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High Circulating Tumor Cell Levels Predict Rapid Progression of Metastatic Breast Ca

High Circulating Tumor Cell Levels Predict Rapid Progression of Metastatic Breast Ca

NEW ORLEANS—By monitoring the levels of circulating tumor cells (CTCs) in peripheral blood, it is possible to predict which patients with metastatic breast cancer will progress rapidly while on apparently futile therapy, Daniel F. Hayes, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, said at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 509).

Results from a prospective multicenter study showed, by multivariate analysis, that the level of CTCs at baseline was the strongest and most significant predictor of a poor outcome, including progression-free and overall survival. "Patients with 5 CTC/7.5 mL of blood or higher at the first follow-up appear to be on futile therapy," Dr. Hayes noted.

The study enrolled 177 breast cancer patients prior to treatment for metastatic disease at 20 treatment sites. The study also included more than 200 healthy age- and sex-matched volunteers.

In 7.5 mL of blood collected from the subjects, the CTCs were immunomagnetically separated based on EpCAM binding. After multicolor fluorescent labeling, cells were classified by microscopy as CTCs if they stained positive for both DAPI and cytokeratin 8, 18, and/or 19, and if they stained negative for CD45. Clinical outcomes were determined by the participating clinical sites without knowledge of CTC levels.

The study first gathered data from a "training set" involving 102 patients, which established that 5 CTC/7.5 mL blood or greater was the optimal cutoff to best distinguish rapid from more indolent progression. The remaining 75 patients were then used as the validation set. Blood was drawn every month for testing, and full assessments (including body imaging) were made at baseline and at 3 and 6 months.

Elevated CTCs at baseline (5 CTCs or more) was documented in 87 patients (49%), and 30% of all patients at first follow-up (usually 3 to 4 weeks after starting therapy) had persistent or newly elevated levels (see Figure ). "CTC levels at first follow-up were usually reduced, compared to baseline, a result we believe is due to the beneficial effects of therapy," Dr. Hayes explained.

The existence at baseline of 5 CTCs or more was significantly associated with very short progression-free survival (2.7 months vs 7.0 months for patients with less than 5 CTCs at baseline) and very short overall survival (10.1 vs 18+ months) (P = .0001 for both comparisons). At first follow-up, presence of 5 CTCs or more was also associated with very short progression-free survival (2.1 months vs 7.0 months for those with less than 5 CTCs at first follow-up) and overall survival (8.2 vs 18+ months) (P = .0001 for both comparisons). The progression-free and overall survival in the training set and the prospective validation set were "remarkably" similar, Dr. Hayes noted.

In a multivariate analysis, the presence of 5 CTCs or more at baseline was the most powerful predictor of outcome and was independently prognostic for both progression-free survival (hazard ratio [HR] 1.76) and overall survival (HR 4.26). For those with 5 CTCs or more at first follow-up, these hazard ratios were 2.52 and 6.49, respectively, both highly significant. [For full results of the study, see N Engl J Med 351:781-791, 2004.]

Dr. Hayes concluded, "Fifty percent of patients with metastatic disease who have recently progressed and are about to start a new therapy have elevated CTCs at baseline. These patients have substantially and significantly shorter progression-free and overall survival."

Perhaps more importantly, he said, "a fraction of these patients convert to low CTC levels fairly rapidly, and their prognosis is relatively favorable. However, the 30% whose CTC levels become or remain at 5 CTC/7.5 mL or higher at first follow-up have a very short progression-free survival and overall survival, and appear to be on futile therapy."

He said that the laboratory test for measuring CTCs has recently been approved by the FDA. While it could be useful in clinical decision-making in regard to patients who are not responding well to treatment, he believes that randomized controlled trials soon to be conducted will help answer whether switching therapy in patients with elevated CTCs at 3 to 4 weeks will improve prognosis. 

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