bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical evaluation of genexol-PM, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer.
Authors: Wang Andrew , Cummings Natalie Dawn , Sethi Manish , Wang Edina , Sukumar Rohit , Moore Dominic T. , Werner Michael Edward
Published: March 2020

e13546

Background: A key research objective in radiation oncology is to identify agents that can improve chemoradiotherapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiotherapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiotherapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer as a model disease. Methods: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM’s efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivousing mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared to that of after Taxol administration. Results: Genexol-PM have a size of 23.91 ± 0.41 nm and surface charge of -8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an excellent radiosensitizer and is more effective than Taxol, its small molecule counterpart at the half maximal inhibitory concentration (IC50). In vivostudy of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung and liver tissue than Taxol at 6 hours post administration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiotherapy for NSCLC.
Targeting Y397 FAK scaffolding compared with FAK kinase inhibition: Efficacy and specificity for tumor cells.
Authors: Golubovskaya Vita , Ho Baotran , Stright Adam , Zajac-Kaye Maria , Hochwald Steven N. , Cance William G.
Published: March 2020

e13547

Background: Focal Adhesion Kinase is a non-receptor kinase which is highly overexpressed and activated or autophosphorylated in many types of tumors and plays a major role in survival signaling and metastasis. Recently, our group developed a highly specific allosteric scaffolding FAK autophosphorylation inhibitor, Y15, that blocked FAK Y397 autophosphorylation, decreased cancer cell viability, and significantly decreased breast, neuroblastoma, pancreatic and glioblastoma tumor growth. In addition, Y15 was not toxic in mice. In this study, we compared side by side efficacy of Y15 with two other FAK inhibitors in clinical trials, Pfizer PF-04554878 and Glaxo GSK-2256098. Methods: MTT, clonogenicity and Western blotting assays were used to detect the effect of FAK inhibitors on different cancer and normal cells. Student’s t-test was used for statistical analysis and p<0.05 was considered significant. Results: We tested different cancer cell lines: kidney 293T, colon SW620 and LoVo; lung A549; glioblastoma U251 and U87; breast: BT474, MDA-231, MDA-361, MDA-453, MDA-468 and T47D and pancreatic PANC-1 cancer cells with different doses of Y15, PF and GSK inhibitors by MTT assay and found that Y15 was the most effective at decreasing cancer cell viability in most cancer cell lines, with higher efficacy than PF and much higher efficacy than GSK inhibitor. The same was observed for clonogenicity assay. In addition, we found that Y15 did not significantly affect viability of normal colon (CCD-112) cells, while viability of these cells with PF and GSK decreased to 54% and 57% at a 2 microM dose, respectively, from 100% in untreated cells. In addition, Y15 significantly decreased Y397-FAK, Y418-Src, phospho- Ser 473-AKT and phospho-ERK1/2, while PF had less effect and GSK only a minimal effect in four different cancer cell lines: U251, A549, 293T and Lovo at 10 microM and 100 microM doses, showing high potency of the FAK Y397 scaffolding inhibitor. Conclusions: These data show that Y15, which inhibits the Y397 site of FAK, is more potent against cancer cells and less toxic to normal cells than FAK inhibitors that target the conserved ATP-binding site in the kinase domain.
International collaboration in personalized medicine for the treatment of advanced and drug-refractory cancers: Clinical application of human tumor primary culture analyses.
Authors: Silva Fabricio Colacino , Maluf Fernando C. , Buzaid Antonio C. , Nagourney Robert Alan , Yamaguchi Nise Hitomi , D'Amora Paulo , Evans Steven , Bernard Paula J , Francisco Federico
Published: March 2020

