bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacoeconomic analysis for K-Ras status–based decisions for first-line therapy of metastatic colorectal cancer (mCRC) in Spain.
Authors: Belda Cristobal 
Published: February 2017

438 Background: Personalized medicine is a challenge for current oncology practice. Nowadays there are no pharmacoeconomic analyses in Spain dealing with the clinical and financial impact secondary to K-Ras based decisions for first-line therapy in mCRC patients. So, this study was aimed to assess the cost- effectiveness of K-Ras status based decisions in first- line therapy of mCRC patients in comparison with non- K-Ras based selection of available therapies. Methods: K-Ras mutation prevalence and efficacy of available therapies (measured as response rate and progression free survival) were extracted from randomized clinical trials (RCT) that allowed on-label use of accessible drugs in Spain. Then, we have simulated all possibilities of combination therapies for first-line mCRC based on K-Ras status (wild- type vs mutated) and confronted with all therapies that could be chosen in absence of K-Ras analysis. Prices for all drugs in Spain were used to assume the best- value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by RCT was used to calculate the final budget. 70 kg and 1.7 m were used as reference for patients dose calculations. Results: First-line therapy that includes a biological drug in absence of K-Ras status based decisions implies an incremental cost per 1% of increased response rate of 1,237 euros for irinotecan based doublets and 3,193 euros for oxaliplatin based doublets. On the opposite, K-Ras based decisions reduce costs per objective response by 69% and 35% for irinotecan and oxaliplatin- based schedules in K-Ras wild-type population incorporating cetuximab as biological agent. These data mimic all calculi based on incremental costs secondary to improved progression free survival measured as HR when all scenarios without prior determination of K-Ras status were confronted with K-Ras based decisions. Conclusions: K-Ras based decisions reduces costs per objective response as well as per improved progression free survival. The most cost- effective scenario among all simulated was cetuximab in combination with chemotherapy for patients that harbor wt K-Ras mCRC.
A comprehensive analysis of clinical and tumor characteristics with BRAF and KRAS mutations status in adjuvant colon cancer trial N0147.
Authors: McWilliams Robert R. , Mahoney Michelle R. , Sargent Daniel J. , Nelson Garth D. , Sinicrope Frank , Limburg Paul J , Thibodeau Stephen N. , Grothey Axel , Hubbard Joleen Marie , Alberts Steven R. 
Published: February 2017

446 Background: MutKRAS and mutBRAF are important predictive and prognostic markers, respectively, in colorectal cancer (CRC). However, little is known about why some tumors harbor these mutations. N0147 is a phase III adjuvant trial for stage III CRC patients (N=3397) in which patients completed questionnaires and tumor variables and KRAS/BRAF mutation status was assessed. Methods: 2,323/3,397 patients who were enrolled prior to a 2008 amendment requiring KRAS testing completed a Patient Questionnaire. Primary tumors were assessed for mutKRAS and mutBRAF using standard methods; MMR status was determined using IHC. Multivariate analysis was performed to identify predictors of mutation status. Results: 60% and 86% of mutKRAS and mutBRAF tumors were right-sided, respectively. MutKRAS was less likely if there was a family history of CRC and in ever-smokers, and was nearly mutually exclusive with mutBRAF. MutBRAF was associated with deficient MMR (dMMR), high grade histology, and 4+ positive lymph nodes at surgery. MutBRAF was more likely in patients age > 70, retired persons, ever-smokers, but was less likely in non-whites and men. Conclusions: Smoking, family history of CRC, and dMMR status are associated with lower frequency of mutKRAS , but higher mutBRAF. Both mutations tend to be right sided, and mutBRAF is more common in the elderly, females, and non-Hispanic whites. [Table: see text]
Correlation of activated AKT and MAPK expression in liver metastases with clinical outcome in colorectal cancer patients receiving irinotecan/cetuximab treatment.
Authors: Scartozzi Mario , Giampieri Riccardo , Mandolesi Alessandra , Maccaroni Elena , Del Prete Michela , Faloppi Luca , Bittoni Alessandro , Bianconi Maristella , Galizia Eva , Silva Rosa Rita , Giustini Lucio , Zaniboni Alberto , Labianca Roberto , Bearzi Italo , Cascinu Stefano 
Published: February 2017

