When is pharmacogenomic testing useful in cancer care?

Dr. Kimathi is a medical oncologist in a community setting where she sees patients with a variety of cancer diagnoses. Recently, she had several patients with toxicities to different treatments, including tamoxifen, cisplatin, and methotrexate. Concerned, she wondered if there was a common factor these patients shared to have experienced these toxicities. On review, she found that these patients had different cancer diagnoses and did not share any known comorbidities or risk factors.

Why do some cancer patients experience toxicities from certain treatments and others don’t?  Drug metabolism is highly variable among patients, and even within the same patient, depending on age and disease state. Both the toxicity and efficacy of cancer chemotherapy can be affected by many different factors, including other medications, foods, dietary supplements, environmental conditions, and genetic variants in drug-metabolizing genes and drug transporters.  

Pharmacogenomics can help identify the best drug & optimal dose

 Germline testing can be useful for assessing genes associated with hereditary risk but can also be used to look at genes involved in drug metabolism, often referred to as “germline pharmacogenomic testing.” Germline pharmacogenomic testing can provide information about how to select the most appropriate drug for a particular patient, the optimal dose, and how to identify patients more likely to experience adverse drug reactions. The US Food and Drug Administration (FDA) lists over 100 cancer drugs that have pharmacogenomic associations with germline (hereditary variants present in all cells in the body) and/or somatic (variants present only in cancer cells) biomarkers.

Assessing utility of pharmacogenomics in cancer care

 Over the past decade, resources have become available that synthesize pharmacogenomic evidence and provide evidence-based prescribing recommendations. The FDA provides genetic information in drug labels when applicable; however, for many approved medications, the evidence to support these associations is not published. Resources such as Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide information for the interpretation of genomic tests so that the results can be used to guide dosing recommendations (Table 1).

Table 1: Select list of cancer therapy with germline pharmacogenomic testing recommendations (Amstutz et al., 2018; Goetz et al., 2018; Relling et al., 2019)

* For definitions of FDA Pharmacogenomic (PGx) labels, see PharmGKB

When to proceed with testing

 Currently, there are several genes with evidence-based utility for cancer care. These include TPMT and NUDT15 for 6-mercaptopurine treatment in acute lymphoblastic leukemia (ALL), UGT1A1 for irinotecan, DPYD for fluorpyrimidines, and CYP2D6 for tamoxifen (Table 1).

We spoke with Christine Walko, PharmD, Associate Member in the Department of Individualized Cancer Medicine and Precision Medicine Program Lead at Moffit Cancer Center, to better understand the role of pharmacogenomics in cancer care. Dr. Walko discussed TPMT and NUDT15 genetic testing for adult and pediatric patients with acute lymphoblastic leukemia (ALL) as an example of how pharmacogenomic testing has been implemented successfully as a routine part of care: “Whenever a patient is admitted for ALL treatment, ultimately 6-MP (6-mercaptopurine, a thiopurine) is typically going to be part of their maintenance therapy.” TPMT and NUDT15 variants are associated with toxicity to 6-MP treatment. “This gives us time to send the blood for TPMT and NUDT15 testing during the initial work-up,” she says, allowing for results to be available at the time they are needed later during treatment. If the patient carries a genetic alteration and is a poor metabolizer of thiopurines, 6-MP doses are significantly reduced to achieve the therapeutic benefit while at the same time reducing the risk of a fatal toxicity.At Moffit, and many other cancer centers, Dr. Walko told us, pharmacogenomic testing is built into the workflow for all new patients with ALL.

When to be cautious about testing

 Sometimes, for drugs with known pharmacogenomic associations such as cisplatin, methotrexate and others, there is not sufficient published evidence to recommend prospective pharmacogenomic testing as described above. This may be because there is conflicting evidence about utility, cost-benefit analysis does not support widespread testing, or clinical implementation has not been studied sufficiently. In some situations, there may be evidence to use pharmacogenomic information if testing has been done previously, even if widespread testing is not recommended on the drug label.

In the absence of clear evidence supporting or contraindicating testing, the clinician and patient can engage in shared decision-making based on the patient’s specific circumstance. Dr. Walko recommends considering clinical factors and the patient’s perceptions and concerns about cancer treatment in areas where evidence is equivocal.

A pharmacogenomic variant may be associated with altered response to multiple drugs

 A benefit of pharmacogenomic testing is that a variant in a specific gene can provide useful information relevant to numerous drugs. Dr. Walko explains that “A particular gene can influence the cancer drug, but it may also have influence on other drugs, like an SSRI. We shouldn’t think of it as one gene, one drug. A lot of drugs go through the same pathway.” A great example to illustrate this is the CYP2D6 gene. Variants in the CYP2D6 gene may impact dosing and prescribing decisions for several drugs, both cancer and non-cancer agents, such as opioids and antidepressants.

