bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Ras-Raf-MEK-Erk/JNK pathway mutations with overall survival for lung squamous cell carcinoma patients.
Authors: Xu Long , Liu Ming , Huang Tanxiao , Peisu Suo , Song Lele , Liu Yuanyuan , Fu Mimi , Zhang Chunmei , Edwards Jeremy , Chen Shifu
Published: May 2019

e14754

Background: Genomic alterations often lead to aberrant signaling pathways which play an important role in tumorigenesis and development. Here we report the mutational status of genes associated with the Ras-Raf-MEK-Erk/JNK signaling pathway as a biomarker for predicting overall survival (OS) for Lung squamous cell carcinoma (SQCC) patients. Methods: We used the cBioPortal platform to analyze a cohort of 494 SQCC samples from TCGA data. The general Ras-Raf-MEK-Erk/JNK signaling pathway includes 26 genes (KRAS, HRAS, BRAF, RAF1, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK12, MAPK14, DAB2, RASSF1, RAB25). We analyzed the number of samples with/without mutations in the Ras-Raf-MEK-Erk/JNK pathway and found is 214 and 284 that had, or didn’t have, mutations in this pathway, respectively. The overall survival of these two groups was analyzed using the Kaplan-Meier Estimate, and the statistical difference between these groups was calculated using the log-rank test afterwards. Results: The log-rank test p-value is 2.086e-3, which indicates a significant difference in the overall survival between the two groups. It shows that the group with alterations in the Ras-Raf-MEK-Erk/JNK signaling pathway had a longer overall survival than the group without those alterations. The details are as follows: Conclusions: Ras-Raf-MEK-Erk/JNK pathway mutations are significantly associated with longer OS for lung SQCC patients. Mutations in this pathway can be a potential indicator for SQCC patients, but the biological reasons behind this relationship remain to be explored.[Table: see text]
How to deal with second line dilemma in metastatic colorectal cancer? A systematic review and meta-analysis.
Authors: Galvano Antonio , Guarini Aurelia , Cusenza Stefania , Barraco Nadia , Castiglia Marta , Incorvaia Lorena , Rizzo Sergio , Fulfaro Fabio , Beretta Giordano D. , Carreca Ignazio Ugo , Bazan Viviana , Russo Antonio
Published: May 2019

e15006

Background: Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy in combination with chemotherapy as second line for metastatic colorectal cancer (mCRC). However, there is still a paucity of evidence or guidelines suggesting the right sequential treatment in all RAS (KRAS/NRAS) wild type(wt)mCRC. Therefore, we aimed to evaluate the impact of these targeted therapies by reviewing literature data. Methods: We used Cochrane, EMBASE and Medline databases to select phase III clinical trials containing efficacy and safety data about chemotherapy (CT) or CT + targeted agents combination (Anti-VEGF and Anti-EGFR) in second line mCRC setting. We performed direct comparisons to obtain pooled data for anti-VEGF + CT versus CT and anti-EGFR +CT versus CT comparisons. Then we performed indirect comparisons between anti-EGFR and Anti-VEGF. Outcomes were disease control rate (DCR), response rate (RR), progression-free survival (PFS), overall survival (OS) and most common G3-G5 toxicities. Results: Eight eligible RCTs (6793 pts) were included: 5 studies compared anti-VEGF + CT and 3 anti-EGFR + CT combinations to CT. After direct comparisons, pooled indirect results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; however, no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Additionally, anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83) too. Furthermore, no significant difference in PFS and DCR all RAS was registered. Anti-VEGF combination significantly increased Only a significant asthenia difference (RR 1.34, 95% CI 1.03–1.75) was registered. Conclusions: At our knowledge, our indirect comparisons between anti-VEGF and anti-EGFR combinations showed for the first time better OS and DCR for anti-VEGF combinations, whereas better RR is observed for anti-EGFR combinatory regimens, defining a role of both targeted agents in second line mCRC setting.
Apatinib combined with Raltitrexed in patients with metastatic colorectal cancer after failure of standard therapy (AHEAD-311): A single-arm phrase II pilot trial.
Authors: Si Haiyan , Gou Miaomiao , Zhang Yong , Yan Huan , Qian Niansong , Wang Zhikuan , Shi Yan , Dai Guanghai
Published: May 2019

e15008

Background: To assess the safety and efficacy of apatinib, an oral vascular endothelial growth factor receptor-2 inhibitor, combined with thymidylate synthase inhibitor raltitrexed in patients with metastatic colorectal cancer (mCRC) as a third- or later-line therapy. Methods: Patients with mCRC after at least 2 lines of chemotherapy were enrolled whenever they previously treated with bevacizumab or not. Apatinib was given orally at 250mg or 500mg daily. Raltitrexed was administered intravenously at 3 mg/m2 on day 1 every 3 weeks. The primary endpoints were progression-free survival (PFS). The second endpoints were objective response rate (ORR), overall survival (OS) and safety. Results: From August 2017 to November 2018, thirty-one patients were enrolled in Chinese PLA General Hospital. After a median follow-up of 6.4 months, the median treatment cycle was 4. four patient achieved partial response(PR), and 11 patients achieved stable disease (SD) and 16 achieved progression disease (PD) in accordance with RECIST version 1.0, illustrating a DCR of 48.4% and an ORR of 12.9% .The Median PFS was 2.4 months and the median OS was 6.4 months. The most common adverse events were hypertension (n=12, 38.7%), nausea and vomiting (n=11, 33.8%), myelosuppression (n=9, 29.0%). The most common grade 3 to 4 adverse events were hypertension (n=2, 6.4%) and hand-foot syndrome (n=2, 6.4%). Grade 3 to 4 hematologic toxicities were rare. One patient died from cardiac arrest after three days treatment. There was no significantly association between PFS or OS, and clinical features including tumor location, KRAS status, and prior surgery or not, and number of metastatic organs. There was no trend showing patients who experienced had hypertension or myelosuppression had longer PFS and OS. Compared to the patients never received bevacizumab, the patients who had previously bevacizumab had the similar PFS and OS (3.9 versus 2.3months, P=0.787; 6.1 versus 6.4months, P=0.287). Grade1-2 nausea and vomiting and age <57 were independent predictors for longer PFS and OS. Conclusions: Apatinib combined with raltitrexed had efficacy but had limited survival benefit in mCRC refractory to standard chemotherapy. This regime showed us a higher risk of adverse event incidence and warrant further exploring of benefit population. Clinical trial information: NCT03344614 .
Clinical efficacy and safety evaluation of nimotuzumab combined with chemotherapy in the treatment of advanced colorectal cancer: A retrospective analysis.
Authors: Bai Sai-xi , Zhang Ruo-rong , Chen Wang-hua , Dong Hongmin , Wang Gang , Li Xiaokai , Wang Ling Wen
Published: May 2019

