Colorectal cancer treatments in the age of precision oncology

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Colorectal cancer (CRC) is the second most lethal cancer in the world and the third most common malignant tumor. In 2018, 1.8 million new CRC cases were recorded, with 881,000 fatalities, accounting for approximately 10% of all new cancer cases and deaths globally, with the number of new cases expected to reach nearly 2.5 million by 2035. For many years, surgery and chemotherapy have been the treatment of choice for cancer patients. However, the prognosis for CRC patients has never been good, particularly for those with metastatic tumors. After decades of research and development, CRC-targeted medications are now being updated for greater patient compliance, fewer side effects, and more tailored treatment regimens. These targeted therapies have effectively improved overall survival in individuals with CRC.

Precision oncology offers potential for tailored approaches to prevent and treat CRC. In CRC, the use of molecular markers and other biomarkers helps researchers to identify genes and biomarkers that may help predict individual prognosis and recurrence rate. It may also improve treatment outcomes and reduce treatment side effects, leading in a reduction in financial burden and, eventually, the adoption of precision medicine in the treatment of CRC patients. Targeting molecular pathways of tumor growth/proliferation has become a key focus of anti-cancer therapy in the development of new and innovative drugs in CRC throughout the last decade. Various pathways mediating the initiation, progression, and migration of CRC like Wnt/-catenin, Notch, Hedgehog, and TGF-β (transforming growth factor-β), as well as those capable of activating signaling cascades, such as phosphatidylinositol 3-kinase (PI3K)/AKT or RAS/rapidly accelerated fibro-sarcoma (RAF), contain ideal sites for targeted therapy.

The treatment paradigm for CRC is rapidly shifting to a more personalized or precision-based approach. Molecular markers now play an increasingly important role in making decisions about targeted therapies. The rapidly growing body of information regarding the roles of genetics and the immune system in cancer has paved the way for the development of medicines that target particular molecular abnormalities or other biologic characteristics, such as those linked to immune suppression. Most precision oncology therapies for CRC specifically target the epidermal growth factor receptor (EGFR) pathway. The RAS and BRAF genes are two other areas where cancer mutations might occur. Another notable type of precision medicine for CRC is the use of immune checkpoint inhibitor therapy. Agents that target the vascular endothelial growth factor (VEGF) route, such as bevacizumab, or the epidermal growth factor receptor (EGFR) pathway, such as cetuximab and panitumumab, have become standard-of-care therapy. The finding that EGFR mutations have a role in the genesis and progression of CRC paved the way for personalized treatment based on the molecular characteristics of each colon tumor.

The use of immune checkpoint inhibitor therapy for the treatment of refractory MSI-H CRC is perhaps the most remarkable achievement in precision treatments for advanced CRC. In these patients, single-agent PD-1 inhibitor treatment (e.g., pembrolizumab or nivolumab) has demonstrated disease control rates of 69% to 77%, with durable responses persisting even after drug termination. According to a study, when administered as first-line therapy for MSI-H–metastatic colorectal cancer, the PD-1 inhibitor Pembrolizumab resulted in considerably longer progression-free survival and fewer treatment-related adverse effects than chemotherapy. Immune checkpoint inhibitor therapy is now being studied as a first-line palliative treatment for MSI-H CRC, adjuvant therapy for resected stage III MSI-H colon cancer, and even as a possible chemoprevention in those who are at risk for MSI-H neoplasia due to Lynch syndrome.

According to the current NCCN Clinical Practice Guidelines for Colon Cancer, all patients with metastatic CRC should have their tumor tissue genotyped for TP53, APC, KRAS, NRAS, and BRAF mutations. Patients with known KRAS (exon 2, 3, 4) or NRAS (exon 2, 3, 4) mutations should not be treated with cetuximab or panitumumab. Unless taken alongside a BRAF inhibitor, patients with the BRAF V600E mutation are unlikely to respond to panitumumab or cetuximab. For hypermutated cancers that are responsive to immune checkpoint suppression, microsatellite instability status is a common and reliable biomarker. After fluoropyrimidine, oxaliplatin, and irinotecan, checkpoint blockade treatment exhibits remarkable response rates and durability in mismatch repair-deficient CRC, and is currently approved by the FDA for MSI-H CRC.

Preclinical and translational research has revealed the underlying mechanisms of key genetic abnormalities, such as the discovery of cancer driver genes and their frequency in advanced-stage CRC patients. Potentially actionable driver genes have been investigated intensively to create therapeutics for advanced-stage CRC patients, including mismatch repair deficiency (MMR-D), BRAF V600E mutant, and human epidermal growth factor receptor 2 (HER2). MMR-D and neurotrophic receptor tyrosine kinase (NTRK) mutations have already led in FDA-approved medications, while the remaining actionable genes offer potential for future clinical application.