Too Soon to Know How Circulating Tumor Cells Might Be Used to Guide Treatment of Breast Cancer

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We don't currently know exactly why these HER2-positive cells are found in circulation, but the images are quite clear, and thus it opens up a whole new area for research.

—Anthony Lucci, MD

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

“A simple blood test.” These were the first words in some media reports about a study to determine if a blood test to measure circulating tumor cells could predict outcomes in patients with nonmetastatic breast cancer. In the study, 24% of women with early-stage breast cancer had one or more circulating tumor cells and those who did had decreased progression-free and overall survival rates. Although the blood test itself may be simple, determining what the results mean and how best to use them to benefit patients is not that simple and could take years.

“I think within the next 5 years, we will clearly know how we can use this data and whether it is going to be useful in clinical decision-making for those traditionally low-risk patients who may or may not benefit from systemic therapy,” the study’s lead author Anthony Lucci, MD, told The ASCO Post. Dr. Lucci is Professor of Surgery, Department of Surgical Oncology, at The University of Texas MD Anderson Cancer Center in Houston.

Circulating Cells and Risk of Recurrence

The study included 302 chemonaive patients with stage I to III operable breast cancer undergoing surgery for their primary tumors between February 2005 and December 2010 at MD Anderson. Patients who had bilateral cancer or another malignancy within 5 years of the current diagnosis were not eligible.

“We don’t know if patients with hematologic malignancies or other solid tumors within the past 5 years could have spurious values that would confound the results,” Dr. Lucci said. “So we thought the safest thing was not to include patients with other tumors within the past 5 years to avoid any interference or confounding data, and the same with bilateral disease.”

Circulating tumor cells were measured at the time of surgery using the CellSearch System by Veridex. “Detection of one or more circulating tumor cells predicted both decreased progression-free survival (log-rank P =·.005; HR = 4.62, 95% CI = 1.79–11.9) and overall survival (log-rank P = .01; HR = 4.04, 95% CI = 1.28–12.8),” the MD Anderson researchers reported in The Lancet Oncology.1

At 2 years, progression-free survival was 87% among the 73 patients with one or more circulating tumor cells vs 99% in the 229 patients with none. Progression-free survival was 79% among the 29 patients with two or more circulating tumor cells and 69% among the 16 patients with three or more. Overall survival was 99% in patients with no circulating tumor cells, 94% in patients with one or more circulating tumor cells, 89% in patients with two or more, and 81% in patients with three or more.

“As the number of cells increased, so did the risk,” Dr. Lucci noted. “I don’t think it is a lot different than if you took a bag of seeds and you poured them into the soil. The chance of some of them taking hold is much greater than if you throw down just one seed,” he said. “We don’t know which patients will get metastatic spread and which ones will not, but I think you can clearly say that if you have more cells, the odds of developing distant metastases certainly increases. That, I feel, is very clear.”

These results were similar to the SUCCESS trial data, presented at the San Antonio Breast Cancer Symposium in 20102 and likely to be published in the near future, Dr. Lucci said. “The SUCCESS investigators concluded that the finding of one or more circulating tumor cells was also a predictor of a worse disease-free survival and overall survival, and they have a large number of patients. Data will continue to emerge, and I think it is going to provide further support for figuring out how we can best use this in the clinic,” he added.

“We didn’t find a correlation with standard tumor markers or with axillary lymph node status, which suggests that possibly these cells travel independently on different routes of spread and could even be biologically different. That is what we are looking at now,” Dr. Lucci said.

Not Routinely Recommended

Dr. Lucci pointed out the CellSearch System has been approved by the FDA for evaluating patients being treated for breast, prostate, and colorectal cancers, but currently neither the ASCO guidelines for biomarker analysis nor the National Comprehensive Cancer Network (NCCN) guidelines recommend routine use of circulating tumor cell information to guide treatment for breast cancer patients.

“We are not using it as a routine test, but we want to continue to gather this important data over the next several years so we can figure out how to best use it in the clinic,” Dr. Lucci said.

