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.

Inflammatory indexes as predictors of prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer

We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2–10.3] and 8.4 (95% CI 7.2–9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70–1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. NCT01878422.

Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition.