Analysis of ESR1 mutations in single circulating tumor cells from metastatic luminal breast cancer patients upon estrogen deprivation therapy

Background:

Mutations in the ligand-binding domain of the ESR1 gene are frequently observed as a resistance mechanism against estrogen deprivation therapy (EDT) such as aromatase inhibition in breast cancer patients. Detection of such mutations offers the chance to optimize therapy strategies. However, the predictive utility of the primary tumor for an acquired resistance is limited and obtaining serial biopsies of metastatic lesions is challenging. To underline the application of a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next generation sequencing approach for the ESR1 coding region.

Materials and methods:

132 CTCs from blood samples of 46 metastatic breast cancer patients were analyzed. CTCs were enriched with the CellSearch® system, isolated and genomic DNA was amplified. Furthermore, tumor tissue samples from corresponding primary tumors and/or metastatic lesions from patients with ESR1 mutations in CTCs were analyzed.

Results:

ESR1 mutations were detected in CTCs from twelve of 46 patients exclusively in the patient group that was treated with EDT. No ESR1 mutations were found in CTCs from patients who received no or other ET (p-value: 0.048). In seven patients mutations were detected in the hotspot regions located in the ligand binding domain. Six novel mutations were detected. ESR1 mutations were absent in primary tumor tissue samples of patients with mutated CTCs.

Conclusions:

Single cell CTC analysis for ESR1 mutations may be of clinical value to identify patients who might progress under EDT and might therefore benefit from an early switch to an alternative ET or other treatment regime.