e15009

Background: To retrospectively analyze the clinical effects and safety of nimotuzumab combined with chemotherapy as the first-line treatment of advanced colorectal cancer (ACRC). Methods: ACRC patients treated by nimotuzumab combined with chemotherapy (40 cases) or chemotherapy alone (44 cases) were enrolled in this study. Responses were evaluated by Respond Evaluation Criteria in Solid Tumors. Adverse events were evaluated by Common Terminology Criteria for Adverse Events 3.0. Results: The combined treatment group had a slightly higher objective response rate (RR) and disease control rate (DCR) (RR: 55.0% vs 36.4%; DCR: 85.0% vs 75.0%) compared to the chemotherapy alone group, although not statistically significant (P > 0.05). The median progression-free survival (PFS) was 9.89 months in the combined treatment group and 7.86 months in the chemotherapy alone group, respectively. The median survival time was 22.32 months in the combined therapy group and 18.10 months in the chemotherapy alone group, respectively (P = 0.060). There was no statistically significant difference regarding the adverse events between these two groups. Conclusions: The nimotuzumab combined with chemotherapy had similar efficacy and safety to chemotherapy-alone treatment in ACRC. The efficacy and safety of the combined treatment should be further studied with a randomized multicentre trial with a larger number of ACRC patient.
Association between hand-foot skin reaction (HFSR) and survival benefit of fruquintinib in FRESCO trial.
Authors: Li Jin , Qin Shukui , Bai Yuxian , Deng Yanhong , Yang Lei , Xu Ruihua , Chen Zhendong , Zhong Haijun , Pan Hongming , Guo Weijian , Shu Yongqian , Yuan Ying , Xu Jianming , Shen Lin , Wang Ning , Zhu Chao , Fan Songhua , Gong Wei , Wang Wei
Published: May 2019

e15012

Background: In phase 3 FRESCO trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese metastatic colorectal cancer (mCRC) patients. As a known adverse effect of vascular endothelial growth factor receptor (VEGFR) inhibitors, hand-foot skin reaction (HFSR) was commonly reported as a drug-related adverse event (AE) in fruquintinib group. This retrospective analysis explored whether HFSR in fruquintinib group is associated with survival benefit in FRESCO. Methods: This analysis used a subpopulation of intent-to-treat population who at least completed one cycle and entered cycle two of fruquintinib treatment. Patients randomized to receive fruquintinib 5 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they reported HFSR. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. P-value was generated from log-rank test. Results: Among a total of 255 fruquintinib-treated patients who at least completed one cycle and entered cycle two, 52% (n = 133) reported HFSR of any grade. The median time-to-onset of HFSR (any grade) was 21 days and approximate 75% patients reported HFSR after cycle two treatment completion. The baseline characteristics were well balanced between HFSR reported and non-reported subgroups. Patients who reported HFSR showed both OS and PFS benefit with statistical significant difference comparing with HFSR non-reported patients in fruquintinib group. Fruquintinib significantly decreased 43% death risk in HFSR reported patients and prolonged the median OS to 11.14 months in comparison with HFSR non-reported patients (median: 11.24 vs 7.54 months; HR = 0.57, 95% CI: 0.42-0.78; p < 0.001). Similarly, Patients reported HFSR had a significantly longer PFS than those who did not reported HFSR in the fruquintinib group (median: 5.49 vs 3.48 months; HR = 0.70, 95% CI: 0.54-0.91; p = 0.008). Conclusions: This post-hoc analysis indicates that patients who had HFSR had a greater survival benefit from fruquintinib in Chinese mCRC patients. Clinical trial information: NCT02314819 .
Cost and effectiveness of genetic testing in metastatic colorectal cancer (mCRC) at Montefiore Medical Center (MMC).
Authors: Ashai Nadia , Stuart Matthew , Mejia Saldarriaga Mateo , Zhang Wei , Huang Renee , Narang Rahul , Chuy Jennifer W. , Kaubisch Andreas , Goel Sanjay , Halmos Balazs , Rajdev Lakshmi
Published: May 2019

