The role of circulating tumor cell-associated genes in the progression of estrogen receptor-positive breast cancer.

Estrogen receptor-positive, human epidermal growth factor receptor negative (ER + /HER2-) breast cancer, poses challenges in adjuvant treatment decisions due to its propensity for late recurrence. We propose a model that leverages our previously identified circulating tumor cell (CTC) genomic signature, linked to metastasis. Furthermore, we investigated the impact of CTC signature intratumour heterogeneity (ITH) on recurrence risk. Using Oncotype DX recurrence score as a surrogate for survival, we trained expression and copy number-based models using 194 early stage ER + /HER2- breast cancer patients and validated them in the METABRIC dataset. Multispectral fluorescence in situ hybridization (Multiplex-FISH) was used to evaluate the ITH of 6 CTC genomic regions in primary tumors. The expression-based model strongly correlated with Oncotype DX, while the copy number-based model achieved a moderate correlation. Both models were able to predict long-term recurrence free survival in METABRIC. Higher CTC signature ITH was associated with increased Oncotype DX risk and higher overall grade. These findings highlight the value of our CTC signature in disease progression and the role of ITH on recurrence risk.