Overview
This lecture reviews the systemic treatment options for metastatic colorectal cancer (mCRC), focusing on chemotherapy, targeted therapy, immunotherapy, and personalized medicine guided by molecular biomarkers.
Epidemiology and Risk Factors
- Colorectal cancer (CRC) is the third most common cancer globally, with a high mortality rate, especially when metastatic.
- Major risk factors include westernized diet, obesity, sedentary lifestyle, smoking, alcohol, older age, male gender, and family history.
- Only a minority of CRCs are hereditary; most are sporadic with significant environmental influence.
- Prevention is aided by routine colonoscopies and high-fiber diets.
Molecular Pathways and Biomarkers
- Three main molecular pathways: Chromosomal instability (CIN/adenoma-carcinoma sequence), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP/serrated pathway).
- KRAS, BRAF, and HER2 are key genes influencing prognosis and therapy selection.
- KRAS and BRAF mutations are associated with poor outcomes and resistance to anti-EGFR therapies.
- HER2 amplification is rare but may offer therapeutic targets.
Systemic Treatment Strategies
- Multi-disciplinary teams determine resectability of metastases, especially liver metastasis.
- First-line therapies combine chemotherapy (FOLFOX, FOLFIRI) with targeted agents: anti-VEGF (bevacizumab) or anti-EGFR (cetuximab, panitumumab) for RAS wild-type tumors.
- Choice of targeted therapy is influenced by tumor location (left vs. right colon) and molecular profile.
- Subsequent lines of therapy use alternative agents or combinations, including BRAF and HER2 inhibitors, or rechallenge strategies.
Immunotherapy
- Immunotherapy with checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab) improves outcomes in dMMR/MSI-H mCRC.
- pMMR/MSS tumors ("cold tumors") generally do not respond to single-agent immunotherapy but may benefit from combination approaches (e.g., AtezoTRIBE, MAYA trials).
Adoptive Cell Therapy
- CAR-T cell therapy (engineered T cells) shows promise in early trials for mCRC with specific antigen targets but requires further research.
Key Terms & Definitions
- mCRC — metastatic colorectal cancer.
- KRAS/BRAF/HER2 — genes commonly mutated or amplified in CRC, affecting treatment choices.
- MSI-H/dMMR — high-level microsatellite instability or deficient mismatch repair; predicts immunotherapy response.
- EGFR — epidermal growth factor receptor, a target for some targeted therapies.
- FOLFOX/FOLFIRI — standard chemotherapy regimens for CRC.
- CAR-T cells — chimeric antigen receptor T cells, a form of adoptive cell therapy.
- TME — tumor microenvironment, influencing tumor growth and therapy response.
Action Items / Next Steps
- Review molecular biomarker testing protocols for mCRC patients.
- Study first- and second-line chemotherapy and targeted therapy regimens.
- Read about the outcomes of BEACON, AtezoTRIBE, and MAYA clinical trials.
- Prepare a summary of immunotherapy indications based on MSI/MMR status.