On-treatment Biomarkers in Metastatic Colorectal Cancer for Life

Study Overview
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Brief Summary
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By virtue of an increased strategic use of cytotoxic and biological agents, and more options for locoregional treatment, the survival of patients with metastatic colorectal cancer (mCRC) has improved considerably in the past decades. The personalized approach to systemic treatment is further aided by the use of complementary molecular biomarkers. However, the evolutionary dynamics of mCRC, a disease harnessed by multiple adaptive genetic alterations towards its final stages, poses a particular challenge to single-sample biomarker analyses and standardized linear treatment protocols. The aim of the On-treatment biomarkers in metastatic ColorectAL cancer for Life (On-CALL) study is to generate further knowledge on the evolutionary progression of mCRC during treatment, and to elucidate the mechanisms underlying the therapeutic failure still seen in a substantial number of patients. The On-CALL study is a prospective, single-arm observational study. All patients diagnosed with synchronous mCRC treated with curative intent at Skåne University Hospital will be invited to participate. Clinical and histopathological data will be compiled at study entry. An individual tissue microarray block with samples from resected primary tumours and metastases representing the full extent of the tumour spread will be constructed for each patient. Blood samples will be drawn for biomarker analyses at multiple time points prior to, during and after systemic treatment. DNA sequencing of tumour tissue and circulating tumour DNA (ctDNA) will be performed to define the spatial clonal landscape in primary tumours and metastases, as well as over time.

Detailed Description
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The aim of the On-treatment biomarkers in metastatic ColorectAL cancer for Life (On-CALL) study is to generate further knowledge on the evolutionary progression of mCRC during treatment with curative intent, and to elucidate the mechanisms underlying the therapeutic failure still seen in a substantial number of patients. The specific objectives are: To comprehensively characterise the spatial intertumoural, intermetastatic and intrametastatic genetic heterogeneity To delineate differences in the prevalence and type of genetic heterogeneity, as well as tumour evolvability, according to metastatic site To examine the associations between spatial and temporal heterogeneity To examine ctDNA quantity and quality as an early biomarker for response to neoadjuvant treatment To examine ctDNA quantity and quality as an early biomarker for response to adjuvant treatment To evaluate the relationship between phylogenetic patterns, i.e. the tumour evolvability, and survival in relation to different treatment modalities To examine the heterogeneity of the tumour microenvironment in relation to the genetic heterogeneity and evolvability of the tumours To examine circulating immune cells and inflammatory biomarkers, and their relationship with the genetic and microenvironmental heterogeneity of the tumours To delineate parallel events at the transcriptomic and proteomic levels, with particular reference to their potential utility as clinically relevant surrogate biomarkers of genetic alterations underlying the evolvability of the tumours

Official Title
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On-treatment Biomarkers in Metastatic Colorectal Cancer for Life: The On-CALL Study

Conditions
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Metastatic Colorectal Cancer, Chemotherapy Effect, Peritoneal Metastases, Liver Metastasis Colon Cancer, Lung Metastases

Intervention / Treatment
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* Drug: Chemotherapy
* Procedure: Resection of the primary tumor
* Procedure: Resection of tumour metastases
* Procedure: Blood sampling during chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of synchronous metastatic colorectal cancer, planned cancer treatment with curative intent at the Skåne University Hospital Exclusion Criteria: Not accepting the study inclusion terms (informed consent not obtained) Age below or above the age limit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Synchronous mCRC patients<br>Patients diagnosed with synchronous metastatic colorectal cancer with planned treatment with curative intent at Skåne University Hospital (Malmö and Lund), who have accepted the study invitation (agreeing to participation - informed consent) | Drug: Chemotherapy<br>* Neo-adjuvant and adjuvant chemotherapy with curative intent, according to the current clinical practice guidelines<br>Procedure: Resection of the primary tumor<br>* Surgical resection of the primary tumour, according to the current clinical practice guidelines<br>* Other names: Surgical resection of the primary tumour;Procedure: Resection of tumour metastases<br>* Surgical resection of tumour metastases, according to the current clinical practice guidelines<br>* Other names: Surgical resection of tumour metastases;Procedure: Blood sampling during chemotherapy<br>* Drawing of blood samples several times during patient visits for chemotherapy regimen<br>* Other names: Drawing of blood samples during chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follow-up examination of tumour remission, progression or recurrence | Radiological/clinical examination of tumour remission, progression or recurrence, and correlation of this clinical information with the available oncogenetic data from histological samples from the primary tumour and metastases, and from data from blood samples (ctDNA analysis) Oncogenetic data will come from genomic profiling of tissue samples. This will be carried out by targeted deep sequencing (TDS), using a comprehensive panel covering cancer-related genes, in combination with genome wide SNP array for detection of copy number aberrations. Data from blood samples will be extracted through quantification of ctDNA and monitoring of the temporal clonal dynamics (circulating cell free DNA will be extracted from plasma samples from all time points). | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life changes | Patients will take quality-of-life surveys (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - version EORTC-QLQ-C30 and EORTC-QLQ-CR29) will assistance of medical professionals prior to and after neoadjuvant and/or adjuvant treatment. These surveys are cancer-specific core questionnaires for use in relation to various cancers. The questionnaire scales the items on a score of 1 (Not at all) to 4 (Very much), and 1 (Very poor) to 7 (Excellent). Scoring result is 0 to 100; for functional and global quality of life scales, higher scores mean a better level of functioning, and for symptom-oriented scales, a higher score means worse/more severe symptoms. Statistical analysis will be performed with the data from the questionnaires, and the evolution/changes of symptoms and subjective experiences of the patients will be quantified and correlated with the clinical findings. | 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer, Chemotherapy, Targeted therapy, Tumor heterogeneity, Tumor evolution