e15043

Background: Upfront testing for MSI, and mutations in KRAS, NRAS, and BRAF is recommended. The most cost-effective way of obtaining this information remains unclear. We examined cost of broad next generation sequencing (NGS), in comparison to hotspot (HT) and individual target (IT) testing in patients with mCRC with Medicare (MC) and commercial insurance (CI) at MMC. As a surrogate of effectiveness, we hypothesize that patients with NGS are more likely to enroll in clinical trials. Methods: Cost of individual and hotspot tests were derived from known reimbursement rates with insurances affiliated with MMC. Due to ongoing changes in current procedural terminology for NGS, we used known reimbursement amounts from our patients. We applied these costs to a model population of 1,000,000 people. We then evaluated clinical trial enrollment of patients who had either NGS or hotspot/individual testing. Results: MC costs for IT, HT, NGS testing were $1,504, $752, and $4,680 respectively. CI costs were $1,910, $814, $2,366 for IT, HT, and NGS testing respectively. When applied to our model population, NGS cost $914,604 and $1,131,016 more than individual and hot spot testing respectively for MC patients, and $21,432 and $72,924 more for CI patients. Analysis of effectiveness included 136 patients, wherein 8% of those with NGS (n = 5/61) were enrolled in clinical trials as a result of testing compared to 1% of those with HT/IT (n = 1/75). Conclusions: Broad spectrum NGS costs more than individual or hot spot testing in mCRC. However, patients with NGS testing were more likely to be enrolled in clinical trials, suggesting the need for studies to further evaluate ideal testing modality. [Table: see text]
Predictors of survival in chemorefractory colorectal liver metastases treated with Y90 radioembolization.
Authors: Dabrowiecki Alexander Michael , Sankhla Tina , Shinn Kaitlin , Bercu Zachary Louis , Ermentrout Robert Mitchell , Newsome Janice , Shaib Walid Labib , Cardona Kenneth , Kokabi Nima
Published: May 2019

e15044

Background: The aim of the study was to evaluate molecular signatures and timing of yttrium-90 (Y90) as prognostic factors of survival following Y90 radioembolization (RE) in patients with chemorefractory colorectal liver metastases (CRLM). Methods: In a retrospective single-institution study, patients with unresectable, chemorefractory CRLM who had undergone genomic analysis prior to Y90 RE from 2013 to 2018 were identified. Timing of Y90 (following failure of first line vs following multiple lines of chemotherapy) and oncogenic mutation status (MAPK and PI3K pathways) were evaluated as predictors of survival length following Y-90. Survival was measured from first Y90 using Kaplan-Meier estimation and predictors of outcome were identified using log-rank analysis. Results: Overall, 58 patients with chemorefractory CRLM who underwent genomic analysis prior to Y-90 were identified. Of these, 26 (44.8%) had MAPK mutations, and 2 (3.5%) had PI3K mutations. Median survival after first Y-90 RE was 12.9 months. There was significantly prolonged overall survival (OS) in patients receiving Y90 immediately following failure of the first line of chemotherapy (FOLFOX ± bevacizumab) versus patients who underwent multiple lines of chemotherapy prior to Y90 (median OS of 16.9 vs 11.4 months for others; p = 0.023). When stratifying the cohort based on the timing of Y90, patients with WT-MAPK (n = 8) had prolonged OS if they underwent Y-90 following failure of the first line of chemotherapy (median OS of 22.3 vs 12.9 mo; p = 0.019). Patients with WT-PI3K (n = 19) had prolonged OS if they underwent Y90 following failure of the first line of chemotherapy (median OS of 16.9 vs 12 mo; p = 0.037). When analyzing the entire cohort non-stratified by timing of Y90, genetic mutation was not found to be a predictor of prolonged OS. Conclusions: Y90 RE after failure of first line of chemotherapy in CRLM appears to confer prolonged survival specifically for WT-MAPK and WT-PI3K oncogenes. Conversely, the prognosis of more favorable genetic status appears to be negated if Y90 RE is performed after failure of second or third line chemotherapies.
Outcomes of metastatic colorectal cancer over fifteen years from an Indian tertiary care center: A retrospective analysis.
Authors: Sharma Vinod , Sharma Atul , Pathy Sushmita , Shukla Nootan Kumar , Deo S V Suryanarayana , Thulkar Sanjay , Kumar Sunil , Sahoo Ranjit
Published: May 2019

e15050

Background: Management of metastatic colorectal cancer (CRC) has revolutionised over the past 2 decades and a number of drugs are part of active disease management including biologicals. Published large database on metastatic CRC outcome has been lacking from India. Methods: A retrospective data analysis of metastatic CRC from prospectively based database was performed from the year, 2001-2015. All patients who have received at least 1 cycle of chemotherapy were enrolled. Kaplan Meier analysis was done for overall survival (OS). Cox-regression model was done to determine prognostic factors of OS. Results: A total of 288 patients including upfront metastatic (n = 197, 68%) and relapsed (n = 91, 32%) with male to female ratio of 1.4:1 and median age of 46 years were studied. CEA was high in 78% with median level of 20 ng/ml. Most common site of primary tumor location was rectum (47%). Proportions of left side, right side and transverse colon was 75%, 20% and 4.2%. Mucinous and signet histologies were seen in 24% and 9.2% of patients. Most common sites of metastases being liver (43%), peritoneum (31%) and lung (18%). Oxaliplatin based therapy was used 71% of patients as 1st line. Median chemotherapy cycles for both 1st and 2nd line regimen was 6. Biologicals were part of 1st line regimen in only 12.5% of patients. Median OS of our cohort was 18.5 months. Predictors of poor OS were ECOG PS > 1 (HR 2, CI: 1.3-3.3, p value = 0.003), high CEA ( > 5ng/ml, HR 2.5, CI: 1.3-4.6, p value = 0.004), low albumin (< 3.5 g/dl, HR 1.7, CI: 1.03-2.9, p value = 0.045), < 2 lines of chemotherapy received (HR 2, CI: 1.3-3.3, p value = 0.001). Conclusions: Outcomes of metastatic CRC in our cohort with use of doublet chemotherapy (small proportion with biologicals) is comparable to published literature worldwide. We have higher proportion of younger population, rectum cancer, signet and mucinous histology and higher incidence of peritoneal involvement.
Evaluation of long term survival in pretreated metastatic colorectal cancer patients undergoing GOLFIG chemoimmunotherapy regimen.
Authors: Correale Pierpaolo , Giannicola Rocco , Staropoli NIcoletta , Ciliberto Domenico , Azzarello Domenico , Tripepi Giovanni , Agostino Rita Maria , Strangio Alessandra , Altomonte Maria , Nesci Antonio , Francini Guido , Pastina Pierpaolo , Tassone Pierfrancesco , Pirtoli Luigi , Caporlingua Nadia , Falzea Antonia Consuelo , Tagliaferri Pierosandro
Published: May 2019

