BBI Contributing Editor

NEW ORLEANS, Louisiana – The 40th annual meeting of the American Society of Clinical Oncology (ASCO, Alexandria, Virginia), held here in early June, provided a venue for the unveiling of a number of advances in cancer management, many of which are expected to create important market opportunities. In spite of concrete progress in reducing the number of cancer-related deaths in the U.S. over the past few years, cancer remains the second leading cause of death, and the number of new cases, as well as the number of individuals living with cancer, is continuing to expand. The American Cancer Society (Atlanta, Georgia) estimates that 1,368,000 new cancer cases will be diagnosed in 2004, and the National Cancer Institute (Bethesda, Maryland) estimates that there are now 9.6 million cancer survivors in the U.S., driving a growing demand for products and services employed in the diagnosis, treatment, and on-going management of cancer patients.

Targeted therapy was a dominant theme at many of the sessions at the ASCO meeting, with significant scientific advances and notable, if incremental, advances in patient survival announced with the use of targeted drug treatments for brain cancer, lung cancer and kidney cancer. Improved technology for targeting of radiation therapy was also described that will make that modality more effective while reducing side effects. A key aspect of the use of targeted drug therapies is the concomitant need for new diagnostic tests to select those patients who carry the molecular target. A number of new diagnostic devices were described at the conference that will play an important role in enabling targeted treatment to be implemented in the clinic, and others that will also improve the ability to detect cancer at an early stage and to identify recurrences when they are most treatable. Important new developments in the detection of circulating tumor cells were announced, including the introduction of a new FDA-cleared system, that promise to allow early detection of metastatic cancer, possibly enabling more effective treatment and improving survival, since metastasis is usually the cause of death from cancer.

Research programs aimed at improving methods for cancer screening and early initial diagnosis also were described at the ASCO conference. Early detection remains the most effective approach for improving patient survival in cancer, since disease detected at an early stage can often be eradicated completely. Noninvasive imaging methods such as magnetic resonance imaging (MRI), including new types of MR contrast agents, as well as advanced mammography techniques, are attracting increased attention as tools to aid in improving the ability to detect cancer early, and to reduce the invasiveness of diagnostic approaches employed for cancer detection. In the future, emerging technologies in the area of next-generation cancer markers could help to further improve early detection for many types of cancer and perhaps provide early detection for some cancer types that now are typically not diagnosed until they have progressed beyond the point at which effective treatment is possible.

Targeted therapies dominate strategies

As discussed by Gordon Mills, MD, PhD, of MD Anderson Cancer Center (Houston, Texas), at a press conference on signal transduction therapy, a number of pharmaceutical companies involved in developing new anti-cancer drugs have now adopted a strategy that requires identification of a molecular target for a new drug before they will commit to initiating a development program. Such a strategy represents acceptance by pharmaceutical companies that targeted drugs, while definitely more effective than broad-spectrum agents for patients who carry the target, nevertheless address a much more limited patient population. Recent experience has shown that only 10% to 30% of patients with a particular type of cancer express any single marker. While that factor limits the potential market for a targeted drug, it also greatly improves upon the chances that a new drug will succeed in clinical trials. Furthermore, the FDA is now suggesting, according to Mills, that it will look unfavorably on clinical trials that do not employ a marker to identify those patients who will respond. An essential element of a targeted drug strategy is to develop or gain access to high-quality molecular diagnostic tests to identify those patients with the marker. The move toward targeted therapy in cancer has consequently created an opportunity for the development of new diagnostic tests.

Table 1 below describes a number of new tests that have been introduced or are under development for applications in guiding cancer therapy. The EGFR pharmDx assay from DakoCytomation (Fort Collins, Colorado) was recently approved for assessment of eligibility for Erbitux therapy in colorectal cancer and represents only the second test to be approved by the FDA for use in conjunction with a specific drug, the first being the DakoCytomation HercepTest for selection of breast cancer patients for treatment with Herceptin from Genentech (South San Francisco, California). DakoCytomation also is developing the C-Kit pharmDx test for the kit receptor targeted by the drug Gleevec from Novartis Pharmaceuticals (Basel, Switzerland); a new fluorescence in situ hybridization (FISH) HER2 pharmDx test that will complete with the Pathvysion test from Abbott/Vysis (Downer's Grove, Illinois); and pharmDx tests for the TOP2A and ER/PR markers used for prognosis and therapy selection in breast cancer. DakoCytomation's EGFR and HercepTest have the advantage of offering users an FDA-approved method, facilitating reimbursement. Two other new tests that have attracted the attention of oncologists are the Oncotype DX assay from Genomic Health (Redwood City, California) and the MammoPrint test from Agendia (Amsterdam, the Netherlands). Those tests are representative of a new genre of cancer tests that analyze the expression of panels of genes and correlate expression patterns with risk of recurrence or poor outcome.

