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Circulating tumor cells can reveal genetic signature of dangerous lung cancers
By Dross at 2008-07-03 07:04
Circulating tumor cells can reveal genetic signature of dangerous lung cancers

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 metastasistermterm, 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 EGFRtermtermterm 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 chemotherapyterm 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.

 

Look for it in our journal section 



4 comments | 2734 reads

by gdpawel on Fri, 2008-07-04 15:41
The interest in and the knowledge of gene expression profiling in cancer medicine has heighten since the completion of the human genome project (the world's most expensive telephone book*). However, researchers have cautioned the science of gene expression profiling, in which scientists examine the genetic signature of a cell.

The gene chip is a device that measures differences in gene sequence, gene expression or protein expression in biological samples. It may be used to compare gene or protein expression under different conditions, such as cells found in cancer.

Hence the headlong rush to develop tests to identify molecular predisposing mechansims whose presence still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The challenge is to identify which patients the targeted treatment will be most effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone.

What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cell being killed regardless of the mechanism?

The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell. Both genomics and proeomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints.

Sources:
Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
BMJ 2007;334(suppl 1):s18 (6 January), doi:10.1136/bmj.39034.719942.94

* The sequencing of the entire human genome gave us the address and the next door neighbors of every human gene, yet we don't know what they do, how they do it, why they do it, or who they do it with. - Dr. Robert A. Nagourney

by gdpawel on Sat, 2011-01-22 23:05
Emile E. E. Voest
Department of Medical Oncology
UMC Utrecht, the Netherlands

Background:

In the era of targeted therapy a multitude of new agents to treat cancer is developed. Unfortunately only 5% of these agents will ultimately be approved for clinical use. One of the reasons for this high failure rate is our inability to select patients for the appropriate therapy. The potential recurrence rate of an individual tumor is relatively well defined by prognostic factors, however, our tools to predict response to therapy are very limited. Developing predictive markers to assess which patients will benefit from treatment are therefore highly needed. This educational session will be devoted to circulating biomarkers. In this presentation I will focus on circulating cells as potential markers for treatment response. Several circulating cell types currently under investigation: circulating tumor cells; circulating (endothelial) progenitor cells (C(E)PC); and circulating endothelial cells (CTC), the value of measuring these cells will be discussed in detail below.

Discussion:

Circulating Tumor Cells

Of all surrogate tumor tissues, CTCs have probably received the greatest attention the last years (1–8). It is becoming increasingly clear that the number, and change in number, of CTCs is prognostic for several types of cancer, including breast, colorectal- and prostate cancer (4–7) In the NIH clinical trials database, currently 298 trials are listed that measure CTC and correlate these measurements with treatment outcome. Few of these trials prospectively uses CTC to make treatment decisions. Now that CTC detection techniques have significantly improved and proper logistics for CTCs have become implemented in trials, a feasible, new goal is to characterize CTCs and to study specific molecular targets on CTCs (8). However, several limitations should be taken into consideration. A substantial percentage of patients have no detectable CTCs. Furthermore, CTCs may serve as surrogate tissue but may not be representative for real tumor tissue. CTCs may represent a subset of tumor cells. Next to this, EpCAM-based CTC detection may cause a bias for cells that have a low or no EpCAM expression.

CTCs have a clear potential as pharmacodynamic biomarker in early oncology trials. Potential applications of measuring actual target modulation are, for example, to provide proof of mechanism of action of the drug and to study the biologically active dose range. With the availability of pharmacodynamic assays for growth hormone receptors on CTCs, opportunities arise in monitoring of activating- or resistance-conferring mutations and measuring change in activity of down-stream signaling molecules intracellularly that can indicate the level of inhibitory activity of the drug. The development of new techniques that improve CTC detection sensitivity allows for increasing sensitivity in subsequent characterization. These advanced techniques may enable further specified CTC analysis which could lead to a more personalized therapy for the patient in the future. In summary, there are many interesting and encouraging developments in the field of CTC detection and their characterization that may lead to further development and incorporation of CTCs as pharmacodynamic biomarker in early clinical trials of targeted anti-cancer therapy.

