Circulating tumor cells can reveal genetic signature of dangerous lung cancers

Jul 03, 2008

Massachusetts General Hospital (MGH) investigators have shown that an MGH-developed, microchip-based device that detects and analyzes tumor cells in the bloodstream can be used to determine the genetic signature of lung tumors, allowing identification of those appropriate for targeted treatment and monitoring genetic changes that occur during therapy. A pilot study of the device called the CTC-chip will appear in the July 24 New England Journal of Medicine and is receiving early online release.

"The CTC-chip opens up a whole new field of studying tumors in real time," says Daniel Haber, MD, director of the MGH Cancer Center and the study's senior author. "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, which is the primary method by which cancer spreads and becomes lethal."

CTCs or circulating tumor cells are living solid-tumor cells found at extremely low levels in the bloodstream. Until the development of the CTC-chip by researchers from the MGH Cancer Center and BioMEMS (BioMicroElectroMechanical Systems) Resource Center, it was not possible to get information from CTCs that would be useful for clinical decision-making. The current study was designed to find whether the device could go beyond detecting CTCs to helping analyze the genetic mutations that can make a tumor sensitive to treatment with targeted therapy drugs.

The researchers tested blood samples from patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the U.S. In 2004, MGH researchers and a team from Dana-Farber Cancer Institute both discovered that mutations in a protein called EGFR determine whether NSCLC tumors respond to a group of drugs called TKIs, which includes Iressa and Tarceva. Although the response of sensitive tumors to those drugs can be swift and dramatic, eventually many tumors become resistant to the drugs and resume growing.

The CTC-chip was used to analyze blood samples from 27 patients – 23 who had EGFR mutations and 4 who did not – and CTCs were identified in samples from all patients. Genetic analysis of CTCs from mutation-positive tumors detected those mutations 92 percent of the time. In addition to the primary mutation that leads to initial tumor development and TKI sensitivity, the CTC-chip also detected a secondary mutation associated with treatment resistance in some participants, including those whose tumors originally responded to treatment but later resumed growing.

"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 such baseline mutations," says Lecia Sequist, MD, MPH, of the MGH Cancer Center, a co-lead author of the NEJM paper. "For those patients we may need to consider other modes of therapy, including combinations+ of targeting agents or second-generation TKIs that can overcome the most common resistance mutation."

Blood samples were taken at regular intervals during the course of treatment from four patients with mutation-positive tumors. In all of those patients, levels of CTCs dropped sharply after TKI treatment began and began rising when tumors resumed growing. In one patient, adding additional chemotherapy caused CTC levels to drop again as the tumor continued shrinking.

Throughout the course of therapy, the tumors' genetic makeup continued to evolve. Not only did the most common resistance mutation emerge in tumors where it was not initially present, but new activating mutations – the type that causes a tumor to develop in the first place – appeared in seven patients' tumors, indicating that these cancers are more genetically complex than expected and that continuing to monitor tumor genotype throughout the course of treatment may be crucial.

"If tumor genotypes don't remain static during therapy, it's essential to know exactly what you're treating at the time you are treating it," says Haber. "Biopsy samples taken at the time of diagnosis can never tell us about changes emerging during therapy or genotypic differences that may occur in different sites of the original tumor, but the CTC-chip offers the promise of noninvasive continuous monitoring." Haber is the Kurt J. Isselbacher/Peter D. Schwartz Professor of Medicine at Harvard Medical School.

Source: Massachusetts General Hospital

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gdpawel
not rated yet Jul 07, 2008
Monitoring of circulating tumor cells (CTC's) can contribute to the understanding of tumor-blood interactions and may provide a valuable tool for therapy monitoring in solid tumors. With cells being alive in circulation, it may mean that a patient would need different or additional treatment.

These ciculating tumor cells can detach from solid tumors and enter the blood stream, thus beginning the process of metastasis, the most life-threatening aspect of cancer. To metastasize, or spread cancer to other sites in the body, circulating tumor cells travel through the blood and can take root in another tissue or organ.

This technology gives the patient and oncology community a great method to monitor treatment. It can be very complimentary to an array of tools that oncologists should be using to counsel their patients. The only problem is that the patient may be receiving potentially toxic and ineffective drugs before circulating tumor cells are measured.

The outcome for metabolic responders and non-responders with CTC monitoring is basically what is going on with a functional profiling assay, showing what patients are benefiting from what drug agents, before introducing them into the patient. Monitoring CTCs could be utilized for confirmation after patient is administered assay-directed most beneficial therapeutic agents.

Anti-cancer treatments often effectively shrink the size of tumors, but some might have an opposite effect, actually expanding the small population of cancer stem cells believed to drive the disease. Some treatments could be producing more cancer stem cells which are then capable of metastasizing, because these cells are trying to find a way to survive the therapy.

The tumor escapes from chemotherapy by induction of stem cell marker expression. The small number of cells that survive the treatment could then generate another tumor that metastasizes.

This may help explain why the expression of stem cell markers has been associated with resistance to chemotherapy and radiation treatments and poor outcome for patients with solid cancers. That tells us that understanding how to target these markers and these cells could prove useful in treating these cancers.

Analysis of stem cell expression before and after treatment reveals that even as some anti-cancer treatments shrank tumors, they increased expression of stem cell markers (which contibute to stem cells' defining ability to renew themselves and differentiate into different cell types). Some treatments are not enough to completely inhibit tumor growth, and the cancer stem cell markers are still present.

Oncologists need to adapt treatment to the patient. There are hundreds of chemotherapeutic agents, all of which have approximately the same probability of working. The tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing individual properties of each patient's cancer.