e13562

Background: Personalized oncology has advanced through genomic and proteomic platforms. BCR-abl; EGFr and ALK have provided drug-able targets and companion diagnostics in several diseases, yet many transforming events in humans are polygenic, complex and incompletely understood at a genomic level. Recognition that oncogenesis reflects changes in the cell and its micro environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma and -vascular signaling. Ex vivo analysis of programmed cell death (EVA/PCD) has been shown to correlate significantly with response, time to progression and survival (Nagourney, R. Curr. Treat Op Oncol, 2006).To explore EVA/PCD functional profiling in Brazil, hospital-based investigators, Centro de Genomas and Rational Therapeutics coordinated the transport of 67 surgical specimens for analyses. Methods: Dose-response curves using metabolic (ATP-content, mitochondrial) and morphologic endpoints, interpolated to LC50's and synergy by median-effect, were compared with databases to identify patient-specific profiles for cytotoxics, targeted agents and combinations. Reports provided day 7. Results: 62/67 (92%) provided adequate tumor for analysis; 39 male (58%); 28 (42%) female; 6 chemo-naive and 61 previously treated. Results provided for < 8 drugs in 14/62 (22%); 8-16 drugs in 34/62 (54%) and > 16 drugs in 14/62 (22%). Of 22 tumor types, breast (8); Melanoma (8); NSCLC (8); ovary (7); pancreas (7) and sarcoma (4) predominated. EVA/PCD was used to select the most active combinations. Agents selected, response rates and durations are being tabulated and will be reported. Conclusions: The transport, processing and reporting of human tumor primary culture analyses is feasible, providing results in 92% of specimens and median of 12 drugs evaluated (range 4-32). Preliminary outcomes in these drug-refractory patients reveal that novel, often unexpected drug combinations (Everolimus and Lapatinib in triple negative breast) were identified and provided objective tumor responses, supporting EVA/PCD in therapy selection (personalized therapy) and drug development.
Evaluation of GPER agonist G-1 combined with navitoclax in platinum-resistant and -sensitive ovarian cancer cells.
Authors: DeSimone Dennis C. , Nguyen Trung T. , Brailiou Eugen , Taylor John C. , Brailoiu Gabriela Cristina , Boyd Jeff , Ariazi Eric A.
Published: March 2020

e13563

Background: Most ovarian cancer patients are treated with platinum-based chemotherapy but eventually relapse with incurable disease. The G protein-coupled estrogen receptor GPER (GPR30) mediates Ca2+ mobilization in response to estrogen and G-1, a synthetic agonist. Large and sustained Ca2+ responses can lead to mitochondrial Ca2+ overload and apoptosis. Hence, we evaluated whether G-1 could induce apoptosis in cisplatin-sensitive A2780 and isogenic cisplatin–resistant CP70 (14-fold resistant), C30 (70-fold resistant) and C200 (157-fold resistant) human ovarian cancer cells. Bcl-2 and Bcl-xL protect mitochondria from Ca2+overload, and were overexpressed in these cisplatin-resistant cells; thus we also examined combining the Bcl-2 family inhibitor navitoclax with G-1. Methods: Cytoplasmic [Ca2+]c and mitochondrial [Ca2+]m were monitored using microscopy and fluorescent Ca2+ probes. Cell cycle, apoptosis and mitochondrial membrane potential (MMP) were assessed by flow cytometry of propidium iodide, Annexin V and DiIC1(5) -stained cells. The intracellular Ca2+ chelator BAPTA was used to block Ca2+mobilization. Results: Expression of the 53kDa GPER but not the 38 kDa isoform progressively increased with increasing cisplatin resistance. G-1 elicited sustained [Ca2+]c rises that correlated with 53 kDa GPER expression, followed by rises in [Ca2+]m. In all cells, 2.5 μM G-1 blocked cell cycle progression at G2/M, inhibited proliferation, and induced apoptosis (A2780 > C30 > CP70 ≥ C200). G-1 induced p53, caspase-3 and PARP cleavage, and MMP loss. BAPTA prevented G-1’s cell cycle and apoptotic effects in cells showing large Ca2+ mobilization responses but did not in cells with small Ca2+responses. Combining navitoclax with G-1 superadditively decreased cell viability and increased apoptosis. Conclusions: G-1 blocked cell cycle progression and induced apoptosis via a Ca2+-dependent pathway in cells expressing high 53 kDa GPER levels, but via a Ca2+-independent pathway in cells with low 53 kDa GPER expression. G-1 also interacted cooperatively with naviticlax. Therefore, G-1 plus navitoclax shows potential for therapeutic use in platinum-sensitive and -resistant ovarian cancer.
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.
Phase II trial of cetuximab (Cmab) plus irinotecan (CPT-11) for chemorefractory Japanese patients with advanced and/or metastatic colorectal cancer (mCRC), to evaluate the efficacy and safety based on KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status (T-CORE0801).
Authors: Shimodaira Hideki , Soeda Hiroshi , Ohori Hisatsugu , Akiyama Shoko , Kambe Mariko , Murakawa Yasuko , Suzuki Takao , Kato Satoshi , Itoh Jugoh , Watanabe Mika , Yamaguchi Takuhiro , Kato Shunsuke , Ishioka Chikashi ,   Tohoku Clinical Oncology Research and Education Society
Published: March 2020

