The researchers from Mayo Clinic have shown that integrating pre-emptive pharmacogenomics testing into clinical practice in real time can help identify gene variants associated with altered efficacy and toxicity of certain chemotherapy agents in cancer patients.
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,” he said.
Based on repeated retrospective studies and meta-analyses the researchers had revealed that the toxicity was higher among individuals who possessed variants in DPYD and UGT1A1 genes.
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.
The results from the study (TRIBE clinical trial of colorectal cancer therapy) had revealed that the proportion of patients with serious adverse events (AEs) was higher in those with the gene variations, and toxicity was dose-dependent.
The study reported findings in 155 patients with colorectal cancer who received 5-FU or irinotecan therapy.
The retrospective PGx analysis revealed 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, said Dr Kasi.
“Clinicians may not be aware that approximately three to five patients per 100 will develop severe adverse events 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.”
The study was presented at the 2019 Gastrointestinal Cancers Symposium.