Device Can Read Genetic Signature Of Circulating Tumour Cells To Guide Therapy

Main Category: Cancer / Oncology
Also Included In: Medical Devices
Article Date: 15 Jul 2008 - 0:00 PDT

email to a friend   printer friendly   view / write opinions   rate article

A microchip-based device that detects and analyses tumour cells in the bloodstream proved effective in determining the genetic signature of lung tumours, allowing identification of patients appropriate for targeted treatment in a pilot study in patients with non-small-cell lung cancer (NSCLC).

Researchers at Massachusetts General Hospital used the device, which detects circulating tumour cells (CTCs) - living cells from solid tumours, such as lung cancers, found at extremely low levels in the bloodstream - to analyse blood samples from 27 patients with metastatic NSCLC. They were looking for mutations in a protein, epidermal growth factor receptor (EGFR), which affect the response of lung tumour cells to tyrosine kinase inhibitors (TKIs).

These drugs are effective in NSCLC, but their efficacy is greatly reduced in patients with mutations in the EGFR gene. The research group hoped that molecular characterisation of circulating tumour cells would provide a strategy for noninvasive monitoring of tumour genotypes during treatment, to determine whether patients would still response to treatment with a TKI.

Results showed that the CTC-chip was able to isolate circulating tumour cells from all 27 patients in the study, but not from healthy control subjects. It identified EGFR activating mutations in 92% of patients, and a mutation that commonly confers drug resistance (T790M) in 55% of patients.

When T790M was detected in tumour biopsy specimens before treatment, the presence of the mutation correlated with reduced progression-free survival (an average of 7.7 months, compared to 16.5 months in patients without the mutation, p<0.001).

Serial analysis of circulating tumour cells with the CTC-chip showed that a reduction in the number of captured cells was associated with a radiographic response in the patient's tumour. In contrast, an increase in the number of cells was associated with tumour progression, with the emergence of additional EGFR mutations in some cases.

Blood samples taken at regular intervals during treatment in four patients with mutation-positive tumours showed that levels of circulating tumour cells dropped sharply after TKI treatment began and began increasing when tumours resumed growing. In one patient, adding further chemotherapy caused CTC levels to drop again as the tumour continued to shrink.

"The CTC-chip opens up a whole new field of studying tumours in real time," suggested Daniel Haber, director of the Massachusetts General Hospital Cancer Center and lead author of the study. "When the device is ready for larger clinical trials, it should give us new options for measuring treatment response, defining prognostic and predictive measures, and studying the biology of blood-borne metastasis, the primary method by which cancer spreads and becomes lethal."

"Patients found to have resistance mutations before treatment probably won't benefit as much or as long from single-agent TKI therapy as those without baseline mutations, said Lecia Sequist, also from MGH Cancer Center, and a co-author of the study. "For those patients we may need to consider other modes of therapy, including combinations of targeted agents or second-generation TKIs that can overcome the most common resistance mutation."

"The ability to detect genetic markers that guide treatment is obviously essential in identifying the appropriate therapy. Equally important, however, is the need to monitor tumour cells to determine whether the therapy is 'hitting the target'," said Joan Schiller, from the University of Texas Southwestern Medical Center, Dallas, USA, in an accompanying editorial.

She noted that lung cancer oncologists have previously been frustrated by the difficulty of obtaining tumour samples over time to determine whether molecular targets are being inhibited. "The capture and analysis of circulating tumour cells from patients with lung cancer represents a new diagnostic approach that may bring us closer to an era of individualised medicine," she concluded, cautioning that a lot more research is required to further determine the clinical value of the CTC-chip.

References

Maheswaran, S, Sequist, L, Nagrath, S et al. Detection of mutations in EGFR in circulating lung cancer cells. N Engl J Med 2008, 359. Published at http://www.nejm.org on 2 July 2008; 10.1056/NEMJoa0800668

Schiller, J Noninvasive monitoring of tumors. Published at http://www.nejm.org on 2 July 2008; 10.1056/NEJMe0804521

Cancer Research Summaries are overviews of important cancer research findings that have been reported in leading cancer publications. The Cancer Research Summaries are provided by the Cancer Media Service (CMS) in collaboration with Nature Clinical Practice Oncology.

"This summary is provided by the European School of Oncology's Cancer Media Service."
http://www.cancerworld.org/mediaservice