Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression‐free survival in patients with advanced and/or metastatic colorectal cancer

ackground Chemotherapy is the treatment of choice in patients with advanced or metastatic colorectal cancer (CRC) where surgical resection of metastases is not an option. Both irinotecan (IRI) and fluoropyrimidines are often included in first‐ or second‐ line chemotherapy treatment regimens in such patients. However, it is not clear whether combining these agents is superior to irinotecan alone. Objectives To compare the efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced CRC when administered in the first or second‐line settings. Search methods We searched the following electronic databases to identify randomized controlled trials: Cochrane Colorectal Cancer Group Specialised Register (January 13, 2016), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 12, 2016), Ovid MEDLINE (1950 to January 13, 2016), Ovid EMBASE (1974 to January 13, 2016), registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field were contacted when necessary. The search from January 2016 identified one eligible study, an ongoing trial currently presented as an abstract, to be considered in an update of this review. Selection criteria Randomized controlled trials (RCTs) investigating the efficacy and safety of IRI chemotherapy combined with fluoropyrimidine compared with IRI alone for the treatment of patients with advanced CRC, regardless of treatment line settings. Data collection and analysis Study eligibility and methodological quality were assessed independently by the two authors, and any disagreement was solved by a third author. The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.3. Main results Five studies were included in this review with a total of 1,726 patients. The top‐up search resulted in an additional ongoing trial, the results of which have not been incorporated in this review. Among five included studies, no reduction in all‐cause mortality was observed in the combination arm, with a summary hazard ratio (HR) of 0.91 (95% CI: 0.81‐1.02). Longer progression‐free survival was observed in those treated with the combination chemotherapy (HR: 0.68, 95% CI: 0.53‐0.87), however, this result may have been driven by findings from the single first‐line treatment setting study. The quality of evidence for overall survival was low and for progression‐free survival was moderate, mainly due to study limitation from the lack of information on randomisation methods and allocation concealment. There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia, and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group. Evidence for toxicity has been assessed to be low to moderate quality. Authors' conclusions There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone, thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC. Given the low and moderate quality of the evidence, future studies with sufficient numbers of patients in each treatment arms are needed to clarify the benefit observed in progression‐free survival with combination irinotecan and fluoropyrimidines

A distinctive requirement for p53 in the genome protective Topoisomerase 2a-dependent G2 arrest in hTERT positive cancer cells

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.SignificanceThe identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality

Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling

The Network of Cancer Genes (NCG):a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens

Abstract The Network of Cancer Genes (NCG) is a manually curated repository of 2372 genes whose somatic modifications have known or predicted cancer driver roles. These genes were collected from 275 publications, including two sources of known cancer genes and 273 cancer sequencing screens of more than 100 cancer types from 34,905 cancer donors and multiple primary sites. This represents a more than 1.5-fold content increase compared to the previous version. NCG also annotates properties of cancer genes, such as duplicability, evolutionary origin, RNA and protein expression, miRNA and protein interactions, and protein function and essentiality. NCG is accessible at http://ncg.kcl.ac.uk/

Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues:an update of the Network of Cancer Genes (NCG) resource

BACKGROUND: Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. RESULTS: Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. CONCLUSIONS: Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02607-z