e14597

Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) antibody (mAb) therapy among patients with mCRC based on Caucasian studies. To date, few studies have examined the relationship between KRAS status and response to Cmab therapy in Asian populations. Therefore, this prospective study investigated the relationship between the mutation status of KRAS and other EGFR-related genes along with clinical outcomes in response to Cmab + CPT-11 therapy in Japanese patients with mCRC. Methods: Samples that had been collected from 43 chemo-refractory patients with mCRC, who had undergone Cmab + CPT-11 therapy at 11 medical centers in Japan, were subjected to direct DNA sequencing to determine their KRAS, BRAF, PIK3CA, NRAS, and AKT1 status. The response rate (RR) was the primary endpoint along with safety, median progression free survival (mPFS), and median overall survival (mOS) as secondary endpoints. Results: The clinical outcomes in response to Cmab + CPT-11 therapy was observed to be better in the wild-type (WT) KRAS subgroup than in the mutant (MT) KRAS subgroup (RR: 17.9% vs. 0%; mPFS: 3.7 vs. 1.6 months (M) ; mOS: 10.3 vs. 7.5 M). The differences in clinical outcomes were more remarkable between patients with both WT KRAS and BRAFand those with MT of either of these genes (RR: 19.2% vs. 0%; mPFS: 5.2 vs. 1.6 M; mOS: 11.8 vs. 7.4 M), as well as between patients with all 5 WT genes and those with MT of either of these genes (RR: 26.3% vs. 0%; mPFS: 5.2 vs. 1.8 M; mOS: 11.8 vs. 7.4 M). Conclusions: Despite identification of a lower than expected RR to treatment among the WT KRAS subgroup, KRAS mutation status appeared to be a useful predictive marker of response to Cmab + CPT-11 therapy in Japanese patients with mCRC . Combined analysis of KRAS and BRAF improved both the sensitivity and specificity of the predictive biomarker. However, the combined analysis of all 5 genes did not result in any considerable improvement compared with that achieved with the KRAS and BRAF analysis alone. Clinical trial information: UMIN000001668.
Hsa-mir-31-3p effects on gene expression in colorectal cancer cell lines and patients.
Authors: Thiébaut Raphaële , Vincent Marc , Vazart Celine , Decaulne Virginie , Le Corre Delphine , Fontaine Karine , Genin Berengere , Carayol Jerome , Rousseau Francis , Liebaert Francois , Laurent-Puig Pierre
Published: March 2020

