Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients

Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
British Journal of Cancer (Impact Factor: 4.84). 05/2003; 88(7):1091-4. DOI: 10.1038/sj.bjc.6600868
Source: PubMed


We investigated the prognostic significance of circulating breast cancer cells in peripheral blood detected by quantitative RT-PCR of marker genes in patients with advanced breast cancer. Blood samples from 94 breast cancer patients with metastatic disease (M1) were examined for circulating tumour cells by studying the mRNA expression of CK19, p1B, PS2 and EGP2 by real-time PCR. Using a score function, developed for predicting circulating tumour cells by quadratic discriminant analysis (QDA), the four expression levels were combined into a single discriminant value. Tumour cells were present in 24 out of 94 (31%) of the patients. In 77% (72 out of 94) of the patients distant metastatic disease was localised in the bone. In 36% (26 out of 72) of the patients with bone metastases at the time of blood sampling, a positive QDA for the four genes was found, in contrast to only 14% (three out of 22) without bone involvement. Overall survival rates by Kaplan-Meier revealed no prognostic effect for the presence of bone metastases (P=0.93). However, patients with a positive QDA value did have a progression-free survival at 1 year of 3% and overall survival at 2 years of 17%, against 22 and 36% for patients with a negative QDA value (P=0.015 and 0.0053, respectively). Breast cancer patients with metastatic disease have a significantly worse progression-free and overall survival when circulating tumour cells can be detected in their peripheral blood.

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Available from: Astrid J Bosma,
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    • "The appearance of metastasis depends on the migratory capacity of cells (circulating tumour cells) from the primary tumor across the lymphatic or blood vessels to distant organs [3]. The presence of circulating tumor cells (CTCs) has been associated with survival and disease progression in patients with metastatic breast cancer [4], [5]. CTCs have also been observed in neoadjuvant-treated breast cancer patients and in women with suspected breast cancer [6], [7]. "
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    ABSTRACT: Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20) performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer.
    PLoS ONE 09/2013; 8(9):e74079. DOI:10.1371/journal.pone.0074079 · 3.23 Impact Factor
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    • "Van der Auwera et al (2010), using a RT-PCR for CK-19mRNA showed that 26% of patients with MBC were CTC-positive, whereas Reinholz et al (2011) were able to detect CK19 þ mRNA cells in 56–75% of 86 patients with metastatic disease. Using a multi-marker RT-PCR assay for four marker genes, including CK-19 (Bosma et al, 2002), tumour cells were detected in 31% of patients with advanced breast cancer (Weigelt et al, 2003), and using the AdnaTest BreastCancer, 52% of metastatic patients were tested positive for CTCs (Tewes et al, 2009). It should be mentioned here, however, that the use of various enrichment procedures, the variability in the millilitres of blood analysed, and the different methods used for the evaluation of the sensitivity and specificity of the assays, preclude firm conclusions to be drawn regarding the actual incidence of CTC detection. "
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    ABSTRACT: To investigate the clinical relevance of CK-19mRNA-positive circulating tumour cells (CTCs) detected before the initiation of front-line treatment in patients with metastatic breast cancer (MBC). The presence of CTCs was detected in 298 patients with MBC using a real-time PCR (RT-PCR assay. In 44 patients, the detection of CTCs was evaluated by both the CellSearch and the RT-PCR assay. Interaction with known prognostic factors and association of CTCs with clinical outcome were investigated. There was a strong correlation between the detection of CTCs by both assays. CK-19mRNA-positive CTCs were detected in 201 (67%) patients and their detection was independent of various patients' clinico-pathological characteristics. The median progression-free survival (PFS; 9.2 vs 11.9 months (mo), P=0.003) and the overall survival (OS; 29.7 vs 38.9 mo, P=0.016) were significantly shorter in patients with detectable CK-19mRNA-positive CTCs compared with patients without detectable CTCs. Multivariate analysis demonstrated that oestrogen receptor status, performance status and detection of CTCs were emerged as independent prognostic factors associated with decreased PFS and OS. The detection of CK-19mRNA-positive CTCs in patients with MBC before front-line therapy could define a subgroup of patients with dismal clinical outcome.
    British Journal of Cancer 06/2012; 106(12):1917-25. DOI:10.1038/bjc.2012.202 · 4.84 Impact Factor
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    • "Although TFFs have been involved in the protection of the gastrointestinal tract against mucosal damage (11), their oncogenic potential has been extensively reported, including their roles in cell proliferation (12–15), apoptosis (12–14,16,17), migration and invasion (14,16,18,19) and angiogenesis (20,21). TFF proteins levels have been found to be related to the development of breast cancer (22–33), gastric cancer (21,22,34–38), colon cancer (39,40), and prostate cancer (41–43). It has also been reported that TFF proteins are related to lung cancers (23,44–48). "
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    ABSTRACT: Lung cancer is the most common cause of cancer-related deaths in the world. The trefoil factor (TFF) family is composed of three thermostable, and protease-resistant proteins, named TFF1, TFF2 and TFF3. TFF protein levels have been found to be related to the development of various types of cancer. However, it is still unclear whether TFF proteins are differentially expressed in the serum of different histological subtypes of lung cancer compared to healthy individuals. In this study, we investigated the levels of TFF proteins in serum and lung tissues of 130 lung cancer patients (58 squamous cell lung carcinoma cases, 43 adenocarcinoma cases and 29 SCLC cases) and 60 healthy individuals. It was found that TFF1 and TFF2 have similar or slightly higher levels in these three subtypes of lung cancer compared to healthy individuals, while TFF3 levels were significantly higher in the examined lung cancer cases compared to healthy individuals. Immunoblot analyses of TFF1, TFF2 and TFF3 indicated that lung cancer tissues and lung cancer cell lines have a higher expression of the TFF3 protein, but not of TFF1 or TFF2 proteins, compared to tissues from healthy individuals or from the normal cell line. Quantitative RT-PCR analysis indicated higher levels of TFF3, but not TFF1 and TFF2, transcripts in lung cancer tissues or cell lines. These results show increased TFF3 levels in serum and lung tissues, suggesting that TFF3 may serve as a promising, easily detected biomarker of lung cancer.
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