e15057

Background: In the last few years, there has been a renewed interest on the potential use of immunotherapy alone or combined to chemotherapy (CHT) for mCRC patients. GOLFIG regimen (biweekly Gemcitabine+FOLFOX and IL2 and GM-CSF) was designed to enhance immunomodulating effects of selected cytotoxic drugs by combining them with cytokines able to promote priming and effector phases of the immune-response. This regimen has been tested in two different phase II and III clinical trials in mCRC patients, whose successful results have been published. Here we present the results a retrospective analyses including all the patients treated in a period of 16 years. Methods: This is a multi-institutional retrospective study including 179 mCRC patients (106 men, 73 women). They received a median of 12 courses of GOLFIG regimen (treated between June 2002 and November 2018). K-RAS mutational status has also been evaluated in 74 pts (41 wild type and 33 mutated); as for sidedness 112 pts had a left disease and 67 pts right disease; 71 pts received only one previous CHT line and 100 more than two lines. PFS and OS were evaluated by Kaplan-Meier curves and Cox-regression analyses in different subgroups (RAS mutational status, sidedness, previous CHT lines) to estimate their effect on survival endpoints. Results: We recorded a mean PFS and OS of 15,28 [95%CI:10,36-20,20] and 24,61 [95%CI:19,07-30,14] months, respectively, with no difference in efficacy outcomes observed among the different subgroups (one vs. more than one previous CHT lines; left vs. right primary side; k-ras status mutated vs. wt). Finally, we recorded a 2, 5 and 10 year OS-rate, in 42, 17 and 14 percent of the patients, respectively. The occurrence of self-limiting autoimmunity was confirmed as highly predictive of longer survival. Conclusions: These results confirm that GOLFIG regimen has strong efficacy in mCRC pts and may represent a reliable option in pretreated setting without evident effect of known prognostic variants. Such data offer a strong basis for future clinical trials in mCRC patients, where GOLFIG may represent a scaffold for combinatory immunotherapy approaches with immune-checkpoint blocking drugs.
FOLFOXIRI versus doublet-regimens in the first-line therapy of MSI-S right-sided (RS) metastatic colorectal cancer (mCRC): A survival analysis.
Authors: Jacome Alexandre A , Kee Bryan K. , Fogelman David R. , Shureiqi Imad , Dasari Arvind , Raghav Kanwal Pratap Singh , Morris Van K. , Johnson Benny , Wolff Robert A. , Overman Michael J. , Kopetz Scott , Rogers Jane , Ahmed Shahab U. , Mehdizadeh Amir , Eng Cathy
Published: May 2019

e15060

Background: Microsatellite stable (MSI-S) RS mCRC patients (pts) have a worse prognosis relative to left sided tumors for overall survival (OS). The present analysis aims to test the hypothesis that a triplet-regimen is superior compared to doublet-regimens (DR; FOLFOX or FOLFIRI) for OS. Methods: Pts with treatment-naive RS mCRC at MD Anderson Cancer Center between January/2011 to December/2018 were selected. We compared the progression-free survival (PFS) and OS of mCRC pts treated with FOLFOXIRI versus DR. Pts treated with anti-EGFR therapy were excluded. Results: A total of 37 pts were treated with FOLFOXIRI and 111 pts with DR. There were no statistical difference between groups regarding gender, KRAS and BRAF mutations, peritoneal metastasis and bevacizumab use. There were statistical difference in age (median: 46y vs 59y) and metastasectomy rates (14% vs 32%) (p < 0.001). KRAS mutation was found in 65% of the population. Median follow-up was 55.3m. Median PFS was 6.5m vs 11.2m (HR: 1.30 95% CI 0.85 – 1.99) and median OS was 17.0m vs 26.3m (HR: 1.01 95% CI 0.60 – 1.68). By univariate analysis, pts who have undergone metastasectomy had superior PFS (14.9m vs 9.2m; p<0.001) and OS (32.4m vs 22.9m; p=0.003). By multivariate analysis adjusted for age, BRAF mutation, metastasectomy, bevacizumab use and, treatment regimen, only age and metastasectomy had prognostic influence for PFS (p=0.039 and p=0.026, respectively). Conclusions: Despite RS having a poor prognosis for OS, our study does not suggest that RS mCRC pts benefit from intensive treatment. Randomized clinical trials may suggest more individualized therapies.
The efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer (ACC) patients: An interim analysis of a multicenter, phase II trial.
Authors: Liu Yunpeng , Teng Zan , Qu Xiujuan , Zhang Yan qiao , Zheng Zhendong , Wen Fugang , Bai Yuxian , Piao Ying , Wang Ying , Teng Yuee , Zhao Mingfang , Jin Bo , Li Xin , Shi Jing , Yu Ping , Qu Jinglei , Luo Ying
Published: May 2019

