bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of vemurafenib, a selective BRAFV600E inhibitor, in combination with a MEK inhibitor in BRAFV600E colorectal cancer models.
Authors: Higgins Brian , Kolinsky Kenneth Daniel , Yang Hong , Kim Min Jung , Li Jia Kui , Go Zenaida , Packman Kathryn , Bollag Gideon , Su Fei 
Published: February 2017

488 Background: BRAF mutations occur in about 10% of colorectal cancer (CRC). Most BRAF mutations involve the V600E amino acid substitution, resulting in constitutive activation of the MAPK signaling pathway. Vemurafenib (RG7204, PLX4032) is a first-in-class, BRAFV600E-specific small molecule inhibitor that dose-dependently inhibits tumor growth in V600E CRC xenografts. However, unlike responses observed in melanoma, single agent vemurafenib in a Phase I extension trial of 20 patients with previously treated metastatic CRC, resulted in only 5% response rate. The goal here was to explore in vitro and in vivo if addition of a MEK inhibitor (MEKi) could increase effects of vemurafenib on anti-proliferation and anti-tumor activity in BRAFV600E CRC cell lines. Methods: Combo of vemurafenib with a MEKi was tested in MTT assay for antiproliferative effect and combination effect was determined by combination index (CI) calculated by the CalcySyn software. Western analysis and Annexin V staining were utilized to evaluate combo effects on pathway inhibition and apoptosis induction. Optimal doses of both vemurafenib and MEKi were tested as single agent and in combination in the Colo205 and LS411N CRC xenograft models in nude mice. Results: Synergistic anti-proliferative effect was observed with the combo of vemurafenib and a MEKi in the V600E positive CRC cell lines tested. More effective pathway inhibition and apoptosis induction were observed with combo than either agent alone. Combination of vemurafenib and a MEKi delivered greater anti-tumor activity and increased life span of animals in the Colo205 and LS411N CRC xenograft models. Conclusions: These in vitro and in vivo data suggest that combined pharmacologic blockade within the RAS/RAF/MEK/ERK pathway is more effective than either agent alone and may be a way to exploit greater antitumor activity CRC patients in clinic.
Cetuximab-related skin toxicity in metastatic colorectal cancer (mCRC) patients and its correlation with molecular markers: Results from the German AIO CRC 0104 trial.
Authors: Stintzing Sebastian , Kapaun Christine , Laubender Ruediger P. , Jung Andreas , Neumann Jens , Modest Dominik Paul , Giessen Clemens Albrecht , Moosmann Nicolas , Wollenberg Andreas , Kirchner Thomas , Heinemann Volker 
Published: February 2017

491 Background: Skin toxicity is a frequent adverse event of EGFR targeting agents. The role of cetuximab induced skin toxicity (Cet-ST), for the most acneiform skin rash, as a prognostic or a predictive factor of treatment efficacy is currently under discussion. Methods: The prognostic and predictive value of Cet-ST in relation to treatment response and survival of patients of a randomized trial investigating CAPIRI plus cetuximab versus CAPOX plus cetuximab as first-line treatment of mCRC was analyzed. Cet-ST was grouped into clinically relevant (grade 2-3) and non relevant (grade 0-1) toxicity (NCI-CTCAE 3.0). KRAS mutations in codons 12 and 13, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism were evaluated in tumor specimens. Results: A total of 149 patients got cetuximab until the first tumor assessment (6 weeks) and were used for this analysis. Overall response rate was higher in patients with grade 2-3 Cet-ST when compared to grade 0-1 (62.1% vs. 41.3%). Patients without Cet-ST (grade 0) had a short PFS (1.9 months) and OS (11.0 months). PFS (7.8 months vs. 5.2 months) and OS (30.3 months vs. 18.0 months) were longer in patients with Cet-ST grade 2-3 than in patients with grade 0-1 Cet-ST. Almost 90% of Cet-ST occurred during the first two cycles of treatment. When only KRAS codon-12 mutated tumors which are thought not to be sensitive to cetuximab were investigated, Kaplan-Meier differences in PFS and OS times between patients with grade 0-1 Cet-ST and grade 2-3 Cet-ST became statistically significant. In a multivariate analysis, male gender, age and EGFR intron-1 polymorphism were significantly correlated with Cet-ST. Conclusions: Cetuximab related skin toxicity is a strong predictor of outcome. It is proposed that Cet-ST is rather a prognostic than a predictive factor since this effect is most evident in patients with KRAS codon-12 mutated tumors. EGFR intron-1 polymorphism appears to be a predictor of Cet-ST.
