 study of breast cancer to date, analysing 1,364 tumors to uncover new driver genes, structural variants, and genomic biomarkers linked to treatment response.){kind=link}
Researchers have published the largest clinically annotated, whole-genome sequencing (WGS) study of breast cancer to date, analysing 1,364 tumors to uncover new driver genes, structural variants, and genomic biomarkers linked to treatment response.
The study, combined WGS, transcriptomic profiling, and long-term clinical outcomes, generating a dataset of more than 10.9 million somatic mutations. Compared with targeted sequencing approaches, whole-genome analysis allowed the team to comprehensively examine structural rearrangements, copy-number alterations, gene fusions, and mutational signatures across the full cancer genome.
The researchers identified 41 breast cancer driver genes, including four not previously reported. Structural variant analysis revealed widespread chromosomal rearrangements and gene amplifications, including extrachromosomal DNA (ecDNA) events involving ERBB2 in some HER2-positive tumors.
Importantly, several genome-wide features correlated with patient outcomes and therapy response. Tumors displaying homologous recombination deficiency (HRD) showed significantly improved disease-free survival among patients with triple-negative breast cancer receiving adjuvant chemotherapy. HRD status also appeared predictive of treatment response in hormone receptor–positive metastatic patients treated with CDK4/6 inhibitors.
In HER2-positive disease, ecDNA-driven ERBB2 amplifications were associated with better responses to neoadjuvant chemotherapy compared to conventional chromosomal amplifications. Measures of intratumor heterogeneity derived from WGS data predicted poorer survival and resistance to anti-HER2 therapy.
The authors also report evidence that genomic instability frequently begins decades prior to clinical diagnosis, offering new insight into early cancer development and potential opportunities for earlier detection.
The cohort, drawn primarily from an East Asian population with a median patient age of 44 years, provides an important genomic reference alongside other international breast cancer projects. The dataset has been made publicly available for research use.