e15061

Background: There are limited therapeutic options for the treatment of advanced colorectal cancer which fail first-line chemotherapy. Phase I studies have shown that the combined application of the irinotecan (CPT-11) and raltitrexed has significant synergistic effect and acceptable toxicity. The aim of this multicenter study was to assess the efficacy and toxicity of second-line raltitrexed plus irinotecan in Chinese patients with advanced colorectal cancer. Methods: This is an open-label,single-arm, multicenter, phase II trial (Registered in clinicaltrials.gov with NCT03053167).Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of oxaliplatin and fluorouracil therapy. Enrolled patients received CPT-11 (180 mg /m2 , d1) and raltitrexed (3 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were disease control rate (DCR), objective response rate (ORR), overall survival (OS), quality of life (QOL) and safety. In all, 100 patients were required for primary point testing. Results: Between November 2016 and December 2018, a total of 70 patients were screened for enrollment and 53 patients reached the primary endpoint. Nine patients achieved a partial response and twenty-seven stable disease. The overall response rate was 17% (9/53) and the disease control rate was 67.9% (36/53). Median progression-free survival (mPFS) was 4.3 months and median overall survival was not observed. The most common adverse events were elevated transaminases (21/53), fatigue (14/53), diarrhea (12/53), neutrocytopenia (10/53), erythrocytopenia (9/53), hypohemoglobin (8/53) and leukocytopenia (6/53). The total incidence of grade 3/4 toxicity was 17% (9/53) , mainly diarrhea (2/53), neutrocytopenia (2/53) and elevated transaminases (2/53). There were no treatment-related deaths. Conclusions: We have demonstrated that CPT-11 plus raltitrexed is active and feasible in patients with second-line treatment in advanced colorectal cancer. This trial will progress as planned. Clinical trial information: NCT03053167.
Human papillomavirus, radiation dose and survival of patients with anal cancer.
Authors: Kabarriti Rafi , Brodin Patrik , Ohri Nitin , Narang Rahul , Huang Renee , Chuy Jennifer W. , Rajdev Lakshmi , Kalnicki Shalom , Guha Chandan , Garg Madhur
Published: May 2019

e15071

Background: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS. Methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 – 2015. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates. Results: We identified 5,927 patients with tumor HPV status for this analysis, 3,523 (59.4%) had HPV positive disease and 2,404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR=0.81 (95%CI: 0.68-0.96), p=0.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR=1.11 (95%CI:0.86-1.43), p=0.43). In the unmatched cohort, there was an increase in 3-year OS for patients with HPV positive tumors or early stage disease up to 45-49.9 Gy (p<0.001), whereas for patients with HPV negative and locally advanced disease there was an increase in survival from 46% at 30-44.9 Gy, to 64% at 45-49.9 Gy (p=0.093) and further to 71% at 50-54.9 Gy (p=0.005). Conclusions: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 50-55 Gy was associated with better OS, mainly for locally advanced disease in HPV negative patients. Multivariable Cox proportional hazards regression for OS. [Table: see text]
Analytical and clinical validation of a novel amplicon-based NGS assay for evaluation of circulating tumor DNA in metastatic colorectal cancer patients.
Authors: Wang Beili , Wu Shengchao , Huang Fei , Shen Minna , Jiang Huiqin , Yu Yiyi , Yu Qian , Yang Yihui , Zhao Ying , Zhou Yiwen , Pan Baishen , Liu Tianshu , Guo Wei
Published: May 2019

e15084

Background: Evaluating the tumor RAS/BRAF status is important for treatment selection and prognosis assessment in metastatic colorectal cancer (mCRC) patients. Correction of artifacts from library preparation and sequencing is essential for accurately analyzing circulating tumor DNA (ctDNA) mutations. Here, we assessed the analytical and clinical performance of a novel amplicon-based next-generation sequencing (NGS) assay, Firefly, which employs a concatemer-based error correction strategy. Methods: Firefly assay targeting KRAS/NRAS/BRAF/PIK3CA was evaluated using cfDNA reference standards and cfDNA samples from 184 mCRC patients. Plasma results were compared to the mutation status determined by ARMS-based PCR from matched tissue. For samples with mutation abundance below the limit of detection (LOD), were retested again by droplet digital polymerase chain reaction (ddPCR) or NGS. Results: Firefly assay demonstrated superior sensitivity and specificity with 98.89% detection rate at allele frequency of 0.2% for 20ng cfDNA. Generally, 40.76% and 48.37% of the patients were reported to be positive by NGS of plasma cfDNA and ARMS of FFPE tissue, respectively. The concordance rate between the two platforms was 80.11%. In pre-treatment cohort, the concordance rate between plasma and tissue was 93.33%, based on the 17 common exons that Firefly and ARMS genotyped, positive percent agreement (PPA), and negative percent agreement (NPA) for KRAS/NRAS/BRAF/PIK3CA was 100% and 99.60%, respectively. Conclusions: Total plasma cfDNA detected by Firefly offers a viable complement for mutation profiling in CRC patients, given highly agreement with matched tumor samples. Together, these data demonstrate that Firefly could be routinely applied for clinical applications in mCRC patients.
Real-world study of cetuximab used every other week versus weekly in US patients with metastatic colorectal cancer (mCRC).
Authors: Lamy Francois-Xavier , Batech Michael , Salim Shaista , Boutmy Emmanuelle , Pescott Chris , Ronga Philippe
Published: May 2019

