DESTINY Breast 06

At ASCO 2025, Dr Laure-Anne Teuwen, a medical oncologist at the University Hospital of Antwerp, and Prof Dr François Duhoux from Cliniques Universitaires Saint-Luc in Brussels discussed the exploratory biomarker results from the DESTINY-Breast06 study. This Phase 3 randomised trial compared trastuzumab deruxtecan (T-DXd) with chemotherapy of physician’s choice in patients with HR+, HER2-low or HER2-ultra-low metastatic breast cancer who were no longer eligible for endocrine therapy. The overall PFS was updated, showing a significant benefit with T-DXd, with a median PFS of 13.2 months compared to 8.1 months in the chemotherapy arm, resulting in an HR of 0.64.

The biomarker analysis focused on three main groups: PI3K pathway aberrations (including AKT, PIK3CA, and PTEN mutations), ESR1 mutations, and BRCA1/2 mutations. Among the 625 patients evaluated for biomarkers, 45% had a PIK3CA pathway aberration, and T-DXd treatment provided a PFS gain of about five months in this population. Similarly, 52% of patients had ESR1 mutations, with a PFS increase of seven months from 8.1 to 15.2 months. Notably, 7.7% of patients had BRCA1 or BRCA2 mutations, and these patients experienced a striking PFS improvement from 5.6 months to 21.4 months, with a HR of 0.14. This dramatic benefit was particularly notable, though it was based on a smaller patient population.

Dr Teuwen and Prof Duhoux discussed that the topoisomerase I inhibitor payload of T-DXd may explain the heightened sensitivity of BRCA1/2-mutated tumours to this treatment. While these results are compelling, they both agreed that it is still too early to use BRCA mutational status to guide treatment decisions in the clinic. Although the PFS data are promising, more research and biomarker-driven studies are needed to confirm these findings before incorporating them into clinical practice.