The Genomic Health test employs RT-PCR analysis and has been developed based on an analysis of thousands of genes to initially identify 384 that showed a relatively high degree of correlation with outcome. Subsequently, the number of genes was reduced to 21, making it feasible to use RT-PCR for expression analysis rather than a microarray format. The test is recommended for estrogen receptor (ER)-positive, node-negative breast cancer patients. A risk of recurrence score is computed that has been shown to have a high degree of correlation with the rate of distant recurrence at 10 years in a validation study involving 668 patient samples. The genes comprising the panel include proliferation genes such as Ki-67 and Cyclin B1, invasion genes such as Cathespsin L2, HER 2, ER and PGR, and GSTM1, as well as five reference genes used for normalization. The test is available from the company's CLIA-certified reference laboratory and is priced at $3,460.

Genomic Health has established a seven-person sales force to market the test in the U.S., and some small oncology practices as well as a few large centers have ordered the test. Importantly, the test can be performed on paraffin-embedded, formalin-fixed tissue sections, making it applicable not only to the types of specimens used routinely by pathologists, but also allowing validation studies to be performed by analyzing archival samples. Oncologists polled at the conference generally did not indicate that they were yet ready to adopt such a test, since a large-scale randomized controlled trial has not yet been performed, and it is not clear that the information provided by the test would result in any significant change in treatment, while adding significant cost. Nevertheless, the Genomic Health test represents one of the first commercial applications in oncology of multi-gene pharmacogenetic testing.

The MammaPrint assay from Agendia uses a larger panel of 70 genes to assess prognosis in breast cancer, and employs a microarray format rather than RT-PCR. The tissue samples used to identify the genes in the assay have been accumulated over the past 20 years by the Netherlands Cancer Institute. The MammaPrint test requires fresh frozen samples, which are shipped to the Agendia reference lab in the Netherlands using a specially designed carrier. The test is priced at EUR 1,650 plus VAT. The MammaPrint test has been designed for use in patients below the age of 55 with Stage I invasive breast cancer or Stage II node negative invasive breast cancer, and is intended for use as an aid in selecting the best therapy. According to the company, risk assessment using conventional parameters such as tumor size, grade and estrogen/progesterone receptor status is indeterminate in up to 40% of breast cancer patients, creating a need for a tool to improve therapy selection. Three controls are run for each of the 70 genes analyzed in the test. Agendia is now performing a validation study that should be completed by the end of the year.

US Labs, in partnership with Arcturus (Mountain View, California) has developed a new gene expression profiling test for classification of Tumors of Unknown Origin (TUO). The test is performed on formalin-fixed, paraffin-embedded biopsy specimens using a 22,000-gene microarray from Agilent Technologies (Palo Alto, California), or a 44,000-gene microarray from Affymetrix. A microgenome of 2,387 genes is used to perform the analysis. According to US Labs, which is preparing to launch the test as a reference lab procedure, about 10% of all cancer cases, or 80,000 to 90,000 cases in the U.S. annually, are initially diagnosed as TUO, and less than 25% of those are subsequently classified as a known cancer type. TUO is one of the top 10 most common cancer types, and the fourth most common cause of cancer mortality. A validation study performed on blinded tissue sections found that the Arcturus test had 88% accuracy in correctly classifying TUO specimens, representing a major improvement compared to existing technology. The test is labeled for research use only in the U.S. and can only be used to generate results for clinical use if validated and performed by a CLIA-certified clinical lab, such as US Labs. The Arcturus test platform, which is priced at $100,000 to $200,000, has now been placed in more than 750 labs worldwide, mostly for research use, but within the past few months the company has begun to place its system in some clinical labs to perform testing using ASR products developed by the company. Reagents cost between $87 and $171 per sample. An important feature of the Arcturus laser capture microdissection system is its ability to allow the user to select out tumor cells from a biopsy specimen, thereby eliminating normal cells and stroma that can confound the analysis.