Colorectal cancer (CRC) KRAS mutational status and response to chemotherapy in absence of influence of epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) therapy.
Authors: Yarom Nirit , Boame Nana , Gresham Gillian , Hill David , Jonker Derek J. 
Published: February 2017

504 Background: KRAS mutations (MUT), present in ~40% of CRC, predict benefit from EGFR MAb treatment. The effect of mutation status on benefit from chemotherapy alone is less clear. Methods: Following ethics approval, 223 CRC patients with known KRAS status treated at a single institution were retrospectively analyzed for response to chemotherapy prior to initiation of EGFR MAb therapy. Tumour response rate and progression-free survival (PFS) were determined retrospectively. Given chemotherapy sequencing variability, a measure of the time to chemotherapy-refractory state (TTCR) was defined as time from start of first line therapy to progression on all drugs; ie fluoropyrimidines (F), irinotecan (I), and oxaliplatin (O), +/- bevacizumab (B). Results: Patients were median age 60 years (25-86), 58/42% male/female, 38% rectal or rectosigmoid, 18% liver-only metastases, 45.6% stage I-III and 54.4% stage IV at initial diagnosis, 43% prior adjuvant chemotherapy, 43/57% KRAS MUT/wild-type(WT) status. With a median follow-up of 27 months, 64 (29%) are alive. TTCR did not vary by KRAS status, with median 16.7 vs 14.8 months in WT vs MUT status patients, respectively, HR 0.85 [0.65-1.12], p=0.26. Overall survival (which now includes influence of any subsequent EGFR MAb therapy, received by 76/126 (60%) of KRAS WT status patients) did not differ significantly by KRAS status, with median survival 34.3 vs 29.2 months for WT vs MUT status, respectively, 0.79 [0.58-1.08], p=0.14. Conclusions: For most treatment strategies KRAS status did not affect 1st line PFS or time to chemotherapy-refractory state. However, for patients who received triple combination therapy, MUT status was associated with early progression. Small sample size, chance or some yet-to-be-elucidated molecular interaction may account for this finding. [Table: see text]
Alternative sequencing of FOLFIRI or mFOLFOX6 with erlotinib in the second-line treatment of metastatic colorectal cancer (mCRC): An ongoing phase II trial.
Authors: Lopez Charles D. , Vaccaro Gina M. , Kampa-Schittenhelm Kerstin M , Strother John M. , Burt Andrea , Masterson Jeff 
Published: February 2017

507 Background: Despite 1st-line response rates (RR) in mCRC of > 50% with FOLFOX or FOLFIRI, 2nd-line RRs are less (FOLFOX ~ 15%; FOLFIRI ~ 4%). Thus, there is a critical need for better 2nd-line strategies. Although use of anti-EGFR antibodies with chemotherapy has validated EGFR as a target in wt-KRAS mCRC, combining anti-EGFR tyrosine-kinase-inhibitors (TKIs) with chemotherapy has not shown consistent activity/tolerability. In vitro, anti-EGFR TKIs can induce a G0/G1 cell cycle arrest that attenuates chemo-induced apoptosis. However, when we alternately sequenced chemotherapy with erlotinib in HCT116p53+/+ CRC cells (mut-KRAS), we found markedly enhanced apoptosis (compared to chemotherapy alone or concurrent chemo/erlotinib). Based on these results, we initiated a clinical trial to alternately sequence 2nd-line chemotherapy with erlotinib in mCRC. Methods: Non-randomized, parallel Simon’s two-stage phase II (optimum design) using 2nd-line (opposite of 1st-line) mFOLFOX6 or FOLFIRI (d1,2; d14,15) alternating with erlotinib (E) 100 mgs qd (d3-8; d16-21). Primary objective: radiographic RRs by RECIST criteria. Secondary objectives: time to progression (TTP), 2nd progression free survival (PFS), toxicity and tolerability. 