Colorectal cancer (CRC) is the second largest cause of cancer mortality in Western
countries, mostly due to metastasis. Understanding the natural history and prognostic factors in
patients with metastatic CRC (mCRC) is essential for the optimal design of clinical trials. The main prognostic factors
currently used in clinical practice are related to tumor behavior (e.g., white blood counts, levels of lactate dehydrogenase,
levels of alkaline phosphatase) disease extension (e.g., presence of extrahepatic spread, number of organs affected) and
general functional status (e.g., performance status as defined by the Eastern Cooperative Oncology Group). However,
these parameters are not always sufficient to establish appropriate therapeutic strategies. First-line therapy in mCRC
combines conventional chemotherapy (CHT) (e.g., FOLFOX, FOLFIRI, CAPOX) with a number of agents targeted to
specific signaling pathways (TA) (e.g., panitumumab and cetuximab for cases KRAS/NRAS WT, and bevacizumab).
Although the response rate to this combination regime exceeds 50%, progression of the disease is almost universal and
only less than 10% of patients are free of disease at 2 years. Current clinical trials with second and third line therapy
include new TA, such as tyrosin-kinase receptors inhibitors (MET, HER2, IGF-1R), inhibitors of BRAF, MEK, PI3K,
AKT, mTORC, NOTCH and JAK1/JAK2, immunotherapy modulators and check point inhibitors (anti-PD-L1 and anti-
PD1). Despite the identification of multiple prognostic and predictive biomarkers and signatures, it is still unclear how
expression of many of these biomarkers is modulated by CHT and/or TA, thus potentially affecting response to treatment.
In this review we analyzed how certain biomarkers in tumor cells and microenvironment influence the response to new
TA and immune-therapies strategies in mCRC pre-treated patients.