e15087

Background: After an initial dose of 400 mg/m², cetuximab (CET) at a dose of 250 mg/m² in combination with chemotherapy (CT) is approved for once-weekly (q1w) use in the treatment of RAS wild-type metastatic colorectal cancer (mCRC). However, off-label use of CET 500 mg/m2 administered every other week (q2w) has been observed in clinical practice. This study aimed to test the noninferiority of q2w vs q1w administration on overall survival (OS) using US claims data. Methods: Using IBM MarketScan, a large US insurance claims database, a cohort of patients with mCRC treated with CET + CT between 2010 and 2016 was identified and classified as q1w or q2w based on observed infusion patterns. The initial CET prescription was defined as the index date, and patient death was determined using a previously published algorithm. Confounding was accounted for using high-dimensional propensity scoring (hdPS) methodology with inverse probability of treatment weighting (IPTW). OS for both groups was compared using Cox proportional hazards regression. Confounders that remained imbalanced after hdPS with IPTW were added to the Cox model. The noninferiority of the q2w regimen was tested with a margin hazard ratio (HR) of 1.25 for q2w vs q1w. Results: 2,869 patients with mCRC exposed to CET were identified of which 1,865 (65.0%) and 1,004 (35.0%) were classified in the q1w and q2w groups, respectively. The mean age of patients was 60.1±11.7 years for q1w and 58.1±11.1 years for q2w. Most patients were male: 57.5% and 60.8% in q1w and q2w, respectively. Approximately 70% of patients in both groups had received prior treatment for mCRC. The most frequently used CT with CET was irinotecan based (64.5% in q1w and 76.5% in q2w). There were 1,628 deaths observed during follow-up (56.7%). After hdPS with IPTW adjustment, differences remained in associated CT (standardized difference <0.25). Crude HR for OS was 1.05 (95% CI, 0.94-1.18), and adjusted HR for OS was 1.04 (95% CI, 0.93-1.17). The inferiority hypothesis was rejected at p<0.001. Conclusions: In this large US claims database, when assessing OS, the q2w administration schedule was found to be noninferior to the q1w schedule in patients with mCRC.
The study of the significance and prognosis of the differential expressed miRNAs and their target genes associated with biological in colorectal cancer.
Authors: Wang Mingyun , Yang Mi
Published: May 2019

e15088

Background: MicroRNAs (miRNAs) have been related to prognostic indicators (such as stage and survival) in colorectal cancer. This study aimed to identify differentially expressed miRNAs and their target genes associated with biological significance and prognosis in colorectal cancer. Methods: The colorectal cancer, colorectal adenoma, and normal samples were obtained from the gene expression profile of GSE71187. A union of differentially expressed genes (DEGs) in the three groups was identified. The significantly different modules with highly interconnected DEGs were identified using weighted correlation network analysis (WGCNA) and were enriched to the KEGG pathway and GO function. Subsequently, the protein-protein interaction (PPI) network for DEGs in the module and the integrated regulatory network of miRNA-DEGs were constructed. In addition, the relationship of target DEGs and prognostic information was analyzed. Results: Three significantly different modules were identified, such as the brown, turquoise, and grey modules. The turquoise module including LTC4S, KLRK1, UNC5C, etc., which was mainly enriched to cell adhesion, cytokine−cytokine receptor interaction, and chemokine signaling pathway, inhibited the development of colorectal cancer. Subsequently, PPI network was constructed with the 678 DEGs in the three modules. Moreover, the miRNA-DEGs network was constructed with the 17 target DEGs (CXCR1, LTC4S, BTK, IGF1, etc.) and 14 miRNA (hsa-miR-335-5p, etc.). Finally, the overexpressed LTC4S was a good prognostic biomarker for colorectal cancer. Conclusions: The hsa-miR-335-5p might have potential prognosis value by targeting LTC4S and CXCR1 in colorectal cancer.
Racial disparities in clinico-pathological features and survival rates of early-onset colorectal cancer.
Authors: Acuna Villaorduna Ana , Kaumaya Meghan , Goel Sanjay
Published: May 2019

e15089

Background: Early-onset colorectal cancer (EO-CRC) incidence is increasing disproportionately among minorities compared to Non-Hispanic Whites (NHW). EO-CRC have aggressive features such as higher grade and advanced stages. The appropriate age to start screening colonoscopy (SC) in NHW and minorities remains controversial; varying between 45 and 50 years old. We aim to compare EO-CRC clinico-pathological characteristics and survival rates by race groups. Methods: Patients with colorectal adenocarcinoma (CRC) with available race and stage as per AJCC 6th edition were identified using the SEER registry (1973-2010). EO-CRC was defined as CRC before age 50 years. Clinico-pathological features, overall survival (OS) by Kaplan Meier curves and mortality predictors by multivariate analysis were evaluated by race groups. Results: 180 605 patients with CRC were identified; 10.2% had EO-CRC. Mean age of diagnosis was 42.7 years and EO-CRC frequency was higher in minorities (Hispanics (H):16.7%, Non-Hispanic Black (NHB):12.7% and Asian (A): 12.8%) compared to NHW (8.7%). EO-CRC in NHB was predominantly seen in females. The rectum was the most common location for all races. Two-thirds of tumors were located between the sigmoid and anal regions in all races except NHB that had higher frequencies of right-sided tumors. Compared to other races, NHB had worse OS at all stages and tumor locations. NHB was associated with 72% increased risk of death by multivariate analysis. Conclusions: Our data suggest that EO-CRC frequency, pathological features and OS differ by race group; hence SC guidelines should be tailored accordingly. SC would be considered early; especially in minorities. Complete colonoscopy should be considered for NHB given higher rates of right-sided tumors and worse OS; while sigmoidoscopy may be adequate for others up to age 50, given higher rates of tumors located in the sigmoid to anal region. [Table: see text]
Toxicity of chemotherapy in patients with colorectal cancer: The role of age in the Latin American setting.
Authors: Namuche Fernando , Montenegro Paola Catherine , Leon Jorge , Flores Claudio J.
Published: May 2019

