The role of pharmacogenomics in cancer

Oncology nurses have long appreciated that the “one size fits all” strategy—basing chemotherapy dosages on body surface area—for treating cancer does not work because of variations in patients’ responses and adverse effects. Now, as a result of genetic and genomic research, the one size fits all strategy is evolving into a more personalized approach called pharmacogenomics.

Pharmacogenomics unites the science of how drugs work (pharmacology) and the science of the human genome (genomics). This science uses a person’s genome to identify the drug and drug doses that are most likely to successfully treat that person’s medical condition. Pharmacogenomics is important in cancer treatment and chemotherapy drug metabolism.

A new approach to cancer treatment

All types of cancer are caused by some type of abnormal gene function that is inherited or acquired. Abnormalities include mutations in tumor suppressor genes, mismatch of repair genes, and activation of proto-oncogenes because of mutations in oncogenes. The accumulation of genetic changes alters cell signaling pathways and other cellular functions.

Traditional cancer chemotherapy uses drugs that destroy not only malignant cells but healthy cells too. Pharmacogenomics-based cancer treatments are designed to interact with specific molecules that are part of the pathways and processes used by cancer cells to grow, divide, and spread throughout the body.

One example of this more personalized approach to cancer treatment is imatinib mesylate (Gleevec), a drug that blocks the signal from an abnormal protein that causes the accumulation of abnormal white blood cells in patients who have chronic myeloid leukemia.

Another example is trastuzumab (Herceptin), a recombinant monoclonal antibody effective in the treatment of breast tumors that over-express the protein product of the human epidermal growth factor receptor 2 gene (HER2). Herceptin binds to HER2 on the tumor cell surface, thereby inducing an antibody-dependent cell-mediated cytotoxicity against the tumor cells.


Drug metabolism

Differences in drug metabolism can cause significant variation in responses to drugs among individuals, and pharmacogenomics helps identify those variations.

For example, the cytochrome P450 group of enzymes is involved in the metabolism of compounds originating both within an organism (endogenous), and outside of an organism (exogenous). Many of the cytochrome P450 enzymes play a central role in the metabolism of drugs that are used clinically to treat cancer. Genetic changes in these enzymes include insertions and deletions of genes, single nucleotide polymorphisms, called SNPs, and gene copy number variations.

Genetic changes in Cytochrome P450 result in four different ways individuals metabolize drugs, called phenotypes:

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  • Ultrarapid metabolizers have an increased efficiency in drug metabolism resulting in a possible decrease in effectiveness at established doses. In addition, there is an increased risk for adverse drug responses as a result of increased metabolite or active drug production.

 

  • Extensive metabolizers have an ordinary response to drugs.
  • Intermediate metabolizers have a decreased efficiency in drug metabolism and therefore an increased concentration of the parent drug with decreased formation of metabolites and a possible decrease in responsiveness.
  • Poor metabolizers have a significant decrease in drug metabolism and as a result tend to have higher levels of the parent drug but with little to no therapeutic benefit and an increased risk for adverse drug responses.Clinical tests are available to screen patients for Cytochrome P450 variants to identify whether they are poor, intermediate, extensive or ultrarapid metabolizers. Knowledge of a patient’s metabolism status can be used to determine the specific dosage of medication prescribed.It is also important to take into account drug inhibitors and drug inducers. Inhibitors and inducers can be other medications, herbal supplements, foods, and/or environmental exposures such as smoking. Inhibitors cause inactivation of the specific CYP enzymes. An individual’s metabolism returns to normal functioning when the inhibitor has been removed and new enzymes have been made. Inducers increase the amount of enzyme produced and increase a person’s metabolism. This causes a lowering of plasma levels of substrates.

    FDA weighs in

    As an example of the recognition of the public health effect of pharmacogenomics, the U.S. Food and Drug Administration (FDA) now recommends genetic testing be performed before giving the chemotherapy drug 6-mercaptopurine (Purinethol) to patients who have acute lymphoblastic leukemia. Some patients have a genetic variant in thiopurine S-methyltransferase, which is an enzyme that methylates thiopurine compounds. (DNA methylation is a modification of DNA in which methyl groups are added to certain positions on the nitrogen bases.) Having a genetic variant interferes with patients’ ability to metabolize the drug. This metabolism problem can cause severe side effects and increase risk of infection, unless the standard dose is adjusted according to the patient’s specific genetic makeup.

    The FDA also advises healthcare providers to test patients who have colon cancer for a particular genetic variant, UGT1A1, before administering irinotecan (Camptosar), which is part of a single agent or combination chemotherapy regimen. Patients who have a UGT1A1 variant might not be able to eliminate the drug from their bodies as rapidly as others. This leads to severe diarrhea and severe neutropenia resulting in increased infection risk. Patients with a variant may need to receive lower doses of the drug.

    Patient education

    Counseling patients about pharmacogenomic-based cancer treatments and testing and how they metabolize drugs is challenging because of limited long-term safety and efficacy data. Another challenge is that availability of testing may be limited to those who have particular insurance or financial resources and those patients enrolled in clinical trials.

    Nurse can access these resources to learn more about pharmacogenomics so they are more comfortable teaching patients about this innovative approach:

    At the time this article was written, Dale Halsey Lea, MPH, RN, CGC, FAAN, was a health educator at the National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. She is now a consultant to the Maine State Genetics Program.

    References

    De Gregori M, Allegri, M, De Gregori S Garbin,G, Tinelli C, Regazzi M, Govoni S, Ranzani GN. How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments. Curr Drug Metab. 2010; 1:11 (3):276-82.

    Ingelman-Sundberg M, Sim SC. Pharmacogenetic biomarkers as tools for improved drug therapy: Emphasis on the cytochrome P450 system. Biochemical and Biophysical Research Communications. 2010; 396:90-94.

    Oliveria S, Alves S, Quental F, Ferreirra L, Norton V, Costa A, Prata, A and MR. Outcome in acute lymphoblastic leukemia: Influence of thiopurine methyltransferase genetic polymorphisms. International Congress Series. 2006; 1288:789-701.

    Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med. 2009; 11(1); 21-34.

    Scripture CD, Figg WD. Drug interactions in cancer therapy. Nature Reviews. 2006; 6:546-558.

    Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, Lai X, Wang JC, Li CG, Tian M, Duan W. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab. 2008 (October); 9(8):738-84.

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