Other companies exhibiting various types of gene profiling cancer tests at the ASCO conference, in addition to those listed in Table 1, include Ipsogen (Marseille, France), with the Breast Cancer ProfileChip, MLL FusionChip and other microarray gene expression profiling chips for prognosis/drug selection in breast cancer, acute leukemia and other cancers. The Ipsogen devices are available for research use only in U.S. at present but are available for in vitro diagnostic use in Europe and will eventually be submitted for FDA marketing clearance. The company plans to obtain FDA clearance first for the FusionQuant MLL chip for acute leukemia diagnosis under the Humanitarian Device Exemption classification. The Ipsogen chips are priced at EUR 300 in Europe. MetriGenix (Gaithersburg, Maryland) has developed the MGX 4D Array, a flow-through chip platform that uses advanced microfluidics technology and chemiluminescence detection to achieve rapid microarray analysis.

Research-use microarrays have been developed for known genes involved in various functional pathways in both colon cancer and lung cancer, along with the MGX 1200CL detection station for readout of the microarrays. Spectral Genomics (Houston, Texas) and Targeted Molecular Diagnostics (Westmont, Illinois) are additional companies that offer gene profiling for oncology-related testing. Spectral Genomics markets devices for performing molecular karyotyping that can be used to track changes in chromosomes as cancer progresses. At present, the microarrays are available only for research use, and the company has not announced the development of clinical versions. Targeted Molecular Diagnostics is an oncology-focused reference laboratory specializing in molecular tests for use by pathologists and oncologists in cancer therapy guidance.

Applications of targeted therapy in cancer management are not limited to drug treatment. Advances also were reported at the ASCO meeting in technologies for improved targeting of radiation therapy. Intensity-modulated radiation therapy (IMRT) and image-guided radiotherapy (IGRT) are the key modalities now being used in an expanding range of applications to reduce treatment-related complications while maintaining or improving treatment effectiveness. As discussed by Lori Pierce, MD, of the University of Michigan Medical School (Ann Arbor, Michigan) at the ASCO conference, IMRT is proving useful in improving outcome for breast cancer patients mainly by allowing a reduction in complications, since recurrence rates with conventional radiotherapy are already quite low at 5% to 10%, limiting the ability to achieve significant reductions in recurrence. IMRT also is being used in the treatment of head and neck, prostate, pancreatic, lung, liver, gynecological and central nervous system cancers. IMRT combines a linear accelerator with sophisticated beam control devices to allow precise, 3-D control of radiation dose.

IGRT is a newer enhancement that adds the ability to integrate diagnostic imaging data with the beam control device to compensate for movement of internal organs and tissues within the body during an irradiation procedure, further improving the ability to precisely target radiation dose to a tumor without damaging surrounding tissue. The market for IMRT and external beam radiation therapy equipment has grown substantially over the past few years as clinicians have recognized the benefits of the technology, as indicated by sales trends for the Oncology business unit of Varian Medical Systems (Palo Alto, California), the leading supplier of external beam radiation therapy equipment, including IMRT equipment, with a global market share of almost 50%.

As shown in Table 2, global sales for Varian Oncology increased at a compound annual rate of over 16% over the past five years, and sales in the U.S. increased even more rapidly. According to Varian representatives, about one-third of the 2,100 centers using the company's linear accelerators are now also employing IMRT. Varian exhibited its latest-generation IMRT system, the Trilogy, at the ASCO conference, along with the new On-Board Imager (OBI). The Trilogy received FDA marketing clearance in January, while the OBI was cleared for U.S. marketing in March. The combination of the Trilogy with the OBI allows tracking of internal structures and repositioning of the conformal radiation beam to ensure constant positioning from day to day for fractionated dose radiotherapy, as well as during a procedure to compensate for movement due to respiration.

