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Peer-reviewedCC BY-NC-ND 4.0ESMO Open

Germline pharmacogenetic variants associated with trastuzumab deruxtecan-induced interstitial lung disease in advanced breast cancer: PROCURE project

  • A. Arenas1
  • C. Saura2,3
  • M. Alva-Bianchi3,4
  • J. de Nicolás-Hernández1,5
  • M. Gion6,7
  • J.M. Cejalvo3,8
  • E. Llabrés9
  • J. Cortés7,10,11,12,13
  • A. Falcón14
  • S. Pernas3,15
  • A. López de Sa16
  • M. Vidal3,17
20 more authors
  • C. Hinojo18
  • T. Curiel19
  • J. Cruz20
  • V. Martínez21
  • B. Cantos22
  • M.J. Echarri23
  • I. Gallegos24
  • C. Bueno25
  • A.M. Vargas26
  • S. Escrivá-de-Romaní2,3
  • B. Fullana15
  • M.A. Cobos4
  • L. Joval-Ramentol27
  • P. Ortiz-Heras4
  • T. Pascual3,17
  • C. Valdivia1,5
  • G. Villacampa2,3
  • E. Ciruelos3,4
  • C. Rodriguez-Antona1,5
  • R. Sánchez-Bayona3,4
27 affiliations
  1. 1Pharmacogenomics and Tumor Biomarkers Group, Institute for Biomedical Research Sols-Morreale (IIBM) CSIC/UAM, Madrid, Spain
  2. 2Medical Oncology Department, Vall D’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
  3. 3SOLTI Breast Cancer Research Group, Barcelona, Spain
  4. 4Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
  5. 5Centro Nacional Investigaciones Oncológicas–CNIO, Madrid, Spain
  6. 6Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
  7. 7IOB Madrid, Institute of Oncology, Hospital Beata María Ana, Madrid, Spain
  8. 8Medical Oncology Department, Hospital Clínico de Valencia, Valencia, Spain
  9. 9Medical Oncology Department, Hospital Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain
  10. 10Medical Oncology Department, International Breast Cancer Center–IBCC, Barcelona, Spain
  11. 11Pangaea Oncology, Quiron Group, Barcelona, Spain
  12. 12Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
  13. 13Medica Scientia Innovation Research (MEDSIR), Barcelona (Spain), Ridgewood (USA)
  14. 14Medical Oncology Department, Hospital Virgen del Rocío, Sevilla, Spain
  15. 15Medical Oncology Department, Institut Catala d’Oncologia-IDIBELL L’Hospitalet, Barcelona, Spain
  16. 16Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
  17. 17Medical Oncology Department, Hospital Clinic Barcelona, Barcelona, Spain
  18. 18Medical Oncology Department, Hospital Marqués de Valdecilla, Santander, Spain
  19. 19Medical Oncology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
  20. 20Medical Oncology Department, Hospital Universitario de Canarias, Tenerife, Spain
  21. 21Medical Oncology Department, Hospital La Paz, Madrid, Spain
  22. 22Medical Oncology Department, Hospital Puerta de Hierro, Majadahonda, Spain
  23. 23Medical Oncology Department, Hospital Severo Ochoa, Leganés, Spain
  24. 24Medical Oncology Department, Hospital Nuestra Señora de Sonsoles, Avila, Spain
  25. 25Medical Oncology Department, Hospital Universitario Infanta Cristina, Parla, Spain
  26. 26Medical Oncology Department, Hospital Doctor Negrin, Gran Canaria, Spain
  27. 27Oncology Data Science Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Abstract

Background: Trastuzumab deruxtecan (T-DXd) has demonstrated substantial clinical benefit in patients with advanced human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer. However, treatment-related adverse events—particularly interstitial lung disease (ILD) or pneumonitis—represent a clinically relevant limitation. While UGT1A1 polymorphisms influence toxicity with other topoisomerase I inhibitor–based therapies, their role in T-DXd−related toxicity appears limited. The PROCURE project aimed to investigate germline pharmacogenetic variants beyond UGT1A1 associated with T-DXd–induced ILD.

Materials and methods: The PROCURE project is a multicenter translational study conducted across 26 Spanish institutions. Germline DNA from patients with advanced HER2-positive or HER2-low breast cancer treated with T-DXd was genotyped using the Infinium Global Diversity Array enriched for pharmacogenomic variants. A candidate gene approach was applied to 14 genes involved in drug metabolism, transport, pharmacodynamics, and immune-mediated drug hypersensitivity. Logistic regression models were used to evaluate associations with ILD/pneumonitis.

Results: A total of 290 patients with clinical and genotyping data were included in the analysis. The median age was 58 years (range, 34-94 years). After a median follow-up of 18.3 months [95% confidence interval (CI): 15.4-20.5], the cohort registered 33 ILD cases (incidence of 11.4%). The strongest association signals mapped to variants within the human leukocyte antigen (HLA) region, with the top single nucleotide polymorphism near HLA-F (rs9258213; OR 6.8, 95% CI 2.6-17.9, P = 9.5 × 10−5). Additional associations were observed in SLCO1B1 and CYP3A4, genes involved in T-DXd transport and metabolism.

