Are CTCs in breast cancer high risk biomarkers for metastasis?

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Breast cancer is the most prevalent cancer in women worldwide (1). While it is the leading cause of death due to cancer for women in the developing world, it is still the second cause of death due to cancer in developed countries (2). Lower rates of breast cancer survival are linked to the disease being detected at a later stage (3). Breast cancer detected late is more likely to have metastasized to other organ sites, and it is these metastases rather than the primary tumor that is more likely to be fatal (4).

Standard treatment for primary breast cancer includes neoadjuvant chemotherapy to reduce tumor size and prevent micrometastases (5). Micrometastases include cells that leave the primary tumor site and circulate through the blood and/or lymph vessels, i.e., circulating tumor cells (CTCs), and those that enter the bone marrow, i.e., disseminated tumor cells (DTCs) (4). Many studies have shown CTCs in the blood and DTCs in the bone marrow are often detected in the same patient, with a correlation between 66–94% (5). This is probably because CTCs in the blood represent one of the first steps in the metastatic process while DTCs represent a more advanced metastatic stage (5). Numerous studies have shown that the presence of CTCs and DTCs may be independent prognostic markers of increased risk for shorter progression free survival (PFS) and overall survival (OS) (6). Thus, these markers have been used to monitor treatment outcome. Residual CTCs, particularly after treatment, appear to be linked to resistant tumor cell populations that may indicate worse outcomes (6).  However, using DTCs to monitor treatment outcome in primary breast cancer is less favorable because bone marrow aspiration is an invasive technique that is often painful and uncomfortable for patients (7). The less invasive technique of detecting CTCs from blood samples is a preferable option for use as biomarkers to determine the risk for recurrence of breast cancer (7).

Resistance to standard chemotherapy treatment, antihormonal, and even targeted therapies based on primary tumor receptor status (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) may be due to the non-proliferative state of DTCs and CTCs, their stem-cell like characteristics and their discordant receptor status compared to the primary tumor (7). In a recent study by Kasimir-Bauer, S. et al. (2016), CTCs and DTCs were targeted using an alternative, receptor independent chemotherapy, the bisphosphonate clodronate. Clodronate may increase OS and reduce metastases in women with breast cancer that are at higher risk for it (7). In this prognostic study, 525 women with primary breast cancer were followed up for a median time of 5 years and their clodronate intake was determined as well as their DTC and CTC status. The CTCs were analyzed using AdnaTest BreastCancer Kits. First, the AdnaTest BreastCancerSelect Kit was used for specific immunomagnetic cell-selection to enrich CTCs from the peripheral blood collected from patients. Then, RNA was isolated and the AdnaTest BreastCancerDetect Kit was used for sensitive gene expression analysis using RT-PCR and multiplex-PCR.

The main conclusion from this study was that CTCs and DTCs have different prognostic value regarding PFS, which may be due to early intake of clodronate per DTC status at primary diagnosis (7). DTCs were not found to have prognostic significance in regards to PFS and OS, however, CTCs were significantly associated with reduced PFS (7). In addition, unlike in other studies, no correlation between CTCs and DTCs was found. Thus, the authors concluded that CTCs may be high risk biomarkers for metastasis that is not limited to bone metastasis and the CTCs could circulate from reservoirs in the lungs or the liver (7). Furthermore, a subset of DTCs/CTCs were found to have stem cell character or epithelial mesenchymal transition (EMT) characteristics which may explain why these cells were still detected after treatment. Therefore, there is a significant need for monitoring CTCs and using new or different therapy options for the treatment of breast cancer patients that have CTCs and/or DTCs.

 

References

  1. 1. World Cancer Research Fund International:
    http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breast-cancer-statistics
  2. 2. Ferlay, J. et al. (2012) GLOBOCAN v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer. Link
  3. 3. World Health Organization: http://who.int/cancer/detection/breastcancer/en/index1.html
  4. 4. Andergassen, U., Kölbl, A.C., Hutter, S., Friese, K., Jeschke, U. (2013) Detection of circulating tumour cells from blood of breast cancer patients via RT-qPCR. Cancers (Basel) 5, 1212–1220. Link
  5. 5. Bidard, F.C., Proudhon, C., Pierga, J.Y. (2016) Circulating tumor cells in breast cancer. Mol Oncol. 10, 418–430. Link
  6. 6. Kasimir-Bauer, S. et al. (2016) Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy. Breast Cancer Res. 12; doi: 10.1186/s13058-016-0679-3. Link
  7. 7. Kasimir-Bauer, S. et al. (2016) Different prognostic value of circulating and disseminated tumor cells in primary breast cancer: Influence of bisphosphonate intake? Sci Rep. 6, doi: 10.1038/srep26355. Link

 

Nesrin Soetkamp

Nesrin Soetkamp, PhD is a Content Marketing Manager at QIAGEN. She received her PhD in Physiology and Biophysics from Georgetown University, where she studied the molecular mechanisms of taxane resistance in breast cancer. Prior to entering the biotech industry, Dr. Soetkamp worked as a postdoctoral fellow at the National Institutes of Health. At the NIH, she developed new methods to distinguish malignant adrenocortical tumors from benign tumors and normal tissue in the adrenal glands/cortex using epigenetic methylation patterns.

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