bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of BRAF gene mutation in Thai sporadic colorectal cancer patients.
Authors: Korphaisarn Krittiya , Roothumnong Ekkapong , Nimmannit Akarin , Limwongse Chanin , Manuyakorn Ananya , Klaisuban Wipawi , Akewanlop Charuwan 
Published: March 2020

e14051 Background: The role of BRAF gene mutation has been studied for its association with prognosis of colorectal cancer (CRC). The prevalence was reported 10-15% in Caucasian patients. However, there is no existing data in Thai patients. This study aimed to determine the prevalence of BRAF V600E mutation, association with various clinicopathological features and outcome in Thai sporadic CRC patients. Methods: DNA was extracted from randomly selected formalin-fixed paraffin-embedded tumor blocks of CRC patients with stage I-IV receiving surgery of the primary tumors at Siriraj Hospital between 2006 and 2007. BRAF V600E mutation was performed by two-round allele-specific PCR and analysis using high sensitivity DHPLC. The association between patient characteristics and BRAF status with overall survival (OS) and disease free survival (DFS) were explored by Kaplan-Meier estimation and log-rank test together with Cox’s proportional hazard regression. Results: BRAF V600E mutation was identified in 7 out of 188 patients (3.7%). Four patients were female. There were more likely to found in tumors on the left side (n=4) compared with right side (n=2) and rectum (n=1). All patients with mutation had stage I-III diseases; one with stage I and 3 with stage II and III each. Four had moderately differentiated tumors. Six patients had neither lymphovascular nor perineural invasion. Patients with mutation seemed to have better survival. In multivariate analysis, BRAF mutation did not have major prognostic value regarding DFS or OS. Conclusions: The prevalence of BRAF V600E mutation in Thai sporadic CRC was 3.7% which was lower than what reported in Caucasian patients. Further study with larger number of patients is warranted to determine whether BRAF mutation has significant prognostic value.
miRNA expression as a predictor of survival in patients with metastatic colorectal cancer treated with EGFR inhibitors.
Authors: Imbeaud Sandrine , Manceau Gilles , Bachet Jean-Baptiste , Emile Jean-François , Bibeau Frédéric , Diebold Marie Danielle , Marcaillou Charles , Rio Frio Thomas , Le Corre Delphine , Bouche Olivier , Liebaert Francois , Laurent-Puig Pierre 
Published: March 2020

e14059 Background: The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. EGFR inhibitors have been tested for treatment of a variety of cancers but they are generally plagued by low response rates, leading to ineffective or non-optimal chemotherapy, unnecessary drug toxicity and expense. In colorectal cancer, KRAS mutations are clearly associated with resistance to anti-EGFR antibodies. A major challenge is to identify, in non-mutated KRAS patients, markers that can predict response to this therapy. This study aimed to develop a miRNA expression-based model for evaluating the responsiveness of patients with KRAS wild-type metastatic colorectal cancer to one or more EGFR inhibitors prior to treatment. Methods: miRNA profiling of KRAS wild-type tumors was performed on a discovery set of 44 patients with metastatic colorectal cancer treated with anti-EGFR inhibitors. A miRNA expression-based predictor of survival risk group was calculated by combining a Cox proportional hazards model and a supervised principal component method. Results: miRNA profiling of the discovery set identified hsa-miRNA-31* whose expression in tumor samples was highly correlated with survival and displayed prediction prospective for disease-free and overall survivals. Parameters of the hsa-miRNA-31* expression-based prediction model were determined on a subgroup of 23 patients. Its discriminative ability was evaluated on the complementary 21 samples that included 19 events. In this validation set, 4 of the 6 patients classified as “low risk” by the model survived for more than 25 weeks as disease-free whereas 11 of the 13 patients classified as “high risk” displayed disease progression within 25 weeks, suggesting a specificity of 85% [95% CI: 54%-98%] and a sensitivity of 67% [95% CI: 22%-96%] for the prediction model. These values were associated with a PPV of 67%, [95% CI: 22%-95%] and a NPV of 85% [95% CI: 54%-98%]. Conclusions: Our findings demonstrated that a prediction model based on the level of expression of hsa-miRNA-31* could evaluate whether a patient with a KRAS wild-type metastatic colorectal cancer is likely to respond to an EGFR inhibitor.
Two decades of therapy in metastatic colorectal cancer (mCRC): An analysis to discern the contribution and progress made by chemotherapy.
Authors: Jawed Irfan , Wilkerson Julia , Duffy Austin G. , Fojo Antonio Tito 
Published: March 2020

