Prognostic and predictive biomarkers in metastatic colorectal cancer constant and evolutionary perspectives

Colorectal cancer (CRC) affects nearly 2 million people each year and accounts for 900 000 deaths worldwide. The main prognostic factor is disease stage at diagnosis and around 40% of the patients presents with or develop metastatic CRC (mCRC). Even if the disease has disseminated, cure is sometimes possible, but despite thorough selection of patients for metastasectomy, most patients will suffer relapse of the disease. Hence, there is a great need for new prognostic and predictive biomarkers in order to better select the appropriate treatment for each patient. The aim of this thesis was to study the prognostic and predictive impact of selected biomarkers, with particular focus on RNA-binding motif protein 3 (RBM3), in mCRC and to perform an extensive mapping of the spatial heterogeneity in mCRC with peritoneal carcinomatosis. In paper I, RBM3 expression was assessed by immunohistochemistry (IHC) in primary tumours from 455 patients with mCRC. High RBM3 expression was an independent predictor of prolonged survival, and in the group with high RBM3 expression, a longer progression-free survival was seen in patients treated with oxaliplatin compared to patients treated with irinotecan in first line. In paper II, RBM3 expression was assessed by IHC in 211 resected lung metastases and 164 paired primary tumours. High RBM3 expression in the lung metastases was an independent predictor of prolonged survival, in particular in patients treated with oxaliplatin at any time point. Other prognostic factors for prolonged survival were age ≤ 60 years, one metastasis, a lung metastasis <3 cm in size, disease free interval >24 months and adjuvant treatment. In paper III, the spatial molecular heterogeneity was delineated in seven curatively treated patients with mCRC disseminated to the peritoneum. Multiregional targeted sequencing and IHC analysis of RBM3, special AT-rich sequence-binding protein 2 (SATB2) and mismatch repair (MMR) proteins were performed. The expression of RBM3 and SATB2 was allover low. Mutations in key CRC driver genes, i.e KRAS, APC and TP53, were homogenous across samples from individual patients, whereas less common mutations were more heterogenous. In some cases, a higher similarity was seen between PC and lymph node metastases than between PC and the primary tumour. Paper IV is a study protocol for the planned On-treatment biomarkers in metastatic Colorectal Cancer for Life (On- CALL) study. The aim of this prospective, observational study is to follow up on relevant findings from the present thesis and to generate further knowledge on the spatial and temporal tumour heterogeneity and evolution of mCRC during curative treatment.