Featured Developments
Device promises improvements in targeted therapy, treatment monitoring
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, PhD, 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.”
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Captured Circulating Tumor Cell |
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Laboratory Setup |
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CTC-chip
80,000 microposts are arranged on a 970-square-millimeter surface. (a size of a business card). |
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.
Additional lead authors of the NEJM paper are Shyamala Maheswaran, PhD, MGH Cancer Center; and Sunitha Nagrath, PhD, MGH BioMEMS Resource Center. Co-authors are Lindsey Ulkus, Brian Brannigan, Elizabeth Inserra, Sven Diederichs PhD, Daphne Bell, PhD, Subba Digumarthy, MD, Alona Muzikansky, MS, Jeffrey Settleman, PhD, and Thomas J. Lynch MD, MGH Cancer Center; Chey Collura, MS, Daniel Irimia, PhD, and Mehmet Toner, PhD, BioMEMS Resource Center; John Iafrate, MD, PhD, MGH Pathology; and Ronald G. Tompkins MD, ScD, MGH Surgery. The study was supported by grants from the National Institutes of Health; the Doris Duke, Ellison and Monell Foundations; the National Foundation for Cancer Research, and the Howard Hughes Medical Institute.
Read First Published Article, Nature. Dec. 20, 2007
Determining Genetic Signature Of Lung Tumors Can Help Guide Treatment
The first U.S. clinical trial using genetic screening to identify lung tumors likely to respond to targeted therapies supports the use of those drugs as first-line treatment rather than after standard chemotherapy has failed. While the study led by Massachusetts General Hospital (MGH) Cancer Center investigators found that upfront gefitinib (Iressa®) treatment considerably improved the outcomes for non-small-cell-lung-cancer (NSCLC), additional research is required before such a strategy can be used for routine treatment planning. The report appears in the May 20 Journal of Clinical Oncology.
“This is a pivotal clinical trial that demonstrates the power of personalized medicine in lung cancer treatment,” says Lecia Sequist, MD, MPH, of the MGH Cancer Center, who led the study. “It is an exciting glimpse into what we hope is the future of cancer care. Instead of a ‘one size fits all’ therapy, we are moving towards finding the best treatment for each patient.”
The most common form of lung cancer, NSCLC is the leading cause of cancer deaths in the U.S. Until recently, there were no treatment options for NSCLC patients in whom chemotherapy failed. Iressa, which disables the epidermal growth factor receptor (EGFR) on the surface of lung cancer cells, was approved in 2003 for treatment of NSCLC even though it shrank tumors in less than 15 percent of patients because, in those whom it did help, responses were rapid and dramatic.
In 2004 MGH Cancer Center researchers and a team from Dana-Farber Cancer Institute both discovered why Iressa’s success was confined to a limited group of patients. Specific EGFR mutations that were probably responsible for a tumor’s development also made the cancer sensitive to Iressa treatment. Subsequent to that announcement, the Laboratory for Molecular Medicine at the Harvard-Partners Center for Genetics and Genomics developed a test to screen for these sensitizing mutations.
Late in 2004 a collaborative group led by MGH investigators began the current study, designed to see whether using Iressa® as an initial treatment for patients with a sensitizing EGFR mutation would improve treatment results. Out of 98 NSCLC patients screened at 11 centers - including the MGH Cancer Center and DFCI - over a two-year period, 34 had a sensitizing mutation. Of those, 31 entered the trial and began receiving daily oral doses of Iressa® instead of standard chemotherapy. Iressa treatment continued indefinitely unless significant side effects occurred or tumor growth continued or resumed.
All but two of the participants responded positively to Iressa treatment, with their tumors either shrinking significantly or not growing for a month or longer. At the end of the study period, 14 patients had died but 17 remained alive. The overall survival rate and the length of time until participants’ tumors resumed growing were two or three times greater than would be expected with standard chemotherapy, Sequist explains. Only one participant dropped out because of treatment side effects.
The current study also analyzed the specific EGFR mutations in participants’ tumors to see if there were differences in the response to treatment. Patients with the two most typical mutations had vigorous responses to Iressa®, but the seven patients found to have atypical mutations had a more limited response. None of the atypical cases had tumor shrinkage, but the majority had disease stabilization for a period of time. Two patients who experienced rapid regrowth of their cancers were found to have additional EGFR mutations that previous research had indicated conferred resistance to the drug. It has been theorized that those resistance mutations develop in response to treatment, but this is the first observation of the mutations’ being present before treatment began.
“It’s starting to look like the strategy of genomically-directed cancer therapy will need to incorporate testing for multiple genotypes - screening for three, four or even more genetic markers, some of which may indicate likelihood of response to treatment, and others the chance of resistance,” says Sequist. “We think these results will also apply to other effective EGFR inhibitors, and we hope they can be duplicated for other types of cancer that involve these mutations. But what is needed next is a larger-scale, randomized clinical trial comparing an EGFR blocker with standard therapy in a genotype-selected population.” Sequist is an instructor in Medicine at Harvard Medical School.
Although Iressa® is currently not being marketed in the U.S., the trial reported in this article was supported by AstraZeneca, the drug’s manufacturer. Several other EGFR inhibitors, including Tarceva® (erlotinib), are either on the market or in clinical trials.
Thomas J. Lynch, MD, chief of MGH Hematology and Oncology and director of the Center for Thoracic Cancers, is the senior author of the Journal of Clinical Oncology report. Other co-authors are Victoria Joshi, PhD, Alona Muzikansky, Georgiana Kuhlmann, Moon Han, Jeffrey Settleman, PhD, John Iafrate, MD, PhD, Jeffrey Engelman, MD, and Daniel Haber, MD, PhD, MGH Cancer Center; Pasi Janne, MD, PhD, and Bruce Johnson, MD, Dana-Farber Cancer Institute; Renato Martins, MD, MPH, University of Washington; David Spigel, MD, Sarah Cannon Research Institute, Nashville; Steven Grunberg, MD, University of Vermont School of Medicine; Alexander Spira, MD, Fairfax-Northern Virginia Hematology-Oncology; David McCollum, MD, Texas Oncology/Sammons Cancer Center, Dallas; Tracey Evans, MD, University of Pennsylvania; and Jonathan Goldberg, MD, Mt. Kisco (N.Y.) Medical Group.