Medicine: Department of Surgery and Cancer, Imperial College London
Doi
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