Circulating Endothelial (Progenitor) Cells

In addition to CTC, circulating normal cells may also predict tumor progression or host responses to treatment. The best studied cells are circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC). The relevance of EPCs in cancer growth suggests that EPCs might be used as a surrogate marker for angiogenic activity (9–12). Both circulating mature endothelial cells (CECs) and endothelial progenitor cells (EPCs) are increased in the blood of cancer patients and correlate with angiogenesis and tumor volume. Therefore these cells might serve as a biomarker to determine prognosis, response to therapy and the optimal biological dose (OBD) of anti-angiogenic agents.

CEC levels correlate with progressive disease, as patients with growing tumors have higher CEC levels compared to patients with stable disease. Conversely, CEC levels return to normal after successful treatment. This suggests that CECs correlate with the presence and the activity of a tumor and indicates that CECs hold the potential to measure changes in disease activity and therefore response to therapy. Clinically this has been investigated in patients with metastatic breast cancer treated with low dose metronomic chemotherapy. In these patients the CEC count after 2 months of continuous therapy could predict both disease-free and overall-survival after a prolonged follow-up of more than 2 years. Others showed that high baseline levels of CECs predicted response to metronomic chemotherapy combined with bevacizumab. We showed that CEC and EPC were increased in the blood of cancer patients after treatment with various chemotherapeutic regimens. The increase in CEC and EPC is seemingly unrelated to the presence of a tumour since adjuvant chemotherapy showed similar kinetics. This suggests that EPC and CEC release after chemotherapy is part of a reactive host response independent of tumor type and chemotherapy regimen. This response may very well be an important factor in determining the outcome of patients, as EPC and CEC have been found to stimulate tumour growth, metastasis formation and limit chemotherapeutic efficacy by prevention of necrosis. The magnitude of the increase of CEC and EPC after chemotherapy was associated not only with response to chemotherapy after 3 cycles but also with PFS and OS. This correlation between CEC/EPC and prognosis of patients is supported by other studies (13, 14). There are several limitations to take into account. EPC and CEC detection techniques are labor intensive, time consuming, often require fresh samples and the number of circulating cells are commonly very low.

In summary, circulating EPC and CEC are biologically interesting but presently the detection techniques and inter- and intrapatient variability prohibit wide spread use of these cells in routine clinical care.

Future Directions: Can We Use Circulating Cells in Clinical Decision Making?

The above described studies have greatly contributed to our understanding of the biology of cancer. Measurement of these cells has clearly prognostic value. It furthermore indicates avenues to further refine specific assays to use circulating cells as biomarkers. However, the data are presently insufficient to consider circulating cells to predict outcome of treatment in such a manner that anti-cancer treatment can be started or even more important stopped. Given the response rates of current anti-cancer treatment and the willingness of patients to undergo treatment even for relatively low success percentages imposes high sensitivity and specificity requirements on potential predictive tests. Presently, none of these circulating cell assays fulfil these requirements but the enormous potential of these circulating cells as pharmacodynamic markers deserves prospective clinical trials to further assess their value.

References:

1. Stebbing J, Jiao LR. Circulating tumour cells as more than prognostic markers. Lancet Oncol 2009; 10: 1138–9.

2. Mostert B, Sleijfer S, Foekens JA, Gratama JW. Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat Rev 2009; 35: 463–74.

3. Dotan E, Cohen SJ, Alpaugh KR, Meropol NJ. Circulating tumor cells: evolving evidence and future challenges. Oncologist 2009; 14: 1070–82.

4. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781–91.

5. Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006; 12: 4218–24.

6. Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 3213–21.

7. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14: 6302–9.

8. Lianidou ES, Mavroudis D, Sotiropoulou G, Agelaki S, Pantel K. What's new on circulating tumor cells? A meeting report. Breast Cancer Res 2010; 12: 307.

9. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008; 319: 195.

10. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005; 438: 820.

11. Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006; 313: 1785.

12. Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008; 14: 263.

13. Roodhart JM, Langenberg MH, Vermaat JS, et al. Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients. Neoplasia 2010; 12: 87–94.

14. Roodhart JM, Langenberg MH, Daenen LG, Voest EE. Translating preclincal findings of (endothelial) progenitor cell mobilization into the clinic; from bedside to bench and back. BBA–Reviews on Cancer, 2009; 1796: 41–9.

[url]http://educationbook.aacrjournals.org/cgi/content/full/2011/1/23

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