Preemptive, comprehensive pharmacogenomics testing of cancer patients identifies gene variants that are associated with altered efficacy and toxicity of certain chemotherapy agents and can be integrated into clinical practice in real time, according to clinicians from Mayo Clinic, who described their approach at the 2019 Gastrointestinal Cancers Symposium.
Pharmacogenomics (PGx) is about “selecting the right drug in the right amount for the right patients,” said lead author Pashtoon M. Kasi, MD, MS, a medical oncologist at Mayo Clinic in Jacksonville, Fla. “There have traditionally been barriers to integrating PGx tests in practice, but our study showed it was feasible in real time,” Dr. Kasi said.
Especially in metastatic colorectal cancer, PGx testing presents a unique opportunity to improve outcomes, because the genes DPYD and UGT1A1, which metabolize 5-fluorouracil (5-FU) and irinotecan chemotherapy, already are well known. Variants of these genes affect tolerability, which could have implications for treatment selection, but they are not routinely checked, according to Dr. Kasi.
Retrospective studies and meta-analyses repeatedly have shown that toxicity is higher in individuals who may carry variants in the two genes. For example, he said, in the landmark TRIBE clinical trial of colorectal cancer therapy, the proportion of patients with serious adverse events (AEs) was higher in those with the gene variations, and toxicity was dose dependent (Oncotarget 2017;9[8]:7859-7866).
As a quality improvement initiative, Dr. Kasi and his team integrated the OneOme RightMed comprehensive gene panel (a buccal swab), which evaluates 28 genes and more than 350 medications of interest. He reported findings in 155 patients with colorectal cancer receiving 5-FU and/or irinotecan who underwent this test and, based on the results, had pharmacist-recommended dosing adjustments (abstract 703).
Rationale From the TRIBE Study
As rationale for using PGx testing, Dr. Kasi referred to the TRIBE study, in which patients received FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan) or FOLFIRI (5-FU, leucovorin, irinotecan) plus bevacizumab (Avastin, Genentech). Retrospective PGx analysis done a decade later showed that the overall rate of serious AEs (grade ≥3) was 30% higher in patients who were heterozygous for the DPYD mutation (80%), compared with DPYD wild-type patients (50%). For UGT1A1, those homozygous for the mutation had a 20% higher rate (62%) than UGT1A1 wild-type patients (42%), and heterozygous patients had a 12% higher rate (54%). When these mutations are identified, chemotherapy dosing can be adjusted for tolerability, he said.
Serendipitous Beginning
“We started using PGx testing serendipitously. I had a patient on 5-FU with horrible toxicity. We had to give her the antidote [uridine triacetate], which is approved for 5-FU poisoning. But if you lack the genes to metabolize 5-FU, then technically it’s an overdose every time you get treated,” he said.
Treatment with uridine triacetate costs approximately $80,000, whereas hospitalization for patients with 5-FU “poisoning” is around $180,000, he pointed out.
PGx testing showed the patient had a thymidylate synthase gene variation that explained the increased AEs. “After this episode, we started asking why we are not doing PGx testing on all patients who are potential candidates for 5-FU- and/or irinotecan-based chemotherapy. Through this and other individual case studies that led to this study, we were able to show [the] value and feasibility [of PGx testing],” Dr. Kasi said.
Clinicians may not be aware that approximately three to five patients per 100 will develop severe AEs or even life-threatening complications from 5-FU-based chemotherapy due to genetic aberrations in DPYD, he continued. PGx testing identifies them and, thus, prevents physical, emotional and financial toxicity.
Almost 60% of the 155 patients in the study had either a DPYD or UGT1A1 aberration (Table), and 100% had at least one actionable aberration related to supportive care medications listed on their PGx report (mainly in the cytochrome family of genes). Almost one-third of patients had a cytochrome P450 2C19 alteration, making them rapid or ultrarapid metabolizers, and 90% had alterations in CYP1A2, meaning they were rapid metabolizers.
| Table. Incidence of Genetic Aberrationsa | |||
| Metabolism Gene | Normal (Wild Type), % | Intermediate (Heterozygous), % | Poor (Homozygous), % |
|---|---|---|---|
| UGT1A1 | 42.6 | 47.7 | 9.7% |
| DPYD | 97.4 | 2.5 | NA |
| a N=155. NA, not applicable Based on 2019 Gastrointestinal Cancers Symposium (abstract 703). | |||
This means the typical patient has at least a 50/50 chance of harboring a mutation that could result in the receipt of more chemotherapy than needed, said Dr. Kasi, noting that this risk is very similar to the distribution seen in other studies using PGx analysis, including the TRIBE study.
“PGx is not just about chemotherapy,” he stressed. “In addition to the two genes that are related to severe complications, we also get information from the cytochrome family of genes that affect the metabolism of other drugs. This may help us optimize the choice and dosage of nausea medication, antianxiety or antidepressant agents, or pain medication we use in a given patient.”
Pharmacogenomics has become standard practice for all patients with gastrointestinal cancer at Mayo Clinic. Depending on the specific aberration and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, patients who are heterozygous for the DPYD mutation, for example, receive a 25% reduction in 5-FU dose; those homozygous for UGT1A1 should receive 50% less, to start.
“Our pharmacists help us interpret the report, and they determine the initial dosage. Drugs are escalated, based on tolerability. We are not giving patients less chemotherapy and expecting fewer side effects. We think we are giving them the right amount, and preemptively, we are improving their quality of life,” Dr. Kasi said.
Evidence of Efficacy
This approach also improves clinical outcomes, he said, citing findings from a recent prospective, multicenter, safety study conducted in 17 hospitals in the Netherlands (Lancet Oncol 2018;19[11]:1459-1467). In that study, dose reductions according to PGx findings diminished AEs and preserved efficacy. Dr. Kasi and his colleagues plan to investigate the benefit of PGx testing in an upcoming randomized clinical trial. However, he said that with the data that have accumulated, genotype (PGx)-guided individualized dosing should become the standard of care.
PGx Should Be Adopted Widely
Cyrine-Eliana Haidar, PharmD, a clinical pharmacogenetics coordinator at St. Jude Children’s Research Hospital, in Memphis, Tenn., said Mayo Clinic’s study on PGx testing “is a great example of why preemptive PGx testing for all patients should be widely adopted and not be delayed anymore.”
Although the widespread uptake of preemptive PGx testing remains low due to limited insurance reimbursement and lengthy turnaround times, it is important to note that a growing number of institutions are adopting this approach (Cincinnati Children’s Hospital, Children’s Minnesota, NorthShore University HealthSystem, St. Jude Children’s Research Hospital, UF Health Shands Hospital and others). This is largely because the cost of PGx testing has dropped to just a few hundred dollars and the turnaround time has improved to as fast as 72 hours, thereby eliminating two of the most common barriers to implementation, Dr. Haidar said.
Dr. Haidar noted that the CPIC guidelines (https://cpicpgx.org/ guidelines/ ) provide recommendations for therapy adjustment based on a patient’s PGx test result, making interpretation and actionability of the PGx result easier for clinicians who are not experts in this area.
—Clinical Oncology News Staff
Dr. Kasi reported financial relationships with Advanced Accelerator Applications, Array BioPharma, Bristol-Myers Squibb, Celgene, Ipsen and Taiho. Dr. Haidar reported no relevant financial relationships.