More than FOLFOX and FOLFIRI: The Management of Metastatic Colorectal Cancer in the Era of Precision Oncology

Metastatic colorectal cancer (mCRC) is a markedly heterogeneous disease, which portends a poor prognosis, with an estimated 5-year overall survival rate of approximately 15%. The standard of care of systemic therapy remains fluoropyrimidine-based chemotherapy, with modest results, despite improvements with the combination with anti-angiogenics and anti-epidermal growth factor receptor therapy. Significant advances in cancer therapy have been observed in the past two decades. The enhanced appreciation of molecular biology in oncology has allowed for the identification of specific molecular subtypes and novel therapeutic targets. Nevertheless, meaningful precision-based advancements in the therapeutic options for mCRC have been challenging and slow to realisation. Comprehensive molecular profiling and circulating tumour DNA highlight a heterogeneous disease at the genomic, epigenomic, and transcriptomic levels, and with a low frequency of actionable alterations. In the present review, the authors describe the current and emerging predictive biomarkers in mCRC, as well as present landmark clinical trials that have allowed for evolving precision in the therapeutic management. The understanding of the benefit of immune checkpoint inhibitors in patients with high microsatellite instability cancer and in those with POLE mutations or high tumour mutational burden, the combination of BRAF with epidermal growth factor receptor inhibition in BRAF V600-mutated patients, the use of allele-specific KRAS G12C inhibitors, the promising findings of dual anti-HER2 therapy in HER2-positive mCRC, and the possibility to offer targeted therapy for patients harbouring gene fusions NTRK/ALK/ROS1 have ushered in a new era of precision oncology for mCRC, providing personalised treatments and sustaining hope for patients affected by this challenging disease.