449 Background: An aberrant activation of the EGFR downstream signaling pathway via MAP-kinase and Akt could be responsible for resistance to anti-EGFR treatment. We tested the interaction between phosphorylated Akt and MAPK in primary colorectal tumours and corresponding metastases and clinical outcome in terms of response rate (RR), progression free survival (PFS) and overall survival (OS) to identify a group of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild type status. Methods: Seventy-two advanced K-RAS wild type colorectal cancer patients treated with irinotecan-cetuximab were analysed. Primary tumour were available in all cases, whereas paired tumour samples from metastatic sites were available in 37 patients. Phosphorylated Akt and MAPK were analyzed by immunohistochemistry. Results: Akt resulted overexpressed in 31 primary tumours (43%) and 23 metastases (62%), whereas MAPK was over-expressed in 32 primary tumours (44%) and 20 metastases (54%). Akt altered expression in primary tumours correlated with a statistically significant worse median PFS (2.4 months vs. 6.5 months, p= 0.0006) and OS (7.8 months vs. 26.7 months, p < 0.0001), without any significant correlation with RR. No significant correlation could be found between MAPK expression in primary tumours and RR, PFS or OS. In metastases Akt expression correlated with RR (9% vs, 58%, p= 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001). Analogously MAPK expression in metastases correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis Akt and MAPK status in metastases was able to independently predict PFS. Akt status in metastases independently correlated with RR as well. Conclusions: We suggest that Akt and MAPK expression in metastases may have a relevant role in determining the activity of anti-EGFR treatment strategies. Our observations seem also to indicate that for some molecular determinants of resistance the biological profile in metastases is prominent.
Significance of neuroendocrine component in mixed adenoneuroendocrine neoplasms.
Authors: Chen Ming-Huang , Kuo Ying-Ju , Yeh Yi-Chen , Huang Pin-I , Li Chung-Pin , Chao Yee 
Published: February 2017

45 Background: Mixed adenoneuroendocrine carcinoma (MANEC) and adenocarcinoma with neuroendocrine differentiation (ADC-NE) are tumors with divergent exocrine and neuroendocrine differentiation. These tumors display variable quantitative extent of the two components. Some studies reported the extent of two components in primary tumor and lymph node are not always the same. The aim of our study is to analyze the neuroendocrine component in primary tumor, angiolymphatic invasion and metastatic lymph nodes. Methods: Tumor histology of 15 patients with MANEC or ADC-NE was evaluated in this study. Neuroendocrine component was confirmed by morphology and immunohistochemistry for synaptophysin and chromogranin A. The extent of neuroendocrine components in primary tumor, angiolymphatic invasion and lymph node were reviewed by two independent pathologists. Results: Fifteen patients with MANEC and ADC-NE tumors were evaluated. Of these, pure neuroendocrine component in angiolymphatic invasion was observed in 9; pure adenocarcinoma component was seen in 4; and both components were seen in 2. The components in lymph node metastases were consistent to angiolymphatic invasion (Table), suggesting the tumor component in angiolymphatic invasion may predict pathology in lymph node metastasis. In high neuroendocrine component group (>50% in primary tumor), 83.3% revealed pure neuroendocrine component in lymph node and 88.9% had angiolymphatic invasion. The pure neuroendocrine component in lymph node and angiolymphatic invasion was higher in high neuroendocrine component group compared to the low neuroendocrine component group, (p=0.012 and p=0.01, respectively). Conclusions: The components of tumor involved in angiolymphatic invasion is consistent with that in lymph node metastasis. High neuroendocrine component predicts the rate percentage of pure neuroendocrine component in lymph node or angiolymphatic invasion. [Table: see text]
A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.
Authors: Atreya Chloe Evelyn , Warren Robert S. , Niedzwiecki Donna , Mayer Robert J. , Goldberg Richard M. , Compton Carolyn C. , Zuraek Marlene , Bergsland Emily K. , Ye Cynthia , Weinberg Vivian K. , Bertagnolli Monica M. 
Published: February 2017

