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

HLA-F, SLCO1B1, CYP3A4

Germline variation in the HLA region (signal near HLA-F) and in genes involved in trastuzumab deruxtecan transport and metabolism (SLCO1B1, CYP3A4)

The PROCURE project, a multicenter translational study across 26 Spanish institutions, searched for germline pharmacogenetic variants associated with trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease in advanced HER2-positive or HER2-low breast cancer, beyond UGT1A1, whose role in this toxicity appears limited. Germline DNA from 290 patients was genotyped on the Infinium Global Diversity Array enriched for pharmacogenomic variants, with a candidate gene approach covering 14 genes involved in drug metabolism, transport, pharmacodynamics and immune-mediated drug hypersensitivity. After a median follow-up of 18.3 months, 33 interstitial lung disease cases were recorded (incidence 11.4%). The strongest signal mapped to the HLA region, with the top SNP near HLA-F (rs9258213; OR 6.8, 95% CI 2.6-17.9, P = 9.5 × 10-5), and additional associations were observed in SLCO1B1 and CYP3A4. The authors acknowledge that no definitive pharmacogenomic predictor was identified.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A P = 9.5 × 10-5 signal in a candidate gene approach, driven by 33 cases, remains a hypothesis: it is far from genome-wide significance and needs independent replication. Its value is to shift the question from UGT1A1 to the HLA region, which points to an immunological component of the lung toxicity rather than a purely pharmacokinetic one. No test should be offered before T-DXd treatment at this stage.

Analysis by Dr Thibaut Benquey