Liu, Hongfang

e24070 Background: We have maintained a living interactive systematic review (LISR) on the treatment of CAT ( CAT LISR ). Recent publications of CASTA-DIVA and CANVAS trials prompted this report of updated analysis. Methods: The approach to creating LISRs has been previously published and is available on our website. ( LIvE synthesis framework ). Patient important outcomes included venous thromboembolism (VTE) recurrence, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), net clinical benefit (NCB) and all-cause mortality. Mantel-Haenszel method was used to pool treatment effect estimates. A Paul-Mendel random-effects meta-analysis was conducted to compare DOACs with LMWH. Mixed-treatment comparisons were computed using fixed-effect model within a Bayesian framework owing to a sparse and open network. Effect estimates were expressed as odds ratio (OR) with 95% confidence intervals (CI). Surface under the cumulative ranking curve (SUCRA) was used to assess relative treatment rankings. Results: This systematic review currently includes six RCTs with a total of 3690 patients and four unique treatment choices. Apixaban was assessed in two trials (ADAM-VTE, CARAVAGGIO), rivaroxaban in two (SELECT-D, CASTA-DIVA) and edoxaban in one (HOKUSAI-VTE). CANVAS trial reported efficacy of DOACs as a class and hence, was only included in direct comparisons with LMWH. Direct comparisons showed that DOACs as a class significantly decreased the odds of VTE recurrence (OR 0.63, 95% CI: 0.49-0.82) without significantly increasing major bleeding (OR 1.23, 95% CI: 0.84-1.79) when compared to LMWH. However, higher odds of CRNMB (OR 1.65, 95% CI: 1.18-2.31) was observed with DOACs when compared to LMWH. Mortality rates were not different between the two groups (OR: 1.03, 95% CI: 0.87-1.21). Mixed treatment comparisons showed decreased VTE recurrences with rivaroxaban (rank 1; OR 0.49, 95% CI: 0.23-0.99) and apixaban (rank 2; OR 0.58, 95% CI: 0.36-0.90) relative to LMWH (rank 4). No significant differences were observed between edoxaban (rank 3) and LMWH in terms of VTE risk reduction. Edoxaban (rank 4) increased the risk of major bleeding (OR 1.77, 95% CI: 1.05-3.15) compared to LMWH (rank 2); there were no significant differences among rivaroxaban (rank 3) apixaban (rank 1), and LMWH. Rivaroxaban (rank 4; OR 3.16; 95% CI: 1.61-6.68) and apixaban (rank 3; OR 1.51, 95% CI: 1.01-2.28) increased the risk of CRNMB compared to LMWH (rank 1). Significant net clinical benefit was observed with apixaban (rank 1; OR 0.66; 95% CI: 0.46-0.94) when compared to LMWH (rank 4). No significant differences were observed among other mixed treatment comparisons. Conclusions: Patients treated with DOACs have 31 fewer VTE events per 1000 CAT patients compared to LMWH. Amongst DOACs, apixaban offers the greatest net clinical benefit with 39 fewer VTE and MB events per 1000 patients compared to LMWH.

Abstract CHEK2 codes for a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks (DSB). CHEK2 has been described as a tumor suppressor with pro-apoptotic, cell cycle checkpoint and mitotic functions. However, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. In the present report, we characterized CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Tumor Cell Line panel (the NCI-60) using genomic and proteomic analyses including exon-specific mRNA expression, DNA copy number variation (CNV) by aCGH, exome sequencing, as well as Western blotting analyses for total and activated (pT68-Chk2) Chk2. We demonstrate that the high heterogeneity of Chk2 levels in the NCI-60 is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy number alterations and premature truncation) or reduction of protein levels. Notably, we also found that a significant percentage of cancer cells (12% of the NCI-60 and the HeLa cervix cell line) display high endogenous Chk2 activation, always associated with p53 loss of function. Notably, all the 12 cancer cell lines characterized as being p53 wild-type showed almost undetectable levels of pT68-Chk2. The potential impact of endogenous Chk2 activation was analyzed by transcriptome profiling of the five highest pT68-Chk2 cell lines, comparing them with five, tissue-matched low pT68-Chk2 and p53-matched deficient cell lines. Two-sided t tests revealed 176 genes differentially expressed with statistical significance (P < 0.01, uncorrected) in the two groups (high vs. low pT68-Chk2). Among the downregulated expressed genes, a significant number codes for proteins involved in DNA recombination, replication and repair (FANCA, FANCG, FANCL, BRCA2, RAD51C, EME1, and RECQL5 being the most relevant), and centromere organization. Several of these downregulated genes were parts of the Fanconi Anemia pathway or related to homologous recombination (HR, P < 0.05 for statistically significant enrichment using Ingenuity Pathway Analysis®). In conclusion, the biology of Chk2 remains complex, multifaceted and fast evolving. Our study provides information on the relationship between different genomic and proteomic parameters related to Chk2 in cancer, and suggests a possible role for activated Chk2 in p53-deficient or HR/Fanconi Anemia-deficient cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2116. doi:1538-7445.AM2012-2116