e14064 Background: The past 20 years have seen progress in mCRC with more effective agents and better medical, surgical and supportive care. Methods: Systematic review of 101 phase III and large phase II trials in mCRC to quantify benefit over time with first-line and subsequent therapies. Outcomes in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), and overall survival (OS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly OS of CA improved 0.58 mos/yr likely reflecting subsequent use of experimental regimens in CA and improvement in mCRC care over time. Chemotherapy has contributed only partly to gains in OS since (1) only modest improvements of PFS (0.33 [EA] and 0.26 [CA] mos/yr) and we have shown OS gains are proportional to PFS gains indicating other factors are as or more important than chemotherapy; and (2) lack of OS improvement in 14 second/subsequent line trials. Furthermore, to assess the contribution of each drug/drug class to improvement in OS we performed linear regression with OS the dependent variable versus time publication. We found oxaliplatin, irinotecan and bevacizumab have contributed to progress; but not cetuximab/panitumumab likely explained by inclusion of pts with tumors harboring mutant ras in studies. Not surprisingly, capecitabine in place of 5-fluorouracil had no impact on progress made. As expected PFS correlates highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD was an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of mCRC patients has improved gradually over the past two decades, with gains from chemotherapy and importantly gains from other factors, including lead-time bias, better loco-regional approaches and supportive care. Gains from first line therapies have been modest but consistent; gains from second line therapies have been disappointing. We believe future progress will be more fruitful if emphasis is given to improving second line therapies.
Immunological effects as a biomarker of chemotherapy in metastatic colorectal cancer.
Authors: Sasatomi Teruo , Ogata Yutaka , Yamana Hideaki , Akagi Yoshito , Shirouzu Kazuo 
Published: March 2020

e14077 Background: Many multiple anti cancer drugs regimens have been established for metastatic colorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 26 metastatic colorectal cancer patients have been started chemotherapies. Their PBMC were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3, CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs (CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less than half. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased patients. (p=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Conclusions: We found that the CTL/T reg ratio of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.
Early outcome of a phase I study of interrupted pulse-dosed axitinib combined with FOLFOX or FOLFIRI in refractory metastatic colorectal cancer.
Authors: Roeland Eric , Shimabukuro Kelly Anne , Fanta Paul Timothy , Parker Bethany H. , Hwang Michael , Reid Tony R. 
Published: March 2020

e14078 Background: Therapeutic inhibition of angiogenesis pathways may improve response of chemotherapy refractory malignancies. We evaluated the combination of axitinib, a multi-target VEGF receptor inhibitor, used intermittently with 5-FU based chemotherapy for refractory mCRC. We hypothesized that intermittent pulse dosed axitinib may improve response by delivering chemotherapy during tumor reperfusion after release from angiogenesis inhibition. We present preliminary data of the Phase I portion evaluating the safety and efficacy of interrupted pulse dosed axitinib + FOLFIRI. Methods: Initially, Pfizer A4061020 was a phase IB study of axitinib + bevacizumab + FOLFOX vs. FOLFIRI to evaluate potential overlapping toxicities. A4061020 was expanded to determine the MTD of 7 days of intermittent pulse dosed axitinib + FOLFIRI or FOLFOX; while secondary outcomes include TTP and OS. Enrollment was open to mCRC with progression on both oxaliplatin and irinotecan-based regimens. Results: Preliminary data of 10 mCRC subjects show intermittent pulse dosed axitinib at 14mg and 20mg in combination chemotherapy treatment is safe and tolerable (few grade 3 and one grade 4 AE). The MTD is 20mg daily. We observed a median clinical TTP of 10.1 mos (0.8 to 21.5 mos) vs. a median TTP of 5 mos on last line of chemotherapy (1 to 13 mos). Subjects treated with pulse dose axitinib appear to demonstrate a favorable OS, however these data are still immature. Conclusions: In 10 heavily pre-treated mCRC subjects, intermittent pulse dosed axitinib demonstrates safety, tolerability, and improved TTP. Subjects treated with this approach demonstrated a favorable TTP compared to the prior line of therapy and OS. Intermittent, pulse dosed axitinib warrants further study in a larger population. [Table: see text]
Mucinous histology to predict disease-free survival in microsatellite stable stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy.
Authors: Ahn Joong Bae , Kim Se Hyun , Shin Sang Joon , Lee Kang Young , Kim Tae IL , Hur Hyuk , Min Byung Soh , Kim Nam Kyu , Chung Hyun Cheol , Roh Jae Kyung 
Published: March 2020