1st stage analysis at 10 pts/arm: mFOLFOX6/E or FOLFIRI/E arms will continue if >2/10 pts, or >1/10 pts, respectively with CR/PRs. 2nd-stage analysis at 29 pts/arm: mFOLFOX6/E or FOLFIRI/E will be considered promising if > 4/29 pts, or > 6/29 pts, respectively demonstrate CR/PRs. Results: n=15 pts to date. Of evaluable pts: 2 PR, 4 SD, 3 PD were observed in the FOLFIRI/E arm (n=9) and 1 SD in mFOLFOX6/E arm (n=1). Gr3/4 toxicities (n=10 evaluable pts): neutropenia (7), rash (1), nausea (1), oral pain (1), diarrhea (1), elevated LFTs (1), hyponatremia (1), elevated INR (1), GI bleed (1), abd pain (1). Dose reductions/treatment delays in evaluable pts: FOLFIRI/E (n=4/9); mFOLFOX6/E (n=0/1). Conclusions: The FOLFIRI/E arm demonstrates sufficient responses to expand accrual into the 2nd-stage. The mFOLFOX6/E arm continues 1st-stage accrual. Toxicities were generally manageable. Molecular correlates are ongoing.
CD133 status influences in prognosis of patients with metastatic colorectal cancer receiving cetuximab.
Authors: Inoue Dai , Matsusaka Satoshi , Yamamoto Noriko , Suenaga Mitsukuni , Mishima Yuji , Shinozaki Eiji , Terui Yasuhito , Mizunuma Nobuyuki , Ishikawa Yuichi , Hatake Kiyohiko 
Published: February 2017

509 Background: Recently, the cancer stem cell (CSC) theory has been proposed, and CD133 has been suggested as a potential marker of CSCs in metastatic colorectal cancer (mCRC). Cetuximab, an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody, has been approved for the treatment of mCRC. The purpose of this study is to evaluate the prognostic significance of CD133 expression in mCRC treated with cetuximab in combination with chemotherapy. Methods: We evaluated the prognosis of pts with mCRC treated with cetuximab retrospectively, and performed immunohistochemical staining to analyze the CD133 status. Non-parametric statistics, univariate and multivariate analysis were used. Results: From October 2008 to June 2009, 56 pts with measurable metastatic colorectal cancer were received cetuximab and 43 were evaluable. Patients characteristics were as follows : median age : 59.6 years (range 28-80) , PS 0/1 : 30/13 , colon/rectum : 28/15 , metastatic site (liver +/- : 35/8 , lung +/- : 32/11 , bone +/- : 6/37 , peritoneum +/- : 6/37 , lymph node +/- : 11/32 , local +/- : 3/40), best response rate was 9.3% (CR/PR/SD/PD : 1/3/19/11). Compared with CD133- pts with colorectal cancer , the progression-free survival (PFS) of CD133+ pts was significantly better (5.5 month; 95% CI, 4.4-6.7,p=0.026), and median overall survival (OS) was also significantly better (11.0 month; 95% CI, 5.4-16.5, p=0.002). In univariate analysis, liver metastasis, lung metastasis, peritoneal metastasis, lymph node metastasis, age, and CD133 at the baseline predicted PFS, and age, gender, liver metastasis, lung metastasis, bone metastasis, peritoneal metastasis, lymph node metastasis at the baseline, the presence of skin rash, and CD133 predicted OS. In order to evaluate the independent predictive effect of chemotherapy, multivariate Cox regression analysis was carried out. It showed that CD133 was the strongest predictor. Conclusions: CD133 status at the baseline was correlated with the prognosis of patients treated with cetuximab, suggesting that CD133 status might play a role to estimate the prognosis.
