Abstract
BackgroundMolecular characterization of circulating tumor cells (CTC) is promising for personalized medicine. We aimed to identify a CTC gene expression profile predicting outcome to first-line aromatase inhibitors in metastatic breast cancer (MBC) patients. Methods: CTCs were isolated from 78 MBC patients before treatment start. mRNA expression levels of 96 genes were measured by quantitative reverse transcriptase polymerase chain reaction. After applying predefined exclusion criteria based on lack of sufficient RNA quality and/or quantity, the data from 45 patients were used to construct a gene expression profile to predict poor responding patients, defined as disease progression or death <9 months, by a leave-one-out cross validation.ResultsOf the 45 patients, 19 were clinically classified as poor responders. To identify them, the 75 % most variable genes were used to select genes differentially expressed between good and poor responders. An 8-gene CTC predictor was significantly associated with outcome (Hazard Ratio [HR] 4.40, 95 % Confidence Interval [CI]: 2.17–8.92, P < 0.001). This predictor identified poor responding patients with a sensitivity of 63 % and a positive predictive value of 75 %, while good responding patients were correctly predicted in 85 % of the cases. In multivariate Cox regression analysis, including CTC count at baseline, the 8-gene CTC predictor was the only factor independently associated with outcome (HR 4.59 [95 % CI: 2.11–9.56], P < 0.001). This 8-gene signature was not associated with outcome in a group of 71 MBC patients treated with systemic treatments other than AI.ConclusionsAn 8-gene CTC predictor was identified which discriminates good and poor outcome to first-line aromatase inhibitors in MBC patients. Although results need to be validated, this study underscores the potential of molecular characterization of CTCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2155-y) contains supplementary material, which is available to authorized users.
Highlights
Molecular characterization of circulating tumor cells (CTC) is promising for personalized medicine
By focusing on genes that are not, or only at a much lower level, expressed by leukocytes, we have previously shown that the expression levels of 96 genes in CTCs can be quantified in metastatic breast cancer (MBC) patients through quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) [18]
8-gene CTC profile predicts for outcome to treatment Of the 45 patients, 19 patients were classified as poor responders due to progression of disease or death
Summary
Molecular characterization of circulating tumor cells (CTC) is promising for personalized medicine. Metastatic breast cancer (MBC) is a highly heterogeneous disease leading to an urgent need for a more personalized treatment approach For those patients with estrogen receptor (ER)-expressing tumors, endocrine therapy is the mainstay of treatment. Numerous factors accounting for resistance to endocrine treatment have been revealed, including loss of ER expression [1,2,3], overexpression of the HER2 receptor [4], hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway [5], and overexpression of Enhancer of Zeste Homolog 2 (EZH2) [6] Determination of these factors in tumor tissue may contribute to a more personalized treatment approach of individual patients. Metastatic tissue is often hard to obtain and only possible through invasive procedures
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