e14084 Background: The prognostic role of mucinous histology of the colon cancer has been studied for decades and remained controversial. The aim of this retrospective study was to investigate whether mucinous adenocarcinoma (MA) is associated with a worse prognosis than that of non-mucinous adenocarcinoma (NMA) in patients with stage III colon cancer. Methods: This study enrolled unselected 402 patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for microsatellite instability (MSI) by polymerase chain reaction (PCR) to determine MSI-high (MSI-H) or microsatellite stable (MSS). Kaplan-Meier method, log-rank test, and Cox proportional hazards regression models were used. Results: Among 402 patients, 42 patients (10.4%) were MA and 26 patients (6.5%) were MSI-H. Compared with MSS tumors, MSI-H tumors was associated with a higher rate of MA (26.9% vs 9.3%, P=0.005). In MSS tumors (n=376), 3-year disease-free survival (DFS) rate was 79% and 55% in NMA and MA, respectively (log rank, P=0.014). In MSI-H tumors (n=26), no statistically significant difference of DFS between MA and NMA was found. In multivariate analysis, MA remained an independent significant poor prognostic factor for DFS (HR=1.9; 95% CI, 1.003-3.717; P=0.049) in MSS patients. Conclusions: Mucinous histology is an independent poor prognostic factor for DFS in patients with microsatellite stable stage III colon cancer after adjuvant FOLFOX chemotherapy. [Table: see text]
Cost-effectiveness analysis of cetuximab and panitumumab as first-line metastatic colorectal cancer therapies in Spain.
Authors: Moreno Victor , Martinez-Amores Brezo , Barriuso Jorge , Mezquita Laura , Ibañez de Cáceres Inmaculada , Ayuso Sacido Angel , Peña Jose Maria , Perona Rosario , Belda-Iniesta Cristobal 
Published: March 2020

e14093 Background: Current practice of clinical oncology is a challenge where increased efficacy of new-targeted therapies is counteracted by increasing costs. International financial crisis forces national health systems to optimize all therapeutic strategies maintaining clinical outcomes. Personalized medicine tries to select specific subpopulation of patients by biomarkers to refine therapeutic algorithms. We have performed a cost-effectiveness analysis to assess incremental cost-effectiveness ratio (ICER) per radiological response (RR) for cetuximab or panitumumab based scheduled as 1st line therapies for mCRC patients in Spain. Methods: Efficacy data were computed from all randomized trials (RT) that guided on-label uses of bevacizumab (K-Ras mut), panitumumab and cetuximab. Non- significant outcomes and toxicity as predictor of efficacy were excluded. Prices for drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For 1st line, median duration of therapy reported by RT was used to calculate the final budget. 70kg and 1.7 m were used as reference for patient dose calculations. Results: We simulated 3 main scenarios based on the possibilities of therapy for K-Ras wt patients assuming that all patients harboring a K-Ras mut. tumor received bevacizumab based chemotherapy. So, in scenario A K-Ras wt patients received weekly cetuximab combined with FOLFOX, ORR reaches 54% and global cost per RR sums €36,964. Scenario B: administering panitumumab-FOLFOX yields 51% ORR and € 38,880 per RR. Scenario C: cetuximab biweekly combined with FOLFOX yields 54% and €36,474. ICER for scenario A vs B is estimated at €4,394 per additional response. ICER for scenario C vs B yields a negative value of €4,432 per additional response. Conclusions: 1st line oxalipatin combinations of biweekly cetuximab for wt and bevacizumab for mutated patients optimize cost per additional response rate rather than panitumumab based schedules. Marginal cost differences between cetuximab and panitumumab therapies are exceeded by efficacy gap as measured by response rates in RT.
Association of marked thrombocytopenia at postoperative day 1 with incidence of liver dysfunction, morbidity, and mortality in metastatic colorectal cancer patients undergoing liver resection.
Authors: Gruenberger Thomas , Perisanidis Beata , Tamandl Dietmar , Stremitzer Stefan , Brostjan Christine , Gruenberger Birgit , Starlinger Patrick 
Published: March 2020

e14095 Background: After major liver resection, the most significant factor determining postoperative morbidity and mortality is the ability of the remnant liver to regenerate. Liver regeneration is a tightly regulated process involving various different growth factors. Recently, platelets have been shown to play a pivotal role in liver regeneration after partial hepatectomy. Methods: Patients treated with liver resection for metastatic colorectal cancer (mCRC) between January 2000 and December 2010 were eligible. Liver dysfunction (LD) was defined as bilirubin > 5 mg/dL or prothrombin time <50% within the first postoperative week. The association of marked immediate postoperative thrombocytopenia with LD, morbidity and mortality was analyzed. Results: 518 patients with mCRC were treated for liver metastasis, of whom 476 underwent liver resection. 67.9% of these had received preoperative CTx. 20.1% of all patients developed LD. Postoperative complications occurred in 39%. 7 patients died within 90 days after liver resection (1.5%). Postoperative platelets < 100 x 103/ml on the first postoperative day were the only liver function parameter predicting postoperative LD in multivariate analyses (p = 0.015). Furthermore, reduced platelets were significantly associated with increased morbidity (p = 0.014) and mortality (platelets < 100 x 103/ml – 4.1%, platelets > 100 x 103/ml – 1.5%, p = n.s.). Conclusions: Platelets < 100 x 103/ml on the first postoperative day seem to be an early marker to predict postoperative LD, increased morbidity and mortality in patients after liver resection. Using this cut-off, it might be possible to identify patients at high risk for developing postoperative LD and complications already on the first day after liver resection. Furthermore, this data suggests a pivotal role of platelets in hepatic regeneration.
Prognostic value of BRAF and KRAS mutations in colorectal cancer patients.
Authors: Murata Paola , Stradella Agostina , Páez David , Tobeña Maria , Sebio Ana , Paré Laia , González Alan , Espinosa Iñigo , Targarona Eduardo , Gich Ignasi , Barnadas Agust , Baiget Montserrat , Martin-Richard Marta 
Published: March 2020