e15095

Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. In our country, the toxicities of systemic treatment have not been analyzed in a large population in the different disease settings. Numerous clinical studies have shown an association between toxicities and age, type of chemotherapy, number of courses, and others. Our objective was to explore the toxicities presented in our population and find if any variables could help us predict these toxicities. Methods: We retrospectively reviewed the electronic medical records of 371 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. The primary outcome measure was if the patient developed toxicity ≥3 assessed with multiple variables: age, sex, tumor location, NLR, PLR, pathological stage group (PSG), type of chemotherapy (CT), liver metastases, metastasectomy performed, albumin level, CEA, nodal involvement, time to CT, number of CT courses. Multivariable analysis in logistic regression model was adjusted for the factors statistically significant in the univariable analysis. Results: A total of 371 patients were included, of which 95 (25.6%) developed a ≥3 grade toxicity. The more frequent toxicity was neuropathy (30.5%). Univariate logistic regression analysis showed that age, albumin level, PSG, time to CT, number of CT courses, type of chemotherapy (CT), tumor location and liver metastases were associated with a ≥3 grade toxicity. Furthermore, multivariate regression analysis demonstrated that stage IV [OR, 0.012; 95% CI, 0.002-0.078; p < 0.001], age ≥70 [OR, 3.475; 95% CI,1.818-6.643; p < 0.001], number of courses [OR, 0.839; 95% CI, 0.763-0.922; p < 0.001] and albumin levels [OR, 0.391; 95% CI,0.257-0.596; p < 0.001]were independently risk factors for ≥3 grade toxicity. Conclusions: Stage IV, age ≥70, a greater number of CT courses and lower albumin levels were independently associated with a ≥3 grade toxicity.
Spatial heterogeneity of KRAS mutations in colorectal cancers: A population-based study in northern France.
Authors: Ploquin Anne , Genin Michael , Hebbar Mohamed , Occelli Florent , Lanier Caroline , Decarpentries Clotilde , Pannier Diane , Turpin Anthony
Published: May 2019

e15101

Background: Somatic mutations in the KRAS gene are present in about 40% of tumors from colorectal cancer (CRC) patients and are associated with a resistance to anti-EGFR therapies. However, no clinical features have been linked to KRAS mutations in CRC. In this study, we attempted to identify the potential geographical population clusters of KRAS mutations in CRC patients in northern France. Methods: All patients with CRC who were identified to have KRAS mutations performed by pyrosequencing between 2008 and 2014 at the Regional Molecular Biology Platform at Lille University Hospital were included. We retrospectively collected demographic and geographic data from these patients. The proportions of KRAS mutation were smoothed to take into account the variability related to low frequencies and spatial autocorrelation. Geographical clusters were searched using spatial scan statistical models. Then, we made an ecological study. Results: 2,486 patients underwent a KRAS status available. A mutation of KRAS codon 12 or 13 performed by pyrosequencing was found in 1,018 patients (40.9%). We report 5 clusters of over-incidence but only one elongated cluster that was statistically significant ranging from the city of Tourcoing to the city of Marquion (Cluster 1; smoothed proportion of KRAS mutation: 0.4570; RR = 1.29; p = 0.0314). The ecological study did not highlight a significant association between KRAS mutations and the distance to the Closest Waste Incineration Plant , and between KRAS mutations and The French Ecological Deprivation Index. There was a greater frequency of KRAS mutations in some areas close to major highways and big cities in northern France. Conclusions: There is a spatial heterogeneity of KRAS codon 12 or 13 mutations in CRC in northern France. These data demand deeper epidemiological investigations to identify environmental factors such as air pollution as key factors in the occurrence of KRAS mutations.
Exosomes derived miR-454-3P to promote the progression of colorectal cancer via MIER1-mediated Notch signaling activation.
Authors: Li Dawei , Zhao Senglin , Xu Ye , Li Xinxiang , Cai Sanjun
Published: May 2019

e15108

Background: Mesoderm induction early response 1 (MIER1) was downregulated and predicted poor prognosis in CRC patients. However, the mechanisms of the down regulation of MIER1 in CRC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors.Here, we identified exosomes derived miR-454-3p as a novel regulator of MIER1 in CRC. Methods: The effect of miR-454-3p expression on cancer proliferation and metastasis was assessed in cells by altering the expression of miR-454-3p in vitro and in vivo. Mechanistic investigation was carried out by using cell and molecular biology approaches. Results: Functionally, ectopic expression or silencing of exosomes derived miR-454-3P, respectively, promoted or inhibited CRC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of CRC cells and epithelial to mesenchymal transition of CRC cells in vitro and in vivo. Molecularly, exosomes derived miR-454-3P functioned as an onco-miRNA by activating the MIER1-regulated NOTCH pathway. Overexpression or silencing of MIER1 could partially reverse the effects of the overexpression or repression of exosomes derived miR-454-3P on CRC progress caused by activation of the NOTCH pathway in vitro and in vivo. Clinically, high miR-454-3P expression predicted poor survival in CRC patients, especially combined with low MIER1 expression. Conclusions: Collectively, we identified exosomes derived miR- 454-3p as an onco-miRNA, which acts by directly repressing MIER1 in CRC.
Completion of adjuvant chemotherapy with Cape/CAPOX in colon cancer: A retrospective database study.
Authors: Chu Edward , Wang Xue , Frohlich Maxfield , Tran Melody , Lee Won Chan
Published: May 2019

