Several studies presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting touched on genotyping pharmacogenes linked to anticancer drugs toxixcity. Here, we report on those underscoring the importance of pre-treatment pharmacogenetic testing in order to avoid or reduce adverse drug reactions.

DPYD

Two abstracts from the Atrium Health Levine Cancer Institute highlight the clinical and economic benefits of implementing pre-treatment DPYD testing in standard oncology care.

In the first one real world data from the largest retrospective cohort study evaluating dosing tolerability and toxicity to fluoropyrimidines (FP) in DPYD variant carriers were presented. Among patients genotyped for the five most clinically relevant DPYD polymorphisms, 5.2% were identified as DPYD variant carriers. The dose of fluoropyrimidines was initially reduced by 50% for all 49 patients and then adjusted for tolerability. A variant-specific dosing titration was necessary to limit chemotherapy toxicity.

The other study demonstrated that pre-treatment DPYD testing and genotype-guided FP dosing allow to reduce hospitalization rate by 39% and save $36.98 per patient. Accounting for outpatients management of adverse events, additional cost savings are expected. [Abstracts 3095, 3097 ]

In the MOLGEN study, sequencing the DPYD gene of European and non-European patients, who experienced grade 3 or 4 toxicities after receiving 5-fluorouracil, found three heterozygous for new DPYD variants, for which there are no current dosing guidelines. [Abstract 12120 ]

UGT1A1

An early analysis of a phase 2 study demonstrated that genotyping all patients for UGT1A1 and adjusting the dose of irinotecan liposome accordingly, allow to avoid grade 5 treatment-related adverse events and limit grade 3-4 toxicity. [Abstracts e155566]

G6PD

Pharmacogenetic (PGx) screening, carried out at the Memphis VA Medical Center, in African American males with different types of cancer, identified G6PD variants linked to G6PD deficiency in 15% of patients. G6PD deficiency can cause acute haemolytic anaemia due to oxidative stress in red blood cells triggered by chemotherapy medications. Overall, pharmacogenetic analysis revealed genetic variations requiring drug dose adjustment in 61% of patients and impacting, for instance, capecitabine (4% patients) and irinotecan (15% patients). [Abstract e13838]

CYP3A4 – CYP3A5

Inherited genetic factors can predict toxicity not only to chemotherapy medications, but also to antibody-drug conjugates (ADC). Patients carrying the minor alleles (intermediate or poor metabolizers) of rs4646437 (CYP3A4) and rs776746 (CYP3A5), with solid or hematologic malignancies treated with ADCs at Dana-Faber Cancer Institute, had a significant higher risk of developing pneumonitis. This potentially severe adverse event may result in treatment discontinuation or mortality. [Abstract 12125]

CYP2C19

Cancer patients treated with immune checkpoint inhibitors (ICI) routinely receive proton pump inhibitors (PPIs) or H2 blockers for acid suppression.
A retrospective analysis on data from four studies with atezolizumab revealed that patients with different types of tumours, treated with this ICI and with a CYP2C19 variant predicting an intermediate/poor metabolizer phenotype, were more likely to experience Grade ? 3 adverse events, if they were exposed to PPI versus if they were exposed to H2 blocker. [Abstract 12128]