This interventional cohort study will evaluate circulating tumor DNA (ctDNA) and tumor-educated platelets (TEP) as blood-based biomarkers in adults with stage III colon cancer who are planned to receive neoadjuvant systemic therapy followed by surgical resection.

Treatment will be given according to routine clinical practice and will depend on the biological characteristics of the tumor, including mismatch repair status. Participants will provide additional blood samples at predefined time points before, during, and after treatment and surgery. These samples will be used to analyze ctDNA and TEP and to assess whether changes in these biomarkers are associated with radiological response, pathological response, and disease-free outcomes.

Approximately 80 participants will be enrolled at the Institute of Oncology Ljubljana. Participants will not receive experimental drugs as part of this study.

This is a prospective interventional longitudinal cohort study of adult patients with histologically confirmed stage III colon adenocarcinoma who are planned to receive neoadjuvant systemic therapy followed by surgical resection with curative intent.

The study will evaluate the dynamics of circulating tumor DNA (ctDNA) and tumor-educated platelets (TEP) during neoadjuvant treatment and follow-up. Neoadjuvant systemic therapy will be selected according to routine clinical practice and tumor biology, including mismatch repair status. Patients with pMMR tumors may receive chemotherapy, while patients with dMMR tumors may receive immunotherapy, according to standard clinical decision-making.

The research intervention consists of additional peripheral venous blood sampling at predefined time points before treatment, during systemic treatment, before surgery, and after surgery. Blood samples will be analyzed for ctDNA and TEP-based biomarkers. Clinical, radiological, pathological, and follow-up data will be collected from routine medical documentation.

The primary objective is to determine whether the presence of ctDNA after completion of neoadjuvant systemic therapy is associated with pathological tumor response, defined as major pathological response (MPR), in patients with stage III colon cancer. Secondary and exploratory objectives include evaluation of the association between ctDNA, TEP profiles, radiological response, recurrence-free outcomes, and disease-free outcomes.

Approximately 80 participants will be enrolled. The study is academic and non-commercial. Participants will not receive experimental drugs as part of this study, and all therapeutic and diagnostic procedures will follow established clinical practice.

Inclusion Criteria:

• Age 18 years or older at the time of enrollment.
• Histologically confirmed adenocarcinoma of the colon.
• Stage III colon cancer, defined according to the applicable TNM classification based on clinical and imaging assessment.
• Confirmed mismatch repair (MMR) status, determined by immunohistochemistry and/or molecular methods.
• Planned neoadjuvant systemic therapy according to MMR status, followed by surgical resection with curative intent.
• ECOG performance status 0-2.
• Ability to understand the study and provide written informed consent.

Exclusion Criteria:

• Stage I, II, or IV colon cancer.
• Concurrent active malignant disease, except adequately treated non-melanoma skin cancer or carcinoma in situ.
• Severe comorbidities or medical conditions that prevent or substantially limit neoadjuvant systemic therapy or surgical resection.
• Known autoimmune disease requiring active immunosuppressive treatment in patients with dMMR tumors.
• Pregnancy or breastfeeding.
• Inability or unwillingness to provide written informed consent.