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Clinical pharmacogenetics in oncology: the paradigm of molecular targeted therapies
Giannis Mountzios1, Despina Sanoudou, Konstantinos N Syrigos
1Oncology Unit, 3rd Department of Medicine, Sotiria General Hospital, Athens Medical School, Building Z, 152 Mesogion Avenue, 115 27 Athens, Greece.
Abstract:
Even though treatment of several types of solid tumors has improved in the past few years with the introduction of molecular targeted agents in the therapeutic armamentarium of the medical oncologist, response rates to these agents are generally modest. Increasing evidence is now revealing that genetic factors are affecting patients' response to these therapeutic agents as well as the frequency and intensity of toxic reactions. Importantly, pharmacogenetic analysis is now required for the administration of several molecular targeted agents in clinical practice. For the vast majority of these agents, however, data remain purely experimental. Herein, we provide an overview of the genetic changes (mutations and polymorphisms) that have been associated with response to treatment with anticancer molecular targeted agents. Special emphasis is given on molecules (monoclonal antibodies and tyrosine kinase inhibitors) that target critical mediators in the epidermal growth factor receptor (EGFR), the human epidermal growth factor receptor 2 (HER2/ERBB2/NEU) and the vascular endothelial growth factor receptor (VEGFR) pathways. The true clinical utility of these applications remains to be proven in future prospective, randomized clinical trials in large patient cohorts of all different ethnic backgrounds.
Insights
Genetic factors influence patient response and toxicity to molecular targeted cancer therapies. Pharmacogenetic analysis is crucial, but clinical utility requires further validation in diverse populations.
Area of Science:
- Oncology
- Pharmacogenetics
- Molecular Biology
Background:
- Molecular targeted agents have improved solid tumor treatment, but response rates remain modest.
- Genetic factors significantly impact patient response and toxicity to these therapies.
- Pharmacogenetic analysis is increasingly required for targeted agent administration.
Purpose of the Study:
- To provide an overview of genetic alterations associated with targeted anticancer agent response.
- To emphasize key pathways including EGFR, HER2, and VEGFR.
- To discuss the role of mutations and polymorphisms in treatment outcomes.
Main Methods:
- Literature review of genetic changes impacting targeted therapy.
- Focus on monoclonal antibodies and tyrosine kinase inhibitors.
- Analysis of genetic factors in EGFR, HER2, and VEGFR pathways.
Main Results:
- Genetic mutations and polymorphisms are linked to variable patient responses to targeted therapies.
- Specific genetic factors influence efficacy and toxicity of agents targeting EGFR, HER2, and VEGFR.
- Current data for many agents are largely experimental.
Conclusions:
- Genetic variations play a critical role in the efficacy and safety of molecular targeted cancer therapies.
- Further prospective, randomized clinical trials in diverse ethnic groups are essential to confirm clinical utility.
- Pharmacogenetics holds promise for personalizing cancer treatment but requires robust validation.
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