Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.

Keywords: chemotherapy precision oncology; colorectal cancer; fluoropyrimidine.

Figure 1

Biomarker-based stratification for front-line treatment of mCRC. ESMO and NCCN guidelines recommend MSI/MSS testing and comprehensive RAS and BRAF mutation status. Most mCRC is MSS (~95%) and treated with a combination of chemotherapy and targeted therapy. MSI (~5%) is treated with immune checkpoint blockade (ICB) immunotherapy. About 40% of mCRC expresses a mutant RAS protein (KRAS or NRAS), and front-line treatment frequently consists of either FOLFOX or FOLFIRI chemotherapy in combination with anti-VEGF therapy (e.g., bevacizumab). Inhibitors for specific RAS mutations (e.g., sotorasib and adagrasib for KRAS^G12C) are in clinical development. About 5% of mCRC expresses BRAF^V600E, and recently, the combination of encorafenib+anti-EGFR (cetuximab) was FDA-approved for front-line treatment. HER2 is amplified in ~5% of mCRC, and a preferred front-line treatment is trastuzumab+lapatinib. For RAS^WT mCRC without BRAF mutation or HER2 amplification, chemotherapy combined with anti-EGFR therapy (cetuximab or panitumumab) is recommended front-line treatment. Acquired resistance to anti-EGFR therapy can result from ALK-fusion or NTRK-fusion with the indicated treatment.

Figure 2

Therapeutic targeting of mCRC. EGFR-family signaling initiates proliferative signaling in mCRC via the RAS/RAF/MAPK cascade. Monoclonal antibodies targeting EGFR dimer and specific heterodimers have activity in mCRC without mutations in a RAS protein or BRAF. Small molecule inhibitors of specific KRAS mutant forms and BRAF^V600E have activity in mCRC. Fluoropyrimidine-based chemotherapy targets thymidylate synthase (TS) and DNA topoisomerase 1 (Top1) and causes DNA damage and replication stress.

Figure 3

Sequential administration of FP-based chemotherapy for the treatment of mCRC that is RAS^MT and microsatellite-stable (MSS) following disease progression. Front-line treatment consists of either FOLFOX or FOLFIRI, which may be combined with anti-VEGF therapy. Second-line treatment generally uses the alternative FP-based regimen (e.g., FOLFOX → FOLFIRI) and may be combined with an alternative anti-VEGF agent (e.g., Aflibercept). Third-line treatment uses an alternative FP-based treatment, TAS-102, in which FP trifluridine is combined with Tiperacil. Regorafenib is also widely used in third-line treatment of mCRC.