Researchers have developed a new genomic model that could improve predictions of long-term recurrence in one of the most common forms of breast cancer, potentially helping clinicians tailor treatment more precisely.
The study focuses on oestrogen receptor–positive, HER2-negative (ER+/HER2−) breast cancer, which accounts for the majority of breast cancer diagnoses. While outcomes are generally favourable, this subtype is known for its risk of late recurrence, sometimes many years after initial treatment, making decisions about adjuvant therapy particularly challenging.
Scientists built on a previously identified genomic signature derived from circulating tumour cells (CTCs), cancer cells that have detached from the primary tumour and entered the bloodstream. This signature has already been linked to metastasis. In the new study, researchers investigated whether the same signature, and its variation within tumours, could help predict recurrence risk.
Model Shows Strong Link to Established Risk Scores
Using data from 194 patients with early-stage ER+/HER2− breast cancer, the team trained two predictive models: one based on gene expression and another on copy number changes. The widely used Oncotype DX recurrence score, which estimates the likelihood of cancer returning and guides chemotherapy decisions, was used as a surrogate marker for survival.
The expression-based model showed a strong correlation with Oncotype DX scores, while the copy number-based model demonstrated a moderate correlation. Both approaches were then validated using the large, independent METABRIC breast cancer dataset, where they successfully predicted long-term recurrence-free survival. These results suggest the CTC-derived signature captures key biological features associated with disease progression, even when assessed using primary tumour samples.
Tumour Heterogeneity Linked to Higher Recurrence Risk
The researchers also examined intratumor heterogeneity, genetic variation within different regions of the same tumour, focusing on six genomic regions linked to the CTC signature. Using multiplex fluorescence in situ hybridisation (FISH), they found that higher levels of heterogeneity were associated with higher Oncotype DX risk scores and more aggressive tumour grade. This finding indicates that tumours with greater genetic diversity may be more adaptable and therefore more likely to recur over time.
The authors conclude that their CTC genomic signature, combined with measures of intratumor heterogeneity, could offer a valuable new tool for assessing recurrence risk in ER+/HER2− breast cancer. While further validation is needed before clinical use, the approach could eventually help refine treatment decisions and identify patients who may benefit from closer monitoring or extended therapy.
Reference
Rotbauer M et al. The role of circulating tumor cell-associated genes in the progression of estrogen receptor-positive breast cancer. Npj Breast Cancer. 2025; https://doi.org/10.1038/s41523-025-00874-0.
