43); 5-year survival was ~25%. After 2L, 278 patients received 3L therapy. For patients who received 3L, median survival from diagnosis was 38.10 months (95% CI, 34.83-43.13); 5-year survival was ~25%. Conclusions: In this study, OS (35.77 months) was greater than in other mCRC observational studies (25.1-27.9 months), which reported survival from start of treatment, but is more comparable when the ~3 months from diagnosis to treatment are not included. The addition of targeted agents and novel chemotherapy has prolonged OS in mCRC patients, yet there is still need for additional advanced agents in later lines of therapies.
Clinical characteristics at diagnosis of patients who survive more than 5 years after diagnosis of metastatic colorectal cancer (mCRC).
Authors: Cruz Abrahao Manuel , Velloso Medrado Santos Joao Paulo , Pavan Thayse , Hoff Paulo M. , Katz Artur , Sabbaga Jorge , Azevedo Fernanda , Freitas Daniela , Saragiotto Daniel F. , Costa Frederico 
Published: March 2020

e14590 Background: Metastatic disease is a prevalent condition that will develop in close to 40% of patients diagnosed with colorectal cancer. Most patients with mCRC will eventually die due to tumor related causes. Advances in surgical intervention and systemic therapies have significantly increased the life expectancy of such patients. Only, a minority of patients with mCRC will survive more than 5 years. The clinical characteristics at initial presentation have not been reported in the era of novel therapies. Methods: All medical charts from patients with colorectal cancer consulted at HSL from 1998 to 2012 were reviewed. Patients with synchronous or metachronous mCRC were selected and only patients who survived more than 5 years from the date of confirmed diagnosis of metastasis were included in the analysis. Results: 1,406 patients with colorectal cancer were reviewed and 793 patients (56,4%) were confirmed with mCRC. 57 of them survived more than 5 years (4%). The clinical characteristics at diagnosis are presented in the Table. 93% of the patients are alive with a median follow-up of 88 months. 91% of them remained ECOG 0/1. The reported objective response to systemic therapy was 97% in first line, 79% in second line, and 66% in third line. All patients with liver only metastasis underwent surgery and 36% are disease-free with median follow-up of 107 months. Conclusions: Patients with mCRC who survived more than 5 years represent a distinctive group not identified by clinical characteristics at the initial presentation. They are highly sensitive to systemic therapy and this seems to be a good marker for patients who will have long survival. Our next step will be to attempt to identify molecular markers for those patients. [Table: see text]
Effect of increased body mass index on time to tumor progression in metastatic unresectable colorectal cancer patients treated with bevacizumab-based therapy.
Authors: Yildiz Ibrahim , Sen Fatma , Kilic Leyla , Keskin Serkan , Ciftci Rumeysa , Ekenel Meltem , Aykan Nuri Faruk 
Published: March 2020

e14594 Background: High body mass index (BMI) is a well known risk factor in the development and recurrence of several solid tumors including colorectal cancer (CRC). Obesity is associated with increased serum levels of vascular endothelial growth factor (VEGF). Bevacizumab is the main targeted therapy inhibiting tumor angiogenesis by blocking VEGF receptor. We evaluated the effect of BMI on time to tumor progression (TTP) in patients who received bevacizumab based therapy due to advanced colorectal cancer in our institution. Methods: Patients with metastatic colorectal cancer who have been treated with fluoropyrimidine-based combination chemotherapy with bevacizumab were included in the study. Data of patients’ clinical treatment characteristics were obtained from the medical records. The height and weight measured during the initiation of bevacizumab were used to assign the patients to group A (BMI<25 kg/m2) and group B (BMI≥25 kg/m2). The time to tumor progression was defined as the day of initiation of bevacizumab based threpay to the date of first documented progressive disease, the date of death regardless of its course or the date of last follow up if no disease progression or no death occured at this time. Results: 236 patients (median age 57, range 27-79 years) were treated withfluoropyrimidine-based combination chemotherapy with bevacizumab between April 2007 and June 2011. 127 (51.3%) patients had a BMI <25 kg/m2 and 115 (48.7%) patients were found to have a BMI ≥25 kg/m2. One hundred ninety-three patients (82.1%) had first line bevacizumab therapy, and 44 patients (22.8%) had second-line bevacizumab therapy. Tumors of 68.4% of patients in group A and 69,1% of patients in group B progressed during a median 10 months (3-57 months) follow up. The median TTP was 9.5 months in the BMI <25 group and 8.2 months in the BMI >25 group.In multivariate analysis, high BMI (≥25 kg/m2) was associated with significantly shorter TTP (p: 0.002; HR, 1.91; 95% CI, 1.26–2.88). Conclusions: High BMI is a relevant prognostic factor in predicting the time to tumor progression in metastatic colon cancer patients treated with bevacizumab.