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KEY CONCEPTS
The therapeutic approach for patients with metastatic cancer includes multigene tissue genomic analysis and assessment of immune markers that include programmed cell death-ligand 1, microsatellite instability (MSI) status, tumor mutational burden, neurotrophic tyrosine kinase receptor (NTRK) fusion, human epidermal growth factor receptor 2 (HER2) amplification, and cell-free DNA analysis to identify drivers of carcinogenesis. The use of targeted therapy against molecular alterations in individual patients has been associated with improved clinical outcomes.
Patients with advanced cancer may have tumor molecular alterations in one or more of the following genes and pathways: RAS-RAF-MEK, PI3K-AKT-mTOR, EGFR, HER-2, BRCA, HER2, RET, ROS-1, KIT, CDK4/6, PDGFR, VEGFR1/2/3, PDGFRα, NTRK, METex1h4, FGF, Trop-2 CSF1R, AR, ER, and other genes. (See text for abbreviations.)
Larotrectinib and entractinib are novel NTRK inhibitors indicated for patients whose tumor has a NTRK fusion, irrespective of tumor type.
Treatment with pembrolizumab (a programmed cell death protein 1 inhibitor) is indicated for patients with MSI-H mismatch repair deficient tumors irrespective of tumor type.
The combination of targeted therapy with either chemotherapy or immunotherapy has shown promising results in various tumors. Prospective trials are warranted to provide biomarkers associated with response or resistance to immunotherapeutic agents.
Novel drug development, complete understanding of mechanisms of carcinogenesis, innovative clinical trials, and harmonization of policy and practice will accelerate the implementation of personalized medicine.
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The Human Genome Project has enabled sequencing of human DNA and led to advancements in technologies that detect genomic, transcriptional, proteomic, and epigenetic changes. The application of these technologies and novel drug development have accelerated the implementation of personalized medicine. Personalized medicine uses concepts of the genetic and environmental bases of disease to individualize prevention, diagnosis, and treatment.1,2 Optimization of treatment by incorporating targeted therapy—the use of molecules that target specific enzymes, growth factor receptors, and signal transducers to interfere with a variety of oncogenic cellular processes—and other strategies made possible by advancements in the field of translational medicine hold the promise of improving patient care.3 In recent years, immunotherapy has revolutionized the field of personalized medicine, and many drugs have been approved for the treatment of patients with specific tumor types and for patients whose tumors express specific immune markers. These drugs are now included in the targeted therapy arsenal.
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This chapter focuses on the evolution of targeted therapy in cancer therapeutics and is organized according to the key drivers of carcinogenesis in humans, focusing on the novel agents designed to target those drivers. It also summarizes the current state-of-the-art applications of personalized medicine.
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RAS-RAF-MEK PATHWAY INHIBITORS
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The mitogen-activated protein kinase (MAPK) cascades contribute to carcinogenesis with upregulation of the MAPK cascades rapidly accelerated fibrosarcoma (RAF) and MAPK/extracellular signal-regulated kinase (ERK) (MEK). Cell-surface molecules activate the RAS family (KRAS, NRAS, and HRAS), which are GTPases that activate downstream RAF protein kinases [rapidly accelerated fibrosarcoma homolog B (BRAF); rapidly accelerated fibrosarcoma homolog ...