But what should the oncologist do with this broadly applicable information, so that it isn’t missed outside of their specific clinic? At the system level, EHR solutions and clinical decision alerts are important to ensure pharmacogenomic information is flagged for relevant future encounters. Dr. Walko emphasizes that patient education and communication is also key. Discussion of an individual patient’s pharmacogenomics results, which have lifelong implications, provides a unique opportunity for patient education.

Building an evidence base

 Ongoing pilot programs and clinical trials through research initiatives such as the Implementing Genomics in Practice (IGNITE) are actively studying the utility and implementation of pharmacogenomics in different clinical settings. Dr. Walko is hopeful that these studies will provide clearer guidance about when to test a particular patient and make a case for insurance reimbursement. She anticipates the evidence for pharmacogenomics in cancer care to grow. “Our technologies are going to get better, our workflow surrounding those technologies are going to get better,” she says. Just as cancer susceptibility testing is becoming standard of care in oncology for ovarian, pancreatic, prostate and breast cancers, she expects there will be cancer types where pharmacogenomic testing will be incorporated as part of the initial workup. There are likely different ways such pharmacogenomic testing will be implemented, depending on the needs and resources of the practice. “It may be a standalone pharmacogenomic clinic that does it all,” she says, which is an innovative model for outpatient pharmacy used at University of South Florida (USF) Health and Moffitt Cancer Center. “Or you work in a practice, and you have a clinical pharmacist who works with you, and it’s part of their regular clinical practice to make sure, just like we're screening for allergies and drug interactions, that a patient has the appropriate germline testing done before we utilize these drugs.”

Navigating pharmacogenomic information in 2022

 There are resources for oncologists to use to familiarize themselves with the short list of drugs with actionable pharmacogenomic associations (Table 1). Clinicians can review prescribing information for the particular drug and publicly available databases including the FDA’s Table of Pharmacogenetic Considerations, the CPIC Genes/Drugs evidence table (CPIC), and PharmGKB’s Drug Label Annotations to identify pharmacogenomic risk factors. NCCN guidelines discuss evidence-based pharmacogenomic associations and the Flockhart tables, maintained by Indiana University, can be useful to identify drug-drug interaction risks for a particular patient.

Considering our example of Dr. Kimathi’s practice, she can start by checking FDA and CPIC resources to see if there are published guidelines for using pharmacogenomic test results to guide therapy. She can also consult her cancer center or hospital’s pharmacist for medication management.

The list of drugs indicated for pharmacogenomic testing is likely to expand as published evidence grows. Even for drugs prescribed in the past without issue, it is important to be aware of pharmacogenomic associations that could affect prescribing and dosing decisions.

Learn More

 Precision Medicine for Your Practice: Exploring Pharmacogenomic Testing (JAX/AMA/Scripps). Learn about the benefits and limitations of pharmacogenomic testing, how to determine whether pharmacogenomic testing is appropriate for the patient and the application of test results to patient management (free CME/CNE).
Clinical Pharmacogenetics Implementation Consortium. (CPIC) Provides detailed gene/drug clinical practice guidelines for clinical implementation that is peer-reviewed on a continuous basis. The Genes/Drugs table is a user-friendly resource that identifies drugs that have FDA recommendations for pharmacogenomic testing.  
Table of Pharmacogenomic Associations. (FDA) Lists pharmacogenetic associations that the FDA has evaluated to have adequate scientific evidence, including predisposition for certain adverse events.
PharmGKB Drug Label Annotations. (Stanford) Classifies pharmacogenomics label information for individual drugs as “testing required,” “testing recommended,” “PGx actionable,” or “PGx informative,” with filters and search features.

References

Amstutz U, Henricks LM, Offer SM et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-216.

Clinical Pharmacogenetics Implementation Consortium (CPIC). Genes-Drugs. https://cpicpgx.org/genes-drugs/.

Goetz MP, Sangkuhl K, Guchelaar HJ et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018;103(5):770-777.

National Comprehensive Cancer Network. Breast Cancer (version 8.2021). Published October 21, 2021. Accessed 9/20/21.
National Comprehensive Cancer Network. Colon Cancer (version 3.2021). Published October 21, 2021. Accessed 9/20/21. 
Relling MV, Schwab M, Whirl-Carrillo M et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105(5):1095-1105.

Wellmann R, Borden BA , Danahey K, Nanda R, Polite BN, Stadler WM, O'Donnell PH (2018). Analyzing the clinical actionability of germline pharmacogenomic findings in oncology. Cancer, 124(14), 3052–3065.