Circulating tumor cells

The process of metastases requires loss of cell-cell adhesion, acquisition of motility, interaction with extracellular environment, migration, survival in a foreign environment, and a critical component is the circulation of malignant cells in the lymphatic and vascular compartments.

Identification of circulating tumor cells in transient may provide information about biology of metastases and may provide the ability to manage the process.

Identified in peripheral blood even in early stage tumors by molecular techniques.

Shedding of tumor cells is related to type, amount, and location of the malignancy.

There are usually fewer than 100 CTC’s in 1 mL of whole blood compared with 10 to the ninth hematologic cells in the same volume of blood.

CTCs known to be present in the peripheral blood with patients with breast, colon rectal, prostate and lung cancers.

Such cells are rare in healthy individuals or in those with nonmalignant disease.

CTCs offer a noninvasive way to sample genetic markers, monitor treatment effectiveness, demonstrate vascular invasion and localized disease, and detect early detection of recurrent disease.

Estimated half life of CTCs is less than 3 hours (Meng S).

Clinically occult tumor cells are released from the original tumor before and during surgical maneuvers.

CellSearch test able to monitor prostate cancer, breast and metastatic colorectal cancers.

Evidence correlates with progression free survival and overall survival in metastatic breast cancer.

The detection of circulating tumor DNA with the use of current assays is associated with a short median lead time before clinical recurrence of 11 months which may reflect undiagnosed macrometastases rather than emergence from breast cancer dormancy.

The detection of circulating tumor cells  in patients  with hormone receptor positive breast cancer five years after diagnosis is associated with an increased risk of recurrence by a factor of 13 and a median time until clinical recurrence  at 2.8 years.

CTC’s can be used to stratify patients in a clinical trial, could classify patients who respond or on non-responders to therapy, can be used as a tool for inclusion or exclusion of individuals in a clinical trial.

Can provide information by predicting the true extent of a cancer’s spread, can you be used to define response or resistance during therapy.

Can be used to determine recurrence or growth of a tumor after treatment.

A decrease in the number of CTC’s correlates with response to chemotherapy, and conversely an increase in the number of CTC’s is associated with a lack of response and disease progression.

The detection of 5 or more CTCs in circulating blood is associated with a shorter median progression free survival and overall survival and the maintenance of decreasing the numbers of such cells to less than 5 is indicative of treatment response and predictive of improved progression free survival and overall survival.

A prospective study demonstrating ciculating tumor cells in patients with metastatic breast cancer indicated a significant correlation between cell levels and radiographic disease progression in patients receiving chemotherapy or endocrine therapy: This correlation applied at the time of imaging, 3-5 weeks before imaging, in 7-9 weeks before imaging with demonstration of progression free survival to be shorter in patients with 5 or more CTCs at 3-5 weeks and 7-9 weeks after the start of treatment.

SUCCESS trial evaluated 2 adjuvant chemotherapy regimens followed by two years or five years of zoledronate in patients with high risk early breast cancer: patients who were CTC positive at follow up 10.6% died in 18.2% had disease recurrence while of the patients who were CTC negative on follow up 2.5% died and 7.3% had disease recurrence at a two-year follow-up.

Unlike other tumor markers the number of circulating tumor cells does not necessarily correlate with the total tumor burden (Gafario, JJ, Cristofanilli M).

There was only limited correlation between circulating cancer cells and radiographic measurement of tumor load in breast cancer (Budd GT).

CellSearch System has a sensitivity of approximately 65% for detecting circulating tumor cells of > 1 cell per 7,5 mL of blood in patients with metastatic breast cancer.

Patients less than 5 circulating tumor cells have prolonged benefit with their current therapy, whereas patients with persistently more than 5 such cells are predicted to experience only short-term benefits, if any.

Higher CTC numbers are detected in breast cancer patients with bone metastases relative to those without bone metastases, and in patients with multiple bone metastases relative to those with one or two bone lesions (De Georgi U).

In a phase III CAIRO study in colorectal cancer patients with 29% of patients with high CTC counts at baseline at 1.5 fold increase in risk for progressive disease and a 2.2 full increase for risk of death versus those with low counts (Tol J et al).

Circulating tumor cells tend to be larger then other circulating cells in the bloodstream.

Epithelial cell adhesion molecules on circulating tumor cells serves as an antigen for which antibodies can capture those cells and identified them as metastases.

The most widely used approach to identify CTCs in uses immune-capture techniques in which a solid-phase medium is coated with anti-bodies against antigens expressed by the malignancy but not by normal hematpoietic cells.

CellSearch technique treats blood sample with magnetic iron particles bound to antibodies specific for epithelial cell adhesion molecule: CTCs become coated with these particles and then CTCs are exposed to a magnetic field and immunofluorescent antibodies are applied and images are taken.

A limitation of the CellSearch technique is that the assay can miss other types of CTCs, and is not useful to detect tumor cells a non-epithelial origin, and is not sensitive to detect very low levels of CTCs.

PSA positive CTCs can’t discriminate between local and metastatic disease (Stott SL et al).

CRPC with unfavorable CTC level have decreased overall survival compared with favorable levels, 11.5 vs. 21.7 months (Schaffer DR et al, De Bono JS et al).

CTCs are able to predict disease progression in patients with metastatic breast cancer, and can predict post therapy relapse in patients with early stage breast cancer (Lucci A et al).

In the above study detection of one or more CTCs predicted decrease rates of 2 year progression free survival, and an increased number of CTCs was associated with lower rates of overall survival: At 2 years overall survival for patients with one or more, 2 or more, and 3 a more CTC his were 94%, 89% in 81% respectively compared with 99% rate for patients with no CTCs.

CTC-iChip a technology which depletes normal blood cells and leaves behind CTCs.

The detection of circulating tumor DNA (ctDNA) could give patients who have been treated for their early breast cancer (BC) warning of any recurrence many months before it could be detected clinically or symptomatically (Dicosmo).

Circulating tumor DNA is able to identify a patient who is going to relapse at the locoregional level.

Circulating tumor cells (CTCs) and ctDNA could potentially identify patients who could be spared further chemotherapy.

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