Colon cancer treatment has seen considerable progress, moving beyond traditional approaches to incorporate more precise strategies. Targeted therapy represents a modern advancement, focusing on the unique molecular characteristics of cancer cells. This approach aims to deliver more effective treatment by specifically interfering with the processes that drive cancer growth and spread.
What is Targeted Therapy?
Targeted therapy is a precision medicine that inhibits specific molecules within or on cancer cells, interfering with their growth, division, and spread. These molecules, often proteins, are produced by cancer-causing genes or the cancer cells themselves. The therapy works by attaching to these targets, preventing their functions to stop or slow cancer progression.
Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells and causes widespread side effects, targeted therapies are more selective. They minimize harm to healthy tissues by identifying specific genetic mutations or protein overexpression unique to cancer cells. This offers a more tailored and less toxic treatment.
Identifying Candidates: The Role of Biomarkers
Targeted therapy requires specific testing to identify suitable candidates. This involves “biomarker testing,” also known as molecular or genomic testing. These tests analyze samples from a patient’s tumor tissue, blood, or other bodily fluids to detect specific genetic mutations or molecular changes. Biomarker presence or absence helps determine effective targeted therapies.
For colon cancer, several biomarkers are routinely tested. Mutations in KRAS and NRAS genes indicate resistance to certain EGFR inhibitors. The BRAF V600E mutation is another biomarker, often associated with poorer prognosis and affecting responsiveness to certain therapies. Testing for HER2 amplification or overexpression is also performed, as HER2-positive tumors may respond to HER2-targeted treatments.
Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status indicates how well the tumor can repair DNA damage. Tumors with MSI-H/dMMR respond poorly to conventional chemotherapy but often show a strong response to certain immunotherapies. These tests help clinicians make informed decisions about personalized treatment, ensuring patients receive therapies most likely to work for their specific tumor characteristics.
Types of Targeted Therapies for Colon Cancer
EGFR Inhibitors
EGFR inhibitors block the activity of the EGFR protein, which promotes cell growth and division. These therapies, such as cetuximab and panitumumab, bind to the extracellular domain of EGFR, preventing receptor activation and inhibiting signaling pathways that contribute to cancer cell survival and proliferation. They are effective in patients with wild-type KRAS and NRAS genes, as mutations can lead to resistance. EGFR overexpression is found in approximately 65-75% of advanced colorectal cancer patients, making it a relevant target.
VEGF Inhibitors (Anti-Angiogenic Agents)
VEGF inhibitors, also known as anti-angiogenic agents, block the formation of new blood vessels tumors need to grow and spread. These drugs target VEGF or its receptors, cutting off the tumor’s blood supply. Examples include bevacizumab (neutralizes VEGF-A), ziv-aflibercept (binds VEGF-A, VEGF-B, and PlGF), and ramucirumab (targets VEGFR-2). These therapies are often used with chemotherapy to enhance efficacy.
BRAF Inhibitors
BRAF inhibitors target the BRAF V600E mutation, present in about 8-12% of colorectal cancer diagnoses and associated with poor prognosis. This mutation causes uncontrolled signaling, stimulating cell proliferation. Encorafenib, a BRAF inhibitor, is used with cetuximab (an EGFR inhibitor) for BRAF V600E-mutated metastatic colorectal cancer. This combination helps overcome a feedback loop where BRAF inhibition alone can lead to rapid EGFR activation.
Immunotherapy (Checkpoint Inhibitors)
Immunotherapy, specifically immune checkpoint inhibitors, shows promise for colorectal cancers with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). These tumors have a defective DNA repair system and respond poorly to conventional chemotherapy. Anti-PD-1 antibodies like pembrolizumab and nivolumab block the PD-1 receptor on immune T-cells, “releasing the brakes” on the immune system to attack cancer cells more effectively. Ipilimumab, an anti-CTLA-4 antibody, can also be used, often with nivolumab, to further enhance the immune response.
Other/Emerging Therapies
Beyond these main classes, other targeted therapies are available for specific rare mutations or are being explored. HER2-targeted therapies are used for HER2-positive colorectal cancer. Trastuzumab deruxtecan, an HER2 antibody-drug conjugate, shows activity in HER2-positive, RAS and BRAF wild-type metastatic colorectal cancer. Tucatinib with trastuzumab is also approved for advanced HER2-positive colorectal cancer. Drugs targeting NTRK gene fusions and RET gene changes are also available for a small subset of colorectal cancers with these alterations.
Understanding Potential Side Effects
Targeted therapies, though more precise than chemotherapy, can still cause side effects related to their specific biological targets. Common issues include an acne-like rash on the face, scalp, neck, chest, and upper back, which may become dry and crusty. Hand-foot syndrome, with painful sensitivity, tingling, numbness, redness, and swelling on the palms and soles, is also possible.
Gastrointestinal issues like diarrhea and constipation are also reported. Fatigue, headaches, and joint aches can occur.
Some targeted therapies, particularly angiogenesis inhibitors, can lead to elevated blood pressure and protein in the urine. Bleeding or blood clotting problems are also possible. Less common but more serious side effects include heart damage, liver problems, or lung inflammation (pneumonitis). Side effects vary by drug and patient, but are typically manageable with medical intervention or dose adjustments.
Targeted Therapy in Treatment Plans
Targeted therapy plays a significant role in colon cancer management, particularly in advanced or metastatic stages. These therapies are often incorporated into metastatic colorectal cancer treatment plans, either with chemotherapy or as standalone treatments. The decision to use targeted therapy is personalized, based on biomarker testing, cancer stage, and the patient’s overall health and previous treatments.
For advanced disease, targeted therapies can improve outcomes and prolong survival. While primarily used in metastatic settings, their potential role in earlier stages, such as adjuvant therapy for high-risk early-stage disease, is being explored, especially when specific biomarkers are identified. This is more commonly seen with immunotherapy in early-stage settings than with other targeted therapies.
Treatment plans are dynamic; if a patient develops resistance to a particular targeted therapy, which can occur, the medical team may adapt the plan by switching to different agents or combinations. This adaptive approach aims to overcome resistance and manage the disease effectively. Ongoing identification of new genetic mutations and proteins in colon cancer continues to expand future targeted treatment options.