___________________________________________________________________________ Colorectal Cancer
Secondary Drug Resistance Patients with chemotherapy-refractory colorectal cancer who initially respond and then become resistant to cetuximab or other monoclonal antibodies have essentially run out of thera- peutic options. This emergence of secondary drug resistance within 9 to 18 months of initiation is a major limitation of anti-EGFR therapies. A substantial proportion of patients with colorectal cancer who initially respond to anti-EGFR therapies have, at the time of disease progression, tumors with focal amplification or somatic mutations in KRAS that were unde- tectable before initiation of anti-EGFR therapy. Drug-resistant KRAS alteration results from pre-existent KRAS mutant and amplified clones and from new mutations arising from ongoing mutagenesis [240]. A mechanism by which KRAS mutation nullifies anti-EGFR therapy involves bypassing the need for upstream EGFR signals to activate downstream oncogenic processes [172; 183]. It is now established that patients with any KRAS or NRAS mutation should not be treated with cetuximab or panitumumab, as these mutations strongly predict resistance to EGFR inhibitor agents. In contrast, non-mutational KRAS , termed wild-type KRAS , responds to targeted therapy [112; 203; 226; 231; 241; 242]. GENERAL APPROACH TO TREATMENT Overall, there is a substantial overlap between treatment approaches for colon and rectal cancer, especially in stage IV and metastasized cancer. Treatment approaches for stage I–III cancer (earlier stage) differs the most. In this section, treatment of earlier-stage colon and rectal cancer are discussed separately, and discussion of metastatic colon and rectal cancer is com- bined. For both cancers, the foundation of care is surgical resection for patients with local or locally advanced tumor, and chemotherapy for stage IV, metastatic, and recurrent tumor. Unlike rectal cancer, radiotherapy has limited use in colon cancer. The timing of chemotherapy and/or radiotherapy is sequenced in relation to surgery as follows: • Neoadjuvant chemotherapy and/or radiation therapy: Delivered before surgery, to downsize the tumor. Most often used in rectal cancer. • Adjuvant chemotherapy and/or radiation therapy: Delivered following surgery with the intent to destroy remaining local or micro-metastasized malignant cells and colonies. • Palliative chemotherapy or radiotherapy: Delivered to downsize or eradicate colorectal cancer tumors that have metastasized to other organs. The objective is to relieve symptoms and pain, instead of cure or prolonging survival. • Liver metastases: The liver is the most common site of metastatic colon and rectal cancer. Treatment of hepatic metastases of primary colorectal cancer can involve surgery with neoadjuvant or adjuvant chemotherapy, local ablation, or intra-arterial chemotherapy.
or mismatch repair deficient (dMMR) colorectal cancer [233]. In 2023, fruquintinib received FDA approval as treatment for patients with refractory metastatic colorectal cancer [234]. Also in 2023, tucatinib (in combination with trastuzumab) received accelerated FDA approval as second-line treatment of RAS wild-type HER2-positive unresectable or metastatic colorectal cancer [235]. In 2024, the FDA granted accelerated approval to encorafenib (in combination with cetuximab and mFOLFOX6) for patients with metastatic colorectal cancer with a BRAF V600E mutation [236]. EGFR is a glycoprotein with three primary components: an extracellular ligand binding domain, a hydrophobic transmem- brane domain, and an intracellular tyrosine kinase domain. EGFR is activated by ligand binding from EGF or transforming growth factor-alpha, which triggers downstream activation in signaling pathways that facilitate development and progression of colorectal cancer. This critical role of EGFR in oncogenesis has made it an attractive target for colorectal cancer therapy, and the targeted biologic agents cetuximab and panitumumab primarily act through binding EGFR to inhibit downstream signaling [172; 237; 238]. Colorectal tumors that grow beyond 1–2 mm 3 require increased access to oxygen and nutrients and develop neo- angiogenesis to enable tumor growth and metastases. Neo- angiogenesis originates from complex interactions between pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF), the most potent pro-angiogenic factor known to date, is overexpressed in gastrointestinal tumors and is essential for the proliferation and metastases of colorectal cancer [238; 239]. VEGF overexpression is associated with increased tumor vascularity, proliferation, progression, invasion, and metastasis. VEGF binds to and activates one of the three VEGF receptors located on the vascular endothelium. Among the VEGF recep- tor types, VEGFR-2 is the primary mediator of the mitogenic and angiogenic effects of VEGF, while VEGFR-3 is involved in lymphangiogenesis [227]. Following VEGF binding, VEGF receptors activate several downstream intracellular signal transduction pathways that promote inhibition of apoptosis, degradation of the extracel- lular matrix to facilitate endothelial cell proliferation and migration to form new blood vessels, and stimulation of mitosis and cytoskeletal changes associated with motility. Colorectal tumors also express VEGF and other proangiogenic factors on their cell surface; their presence is associated with increased vascularity, advanced disease, and poor prognosis [239]. Findings of elevated VEGF levels in patients with metastatic colorectal cancer led to the development and FDA approval of several anti-VEGF agents (i.e., bevacizumab, ramucirumab, regorafenib, ziv-aflibercept, and fruquintinib) [231; 232; 238]. In addition to the therapeutic targeting of VEGF, VEGF antagonists have also shown the ability to increase intratu- moral delivery of chemotherapeutic agents to improve their antitumor efficacy [226; 227].
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