Short summary

The aim of the studies are to determine the prognostic value of selected morphologic,immunohistochemical and molecular markers in a population of patients with stage II colon cancer. These biomarkers should help identify patients with high risk of recurrence whom will likely benefit from adjuvant chemotherapy. The results of the studies will contribute to improve the clinical guidelines in order to obtain a more personalized treatment for patients with stage II colon cancer.

Rationale

Colon cancer (CC) is one of the most common type of cancers in the western world. The pathogenesis involves both genetic and environmental factors and the risk is associated with western lifestyle. In 2018, 3.064 new cases of CC were registered in Denmark, which is the lowest numbers of new cases since the national screening program for colon and rectal cancer was introduced in March 2014. Stage II patients have locally advanced disease with tumor invasion through muscularis propria of the intestine or tumor invasion through the peritoneal layer or into neighboring organs without node or distant metastasis. They represent approximately 25% of all CC patients. Stage II patients are offered surgery, but despite radical resection some patients will experience recurrence. Therefore, adjuvant chemotherapy is offered to selected patients with high risk of recurrence by guidelines assessed from a set of risk factors provided by The Danish Colorectal Cancer Group (DCCG). Some high-risk patients never benefit from adjuvant treatment, while some low-risk tumors will recur and ultimately cause cancer-associated death. In addition, treatment with chemotherapy is associated with adverse side effects as well as a not negligible mortality rate. The indication for adjuvant chemotherapy should be imperative, and the gain in disease free survival and overall survival should compensate for the side effects. Various studies have investigated the benefits from adjuvant chemotherapy in CC but to date the results have been inconclusive, and the current guidelines and adjuvant treatment of stage II CC remain controversial.

Thus, there is an urgent need for better prognostic markers (high-risk factors) in this selected group of patients, especially with the introduction of screening for CC as a larger proportion of CC patients are expected to be diagnosed in an earlier stage in the years to come. Studies suggest that a number of morphologic,immunohistochemical and specific molecular characteristics can be used as prognostic markers.

In these present studies, we want to determine the prognostic role of selected morphologic and molecular parameters, and their clinical potential as biomarkers in stage II CC. The analyses are conducted on a modern CC cohort. The morphologic parameters includes tumor stroma ratio (TSR), tumor budding (TB) and cancer-associated fibroblasts (CAF). In addition, the presence of tumor infiltrating lymphocytes (TILs) will be explored. The molecular parameters will be assessed by measuring and characterizing the circular RNA present in the tumor tissue.

The analyses conducted in this study are based on an existing biobank consisting of tissue collected for diagnostic purposes from all patients in the Southern Region of Denmark with surgically treated stage II CC in 2014-2016. Morphological and molecular biomarkers could help identify patients whom will benefit from adjuvant chemotherapy in order to target the individual patient with personalized treatment.

The results of the study will contribute to improve the clinical guidelines in order to obtain a more personalized treatment for patients with stage II

Description of the cohort

The cohort consists of patients with stage II colon cancer surgically treated in 2014-2016 in the Southern Region of Denmark. We expect to include approximately 500 cases.

Data and biological material

Data regarding recurrence and survival obtained from regional and national registers e.g. The Danish Colorectal Cancer Database (DCCG). Biological material comprises formalin-fixed, paraffin-embedded tissue derived from an existing biobank collected for diagnostic purposes from stage II CC resections. Tissue blocks representing the deepest invasive area of the primary tumor are the basis of the analysis.

Collaborating researchers and departments

Department of Clinical Pathology, Lillebaelt Hospital

• Associate Professor, PhD, MD Henrik Hager
• PhD, MD, Physician Sanne Kjær-Frifeldt
• MD, PhD-Student Ulrik Korsgaard
• Senior Consultant, MD, Jan Lindebjerg

Department of Oncology, Lillebaelt Hospital

• Associate Professor, PhD, MD Torben Frøstrup Hansen

Institute of Pathology, University of Bern

• Professor, Dr. phil. nat Inti Zlobec

Aarhus University

• Associate Professor, PhD, Lasse Sommer Kristensen