e15116

Background: Fluorouracil-based adjuvant chemotherapy has been shown to improve survival of patients with early-stage colon cancer. Suboptimal adherence to oral chemotherapy, such as capecitabine, remains a serious issue and reduces treatment efficacy. Patient barriers to adherence include adverse effects and high medical costs. This study assesses the completion rates and associated factors in patients on capecitabine monotherapy (Cape) and capecitabine with oxaliplatin (CAPOX) for adjuvant treatment of early-stage colon cancer. Methods: Patients with a primary/secondary diagnosis of early-stage colon cancer between April 2013-March 2017, and 1+ claim of Cape or CAPOX within 60 days of colectomy were identified from the MarketScan Commercial/Medicare Database. Therapy completion rates (treatment ≥7 cycles) were calculated. Multivariate logistic regressions analyses were used to assess the factors (patients’ age, gender, payer type, geography, comorbidities, healthcare costs, etc.) associated with treatment completion. Results: A total of 679 patients met the eligibility criteria (mean age ± SD: 57.3 ± 11.5 years, 54% male), of which 382 (56%) were on Cape (mean age ± SD: 60.2±12.4) and 297 (44%) on CAPOX (mean age ± SD: 53.6±9.0). Completion rates were 43% in Cape and 42% in CAPOX. The baseline overall mean monthly healthcare cost was significantly higher in non-completers vs. completers (Cape: $9,870 vs $7,169, P=0.003; CAPOX: $10,009 vs $8,068, P=0.01). Multivariate logistic regression showed that patients <65 years of age on CAPOX were more likely to complete treatment than patients ≥65 years on CAPOX (Odds Ratio=5.1, P=0.03). Conclusions: Cape and CAPOX completion rates are suboptimal in patients with early-stage colon cancer. Non-completion of therapy is associated with significantly higher baseline healthcare costs for both Cape and CAPOX, as is older age for CAPOX. The low completion rates highlight the unmet need for more effective strategies to optimize oral chemotherapy for the adjuvant treatment of early-stage colon cancer. [Table: see text]
Exosomal markers (CD63 and CD9) expression using immunohistochemistry (IHC) in patients with right-sided and left-sided colon cancer.
Authors: Prodduturvar Pranitha , McCormick Ben , Mneimneh Wadad , Dal Zotto Valeria , Grimm Leander , Rider Paul , Hunter John , Iliff Greire , Smith Clayton , Patel Girijesh K. , Pannell Lewis , Singh Seema , Singh Ajay , Perry Josiah , Khushman Moh'd M.
Published: May 2019

e15119

Background: Embryologically, the right colon (cecum, ascending colon, hepatic flexure and proximal two-thirds of the transverse colon) is derived from the midgut, whereas the left colon (sigmoid colon, descending colon, splenic flexure and distal third of the transverse colon) is derived from the hindgut. There are clinical, pathological and molecular differences between patients with right-sided colon cancer (RSCC) and left-sided colon cancer (LSCC). Exosomes mediate intercellular communications and interactions and have pivotal roles in cancer behavior. CD63 and CD9 are widely accepted exosomal markers. Here we explored CD63 and CD9 expression using immunohistochemistry (IHC) in patients with RSCC and LSCC. Methods: Between 2015 and 2018, 63 patients underwent colon surgical resection for whom we had available tissues for CD63 and CD9 IHC staining. Two pathologists independently scored CD63 and CD9 expression in the tumor and adjacent normal mucosa (ANM). Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean quick-score (Q-score) was calculated (intensity x percentage). Unpaired t test was used for statistical analysis. Results: Median age was 64 (range 33-78). Females represented 60% of our cohort. Caucasians, African Americans and other Ethnicities represented 55%, 40% and 5% respectively. The sidedness was designated as RSCC in 52% and as LSCC in 48%. The ANM and Tumor CD63 Q scores were 225 vs 191 (p = 0.009) in RSCC and 224 vs 154 (p = 0.0001) in LSCC respectively. The ANM and Tumor CD9 Q scores are 134 vs 152 (p = 0.142) in RSCC and 135 vs 154 (p = 0.137) in LSCC respectively. In patients with RSCC and LSCC, the mean Tumor CD63 Q score is 191 vs 154 (p = 0.024), while the mean ANM CD63 Q score is 225 vs 224 (p = 0.920). The mean Tumor CD9 Q score is 152 and 154 (p = 0.883) and the mean ANM CD9 Q score is 134 vs 135 (p = 0.926). Conclusions: In our cohort of patients with RSCC and LSCC, the exosomal marker CD63 expression is lower in the tumor compared to the ANM. While ANM CD63 expression was similar between RSCC and LSCC, tumor CD63 expression was higher in RSCC compared to LSCC. The exosomal marker CD9 was not found to have significant differential expression between ANM and tumor and between RSCC and LSCC. To our knowledge, this is the first study to explore exosomal markers expression using IHC in patients with RSCC and LSCC.