A Cancer Research UK multicenter randomized phase II study of induction chemotherapy followed by gemcitabine- or capecitabine-based chemoradiotherapy for locally advanced nonmetastatic pancreatic cancer.

TPS222Background: around 7,400 patients are diagnosed with pancreatic cancer in the UK each year and mortality from the disease parallels its incidence, indicating that an effective treatment is required. Localized inoperable cancer accounts for 30-40% of advanced disease and its optimal management is unclear. Chemotherapy alone is the predominant modality in the UK while CRT is the treatment of choice in the USA. It has been reported that participants receiving either modality have a median survival in the region of 10 months. Nonrandomized studies have shown that selected participants who attain stable or responsive disease after 3 to 4 months of induction chemotherapy may benefit from consolidation CRT. Both gemcitabine and capecitabine have been shown to be potential radiosensitisers.Methods: the Cancer Research UK funded National Cancer Research Institute SCALOP trial is a two-arm randomized phase II trial using a Fleming's single stage design for each arm. Patients will receive 16 weeks of GEMCAP induction chemotherapy; 76 of those who have responded, or have stable disease, will then be randomised to receive 5.5 weeks of either gemcitabine- or capecitabine-based consolidation chemoradiation (50.4 Gy in 28 fractions with either gemcitabine 300 mg/m2 weekly or capecitabine 830mg/m2 bd ). The trial will assess: 1) What are the activity, toxicity, and feasibility of use of the regimens and does either justify consideration as an arm in a future phase III trial? 2) Is it possible to deliver high quality CRT across centres in the UK? 3) In participants who progress following induction chemotherapy, what is the pattern of care in UK centres and what is their prognosis? The trial incorporates a radiotherapy quality assurance element consisting of a radiotherapy protocol, a test case that must be successfully completed before recruitment can begin at a centre, and ongoing assessment of all plans for compliance with protocol. The trial will also store blood samples for future translational studies. The trial has just opened to recruitment in 5 centers in the UK with 23 further centers in set up.No significant financial relationships to disclose

The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer.

The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression. Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids. Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway. Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway

Re: Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis

Hereditary cancer genetic

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers