Do Rare Cancer Cells Have a Tale to Tell?
A somewhat different randomized clinical trial was launched earlier this year in women undergoing their first treatment for metastatic breast cancer. It won't pit a standard therapy against an experimental therapy or a new combination of existing agents, or even an experimental therapy against placebo.
Instead, after a single chemotherapy treatment cycle, participants will undergo a blood test that may help predict whether the chemotherapy is working. Women with test results indicating ineffective therapy will then be randomized to either continue on their current therapy until evidence of progression, which is the current standard of care, or to switch immediately to a different chemotherapy regimen.
"Our goal is to study a strategy of treatment, not the drugs themselves," explains the study's lead investigator, Dr. Jeffrey Smerage from the University of Michigan Comprehensive Cancer Center. "We want to identify early on those patients who will benefit before they suffer significant side effects and toxicity, and increase the likelihood that they'll receive a drug that's active."
The test being used in the NCI-funded clinical trial, which is being led by the Southwest Oncology Group (SWOG), measures the number of tumor cells floating freely among the billions of other cells in the blood, typically called circulating tumor cells (CTCs). Studies in patients with metastatic disease, mostly breast cancer, have found that patients whose CTC count just prior to treatment and in the first few weeks following treatment exceeds a particular threshold - 5 CTCs per 7.5 mL of blood - have far shorter progression-free and overall survival than those who have low or no detectable CTCs at those times.
Although the majority and largest of these studies have been conducted in breast cancer, smaller studies involving patients with melanoma, prostate, and colorectal cancer have yielded similar results.
As the SWOG trial demonstrates, researchers are now trying to determine just how much clinically relevant information can be wrenched from these rare cells, including whether they can point the way to more tailored therapies, serve as surrogate markers for response to treatment in clinical trials, or provide new insights into the cause of more than 90 percent of cancer deaths - metastasis.
What exactly are they saying?
Although several companies have developed tests and investigators around the world continue to refine and improve the CTC detection process, in the United States, Immunicon Corporation's CellSearch assay is the only CTC test to receive FDA clearance to monitor patients with metastatic breast cancer; several studies described in this article used the CellSearch system and were funded at least in part by Immunicon.
Even with some of the optimism surrounding CTCs, says Dr. George Sledge, from the Breast Care and Research Center at the Indiana University School of Medicine, there currently are serious limits to what measuring CTCs can help accomplish.
"My concerns are not over technology itself, but rather what to do with the result once you have it," he says.
Even though measuring CTCs can predict that a treatment isn't working, Dr. Sledge continues, it doesn't tell oncologists which therapy would do better - a critical need in caring for women with metastatic disease, for which there is no current standard first-line regimen.
The SWOG-led trial is a partial step toward determining whether measuring CTCs can, at least, improve the process by which treatment decisions are made. It is based largely on the results of a prospective clinical trial led by Dr. Massimo Cristofanilli at the University of Texas M.D. Anderson Cancer Center. Initial results from the study, published in 2004 in the New England Journal of Medicine, showed that in women with either recurrent or newly diagnosed metastatic breast cancer, CTC levels at baseline and 3 weeks follow-up were the most significant predictors of progression-free and overall survival. When a 2005 analysis was confined only to women undergoing first-line treatment, the results were the same.
The available data - including a pivotal study of women treated for metastatic breast cancer published last year - also suggest that CTCs may be a quicker, more accurate predictor of therapeutic effectiveness than the current gold standard, imaging studies typically performed 10 to 12 weeks after treatment to measure whether tumors have grown or shrunk.
The CTC assay was highly reproducible and reliably predicted disease progression, the study found, both of which have been problems in clinical trials that rely on more standard techniques, says Dr. Sledge.
It's unclear whether CTCs may offer the same prognostic insight in patients with operable, early-stage disease. To date, only a handful of studies have been done in this setting, with some promising results reported.
Writing the next chapter
Dr. Weiner points to a study in which he was involved that focused on patients with metastatic colorectal cancer, one of only a few studies that have attempted to perform gene expression profiling of CTCs.
"There were very few CTCs in most patients," he notes. "It's beginning to appear that measuring CTCs will be most beneficial in cancer types associated with bone marrow involvement, where you would expect to find more CTCs in the peripheral blood and thus be more accessible to the technology."
So far, CTC-related findings have generated more questions than answers. For example, Dr. Weiner notes, it hasn't been resolved whether CTCs are representative of what's happening at the tumor site, are "adventurous metastasis-prone cells, or…have been kicked out of the tumor neighborhood and are preparing to undergo cell death."
It's questions like these that researchers are now trying to answer, undertaking the task of molecularly characterizing CTCs to determine just what their fate may be or how they differ from cells in the primary tumor. For example, in a small German study of 35 women with stage I to III breast cancer, 12 patients with HER2-positive CTCs had HER2-negative primary tumors.
Other evidence suggests that such HER2 "conversions" aren't uncommon. Such information, says Dr. Sledge, "could potentially be useful in guiding treatment decisions or following the fate of a cell population after completing a form of therapy."
Several studies have suggested that some CTCs have properties associated with chemotherapy resistance and could even be another type of rare cell, a cancer stem cell, which a growing body of evidence indicates may fuel several cancers and be responsible for recurrent disease.
Although there is still much work to do, concludes Dr. Cristofanilli, he is hopeful that CTCs may represent a way "to divide cancer into two different types of disease: more aggressive disease and more indolent disease, so we can start to think about how to develop treatments in a different way."
By Carmen Phillips