Clinical relevance of circulating CK-19mRNA-positive tumour cells before front-line treatment in patients with metastatic breast cancer

Androulakis, N.; Agelaki, Sofia; Perraki, Maria; Apostolaki, Stella; Bozionelou, V.; Pallis, Athanasios; Kalbakis, Kostas; Xyrafas, A.; Mavroudis, Dimitris; Georgoulias, Vassilis

doi:10.1038/bjc.2012.202

Cited by 36 publications

(28 citation statements)

References 31 publications

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“…Increased numbers of CTC before the second cycle of therapy was an early predictive marker of poor PFS and OS, and could be used to monitor treatment benefit, whereas CTC decrease under treatment was stronger with targeted therapy (14). The detection of CTCs in patients with MBC before front-line therapy could define a subgroup of patients with dismal clinical outcome (15). A recent meta-analysis clearly indicated that the detection of CTCs is a reliable prognostic factor in patients with earlystage and MBC (16), whereas numerous ongoing trials evaluate CTCs as markers for early prediction of treatment efficacy (17).…”

Section: Introductionmentioning

confidence: 99%

PIK3CA Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

Markou

Farkona

Schiza

et al. 2014

Clinical Cancer Research

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Purpose: Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while PIK3CA somatic mutations play a crucial role in therapy response. We investigated the presence of PIK3CA mutations in CTC and whether this is associated with clinical outcome.Experimental Design: We developed and validated an ultrasensitive methodology for the detection of PIK3CA mutations that is based on a combination of allele-specific, asymmetric rapid PCR and melting analysis. We analyzed PIK3CA hotspot mutations in: (i) a training group consisting of EpCAM-positive CTC fraction from 37 patients with clinically confirmed metastasis, and 26 healthy female volunteers and 15 primary breast tumor tissues and (ii) an independent group consisting of EpCAM-positive CTC fraction from 57 metastatic and 118 operable breast cancer patients and 76 corresponding primary tumors.Results: The assay could detect 0.05% of mutated dsDNA in the presence of 99.95% wtDNA for both exons (9 and 20) and was highly specific (0/26 healthy donors). PIK3CA mutations were identified in EpCAM-positive CTC in 20 of 57(35.1%) and in 23 of 118 (19.5%) patients with metastatic and operable breast cancer, and in 45 of 76(59.2%) corresponding FFPEs. Our data indicate that PIK3CA mutational status in CTCs can change during disease progression and is associated with worse survival (P ¼ 0.047).Conclusions: PIK3CA hotspot mutations are present at a relatively high frequency in CTCs and their presence is associated with worse survival in patients with breast cancer with metastasis. Evaluation of PIK3CA mutational status in CTCs is a strategy with potential clinical application.

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Section: Introductionmentioning

confidence: 99%

PIK3CA Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

Markou

Farkona

Schiza

et al. 2014

Clinical Cancer Research

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“…The detection of tumor cells in the peripheral blood (circulating tumor cells; CTCs) and bone marrow aspirates (disseminated tumor cells; DTCs) has been described in cancer patients567891011 and has been shown to be associated with shorter progression free (PFS) and overall (OS) survival in various tumor types, including SCLC121314151617181920. In SCLC patients, the detection of CTCs before the initiation of systemic treatment as well as post-treatment and at the time of clinical relapse has been shown to be associated with a worse overall survival1517181920.…”

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confidence: 99%

TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC)

Messaritakis

Stoltidis

Κotsakis

et al. 2017

Sci Rep

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The aim of the study was to evaluate the phenotypic CTCs heterogeneity (TTF-1+ and/or CD56+) in SCLC patients and correlate it with the CellSearch. Peripheral blood was obtained from 108 consecutive patients. CTCs were detected by CellSearch and double-immunofluorescence using anti-CD45, anti-TTF-1 and anti-CD56 antibodies. Before chemotherapy TTF-1+/CD45−, CD56+/CD45− and TTF-1+/CD56+ CTCs were detected in 66(61.1%), 55(50.9%) and 46(42.6%) patients, respectively; 60.2% of patients were CellSearch+. Among the 22 patients with 0 CTCs/7.5 ml on CellSearch, TTF-1+/CD45−, CD56+/CD45− and TTF-1+/CD56+ CTCs were detected in 8(36.4%), 6(27.3) and 6(27.3%) patients, respectively; no CK+/EpCAM+ or TTF1+/EpCAM+ CTCs were detected in these patients. One-chemotherapy cycle decreased both the number of positive patients (p < 0.001) and their CTC number (p < 0.001), irrespectively of their phenotype and the detection method. The incidence and number of the different CTC subpopulations on PD, was significantly increased at their baseline levels. Multivariate analysis revealed that the increased number of CTCs at baseline and on PD were significantly associated with decreased PFS (p = 0.048) and OS (p = 0.041), respectively. There is an important CTC heterogeneity in such patients according to the expression of TTF-1 and CD56 which could detect EpCAM− CTC subpopulations and, thus, undetectable by CellSearch. These CTC subpopulations are dynamically correlated with treatment efficacy and disease-progression.

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“…Specifically, the detection of CK19 mRNA-positive cells either before the initiation or after the completion of adjuvant chemotherapy as well as during follow-up, was predictive of poor clinical outcome in patients with early stage breast cancer [7, 8, 20]. In the metastatic setting, the presence of CK19 mRNA-positive cells before the initiation of front-line chemotherapy identifies a group of patients with dismal prognosis [21]. …”

Section: Introductionmentioning

confidence: 99%

A Comparison of Three Methods for the Detection of Circulating Tumor Cells in Patients with Early and Metastatic Breast Cancer

Politaki

Agelaki

Apostolaki

et al. 2017

Cell Physiol Biochem

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Background: We directly compared CTC detection rates and prognostic significance, using three different methods in patients with breast cancer (BC). Methods: Early (n=200) and metastatic (n=164) patients were evaluated before initiating adjuvant or first-line chemotherapy, using the CellSearch^TM System, an RT-qPCR for CK-19 mRNA detection and by double immunofluorescence (IF) microscopy using A45-B/B3 and CD45 antibodies. Results: Using the CellSearch^TM System, 37% and 16.5% of early BC patients were CTC-positive (at ≥1 and ≥2 CTCs/23 ml of blood), 18.0% by RT-qPCR and 16.9% by IF; no agreement was observed between methods. By the CellSearch^TM 34.8% and 53.7% (at≥ 5 and ≥ 2 CTCs/7.5 ml) of metastatic patients were CTC-positive, 37.8% by RT-qPCR and 28.5% by IF. A significant agreement existed only between the CellSearch^TM and RT-qPCR. In 60.8% of cases, differential EpCAM and CK-19 expression on CTCs by IF could explain the discrepancies between the CellSearch^TM and RT-qPCR. CTC-positivity by either method was associated with decreased overall survival in metastatic patients. Conclusion: A significant concordance was observed between the CellSearch^TM and RT-qPCR in metastatic but not in early BC. Discordant results could be explained in part by CTC heterogeneity. CTC detection by all methods evaluated had prognostic relevance in metastatic patients.

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Clinical relevance of circulating CK-19mRNA-positive tumour cells before front-line treatment in patients with metastatic breast cancer

Cited by 36 publications

References 31 publications

PIK3CA Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

PIK3CA Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer

TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC)

A Comparison of Three Methods for the Detection of Circulating Tumor Cells in Patients with Early and Metastatic Breast Cancer

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