A key focus of our pharmacogenomics research is identifying germline variants that increase the risk of drug-related toxicity. For example, the PROCURE project investigates trastuzumab deruxtecan–induced interstitial lung disease in breast cancer patients, aiming to uncover pharmacogenomic markers that predict adverse events and enhance treatment safety.
A core aspect of pharmacogenomics research is identifying germline variations that increase the risk of adverse drug reactions. To uncover these risk factors, researchers employ a range of genomic strategies, including targeted candidate gene approaches and unbiased genome-wide association studies (GWAS), which can reveal both known and novel pharmacogenetic markers. Furthermore, existing whole-exome sequencing data can be repurposed to extract pharmacogenetic toxicity signals, offering an additional resource to identify patients at higher risk for drug-induced complications. These approaches ultimately aim to guide safer and more personalized therapeutic strategies (Figure 1).
Figure 1. Pharmacogenomic variability in drug response. Genetic differences determine individual patient responses to medications, ranging from standard efficacy to altered dosing requirements or contraindications, highlighting the basis for personalized medicine approaches.
Currently, we are responsible in the PROCURE Project for the genomic study design and analysis, including genome-wide association studies (GWAS), a strategy we previously applied in our neuropathy research (Figure 2). PROCURE is a translational study involving 26 Spanish institutions that aims to identify genetic variants associated with the toxicity risk of breast cancer patients treated with the novel drug trastuzumab deruxtecan.
Trastuzumab deruxtecan, an antibody-drug conjugate, has shown substantial clinical benefit in patients with advanced HER2-positive and HER2-low metastatic breast cancer. However, 15–20% of patients discontinue treatment due to adverse events, primarily interstitial lung disease (ILD), which can be fatal. The risk factors for trastuzumab deruxtecan-induced ILD remain poorly understood. Through PROCURE, led in collaboration with Rodrigo Sánchez-Bayona from Hospital 12 de Octubre, we aim to identify germline pharmacogenomic markers associated with trastuzumab deruxtecan-induced ILD. With over 330 patients already recruited, we are conducting a candidate gene study and genotyping samples using the Infinium Global Diversity Array with Enhanced PGx (Illumina), a SNP microarray containing over 1.93 million markers enriched for pharmacogenomic variants.
Figure 2. Discovery of EPHAs as risk markers of paclitaxel-induced peripheral neuropathy. A) A GWAS (hypothesis-free strategy) and posterior meta-analysis identified germline variants in EPHA5 associated with paclitaxel neurotoxicity risk. Adaptation from Leandro-Garcia et al. 2013. J Med Genet; PMID 23776197. B) Targeted Sequencing (hypothesis-driven strategy) revealed low-frequency variants in EPHA Genes as markers of paclitaxel-induced peripheral neuropathy. Adaptation from Apellaniz-Ruiz et al. 2017 Clin Cancer Res; PMID 27582484.