Prognostic and predictive factors for colorectal cancer

Sammanfattning: Colorectal cancer is the third most common cancer worldwide of which approximately 30% of cases are localized in the rectum. Rectal cancer accounts for around 700, 000 cases and 310, 000 deaths annually across the world with a global distribution that varies due to different lifestyles. Treatment of rectal cancer has evolved significantly during the past few decades, from being treated with surgery only to a multidisciplinary multimodal complex treatment plan with radiotherapy and chemotherapy. Consequently, a major improvement in oncologic outcomes has been witnessed with dramatically reduced local recurrence (LR) rates from more than 30%-40% 40 years ago to today’s level of 5%-6%. Study I aimed to find natural products in the NCI (National Cancer Institute, US) database with selective antitumoural effects towards cancer cells with a mutated p53 gene. For this purpose, we performed a screen of the NCI bank of natural extracts for substances with potential selective effects on cancer cells harbouring a mutated p53 gene. Only one of several selected natural extracts, N37063 demonstrated this selectivity towards p53 in our in vitro assay in several cancer cell lines. Two substances were purified from the extract which harboured most of the preferential cytotoxic effect in p53-mutated cancer cells. Study II aimed to examine the spectrum of tumours in Swedish Lynch syndrome families. Lynch syndrome is characterized by hereditary colorectal cancer (CRC) that emerges at a young age. These patients experience colorectal cancer and endometrial cancer in their 40s and are predisposed to other malignant diseases that affect these individuals more than the general population. In this study, we demonstrated that urothelial cell cancer is the most common malignancy in the Swedish Lynch population after CRC and endometrial cancer. Furthermore, an increased proportion of gastric cancer, small bowel cancer, nonmelanoma skin cancer, and ovarian cancer were observed. Study III aimed to identify clinical parameters which could potentially predict a pathologic complete response (pCR) in preoperatively treated rectal cancers. Clinical parameters consisted of baseline imaging parameters of the rectal tumour and baseline pretreatment clinical and laboratory parameters before the start of oncologic treatment. We identified associations between pCR and preoperative treatment, low carcinoembryonic antigen (CEA), non-elevated leucocytes, cT (magnetic resonance imaging [MRI]-defined Tstage), and MRI-estimated tumour length. A predictive model based on significant parameters was proposed. Study IV aimed to examine the value of the neoadjuvant rectal score (NAR score) as a short-term surrogate endpoint for oncological outcomes, including time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS), in rectal cancer patients treated preoperatively with short course radiotherapy (scRT), chemoradiotherapy (CRT), or one of these schedules in combination with systemic chemotherapy (scRT/CRT+CTX). We investigated correlations between NAR score for outcomes for all patients and in different treatment cohorts. A statistically significant correlation between NAR score and TTR, CSS, and OS outcomes in a treatment-dependent manner was observed. The prognostic value of NAR could be improved by combining pathological extramural vascular invasion and perineural invasion.