Use of the intensity of membranous EGFR staining by immunohistochemistry to predict the efficacy of chemotherapy containing cetuximab in KRAS wild-type patients with metastatic colorectal cancer: A retrospective analysis.
Authors: Takahashi Naoki , Yamada Yasuhide , Taniguchi Hirokazu , Akiyoshi Kohei , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro 
Published: February 2017

516 Background: KRAS mutation status is a strong predictive factor for anti-EGFR monoclonal antibody therapy efficacy in metastatic colorectal cancer (mCRC). In the BOND trial, objective response rates to cetuximab in irinotecan-refractory mCRC were not significantly different based on the intensity of EGFR staining by immunohistrochemistry (IHC). However, this result was not evaluated by KRAS mutation status, so we retrospectively evaluated the relationship between the efficacy of chemotherapy containing cetuximab and the intensity of membranous EGFR staining in KRAS wild type (KRAS-WT) patients. Methods: Between August 2008 and July 2011, specimens of 391 CRC patients were collected by endoscopic biopsy or surgical resection. EGFR staining by IHC and genetic screening for KRAS status were performed and intensity of EGFR staining was scored by the Guidelines for Interpreting EGFR pharmDx, DAKO. We analyzed 94 KRAS-WT patients who received combination chemotherapy with an irinotecan-regimen plus cetuximab or cetuximab monotherapy and met the following criteria: histologically proven mCRC adenocarcinoma , at least 1 previous regimen of standard fluoropyrimidine - containing chemotherapy , ECOG PS score 0-2, and adequate hepatic and renal function. Patients were classified into 2 groups by intensity of EGFR staining: (A) absence of staining and weakly to moderately positive (IHC 1+ and IHC 2+), (B) strongly positive (IHC 3+). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared in Groups A and B by the log-rank test. Results: There was no significant difference in patient characteristics between the 2 groups except for primary site. The median PFS of Groups A (n=76) and B (n=18) were 5.4 months and 9.1 months (p= 0.029), the median OS was 8.1 months and 13.2 months (p=0.054) and response rate was 20.1% and 33.3%, respectively. Conclusions: In KRAS-WT patients with fluoropyrimidine-containing chemotherapy-refractory mCRC, strong intensity of EGFR staining by IHC might be predictive for efficacy of chemotherapy containing cetuximab.
Role of presurgery circulating cancer cells (CTCs) as a potential pronostic factor in patients (pts) with liver surgery (LS) of colorectal cancer (CRC) metastases (M).
Authors: Teijeira Lucia , Viúdez Antonio , Antelo Maria L. , Tarifa Antonio , Zazpe Cruz , Herrera Javier , Hernandez Irene , Vera Ruth 
Published: February 2017

518 Background: Kinetic behavior of perioperative CTCs in pts with liver CRC M has been little explored. The aim of this study was to quantified CTCs performance before, just performed and 3 months after radical LS in pts with CRC M and analyzed the surrogate role of CTCs determinations in DFS and OS. Methods: 7.5 ml of blood were drawn in CellSave tubes. CTCs were enumerated before, just performed and 3 months after radical LS. CTCs were immunomagnetically separated and fluorescently labeled using the CellSearch System (Veridex/Immunicon Corp.) Results: From February 2009 to August 2011, 30 pts with LS of CRC M were included. Median age was 59 (45-75); 63.3 % men. Kras status: 63.2% wild-type and 36.8% mutated; 46.7% with synchronous disease. Fong-Criteria (FC) distribution: 30% pts with 1 FC, 36.7% pts with 2 FC and 33.3% pts with 3 FC, of whom 56.7% received neoadjuvant (76.4% fluoropirimidines-based; 29% cetuximab-based; 47% bevacizumab-based) and 73.3% adjuvant treatment. PR and SD were observed in 68.8% and 31.3% of pts, respectively (100% DCR). In 83% of cases, limited LS were done (79.3% R0, median M resected: 2), 20% of pts with synchronous surgery of primary tumour. Of the 15 pts analysed, pCR were observed in 2 (13.3%) with 6 other pts (40%) with major pathological response. With a median of follow-up of 21 months, progression disease occurred in 9 pts (55.6% with liver progression), and 4 pts died. Median CTCs was 0 before (0-2: 85%; ≥3: 14.8%), just performed (0-2: 78%; ≥3: 21%) and 3 months after surgery (0-2: 94.1%; ≥3: 5.9%). DFS for pts with pre-surgery CTCs ≥3 was 10 months, and not reached for 0-2 CTCs group. OS has not been achieved in any CTCs group. In the multivariate analysis, with FC and pre-surgery CTCs, pre-surgery CTCs ≥3 tends to be an independent predictor of outcome (HR: 2.83; CI:0.53-15). Conclusions: Independently of neoadjuvant treatment, pre-surgery CTCs levels ≥3 could be a surrogate of short DFS in pts with LS of CRC M. Our study shown a slight increase in CTCs quantification after LS, instead a significant CTCs decrease was observed after adjuvant therapy. Role of radical LS in kinetic of CTCs should continue to be analysed in future studies.
