A genetic analysis of 290 patients with advanced breast cancer treated with trastuzumab deruxtecan (T-DXd) at 26 Spanish hospitals finds that certain inherited variants, mainly in the HLA region of the immune system, are associated with a higher risk of interstitial pneumonitis, the side effect that most limits the use of this drug.
What was known
Trastuzumab deruxtecan is an antibody-drug conjugate with proven benefit in advanced breast cancer with high or low HER2 expression. Its main limitation is interstitial lung disease, or pneumonitis, which sometimes forces treatment to be stopped. In other therapies with topoisomerase I inhibitors, variants of the UGT1A1 gene influence toxicity, but in T-DXd that role appears limited: which other genes might be involved remained unclear.
What this work adds
The PROCURE project is a multicentre translational study carried out at 26 Spanish institutions. Germline DNA — the inherited DNA, not the tumour’s — was genotyped in patients with HER2-positive or HER2-low advanced breast cancer treated with T-DXd, using a platform enriched for pharmacogenomic variants. Fourteen genes of drug metabolism, transport, mechanism of action and immune-mediated hypersensitivity were analysed, and their link to pneumonitis was assessed with logistic regression.
Main results
The analysis included 290 patients with clinical and genotyping data, with a median age of 58 years (range, 34 to 94). After a median follow-up of 18.3 months (95% confidence interval: 15.4 to 20.5), 33 cases of pneumonitis were recorded, an incidence of 11.4%. The strongest signals mapped within the HLA region, with the top variant near the HLA-F gene (rs9258213; odds ratio 6.8; 95% confidence interval: 2.6 to 17.9). Associations were also seen in SLCO1B1 and CYP3A4, drug transport and metabolism genes. The authors stress that no definitive pharmacogenomic predictor was identified.
What it means
The work suggests that susceptibility to T-DXd pneumonitis depends not only on the drug or the dose but also on each patient’s genetic make-up, particularly the immune system. There is still no test that can predict who will develop this toxicity, so it does not change treatment or monitoring. Its value lies in guiding research towards possible risk biomarkers.
Reading from the breast unit
The study reflects a common collaboration in Spanish healthcare: 26 hospitals contributing samples and clinical data from patients treated in real-world practice to answer a question none could address alone. For a breast unit, the reading today is cautious: pneumonitis is still monitored clinically, and genetic prediction is for now research, not a care tool.
Reference: Arenas A, Saura C, Alva-Bianchi M, de Nicolás-Hernández J, Gion M, Cejalvo JM, et al. Germline pharmacogenetic variants associated with trastuzumab deruxtecan-induced interstitial lung disease in advanced breast cancer: PROCURE project. ESMO Open, 2026. https://doi.org/10.1016/j.esmoop.2026.108607
