Whole-genome sequencing in breast cancer: is it ready for clinical application?
Menée en Angleterre à partir de l'analyse de données cliniques et génomiques portant sur 2 445 tumeurs issues de 2 403 patientes atteintes d'un cancer du sein, cette étude évalue la valeur pronostique et le potentiel clinique des données de séquençage du génome tumoral entier liées aux données statistiques de mortalité
In The Lancet Oncology, Daniella Black and colleagues1 report whole-genome sequencing (WGS) data of 2445 breast cancer tumours from a UK cohort (100 000 Genomes Project [100kGP]). As well as linking these data to clinical and mortality data, the authors externally validated their results in a Swedish cohort (SCAN-B) of 502 cases. By integrating driver mutations, mutational signatures, and structural variation (SV) burden, the authors show that, alongside a handful of drivers known from other tumour types, a single WGS assay could identify potentially actionable alterations in 656 (26·8%) of all 2445 breast cancer cases in the 100kGP cohort. Homologous recombination deficiency (HRD) was indicated in 298 (12·2%) cases. Excluding stage IV breast cancer cases, HER2 amplification was found in 238 (9·8%) cases, ESR1 structural variants were found in 33 (2·2%) of 2412 cases, and mismatch repair deficiency in 16 (0·7%). The authors also derive a WGS-based prognostic model for early-stage ER-positive, HER2-negative disease, incorporating SV burden, TP53 mutation status, and mutational signatures related to APOBEC activity. These findings underscore that structural and mutational processes could add prognostic value beyond conventional clinical and pathological factors and existing gene expression assays, such as Oncotype DX (Exact Sciences; Madison, WI, USA). The study sharpens our perceptions of intrinsic tumour risk in patients with breast cancer, highlighting that adverse cancer biology can be detected at the DNA level in a substantial number of patients with low-grade and stage I and II cancers. Beyond more accurate prognostic modelling, routine WGS could unveil treatment targets and enable genotype-matched trials or approved targeted therapies for roughly 15 000 patients in the UK annually.
The Lancet Oncology , commentaire, 2025