452 Background: The p53 tumor suppressor gene is frequently mutated in colorectal cancer, but reports on the effect of p53 mutations on response to adjuvant chemotherapy and survival are inconclusive. This study investigates whether p53 mutational status (wild-type, zinc or non-zinc binding mutations) impacts survival following adjuvant therapy containing fluorouracil/leucovorin with or without irinotecan (5FU/LV or IFL) in women and men with stage III colon cancer. Methods: As part of a retrospective analysis of prospectively accrued data, p53 mutational status was determined for 609 patients with stage III colon cancer who were randomized on CALGB 89803, a phase III adjuvant chemotherapy trial. p53 exons 5-8 were analyzed by direct sequencing or sequencing by hybridization. p53 mutations were identified in 276 tumors (45%), of which 134 were in the zinc binding and 142 were in the non-zinc binding regions of the core domain. Cox regression was used to study the impact of p53 mutational status, sex, and adjuvant chemotherapy on disease-free (DFS) and overall survival (OS). Results: p53 mutational status did not predict differential survival or response to adjuvant therapy among the 609 patients assessed. However, a significant sex by treatment interaction was observed for both DFS (Pinteraction=0.008) and OS (Pinteraction=0.002). Significant differences in DFS by p53 mutational status were observed among women (logrank P = 0.009). No such differences were observed among men (logrank P = 0.33). Similar results were observed for OS. There was marginal evidence of a treatment-related impact on the interaction between sex and p53 mutational status for both DFS and OS (DFS Pinteraction = 0.07; OS Pinteraction = 0.11). There was a trend toward improved OS when women with zinc binding mutations received IFL versus 5FU/LV (P = 0.08) and toward worse DFS when women with non-zinc binding mutations were treated with IFL versus 5FU/LV (P =0.08). Conclusions: This exploratory subset analysis suggests that p53 mutational status may be used to predict prognosis in a sex- and potentially chemotherapeutic regimen-specific manner.
Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer.
Authors: Zhang Wu , Gerger Armin , Labonte Melissa Janae , Yang Dongyun , Bohanes Pierre Oliver , Ning Yan , Winder Thomas , Wilson Peter M.D. , Benhaim Leonor , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef 
Published: February 2017

454 Background: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERα) transcriptional activity in breast cancer. The mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR), suggesting these SNPs were functionally significant. In colon cancer (CC), ERβ expression has been shown to be predominant with low levels of ERα also expressed. ERα stimulates cell proliferation, while ERβ negatively regulates the estrogen-dependent activity of ERα. Based on these previous findings, we hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in stage II and III CC. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs (range 22–78 yrs)) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK). Results: The minor allele of LMTK3 rs9989661 (C; frequency=30.5%) showed significantly longer median TTR (5.9 vs 12.2+ yrs; HR: 0.41, 95%CI: 0.15-1.18, log-rank p=0.086; univariate analysis) in female CC patients. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.25, 95%CI: 0.077-0.778, Wald test p=0.017). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This is the first report demonstrating LMTK3 rs9989661 associations with gender-related TTR in CC. We hypothesize that there is an ERα-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERβ. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.
Activity of bevacizumab at the time of surgery after 6 weeks of preoperative cessation.
Authors: Starlinger Patrick , Alidzanovic Lejla , Schauer Dominic , Maier Thomas , Sommerfeldt Silvia , Herberger Beata , Tamandl Dietmar , Gruenberger Birgit , Gruenberger Thomas , Brostjan Christine 
Published: February 2017

