A better knowledge of the complex interactions between cancer cells and the immune system has led to novel immunotherapy approaches. Treatment with selective anti-PD1, anti-PD-L1 and/or anti-CTLA-4 monoclonal antibodies (mAbs) has been a revolution in the therapeutic scenario of several cancer types, with the highest clinical efficacy in melanoma and in lung cancer. Colorectal cancer is one of the tumours in which immunotherapy has been shown less effective. Whereas in deficient mismatch repair (MMR) or in highly microsatellite instable (MSI-H) metastatic colorectal cancer there is clear clinical evidence for a therapeutic role of immune checkpoint inhibitors, the vast majority of patients with proficient MMR or with microsatellite stable (MSS) tumours do not benefit from immunotherapy. Defining the molecular mechanisms for immunogenicity in metastatic colorectal cancer is needed in order to develop predictive biomarkers and effective therapeutic combination strategies. A major challenge will be to identify, among the heterogeneous spectrum of this disease, those patients with specific tumour and tumour infiltrating stroma molecular and functional characteristics, that could be effectively treated with immunotherapy. In this review, we discuss the role of immune response in the context of metastatic colorectal cancer. We summarize the available clinical data with the use of anti PD-1/PD-L1 mAbs as single agents or in combination with anti CTLA-4 mAbs in MSI-H patients. Finally, we address the challenges and the potential strategies for rendering the more frequent microsatellite stable (MSS) tumours "immune-competent" and, therefore, amenable for effective immunotherapy interventions.

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

Click here to listen to the Podcast

Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.

Present and future of metastatic colorectal cancer treatment: A review of new candidate targets