Conclusions: This study identifies host genetic variation within the HLA locus and drug pharmacokinetic pathways as potential contributors to T-DXd–induced ILD in patients with advanced breast cancer. Although no definitive pharmacogenomic predictor was identified, these findings provide insights into the biological mechanisms underlying this toxicity and support further investigation of pharmacogenomic biomarkers to improve risk stratification and guide personalized T-DXd therapy.

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Cite

BibTeXRIS
BibTeX
@article{arenas2026germline,
  title = {{Germline pharmacogenetic variants associated with trastuzumab deruxtecan-induced interstitial lung disease in advanced breast cancer: PROCURE project}},
  author = {A. Arenas and C. Saura and M. Alva-Bianchi and J. de Nicolás-Hernández and M. Gion and J.M. Cejalvo and E. Llabrés and J. Cortés and A. Falcón and S. Pernas and A. López de Sa and M. Vidal and C. Hinojo and T. Curiel and J. Cruz and V. Martínez and B. Cantos and M.J. Echarri and I. Gallegos and C. Bueno and A.M. Vargas and S. Escrivá-de-Romaní and B. Fullana and M.A. Cobos and L. Joval-Ramentol and P. Ortiz-Heras and T. Pascual and C. Valdivia and G. Villacampa and E. Ciruelos and C. Rodriguez-Antona and R. Sánchez-Bayona},
  journal = {ESMO Open},
  year = {2026},
  month = oct,
  doi = {10.1016/j.esmoop.2026.108607},
  url = {https://doi.org/10.1016/j.esmoop.2026.108607},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Germline pharmacogenetic variants associated with trastuzumab deruxtecan-induced interstitial lung disease in advanced breast cancer: PROCURE project
AU  - A. Arenas
AU  - C. Saura
AU  - M. Alva-Bianchi
AU  - J. de Nicolás-Hernández
AU  - M. Gion
AU  - J.M. Cejalvo
AU  - E. Llabrés
AU  - J. Cortés
AU  - A. Falcón
AU  - S. Pernas
AU  - A. López de Sa
AU  - M. Vidal
AU  - C. Hinojo
AU  - T. Curiel
AU  - J. Cruz
AU  - V. Martínez
AU  - B. Cantos
AU  - M.J. Echarri
AU  - I. Gallegos
AU  - C. Bueno
AU  - A.M. Vargas
AU  - S. Escrivá-de-Romaní
AU  - B. Fullana
AU  - M.A. Cobos
AU  - L. Joval-Ramentol
AU  - P. Ortiz-Heras
AU  - T. Pascual
AU  - C. Valdivia
AU  - G. Villacampa
AU  - E. Ciruelos
AU  - C. Rodriguez-Antona
AU  - R. Sánchez-Bayona
PY  - 2026
DA  - 2026/10/20
JO  - ESMO Open
DO  - 10.1016/j.esmoop.2026.108607
UR  - https://doi.org/10.1016/j.esmoop.2026.108607
AB  - Background: Trastuzumab deruxtecan (T-DXd) has demonstrated substantial clinical benefit in patients with advanced human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer. However, treatment-related adverse events—particularly interstitial lung disease (ILD) or pneumonitis—represent a clinically relevant limitation. While UGT1A1 polymorphisms influence toxicity with other topoisomerase I inhibitor–based therapies, their role in T-DXd−related toxicity appears limited. The PROCURE project aimed to investigate germline pharmacogenetic variants beyond UGT1A1 associated with T-DXd–induced ILD.  Materials and methods: The PROCURE project is a multicenter translational study conducted across 26 Spanish institutions. Germline DNA from patients with advanced HER2-positive or HER2-low breast cancer treated with T-DXd was genotyped using the Infinium Global Diversity Array enriched for pharmacogenomic variants. A candidate gene approach was applied to 14 genes involved in drug metabolism, transport, pharmacodynamics, and immune-mediated drug hypersensitivity. Logistic regression models were used to evaluate associations with ILD/pneumonitis.  Results: A total of 290 patients with clinical and genotyping data were included in the analysis. The median age was 58 years (range, 34-94 years). After a median follow-up of 18.3 months [95% confidence interval (CI): 15.4-20.5], the cohort registered 33 ILD cases (incidence of 11.4%). The strongest association signals mapped to variants within the human leukocyte antigen (HLA) region, with the top single nucleotide polymorphism near HLA-F (rs9258213; OR 6.8, 95% CI 2.6-17.9, P = 9.5 × 10−5). Additional associations were observed in SLCO1B1 and CYP3A4, genes involved in T-DXd transport and metabolism.  Conclusions: This study identifies host genetic variation within the HLA locus and drug pharmacokinetic pathways as potential contributors to T-DXd–induced ILD in patients with advanced breast cancer. Although no definitive pharmacogenomic predictor was identified, these findings provide insights into the biological mechanisms underlying this toxicity and support further investigation of pharmacogenomic biomarkers to improve risk stratification and guide personalized T-DXd therapy.
SN  - 2059-7029
ER  -