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INTRODUCTION

LEARNING OBJECTIVES

  1. Define the difference between germline and somatic pharmacogenomics.

  2. Recognize and be able to interpret common germline pharmacogenetic relationships that affect chemotherapy toxicity or efficacy.

  3. Recognize and be able to interpret germline pharmacogenetic relationships that affect supportive care therapies.

Pharmacogenomics in oncology is more complex than pharmacogenomics in other disease states because there can be clinical considerations for two different genomes: the tumor’s somatic genome and the patient’s germline genome. The somatic genome acquires genetic variation that causes oncogenic transformation, while the germline genome is the deoxyribonucleic acid (DNA) that is inherited; however, both can have implications for treatment decisions. Somatic genetic aberrations can be used to select a targeted agent for treatment. In some cancer types, these targeted therapies have now become the standard of care in first-line treatment, such as the use of imatinib in the treatment of Philadelphia chromosome–positive leukemia. Other examples of somatic pharmacogenomics include the use of epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib, or B-rapidly accelerated fibrosarcoma (BRAF) inhibitors. The BRAF inhibitors, such as dabrafenib, are recommended as first-line treatment for patients with non–small cell lung cancer (NSCLC), with specific EGFR or BRAF mutations, respectively.1 Historically, targeted therapies received approval for a specific cancer type harboring a specific genetic alteration; recently, however, the targeted therapy drug approval is shifting, where the indication for use is tied only to the genetic alteration. An example of this is the recent approval of the neurotrophic receptor tyrosine kinase (NTRK) inhibitor larotrectinib, which is indicated for the treatment of any metastatic solid tumor that harbors an NTRK gene fusion.2 The clinical application of somatic pharmacogenomics is continuously evolving as new gene targets are discovered and new targeted therapies are developed.

The germline genome can provide information regarding cancer predisposition risk. This information can be used to identify patients who may benefit from enhanced cancer screening or cancer prevention interventions. Germline cancer predisposition genes may also have implications for treatment, such as the use of poly-ADP ribose polymerase (PARP) inhibitors (olaparib, rucaparib, and niraparib), which are specifically indicated for the treatment of patients who carry mutations in the breast cancer gene (BRCA). Additionally, germline pharmacogenomics can be used to predict the pharmacokinetics or pharmacodynamics of anticancer and supportive care therapies. A review of targeted therapies for somatic mutations and germline cancer predisposition genes is beyond the scope of this chapter, which will focus on the application of germline pharmacogenomics for anticancer and cancer supportive care therapies.

CHEMOTHERAPIES WITH GERMLINE PHARMACOGENETIC ASSOCIATIONS

There are multiple examples of germline pharmacogenetic relationships that can predict clinical outcomes associated with chemotherapies frequently used to treat patients with cancer. Associated clinical outcomes can be rates of adverse events related to the therapy or assessments of therapeutic efficacy. Additionally, new pharmacogenetics associations are continuing to be discovered, and this chapter will both discuss clinically actionable ...

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