Assessment of clinically related outcomes and biomarker analysis for translational integration in colorectal cancer (ACROBATICC): study protocol for a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastasis

Kjetil Søreide, Martin M Watson, Dordi Lea, Oddmund Nordgård, Jon Arne Søreide, Hanne R Hagland, ACROBATICC collaborators, Kjetil Søreide, Martin M Watson, Dordi Lea, Oddmund Nordgård, Jon Arne Søreide, Hanne R Hagland, ACROBATICC collaborators

Abstract

Background: More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis.

Methods: An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases. Long-term outcomes will be cancer-specific survival, recurrence-free survival and overall survival at 5 years from diagnosis. Beyond routine clinicopathological and anthropometric characteristics and laboratory and biochemistry results, the project allows for additional blood samples and fresh-frozen tumour and normal tissue for investigation of circulating tumour cells (CTCs) and novel biomarkers (e.g. immune cells, microRNAs etc.). Tumour specimens will be investigated by immunohistochemistry in full slides. Extracted DNA/RNA will be analysed for genomic markers using specific PCR techniques and next-generation sequencing (NGS) panels. Flow cytometry will be used to characterise biomarkers in blood. Collaboration is open and welcomed, with particular interest in mutual opportunities for validation studies.

Status and perspectives: The project is ongoing and recruiting at an expected rate of 120-150 patients per year, since January 2013. A project on circulating tumour cells (CTCs) has commenced, with analysis being prepared. Investigating molecular classes beyond the TNM staging is under way, including characteristics of microsatellite instability (MSI) and elevated microsatellite alterations in selected tetranucleotides (EMAST). Hot spot panels for known mutations in CRC are being investigated using NGS. Immune-cell characteristics are being performed by IHC and flow cytometry in tumour and peripheral blood samples. The project has ethical approval (REK Helse Vest, #2012/742), is financially supported with a Ph.D.-Grant (EMAST project; Folke Hermansen Cancer Fund) and a CTC-project (Norwegian Research Council; O. Nordgård). The ACROBATICC clinical and molecular biobank repository will serve as a long-term source for novel exploratory analysis and invite collaborators for mutual validation of promising biomarker results. The project aims to generate results that can help better discern prognostic groups in stage II/III cancers; explore prognostic and predictive biomarkers, and help detail the biology of colorectal liver metastasis for better patient selection and tailored treatment. The project is registered at http://www.ClinicalTrials.gov NCT01762813.

Keywords: Biomarker; Cancer; Circulating tumour cells; Colorectal cancer; Genetics; Liver metastasis; Population-based; Translational research.

Figures

Fig. 1
Fig. 1
The ACROBATICC project flow sequence and rationale for cancer biology investigation. a Illustrated is a simple workflow of patients’ recruitment and samples of blood (red vials) and tissues (blue vials) from initial diagnosis, before and after surgery and during follow up. Overall, disease-free and cancer-specific survival will be analysed at 5 years. b Illustrated are the specific levels of patient information gathered for prognostic and predictive use, ranging from clinicopathological characteristics (such as sex, age, body weight and height) to genetic and epigenetic mechanisms (including microsatellite instability; CpG-island methylator phenotypes and chromosomal instability) and specific tumour-host interactions (such as immune-response in tumor; cancer metabolism and role of circulating tumor cells). With access to newer techniques and development of novel hypothesis, the project will allow for exploration of other predictors, as well as serve as external validation cohort in collaborative research

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