Playing by the Oncology Pharmacogenomics Rules

Pharmacogenomics (PGX) is the study of how the same drug responds to different gene expression in each patient.¹ Different gene expression increases or decreases medication retention, which may cause adverse effects or reduced medication effectiveness. This can be particularly impactful for patients with cancer; consequently, individualizing therapy is essential. Recently, members of the American Society of Clinical Oncology created a guideline for individualizing testing, choosing the optimal therapy, and dosing the medication.^1,2

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A review article in the March 2025 issue of Frontiers in Pharmacology summarized the guidelines, including how to test patients to obtain PGX data. One option is a cell-free DNA (cfDNA) assay, which has a processing time of at most 14 days and provides large quantities of disease information, such as if a chromosome or gene is altered.¹

One example of altered gene expression is the dihydropyridine dehydrogenase (DPyD) gene.¹ DPyD genes make enzymes that accelerate how quickly the body removes the fluoropyrimidine medication class, such as 5-fluorouracil.¹

A second example is uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1).¹ This enzyme, UGT1A1, speeds up a chemical reaction that adds glucuronic acid to medications or bilirubin. This transformed compound is more water soluble, and the body does not retain it. If that enzyme is formed differently, the body may retain the medication. The shorthand notation for this gene has a notation with an asterisk and a number. In this case, if the PGX shows UGT1A1 with *28/*28 or *6/*28, UGT1A1 excretes medications quickly. Thus, chemotherapies such as govitecan are retained in the body, leading to adverse effects.¹

Yet another example is the O-6-methylguanine-DNA methyltransferase (MGMT) gene.¹ MGMT reverses alkylation. Two oncology medications, temozolomide and dacarbazine, work by alkylation. Under typical conditions, temozolomide and dacarbazine work fine. Yet in a different form, the cancer cells will be able to reverse the work of temozolomide and dacarbazine.¹

The fourth example is thiopurine S-methyltransferase (TPMT).¹ The TPMT gene makes the TPMT enzyme. This enzyme’s job is to speed up a chemical reaction to remove the thiopurine from the body. However, if the TPMT gene is altered, the thiopurine may stay in the body longer, leading to patient harm.¹

Some examples of adverse effects are a lower platelet count or a lower red and white blood cell count. Examples of drugs affected by this gene are azathioprine, 6-mercaptopurine, and thioguanine, all of which are prodrugs. A prodrug is changed by the body from an inactive form into a more active form. Once active, the medication’s job is to destroy cancerous cells.¹

A fifth example is cytochrome P450 (CYP) isoenzymes. Researchers have identified 58 different human CYP genes, but the most clinically relevant are CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Multiple isoenzymes may metabolize a medication. For example, irinotecan is metabolized by CYP3A4, carboxylesterase, and UGT1A1.

The primary takeaway of the guidelines is that clinicians should not just focus on one single nucleotide polymorphism (SNP), but rather consider all SNPs because each factor causes unique adverse effects.¹ Cell-free DNA (cfDNA) assays provide large quantities of disease information for clinicians, which can be crucial tools to provide the best care for patients.¹

REFERENCES

1. Steurwald NM, Morris S, Nguyen DG, Patel JN. Understanding the biology and testing techniques for pharmacogenomics in oncology: a practical guide for the clinician. JCO Onc Pract. 2024;20(11). doi:10.1200/OP.24.00191

2. Jiang Y, Wen GA. Deciphering gene mutations in the efficacy and toxicity of antineoplastic drugs: an oncology pharmacist’s perspective. Front Pharmacol. 2025;16:1574010. doi:10.3389/fphar.2025.1574010