e14104 Background: KRAS mutation has been established as a predictive marker of resistance to antiEGFR therapy in patients (pts) with colorectal cancer (CRC) but the role of BRAF is not yet clear. Both gene mutations have also been studied as prognostic factors but results are contradictory. AntiEGFR therapies impair evaluation of KRAS and BRAF as prognostic factors when overall survival is an endpoint. We hypothesized that if KRAS or BRAF were prognostic factors, they would influence time to relapse (TTR) after complete tumor resection. Methods: Patients who underwent surgery between 2007 and 2011 for stage II and III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and V600E BRAF mutation were analyzed. Clinical characteristics and mutation status were correlated with TTR. Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were located in the right colon in 27% of pts, in the transverse colon in 3%, in the left colon in 41%, and in the rectum in 29%. Most (55.3%) were stage III; 59% received adjuvant chemotherapy. KRAS and BRAF mutations were present in 66 (38.8%) and 5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71 weeks (w) (95% CI 63-79). V600E BRAF mutation was the only factor associated with TTR. TTR was 42 w in tumors with the BRAF mutation and 74 w in wild-type tumors (p=0.041). Among KRAS mutations, KRAS G12V conferred a significantly longer TTR (100w) than the other subtype mutations (69 w; p=0.05). Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic factor in CRC, conferring a shorter time to relapse. Additionally, the KRAS G12V determines a different behavior among KRAS mutation tumors.
Differences in survival for advanced-stage colorectal cancer (CRC) patients by lines of therapy received in a U.S. local oncology practice.
Authors: Foltz Boklage Susan H , Kreilick Charles , Asche Carl V , Haislip Sally , Gilmore James W. , Szabo Stephen , Williamson Todd E. , Valluri Satish , Seal Brian S. 
Published: March 2020

e14106 Background: Improvements in survival for advanced-stage colorectal cancer (CRC) patients who receive chemotherapy have been reported. We compared survival rates for patients with 3+ vs. <3 lines of therapy using electronic medical records of a local oncology practice in Georgia, USA. Methods: The Georgia Cancer Specialist (GCS) EMR Database (1/1/2005–07/ 31/2010) was used. The database contains data on patient demographics, cancer diagnostic information, chemotherapy and non-chemotherapy drugs administered written prescriptions, chemotherapy/radiation protocols, chemotherapy protocol changes, office visit information, and hospitalizations. Patients newly diagnosed with CRC between 01/01/05 and 06/31/10 treated with systemic therapy for CRC were identified. Patients were followed from initial CRC diagnosis to death, loss to follow-up, or end of study. Patients were categorized by number of lines of therapy received (1, 2, 3+) and original stage at diagnosis (III b/c, IV, unknown). Survival following initial line of therapy was evaluated using Cox proportional hazards models controlling forstage at diagnosis, type of 1st line treatment, and other patient characteristics. Results: The study included 704 patients with a median age of 63 years (age range 26-85 years) at diagnosis and 49% (n=345) female. 45% (n=317) and 42% (n=296) had stage IV and III b/c CRC at diagnosis, respectively. 53% (n=373) received only 1st line treatment, 27% (n=190) received 1st and 2nd line treatment and 20% (n=141) received 3rd line and beyond. The median follow up was 431 days and death was reported in 27%(n=190) of subjects. The multivariate Cox proportional hazard analysis indicated that there was no statistical difference in survival between patients who received 2nd line of therapy vs. 3 plus lines of therapy (HR=1.42; p<0.067). Conclusions: A non-statistical significant association between 2nd and more than 3 total lines of therapy in survival was found in subjects diagnosed with stage III B/C and IV. However the trend towards survival was present, indicating that some patients could benefit from the addition of 3rd line but it would require additional studies to confirm this.