Roxanne Nelson

October 01, 2010

October 1, 2010 — Circulating tumor cells (CTCs) could prove to be an alternative to biopsies for assessing tumor tissue for biomarker status.

According to new data presented at the 4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development in Denver, Colorado, HER2 status derived from CTCs from breast cancer patients was generally concordant with that derived from tumor tissue.

CTCs present a very intriguing opportunity to look at biomarkers, obviating the need for biopsy, explained first author Siminder Kaur Atwal, PhD, senior research associate at Genentech, during a press briefing.

"CTCs can also provide real-time information about the disease, acting as a liquid biopsy," she said, "and it can be done with a simple blood draw."

This makes it a much less invasive procedure than tumor biopsy; CTCs can easily be obtained as part of routine blood work, Dr. Atwal added. "CTCs can also tell you the current status of the patient's disease, which may be different from archival tissue."

In addition, comparing CTCs collected prior to treatment with those collected during repeated sampling allows biomarkers to be monitored during the course of treatment.

Previous research has looked at using CTCs for diagnosis, prognostic indicators, and predicting response to therapy. As reported previously by Medscape Medical News, CTCs have been discovered in men with early-stage prostate cancer. One study, also reported by Medscape Medical News, demonstrated that the detection of CTCs after treatment might indicate that the patient is more likely to develop metastases, and so might warrant repeat and aggressive chemotherapy.

There has also been great interest in developing tools to effectively capture CTCs, as Medscape Medical News has previously reported.

Platform Efficiency Similar, Dependent on EpCAM Level

For their study, Dr. Atwal and colleagues compared CTC capture platforms — the CellSearch platform, which has been approved by the US Food and Drug Administration as a prognostic assay, and 2 CTC biochip platforms. Their goals were to compare the platforms for CTC detection, to evaluate whether biomarkers can be detected in CTCs, and to compare biomarker status in CTCs and matched tumor tissue.

Using tumor cell lines spiked into whole blood, the authors compared HER2 status in CTCs with that in archival tumors, because "HER2 testing is the gold standard in biomarker validation and is typically evaluated in tumor tissue by [immunohistochemistry] and/or [fluorescence in situ hybridization]," the authors write

In addition, they attempted to detect epidermal growth-factor receptor (EGFR) protein expression in CTCs from patients with lung cancer.

They found that CellSearch and the newer biochip platforms offered similar efficiency. The authors also noted that capture efficiency was dependent on the level of epithelial cell adhesion molecules (EpCAM), which are present in tumor cells but absent in white blood cells.

Amenable to Biomarker Analysis

Dr. Atwal and her colleagues were able to demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, quantitative reverse-transcription PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence. HER2 status in CTCs was generally concordant with that from patient tumor tissue (89%), although in one subset of patients (11%), HER2 status had changed from the primary tumor at diagnosis.

Unexpectedly, the authors found that CTC counts were higher in estrogen-receptor-positive patients than in HER2-positive and triple-negative patients, despite the more aggressive phenotype.

An explanation for this might be the low EpCAM expression of basal-like molecular subtypes of breast cancer, and a more mesenchymal phenotype, they write. "CTCs will likely not be efficiently captured using EpCAM alone in tumors that arise from this subtype."

The results also showed that the cell-surface expression of EGFR can be quantitated in CTCs from metastatic lung cancer patients.

"These results are encouraging because they support the use of CTCs for HER2 testing, and we hope to establish a role for CTC testing," said Dr. Atwal. "But a limitation of these platforms is that CTC capture efficiency is dependent on EpCAM expression, which we know can vary in different tumor types."

Some improvements are necessary in CTC detection and capture before the technology can be generally useful in clinical biomarker analysis, she noted. An example would be an antibody cocktail with mesenchymal markers, along with EpCAM, which could be used to improve the capture of CTCs.

"There is a major need for a noninvasive approach to characterize patient tumors and to assess response to therapy. In exciting preliminary studies, Dr. Atwal and colleagues have implemented rigorous approaches that demonstrate that CTCs can offer a real-time view of changes in the tumor," Gordon B. Mills, MD, PhD, chair of the Department of Systems Biology at the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News.

"If validated in future studies, this could provide exciting and important approaches to implement personalized therapy," he added.

4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development (AACR-MDCTD): Abstract PR3. Presented September 28, 2010.

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