e14600

Background: Recently, hsa-miR-31-3p was found to be up-regulated in some tumors of metastatic colorectal cancer (mCRC) patients and was proposed as a prognostic marker for anti-EGFR therapy in KRAS wild-type (WT) patients. The aim of this study was to identify the target genes of hsa-miR-31-3p in a CRC context. Methods: Three different KRAS WT CRC cell lines, Caco-2, Colo205 and Colo320HSR were transfected with hsa-miR-31-3p mimic or control mimic. After 24h, cells were harvested and total RNA was extracted for an expression array analysis. Linear models for micro-arrays analysis from R package was used to analyze the results. A miRNA predictive target database including 6 available databases (microRNA.org, MicroCosm, TargetScan, PicTar, PITA, miRDB) was created. Validation of the identified target genes was performed on tumors sample of 39 patients treated with panitumumab and irinotecan as third line. Results: After transfection of the 3 cell lines with hsa-miR-31-3p mimic, an expression profile analysis was done. Results obtained in each cell lines were first compared in a pair wise analysis and secondly tested with eBayes procedure without matching. Fifty –four genes were down-regulated (fold change: fc≤0.77, p<0.05). Using the predictive target database, hsa-miR-31-3p was the second most common miRNA as it targeted putatively 25 out the 54 genes, among which STAT3. To identify indirect target genes, we then studied the genes up-regulated by hsa-miR-31-3p over-expression in the 3 different cell lines and identified 27 genes. As expected all but one were not predicted to be direct target genes of hsa-miR-31-3p using the predictive target database. Interestingly, the proto-oncogene MET was up regulated by the over expression of hsa-miR-31-3p. Validation of the 25 putative targets and of the 27 genes up-regulated genes was done with RT qPCR on tumor samples of patients treated with anti-EGFR and some of the direct and undirected target genes were confirmed. Conclusions: This study shows that hsa-miR-31-3p, which expression level was shown to be correlated with prognosis of mCRC patients treated with anti-EGFR, plays an important role in CRC by regulating genes involved in cancer like STAT 3 and MET.
Use of biologics in addition to chemotherapy in the treatment of elderly Medicare patients with stage IV metastatic colon cancer.
Authors: Mullins C. Daniel , Wang Fenghao , Bikov Kaloyan A. , Seal Brian S. , Hanna Nader
Published: March 2020

e14602

Background: On February 12 and 26, 2004, the FDA approved bevacizumab and cetuximab, respectively, two biologic drugs for the first–line treatment of metastatic colorectal cancer (mCC), followed by panitumumab, another biologic approved on September 27, 2006. NCCN guidelines suggest that biologics may be added to fluorouracil and leucovorin (5-FU/LV), irinotecan (IRI), or oxaliplatin (OX), yet a number of recent articles raise questions regarding the added benefit of biologics on top of a backbone chemotherapy regimen, which might affect the utilization pattern of biologics. To examine the adoption of biologics, we document the rate of treatment with biologics in addition to backbone chemotherapy as first-line treatment (Tx1) of mCC. Methods: This study uses the Surveillance, Epidemiology and End Results (SEER)-Medicare data and examines mCC patients diagnosed in 2003-2007 who received chemotherapy with or without biologics as Tx1. Due to the small sample size of cases involving the combined use of irinotecan and oxaliplatin (IROX) as Tx1, IROX patients were excluded from this study. The remaining 2995 observations are broken down by regimen and by year of Tx1 initiation (Table). Results: The use of biologics (90% of which was bevacizumab) in addition to chemotherapy as part of Tx1 exploded from 9% in 2004 to 55% in 2005. Utilization was highest (62%) in 2006 and fell slightly in 2007 to 57%. Of all cases utilizing biologics, 67% were oxaliplatin-based regimens, 19% were fluorouracil-based regimens and 15% were irinotecan-based regimens. Conclusions: In the first few years following FDA approval, the use of biologics in addition to backbone chemotherapy increased rapidly as first-line treatment of elderly Medicare metastatic colon cancer patients, leveling out at around half of all patients receiving chemotherapy. Biologics use has been most common among patients treated with oxaliplatin. [Table: see text]
Understanding why some people with stage III colon cancer do not receive adjuvant chemotherapy.
Authors: Heong Valerie , Wong Hui-Li , Tie Jeanne , Jefford Michael , Field Kathryn Maree , Kosmider Suzanne , Desai Jayesh , Croxford Matthew , Jones Ian , Gibbs Peter
Published: March 2020