He noted that there is already a great deal of data from several large studies to support using microscopic disease in blood or bone marrow for staging algorithms. “The next big step will be to figure out how best to use that so we don’t overtreat patients or cause unnecessary anxiety,” he said. “But we would still not recommend it be used for routine treatment decisions in the clinic until we know more.”

Less Invasive Staging

More reliance on information from blood, bone marrow, or predictive gene signature analyses such as the Oncotype DX assay could mean a “move toward a less invasive type of staging and treatment protocol,” Dr. Lucci said. The study report stated that prognostic information about circulating tumor cells might be useful in identifying patients at high risk “especially since many of these patients will undergo only restricted lymph-node removal with the acceptance of the American College of Surgeons Oncology Group (ACOSOG) Z0011 data showing no reduced local control or survival for patients who had sentinel-node biopsy alone with limited axillary-nodal disease.” The article also mentions that “complete lymph-node removal results in complications for a substantial number of patients whereas drawing blood has few sequelae.”

“If we can move away from taking out all of the lymph nodes to try to get prognostic information on the number of nodes, and perhaps use this blood test or bone marrow sampling or predictive gene signatures on the primary tumor to estimate risk, we will be much less likely to cause permanent morbidity than does complete lymph node removal,” Dr. Lucci said.

Expanded and Related Studies

The MD Anderson study protocol has been amended to permit sequential circulating tumor cell measurements during routine follow-up. In addition, the cohort was expanded to nearly 600 patients.

“We expanded it because we wanted to see the effect of chemotherapy on the cells,” Dr. Lucci said. “We can take a sample prior to chemotherapy or neoadjuvant chemotherapy. When patients complete their therapy, we can get another sample, and then get a sample even further down the road, because I think sequential time points would also be helpful and may be a way to design future trials to test the efficacy of certain agents to get rid of these cells,” he explained.

“In the preliminary analysis that we have done, we can still identify circulating tumor cells in a significant number of patients even after the completion of their systemic therapy,” he reported. “I think in the very near future, we will have additional data to show the importance of these cells when they are present after the completion of systemic therapy.”

In another study, presented at this year’s ASCO Annual Meeting,3 Dr. Lucci’s team reported finding HER2-positive cells in the blood of patients with HER2-negative disease. “It is actually a parallel study,” he said, “where we take the blood sample and we look at the markers on that blood sample to see if the HER2 status of the circulating tumor cell is the same or different from the primary tumor. What we found was that in a significant number of patients, you can find changes in the circulating cells—either HER2 amplification or HER2 loss—that are different from the primary tumor,” he said.

“This suggests that either: (1) We have to look at the primary tumors more carefully to ascertain if they are really HER2-negative or -positive; or (2) Some patients may have a change in the HER2 status of certain cells released into the circulation,” he continued. “We don't currently know exactly why these HER2-positive cells are found in circulation, but the images are quite clear, and thus it opens up a whole new area for research. That is something that could affect treatment in the very near future, and we are continuing that study currently.”

The accompanying commentary to the study report in The Lancet Oncology noted that just having circulating tumor cells doesn’t mean they will form metastases.4 Research at MD Anderson is also exploring that issue. “We are trying to determine which cells have the potential to grow into new tumors and which ones are likely to die and not form new metastases,” Dr. Lucci said. ■

Disclosure: Dr. Lucci reported no potential conflicts of interest.


1. Lucci A, Hall CS, Lodhi AK, et al: Circulating tumour cells in non-metastatic breast cancer: A prospective study. Lancet Oncol. June 6, 2012 (early release online).

2. Rack BK, Schindlebeck C, Andergassen U, et al: Prognostic relevance of circulating tumor cells in the peripheral blood of primary breast cancer patients. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S6-5. Presented December 11, 2010.

3. Krishnamurthy S, Bischoff FZ, Mayer JA, et al: Detection of discordant HER2 status by FISH in circulating tumor cells and disseminated tumor cells in early-stage breast cancer using a microfluidic-based cell enrichment and extraction platform (OncoCEE). 2012 ASCO Annual Meeting. Abstract TPS10631. Presented June 4, 2012.

4. Krell J, Stebbing J: Circulating tumour cells as biomarkers in early breast cancer. Lancet Oncol. June 6, 2012 (early release online).

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