Growth patterns of liver metastases as compared to resected tumors of the same colorectal cancer patients.
Authors: Eefsen Rikke Loevendahl , Van den Eynden Gert G. , Brodt Pnina , Burnier Julia V. , Hoyer-Hansen Gunilla , Christensen Ib Jarle , Metrakos Peter , Laerum Ole Didrik , Federspiel Birgitte , Willemoe Gro , Osterlind Kell , Illemann Martin 
Published: February 2017

519 Background: Colorectal cancer (CRC) affects one million people a year. 25% of the patients have metastatic disease at the time of diagnosis. Metastatic disease is one of the major challenges in the treatment of cancer. Even though the TNM staging system is a good prognostic marker, tumours have a biological diversity that cannot be evaluated by the TNM system. Recently three different growth patterns of CRC liver metastases were identified. The aim of this study was to determine the growth patterns of CRC liver metastases from patients with more than one metastasis. Methods: A pilot study was conducted including 34 patients resected for CRC liver metastases, 28 patients selected from a database of 200 patients, operated in Copenhagen between 2007-2010 and 6 patients, operated in Montreal. From these 34 patients, 15 patients were resected for two or more liver metastases. All paraffin embedded tissue sections were stained for reticulin and haematoxylin and eosin at the Finsen Laboratory. Evaluation of the growth pattern was done by three different observers from Antwerp and Copenhagen. Reproducibility was >90%. Results: In the fifteen patients, 9 from Copenhagen and 6 from Montreal, that had multiple hepatic metastases, there was uniformity in the growth pattern of the individual metastases. 40% had a desmoplastic, 33% a pushing and 20% a replacement growth pattern and 7% had a mix pattern. Of the 9 patients from Copenhagen 33% were synchronous and 67% metachronous metastases. Within patients, all patterns were identical. Conclusions: The uniformity of growth patterns seen in each patient suggests that these patterns are not random. The identical growth pattern may be determined by specific interactions between the tumor and the host microenvironment, as postulated by Paget’s seed and soil theory. This could represent three different stromal and cytokine responses or oncogenic pathway responses and could represent metastatic tumour growth in different microenvironments.
Changes in expression levels of excision repair cross-complementing group 1 (ERCC1) and dihydropyrimidine dehydrogenase (DPD) during first-line oxaliplatin-based treatment of advanced metastatic colorectal cancer (mCRC).
