Overview of Colorectal Cancer Treatment
Metastatic colorectal cancer (mCRC) treatment is guided by molecular profiling including RAS/BRAF mutation status, microsatellite instability (MSI), and HER2 amplification. Anti-VEGF therapy (bevacizumab) and anti-EGFR antibodies (cetuximab, panitumumab) for RAS wild-type disease form the backbone. BRAF V600E-mutated CRC (~10%) is treated with encorafenib-based combinations. MSI-H/dMMR tumors respond dramatically to checkpoint inhibitors.
Treatment Selection by Molecular Profile
RAS Wild-Type, Left-Sided
- FOLFOX/FOLFIRI + anti-EGFR (cetuximab or panitumumab)
- Bevacizumab-based regimens as alternative
RAS Mutant
- FOLFOX/FOLFIRI + bevacizumab
- Anti-EGFR therapy contraindicated
BRAF V600E Mutant
- Encorafenib + cetuximab (BEACON regimen)
- Triplet: encorafenib + binimetinib + cetuximab
MSI-H/dMMR
- Pembrolizumab first-line (KEYNOTE-177)
- Nivolumab ± ipilimumab for pretreated
HER2-Amplified (3-5%)
- Tucatinib + trastuzumab (MOUNTAINEER)
- Trastuzumab deruxtecan (Enhertu)
Epidemiology & Impact
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States, with approximately 152,810 new cases and 53,010 deaths projected for 2024. A concerning trend has emerged: while overall incidence has declined by ~1% annually in patients over 50 (attributable to screening colonoscopy), incidence in adults under 50 has been rising by approximately 1-2% per year since the mid-1990s. This early-onset CRC phenomenon has prompted the 2021 lowering of the recommended screening age to 45. Five-year survival varies dramatically by stage: localized (91%), regional (73%), and distant (15%). Risk factors include family history, inflammatory bowel disease, hereditary syndromes (Lynch syndrome, FAP), obesity, processed meat consumption, physical inactivity, and heavy alcohol use.
Molecular Biology & Biomarkers
Molecular profiling is essential for CRC treatment planning. Key biomarkers include RAS mutations (KRAS/NRAS, present in ~50-55% of mCRC, precluding anti-EGFR therapy), BRAF V600E mutation (~8-12%, associated with poor prognosis, targetable with encorafenib-based combinations), microsatellite instability (MSI-H/dMMR, ~15% of all CRC, ~5% of metastatic, highly responsive to immunotherapy), HER2 amplification (~3-5%, targetable with trastuzumab-based combinations), and NTRK fusions (<1%, targetable with larotrectinib or entrectinib). Primary tumor sidedness is a validated prognostic and predictive factor: left-sided (splenic flexure to rectum) tumors have better prognosis and preferentially benefit from anti-EGFR therapy, while right-sided tumors have higher rates of MSI-H, BRAF mutations, and poorer outcomes. Circulating tumor DNA (ctDNA) is emerging as a powerful tool for post-surgical MRD detection and is being evaluated prospectively as a tool to guide adjuvant chemotherapy decisions (DYNAMIC trial).
Evolving Treatment Landscape
The CRC treatment landscape has evolved significantly with molecularly guided therapy. For MSI-H/dMMR metastatic CRC, pembrolizumab first-line (KEYNOTE-177) has established immunotherapy as the preferred approach over chemotherapy, with durable complete responses observed in a substantial minority. The BRAF V600E space was transformed by the BEACON trial establishing encorafenib + cetuximab as standard. HER2-amplified CRC has gained two targeted options: tucatinib + trastuzumab (MOUNTAINEER) and trastuzumab deruxtecan (DESTINY-CRC02). Fruquintinib (Fruzaqla), a selective VEGFR inhibitor, has filled a late-line niche. In the perioperative space, circulating tumor DNA-guided adjuvant therapy (the DYNAMIC approach) represents a potential paradigm shift from the current stage-based treatment decisions, allowing molecular risk stratification to determine which patients truly benefit from adjuvant chemotherapy.
Approved Therapies
Treatment Strategies
First-line: FOLFOX or FOLFIRI + bevacizumab OR cetuximab/panitumumab (RAS wild-type); pembrolizumab first-line for MSI-H/dMMR. Second-line: Alternate regimen + targeted therapy. BRAF V600E: Encorafenib + cetuximab (BEACON doublet). HER2+: Tucatinib + trastuzumab. Later lines: Regorafenib, trifluridine/tipiracil, fruquintinib.