e14608

Background: Adjuvant chemotherapy is a standard of care for patients (pts) with stage III colon cancer. While many retrospective series have concluded that treatment is underutilised in routine clinical practice, particularly in older pts, reasons for this remain unexplored. Methods: Data was collected on all pts with stage III colon cancer attending four community hospitals in Australia between January 2003 and July 2012. Every patient was referred to a medical oncologist. For each case where adjuvant therapy was not delivered, reason(s) were prospectively documented by clinicians in a consensus database. Results: Data was collected on 875 pts. Median age 67 years (range 15 - 92). Overall, 147 (25.9%) did not receive adjuvant therapy. Comorbidity was the main reason for non-treatment in all age groups. Age alone was the reason for not recommending treatment in a small number of elderly pts (n=20, 20.4%). Risk of recurrence (N1 vs N2 disease) did not impact recommendations of clinicians (75% vs 76%) or pt acceptance (92% vs 93%). Pts with a lower socioeconomic status were less likely to be offered treatment; however this reflected greater comorbidity in these pts. Treatment acceptance was similar across all socioeconomic groups (data not shown). Conclusions: In routine clinical practice adjuvant chemotherapy should be recommended to, and can be safely delivered to a very high proportion of younger patients. Clinicians are comfortable recommending adjuvant chemotherapy to older pts, with co-morbidity the dominant reason that treatment was not recommended for pts >65 years. The rate of pts declining treatment increased with age, and further study of the factors involved in treatment refusal should be pursued [Table: see text]
Prognostic factors in KRAS wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts) treated with biweekly cetuximab (C) plus irinotecan, fluorouracil, and leucovorin (FOLFIRI): A phase II study.
Authors: Personeni Nicola , Rimassa Lorenza , Verusio Claudio , Barni Sandro , Destro Annarita , Raschioni Carlotta , Armenia Silvia , Floriani Irene , Gerardi Chiara , Monteforte Marta , Villa Eugenio , Bozzarelli Silvia , Roncalli Massimo , Torri Valter , Labianca Roberto , Santoro Armando
Published: March 2020

e14611

Background: Retrospective studies showed that efficacy of C increases in molecularly-defined subsets of KRAS wt mCRC pts. In pretreated pts, biweekly C seems as effective as a weekly schedule. Aim of this field-practice study was to evaluate the efficacy of FOLFIRI plus biweekly C (C-FOLFIRI) as first-line treatment for mCRC and prospectively validate PTEN expression as a prognostic marker. Methods: Pts with previously untreated metastatic KRAS wt mCRC not suitable for curative-intent resection were eligible. Initially, pts were randomized to receive FOLFIRI alone or in combination with C (500 mg/m2 every two weeks). After a protocol amendment, pts were assigned to receive only C-FOLFIRI, while the FOLFIRI alone arm was discontinued. Clinical outcome was assessed according to expression of PTEN and MET by immunohistochemistry (IHC), as well as to BRAF mutations. Results: From April, 2009 to June, 2012, a total of 89 pts were enrolled. 35 pts were randomly assigned to receive FOLFIRI alone, while 54 pts received C-FOLFIRI: 33 were treated in the random phase and 21 after protocol amendment. Median overall survival (OS) was 17.7 months for FOLFIRI and 23.3 months for C-FOLFIRI. Corresponding median progression-free survival was 8.2 and 6.8 months, respectively. Objective response rate was 52.0% for FOLFIRI and 52.3% for C-FOLFIRI. The toxicity profile of C-FOLFIRI was consistent with that expected from a weekly C schedule. 23/38 pts (61.0%) assessed for PTEN were positive for IHC expression, 8/39 pts (21.0%) had a MET high status, 6/45 pts (13.3%) had BRAF mutations. In pts treated with C-FOLFIRI, only BRAF mutations negatively affected OS (Hazard ratio mutations vs. wt: 4.77; 95%CI 1.41-16.13; p = 0.01). Conclusions: Safety, effectiveness and generalizability of C-FOLFIRI validate in field practice results gained with FOLFIRI plus a weekly C schedule. Despite the small sample size, analysis of BRAF mutations reaffirms the strong prognostic impact of this biomarker. The extended analysis of BRAF mutations, PTEN and MET expression on all pts is ongoing. Data will be presented. Clinical trial information: NCT01068132.
HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.
Authors: Sclafani Francesco , Roy Amitesh Chandra , Chau Ian , Wotherspoon Andrew , Peckitt Clare , Dewdney Alice , Oates Jacqueline Rose , Cunningham David
Published: March 2020

e14616

Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.