Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine?

Abstract

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.

Keywords: cfDNA; colorectal cancer; heterogeneity; liquid biopsy; metastasis; response to therapy; tumor tissue.

Figure 1

Overview of the main types of heterogeneity in colorectal cancer (CRC), and the central role of liquid biopsy.

Figure 2

Spatio-temporal heterogeneity and the role of liquid biopsy in the management of mCRC. Example based on RAS mutational status analysis. (a) RAS wild type (wt) tumors. Even in an apparently homogeneous genetic context, the selective pressure exerted by drugs can induce de novo mutations or the selection of mutations present at subclonal level in the primary tumor. (b) RAS mutated tumors. Heterogeneity can be present within the primary tumor, within metastases, and between primary tumor and metastases. Treatment based on chemotherapy + anti-angiogenic drugs can determine a switch to prevalently wt RAS circulating tumor DNA (ctDNA).