Authors: Baba Hideo , Watanabe Masayuki , Okabe Hirohisa , Miyamoto Yuji , Sakamoto Yasuo , Baba Yoshifumi , Iwatsuki Masaaki , Chikamoto Akira , Beppu Toru 
Published: February 2017

520 Background: We previously reported the updated results of the FIRIS study, reconfirming the non-inferiority of IRIS (irinotecan/S-1) to FOLFIRI with progression-free survival (PFS) as the primary endpoint (ASCO2011 #3562). Moreover, in patients who had received prior oxaliplatin-based chemotherapy, median OS was significantly longer in the IRIS group than in the FOLFIRI group (adjusted HR=0.755, 95% CI: 0.580–0.987). The aim of this retrospective study was to elucidate molecular mechanisms underlying the better survival in the IRIS group among patients who had previously received oxaliplatin. Methods: Irinotecan-naive mCRC patients (ECOG PS 0–1, adequate organ function, resectable liver metastases) were enrolled. Resected liver metastases were available for 17 patients who had received FOLFOX and 21 patients who had received no prior oxaliplatin-based chemotherapy. Using laser captured microdissection and real-time RT-PCR, we analyzed mRNA expression of excision repair cross complementing group 1 (ERCC1) and dihydropyrimidine dehydrogenase (DPD), factors related to drug resistance and metabolism. Results: Baseline factors (sex, age, histology) of the subjects were similar in the two groups. Expression levels of nucleotide excision repair pathway gene ERCC1 and pyrimidine catabolic pathway gene DPD differed significantly between the FOLFOX group and non-oxaliplatin group. Mean expression levels of ERCC1 and DPD were respectively 1.9 and 7.4 times higher in the FOLFOX group than in the non-oxaliplatin group (ERCC1: 1.58 vs. 0.85, P=0.0005; DPD: 0.580 vs. 0.078, P=0.01). Conclusions: Increased expression of ERCC1 and DPD after first-line oxaliplatin-based chemotherapy is probably related to chemosensitivity to subsequent therapy. Tumor heterogeneity and clonal selection of tumor cells resistant to oxaliplatin may also be involved.
Prognostic and predictive effect of COX-2 expression in appendiceal adenocarcinomas.
Authors: Raghav Kanwal Pratap Singh , Kazmi Syed Mohammad Ali , Shetty Aditya V. , Taggart Melissa W. , Fournier Keith F. , Royal Richard E. , Mansfield Paul F. , Eng Cathy , Wolff Robert A. , Overman Michael J. 
Published: February 2017

526 Background: Cyclooxygenase-2 (COX-2), an inducible isoenzyme, is upregulated in inflammation and involved in cancer progression by promoting angiogenesis, cell proliferation and migration and by inhibiting apoptosis. COX-2 is implicated in colorectal tumorigenesis and by extension COX-2 expression testing and therapeutic inhibition has been considered in appendiceal adenocarcinomas (AAs). However, its role in this setting has never been well studied. The purpose of our study was to investigate COX-2 expression in AAs and to evaluate its prognostic and predictive significance. Methods: We performed a retrospective review of 607 patients with AAs treated at MD Anderson Cancer Center between 2002 and 2010. Immunohistochemistry was performed for COX-2 expression (COX2 mAb Clone CX229, Cayman Chemical) in 49 (8%) patients. Thirty (61%) stained positive and 19 (39%) showed no staining. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine association between OS, COX-2 expression and other characteristics. Results: Median age at diagnosis was 47 yrs (range 34-78 yrs). Grade (P = 0.003), completeness of cytoreduction score (P = 0.010) and stage (P = 0.023) were significantly associated with OS. Median OS for patients with COX-2 positive and COX-2 negative tumors was 58.3 and 42.8 months, respectively (P = 0.232). Nine COX-2 positive patients received celecoxib (selective COX-2 inhibitor) in combination with other chemotherapy. Mean treatment duration was 5.5 months with best radiographic response being stable disease in 7 patients. Reduction in tumor markers (CEA or CA19-9) was seen in 7 cases (median reduction of 30%). Similar treatment duration (6.6 months), rate of stable disease (6/8 pts) and tumor marker reduction (7/8 pts) was seen on the preceding non-celecoxib containing chemotherapy in these patients. Median OS, with and without COX-2 inhibition, was 55.7 and 57.6 months respectively (P = 0.57). Conclusions: In this cohort, COX-2 expression is not a significant prognostic factor in AAs. Benefit from COX-2 inhibition in COX-2 expressing AAs is unclear. Current data does not support the routine use of either COX-2 testing or COX-2 inhibition therapy in AAs.