NEW ORLEANSBy 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.
