FISH FOR ABNORMAL CIRCULATING CELLS IN NSCLC PATIENTS

July 28, 2010 — A simple blood test in development may identify patients with non-small cell lung cancer (NSCLC) who are at high risk for metastasis, say authors of a pilot study reported online July 22 in Clinical Cancer Research.

Welcoming the news, several lung cancer experts said that it would be very useful to have a noninvasive test to monitor disease, but cautioned that this test is not ready yet for clinical use.

The test uses fluorescent in situ hybridization, or FISH, to spotlight abnormal circulating cells in chromosomal sites known to harbor genetic abnormalities in patients with NSCLC.

Looking at blood samples from 59 patients with stages I to IV NSCLC and 24 high-risk control patients (participants in a lung cancer screening program), the test identified significantly higher numbers of cytogenetically abnormal cells (CACs) in patients with cancer vs control patients, with the numbers rising in proportion with disease stage, write Ruth L. Katz, MD, professor of pathology at the University of Texas M D. Anderson Cancer Center, in Houston, and colleagues.

"We showed that the numbers of CACs were much higher in patients with advanced lung cancer, such as stage IV with cancer spread throughout the body, compared to patients with stage IA, small cancers confined to the lung," said Dr. Katz in a media briefing.

When the team looked at 12 DNA biomarker abnormalities in peripheral blood and tumor tissue from 21 patients who underwent surgical resection of their lung tumors, "we showed that there was generally an excellent correlation between most of the biomarkers in the CACs in the blood and in the tumor cells. We also showed that the CACs in general had few genetic abnormalities compared to most tumor cells. However, there was always a cell population in the tumor that matched the genetic abnormalities seen in the circulating CACs," she added.

Noninvasive Test Would Be Useful

At the same media briefing, organized by the American Association for Cancer Research, several lung cancer experts who were not involved in the study commented on the findings.

This test appears to be more accurate than current methods for isolating circulating tumor cells using antibody capture of circulating epithelial cells, said Fred R. Hirsch, MD, PhD, professor of medicine and pathology at the University of Colorado Cancer Center in Aurora. If it is validated in larger studies, it could help with early detection of primary disease and relapse, and also with treatment monitoring, he added.

"In terms of early diagnosis of lung cancer, and also monitoring recurrence and monitoring effect of therapy, we use most often invasive procedures, which might be more traumatic for the patient. If it is possible to use circulating blood cells, it would be much easier to get access to it, and much more comfortable for the patient, and I think those are 2 important factors here," Dr. Hirsch commented at the briefing.

Not Ready for Prime Time

"The ability to use a blood sample as a means by which to follow patients getting therapy for whatever malignancies is incredibly important and has a huge potential advantage for our patients," commented Minetta Liu, MD, director of the Translational Breast Cancer Research Program at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, DC.

Dr. Liu cautioned, however, that the study only involved 59 patients, and that a great deal more work needs to be done before the test is ready for the clinic.

"Although there is a lot excitement about the work that was presented here by Dr. Katz, we're not sure that this should be used in any way, shape, or form yet in terms of guiding what we should be doing with our patients," she said, a remark echoed by Roy Herbst, MD, PhD, chief of the section of thoracic medical oncology at the University of Texas M.D. Anderson Cancer Center, and a senior editor of Clinical Cancer Research.

Are They Circulating Tumor Cells?

Dr. Katz and colleagues are reluctant at this stage to state unequivocally that the CACs they identified are circulating tumor cells, but the evidence points in that direction based on several factors, they say.

For one, 8 of the DNA biomarkers in the peripheral blood mononuclear cells tested correlated with those in resected lung tumors. In addition, for each of the 12 biomarkers tested, mean percentages of genetically altered cells correlated with the stage of NSCLC, with the highest levels occurring in samples from patients with stage III or IV disease; control patients had significantly fewer abnormal cells than the patients with cancer.

The investigators plan to develop the antigen-independent test for clinical use.

"We are trying to work out exactly which panel of biomarkers we should be using," Dr. Katz said. "In this particular paper we used 12 biomarkers, but it was really redundant, because all of the biomarkers showed very similar things, so we want to use biomarkers that are very easy to quantitate."

If it proves its mettle in further studies, the test could be rolled out across the United States, because it uses a platform currently employed in laboratories for examining cytogenetic abnormalities in urine, Dr. Katz added.

The study was supported by the National Cancer Institute and by AstraZeneca. Dr. Katz has disclosed receiving a commercial research grant from AstraZeneca and has a patent pending.

Clin Cancer Res. Published online July 22, 2010.