RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.

Background: Maintaining a sufficient health-related quality of life (HRQoL) is important in the palliative treatment of patients with metastatic colorectal cancer (mCRC). The ORCHESTRA trial (ClinicalTrials.gov identifier: NCT01792934) is designed to prospectively evaluate overall survival benefit and impact on HRQoL of tumor debulking when added to first-line palliative systemic therapy in patients with multiorgan mCRC. In the present study, we report the HRQoL associated with this combination treatment compared with standard systemic therapy. Methods: Patients included in the ORCHESTRA trial with clinical benefit after 3 or 4 cycles of first-line palliative systemic therapy with fluoropyrimidines and oxaliplatin with or without bevacizumab were randomly assigned to maximal tumor debulking followed by systemic therapy versus systemic therapy alone. Patients completed the EORTC Quality of Life Questionnaire-Core 30 and the Multidimensional Fatigue Inventory questionnaire at prespecified time points during treatment. Between-group differences in HRQoL over time were evaluated with linear mixed model analyses. A pattern mixture approach was applied to correct for missing questionnaires due to progressive disease. Results: A total of 300 patients were randomized to the intervention arm (n=148) or the standard arm (n=152). No statistically significant or clinically relevant differences in HRQoL and fatigue were observed when tumor debulking was added to systemic therapy. In patients of both study arms, HRQoL after 1 year of treatment was not significantly different from HRQoL at the time of randomization. Patients in the intervention arm experienced serious adverse events (SAEs) twice as often as patients in the standard arm (P≤.001). Conclusions: Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was significantly associated with more SAEs resulting from local therapy but no difference in HRQoL compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and impact on HRQoL.

CD276 can discriminate between tumor derived and normal CECs (circulating endothelial cells). We evaluated whether CD276⁺CEC is a clinically relevant biomarker to predict response to palliative systemic therapy in patients with metastatic colorectal cancer (mCRC). Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial (NCT01792934). At baseline and after three cycles of 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, CECs were measured by flowcytometry (CD34⁺CD45^negCD146⁺DNA⁺; and CD276⁺). A clinically relevant cut-off value of (CD276⁺)CECs was determined as 100% sensitivity (and 80% specificity in 95% confidence interval) identifying patients with progressive disease within 6 months. There were 182 baseline samples and 133 follow up samples available for analysis. CEC and CD276⁺CEC counts significantly increased during treatment from 48 to 90 CEC/4 mL (p = 0.00) and from 14 to 33 CD276⁺CEC/4 mL (p = 0.00) at baseline and at first evaluation, respectively. CEC and CD276⁺CEC counts were not predictive for poor response (area under the curve (AUC) 0.53 for CEC and AUC 0.52 for CD276⁺CEC). Despite numerical changes during therapy, CEC and CD276⁺CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC.