Elusive disseminating cancer cells hold key to metastatic cancer relapse

SAN ANTONIO-The cure for cancer lies in the biology of circulating and disseminating tumor cells that, unfortunately, evade detection and treatment very easily, according to one of the world's leaders in the field. In a plenary lecture, Klaus Pantel, MD, described the properties and clinical relevance of the cells that eventually cause metastatic relapse but remain elusive at primary diagnosis.

Tumor cell dissemination occurs when cells bypass escape routes and travel through the lymph nodes into the circulation, resulting in circulating tumor cells (CTCs), said Dr. Pantel, who is director of the Institute of Tumor Biology at University Medical Center Hamburg-Eppendorf in Germany.

A fraction of these CTCs ultimately invade organs, where they are detected in the form of disseminated tumor cells (DTCs), he said. DTCs can be detected in the bone marrow, and CTCs in the peripheral blood, through highly sensitive and specific cytometric and molecular methods.

The goals of researching CTCs and DTCs are to be able to estimate the risk for metastatic relapse, stratify patients for adjuvant therapy, identify therapeutic targets, monitor adjuvant therapies, and understand the biology of metastatic development, Dr. Pantel said.

DTCs in the bone marrow have prognostic importance for metastatic relapse, overall survival, and even local relapse. DTCs can be detected in about one third of breast cancer patients who lack evidence of overt metastasis (compared with 1% of nonmalignant controls).

"So there is a clear association between the finding of these cells in the bone marrow and tumor formation. It seems the bone marrow is a common homing organ," Dr. Pantel said.

But are DTCs clinically relevant? Yes, according to several large studies that have correlated the cells with lymph node stage, disease-free survival, and overall survival, making DTCs a fairly robust prognostic factor.

In a pooled analysis of nearly 5,000 patients, DTC-positive patients had significantly worse survival than DTC-negative patients. Some patients with DTCs, however, survived for years, suggesting that "the biological relevance of DTCs may be heterogeneous," Dr. Pantel said (N Engl J Med 2005;353:793-802).

HER2 status may be an important factor in this setting, he added, as HER2-positive patients with DTCs have been shown to have worse outcomes than HER2-negative patients with DTCs. Dr. Pantel believes that HER2 positivity may confer malignant potential on the DTCs. Interestingly, it is far more likely to find HER2-positive cells in DTCs than in the primary tumor, he added.

But since bone marrow testing is not acceptable in clinical management, most research is now directed at CTC detection in the blood. The prognostic significance of this has been established in metastatic breast cancer and appears promising in primary breast cancer as well.

The prognostic value of CTCs is being evaluated by Dr. Pantel and colleagues in the GeparQuattro Study, where they have found CTCs in 22% of patients at baseline, dropping to 11% after systemic treatment.

"There is an indication that treatment has a positive effect on CTCs," he reported.

The researchers have also found discordance, similar to that seen in the bone marrow, between the expression of HER2 in the primary tumor and in the CTCs. They are now evaluating the best means of detecting HER2 in CTCs in the DETECT trial.

Part of the micrometastasis model also includes the idea of dormancy, which reflects the observation that metastasis may occur years after initial therapy. Much remains to be learned about dormancy:

• Do all patients have dormant cells?
• Where do dormant cells reside?
• Does the immune system play a role in dormancy?
• What causes dormant cells to reactivate?

Finally, what treatments can affect dormant cells given that chemotherapy does not appear to kill them? It is likely that the tumor microenvironment, as well as host genetic factors, may be important in the activity of dormant cells.

Micrometastases and CTCs may ultimately be linked through molecular profiling, Dr. Pantel predicted, as a set of candidate genes for micrometastases has recently been identified. This gene set is now being analyzed for its expression in CTCs.

Dr. Pantel said that the most effective means of ridding the body of CTCs and DTCs may be through targeting the tumor microenvironment with such drugs as bisphosphonates or compounds aimed at RANK ligand. These may interfere with the bone marrow/tumor cell interaction, making the tumor cell more vulnerable.