The clinical and prognostic use of circulating tumour cells in breast cancer

Abstract

Adjuvant therapies such as endocrine or cytotoxic chemotherapy have been demonstrated to improve overall survival in early breast cancer patients. A blood test to monitor patients at risk of relapse is needed to identify those patients who would benefit from these treatments and those for whom it is not necessary. This is in favour of detecting disseminated tumour cells (DTCs) from painful bone marrow aspirates, currently the gold‐standard method for detecting minimal residual disease (MRD). The use of circulating tumour cells (CTCs) enriched from the blood was investigated for this purpose along with their characterisation in the metastatic setting to enable individualised therapy. Sixty‐four primary breast cancer patients were followed up for up to 12 years post surgery for any MRD present. This analysis looked at measurements of DTCs in the bone marrow, CTCs in the blood and circulating‐free DNA (cfDNA) in the plasma over the follow up period. Patients who had involved lymph nodes at surgery, were significantly more likely to have CTCs present than low risk patients with no nodes positive, (70% compared to 39% respectively, p = 0.042). Our analysis also looked at the relationship of cfDNA to DTCs and CTCs. An inverse relationship of cell death in the blood (manifesting as blood cfDNA) to bone marrow DTCs by qRT‐PCR was apparent. This may be due to tumour dormancy mechanisms ‐ cycles of tumour cell proliferation and cell death occurring in the bone marrow, evidence not shown before in patient samples. Combined use of these markers could therefore be used as a monitoring system for impending metastatic disease and a rationale for further treatment. We also participated in a multi–centre study to assess the effects of lapatinib; a targeted therapy against two members of the human epidermal growth factor receptor family (EGFR and HER2). This was in advanced breast cancer patients and used CTCs as a surrogate marker. Our study selected patients on the basis of EGFR positivity in CTCs that were present in the blood. Four out of 12 patients (33%) demonstrated an initial decrease in the number of EGFR positive CTCs in response to Lapatinib, however this was limited and all patients were taken off study with progressive disease. We also explored a novel method in development to detect viable CTCs. This used an in situ hybridisation method to amplify signals from mRNA transcripts of tumour markers in CTCs. The use of CTCs is a very useful and promising tool for studying both the biology of breast cancer, and also as a non‐invasive analytical tool in the clinical setting to gain predictive and prognostic information.