Monoclonal antibodies for the treatment of metastatic colorectal cancer and include Cetuximab and panitumumab.
Bind to the extracellular domain of the EGFR and prevent its activation by EGFR ligands such as epidermal growth factor and amphiregulin.
EGFR is a receptor tyrosine, kinase of the ERBB protein family, is crucial in promoting cell proliferation, migration, angiogenesis, adhesion, and survival.
They inhibit the subsequent downstream signaling mediated by the RAS-RAF-extracellular signal-related kinase and phosphoinositide 3-kinase (PI3K) -phosphatase and tensin homolog (PTEN)-AKT pathways.
KRAS, NRAS, and BRAF mutations confer inherited resistance to anti-EGFR agents and benefits in colorectal cancer is restricted to wild-type KRAS tumors.
Predictive mutations initially noted in exon 2 (codons 12 and 13) and are present in approximately 40% of patients with metastatic colon rectal cancer.
KRAS exons3 ( codons 59 and 61) and 4 (codons 117 and 146) as well as respective mutations in in NTAS found an additional 10 to 15% of colorectal tumors, predicting similar lack of response to anti-EGFR therapies.
Mutations at exon 2 at codons 12 and 13 preclude response to anti-EGFR therapy.
BRAF V600E mutations occur in 5-10% of patients with colorectal cancer are also associated with lack of benefit from EGFR monoclonal antibodies.
Mutations in BRAF, KRAS and NRAS are mutually exclusive and such patients are unlikely to benefit from standard anti-EGFR therapy.
Most patients who benefit from anti-EGFR treatment with eventually develop resistance.
Mutations in KRAS, NRAS, BRAF, and PIC3CA, and loss of PTEN results in resistance to anti-EGFR therapies.
Epidermal growth factor receptor targeting antibodies such is Panitumumab and cetuximab are associated with improvements in response rate, progression free survival, and overall survival when combined with systemic therapy in the first line treatment of left sided RAS/BRAF wild type mettastatic colorectal cancers.
More than 30% of patients with these above characteristics do not benefit from anti-EGF or therapy.
HER2 amplfication is anti-EGFR antibody resisitant.
Treatment with anti-– EGFR antibodies is associated with skin and pulmonary toxicity, as well as electrolyte imbalances.
Adverse effects of these agents are: diarrhea, rash, acneiform dermatitis ,stomatitis, infusin-related reactions.
Electrolyte abnormalities from anti-– EGFR’s includes hypomagnesia, which is a common cumulative toxicity.
Using skin moisturizers, sunscreen, topical steroids, and doxycycline can reduce the incidence and severity of skin toxicities associated with the EGFR inhibitors