455 Background: The use of bevacizumab (BV), a monoclonal antibody against VEGF, and combination chemotherapy (CTx) together with an increase in hepatic resection has improved the outcome of colorectal cancer (CRC) patients with liver metastasis. However, despite the frequent use of BV, its accurate timing prior to liver resection to avoid surgical complications and to allow for hepatic regeneration remains discussed controversially. In this context, it remains unclear to which extent VEGF is complexed by BV at the time of surgery. Methods: Fifty CRC patients with liver metastases, potentially curable by resection, were included. Patients received neoadjuvant CTx either with or without concomitant biweekly BV. The last cycle of therapy did not include BV, resulting in 5 weeks between the last administration of BV and surgery. Plasma and wound fluid subcutaneously and intra-abdominally were obtained perioperatively. Immunoprecipitation was applied to determine the proportion of BV-bound VEGF. Results: 42 patients underwent surgery. Median time of BV cessation was 5-6 weeks. No increased perioperative complications in this BV treated patients were observed (patients without complications: 59 % of BV + CTx patients versus 50 % in CTx patients). At the time of surgery, the majority of plasma VEGF was inactivated by BV. In wound fluid, the actual site of wound healing and hepatic regeneration, VEGF was remarkably low and also complexed by BV. This resulted in a highly significant reduction of unbound/biologically active VEGF levels in plasma and wound fluid of BV treated patients (both: P < 0.001). Conclusions: These data documents that, after the clinical standard cessation time point of 5-6 weeks, BV is still fully active and binds to the majority of circulating and local (wound fluid) VEGF. Despite the potent VEGF inactivation, at the time of liver resection no substantial increase in perioperative morbidity after neoadjuvant BV therapy has been documented in our study and the current literature.
Prognostic value of chromosomal imbalancies and the colon gene expression signatures in rectal cancer.
Authors: Doyen Jerome , Letouze Eric , Romestaing Pascale , Chapet Olivier , Gérard Jean-Pierre 
Published: February 2017

465 Background: Some studies have suggested colon and rectal cancer as two different entities when considering DNA mutations or chromosomal imbalances. We therefore wondered if two colon gene expression signatures could predict specific survival. We also tested the influence of chromosomal imbalancies on prognosis in rectal cancer. Methods: Between 1998-2001 a series of 94 patients (pts) with rectal adenocarcinoma (T1-2-3 M0) were treated with preoperative radiotherapy (RT) with or without concurrent chemotherapy (CT) (78 pts) or with curative RT alone using contact X Ray therapy (CXRT) (18 pts). High-throughput analysis of genomic imbalancies and DNA expression were performed within the frame of the Carte d’Identité des Tumeurs (CIT) programme of Ligue du Cancer- France. Biostatistical analysis were performed and correlated with metastasis-free survival (MFS) and specific survival (SS). Coloprint and Oncotype DX colon signatures were tested on this cohort. Results: The median survival of the 96 patients was 105 months. The overall specific survival rate at 8 years was 75% for the preoperative group and 65 % for the RT alone group. Overall the rate of distant metastases was 30 % at 8 years (26 pts). A validated biopsy specimen was analysed in 67 pts for DNA expression and for genomic imbalances. Deletion of 8p and 1p36-35 correlated with MFS (p=0.001 and p=0.02 respectively) and SS (p=0.0002 and p=0.008 respectively). Multivariate analysis identified -8p as an independent prognostic factor of MFS (p=0.004) and SS (p=0.003). Validation of this deletion on an independent cohort is on-going. Regarding mRNA profile analysis, no stable consensus could identify clusters that accurately separate patients of bad and good SS or MFS, whatever the method used (28 methods of clustering). Coloprint signature could discriminate patients with the worst prognosis (SS: p<0.05) whereas Oncotype DX colon signature did not (SS: p=0.4). Conclusions: By analysing this series of patients from a single center we have been able for the first time in rectal cancer to identify -8p as an independent prognostic factor of MFS and SS. mRNA analysis suggest that colon and rectal cancer may not always share the same DNA expression profile.
Development and validation of a genomic signature to identify colorectal cancer patients with microsatellite instability.
Authors: Salazar Ramon , Tian Sun , Santos Cristina , Rosenberg Robert , Nitsche Ulrich , Mesker Wilma E , Bruin Sjoerd , Roepman Paul , Capella Gabriel , Simon Iris 
Published: February 2017

466 Background: Microsatellite Instability (MSI-H) occurs in 10-20% of colon tumors and has been attributed predominantly to gene silencing of DNA mismatch repairs (MMR) genes by mutation or methylation, including MSH2, PMS2 and in particular MLH1. Methods: MSI status for 276 primary stage II and III colorectal tumors have been determined (n=29 MSI-H, n=247 MSS and MSI-L) by immunohistochemically staining of MLH1 and PMS2 (for 90 patients) or by PRC amplification of six microsatellite DNA regions from paired normal and tumor tissues (for 186 patients). Full genome gene expression data for the same 276 tumors was available and used to identify genes that correlate with MSI-H status. All samples had full clinical information including 5-year follow-up and ColoPrint results (as described in Salazar et al. JCO 2011). Results: Most MSI-H patients were classified as ColoPrint low risk (26 of 29 patients; 90%) however this is only as subgroup of the 195 patients identified by ColoPrint as low risk. While ColoPrint had great prognostic power in this dataset (HR 2.37, p=0.0006), it does not identify MSI-H patients with high specificity. We therefore developed a MSI-gene signature of 64 genes using a 10-fold cross validation procedure to complement ColoPrint. The MSI-signature identifies MSI-H patients with high sensitivity (93.1% (27/29)) and high specificity (87.9% (217/247)) and an overall accuracy of 88.4% (244/276). The MSI-signature has prognostic power in the subset of stage II patients (n=215) with HR = 2.38 (95% CI 1.15-4.93, p=0.06. However, in multivariate analysis of MSI status and all clinical factors, ColoPrint was the only significant prognostic factor (HR 3.2; p=0.0014). The MSI-signature is currently validated in an independent patients set of 132 stage II patients (31 MSI-H, 101 MSS). Conclusions: The diagnostic MSI signature identifies patients with MSI-H status with high accuracy. In combination with the prognostic power of ColoPrint, the identification of MSI-H patients might add additional information for treatment of stage II patients.
Phase II study of ganetespib, an hsp-90 inhibitor, in patients with refractory metastatic colorectal cancer.
Authors: Cercek Andrea , Shia Jinru , Gollub Marc , Raasch Pamela Joan , Hollywood Ellen , Reidy Diane Lauren , Janjigian Yelena Yuriy , Stadler Zsofia Kinga , Segal Neil Howard , O'Reilly Eileen Mary , Ilson David , Kemeny Nancy E. , Saltz Leonard 
Published: February 2017

467 Background: To evaluate the safety and efficacy of ganetespib, a heat shock protein 90 (Hsp90) inhibitor, as monotherapy in patients with refractory metastatic colorectal cancer. Methods: A phase II study utilizing a two-stage design was performed in which patients received Ganetespib 200 mg/m2 intravenously (IV) one time per week for three weeks followed by a one week break. Patients underwent pre and 48 hour post treatment tumor biopsies. Immunohistochemistry (IHC) was performed for p/Erk, CyclinD1, p/Akt, HIF-1a, VEGFr2 , p70S6 and Hsp70. Archived and pre dose biopsy tissue was utilized for KRAS, BRAF and PIK3CA genotyping using a Sequenom platform. Results: Fifteen patients were treated (median age 58, range 44-79). There were no responders. Two patients had stable disease lasting 31 and 23 weeks. The most frequent grade 1/2 toxicities were diarrhea, fatigue, nausea/vomiting and elevated transaminases ( Table ). These complications did not result in any treatment interruption. The most frequent grade 3 adverse events were diarrhea (12%), fatigue (24%), and elevated AST(12%) and Alk phos(29%). Three (20%) patients required dose reductions, 1 grade 3 AST, 1 grade3 ALT and 1 grade 3 fatigue. Conclusions: This was the first study of an Hsp90 inhibitor in colorectal cancer. Ganetespib treatment did not produce tumor responses when administered as a single agent in refractory metastatic colorectal cancer with this dosing regimen. Overall the drug was well tolerated and the toxicity profile was minimal. Ganetespib may be used in combination in future studies. Correlative IHC analyses will be presented. [Table: see text]