Later this year, Varian will add 3-D cone beam imaging capability, further enhancing the imaging capabilities of the Trilogy system. Future generations will add fluoroscopic gating, allowing the use of live imaging during therapy, along with pulsed radiation beams. The OBI, which is priced at under $1 million, also can be added to Varian's existing Clinac linear accelerators. The first Trilogy system was installed at the Karolinska Institute in Sweden in late spring, and three U.S. installations were under way as of early last month. GE Healthcare (Chalfont St. Giles, UK) exhibited its Advantage 4D system, which has been designed specifically for use with IMRT equipment. The Advantage 4D acquires image data from the Varian camera, and sorts the data into 10 phases of the respiratory cycle. The software can then determine the optimum point during the cycle at which to treat. The RPM Respiratory Gating System is available from GE Healthcare for $100,000 to $125,000.

Brachytherapy is another approach to targeted radiotherapy that employs radioactive seeds or particles that are implanted into a tumor to deliver a localized radiation dose over an extended period of time. Suppliers of brachytherapy products include Varian, the Theragenics (Norcross, Georgia) unit of GE Healthcare, Nucletron (Veenendaal, the Netherlands), IsoRay (Richland, Washington) and SIRTeX (North Ryde, New South Wales, Australia), among others. IsoRay recently introduced the CS131 radioactive cesium seed for use in brachytherapy procedures, which offers a much shorter (9.7 day) half-life vs. the 60-day half-life of I125, or 17 days for palladium103. The shorter half-life allows delivery of a radiation dose over a shorter time period, which is more effective in reducing cancer cell repopulation rates, providing equivalent therapeutic effect while resulting in delivery of a significantly lower physical radiation dose. The CS131 seeds also provide a more uniform radiation field, providing improved control of the dose. The IsoRay seeds are used mainly in the treatment of prostate cancer at present but are cleared for use in treatment of any confined tumor. Seeds are priced at $44 each, similar to pricing for palladium seeds, but 20% fewer seeds are needed to achieve the same dose, making them cost-effective while also reducing procedural side effects.

The SIR-Spheres from SIRTeX are another type of brachytherapy product that has its main application in the treatment of colorectal cancer metastases to the liver. Such advanced cancers typically have a high mortality rate, with a 4.7-month median survival using standard chemotherapy. Recent clinical studies with SIR-Spheres have demonstrated a 15.6-month survival. SIR-Spheres, which are polymer microspheres containing Yttrium-90, are in use at about 40 sites in the U.S. for treatment of metastatic colorectal cancer, and at an additional 10 to 15 sites in Europe for treatment of both metastatic colorectal cancer and primary liver cancer. The 35-micron particles can be delivered to the target tumor using a hepatic artery catheter, making the treatment a minimally invasive one, further reducing side effects.

Advances in cancer detection, monitoring

A new development in cancer diagnosis and treatment monitoring was described at the ASCO meeting by Veridex (Raritan, New Jersey), a Johnson & Johnson (New Brunswick, New Jersey) company. Veridex, in partnership with Immunicon (Huntingdon Valley, Pennsylvania), introduced the CellSearch System, which employs immunomagnetic selection and fluorescence characterization of rare cells in blood to detect circulating tumor cells. Circulating tumor cells, or CTCs, are indicative of metastasis, and the presence of a threshold level of CTCs in peripheral blood has been shown by Veridex to be correlated with progression free survival and overall survival in patients under treatment for metastatic breast cancer. To perform the CellSearch assay, a 7.5 ml whole blood sample is collected and shipped in the CellSave Preservative Tube developed by Veridex to a central laboratory. Analysis is performed using the CellSearch Circulating Tumor Cell Kit, the CellTracks AutoPrep System for sample prep and the CellSpotter Analyzer, a digital fluorescence imaging system that semi-automates the readout. Circulating epithelial cells in the blood sample are immunomagnetically separated using an antibody to EPCAM, a cell surface marker present on epithelial cells. After separation, the cells are re-suspended, stained with CD45 (to identify leukocytes that would otherwise produce a false positive result), Cytokeratin (to stain CTCs) and DAPI (to stain nuclear material), and injected into the MagNest cartridge. Magnetically labeled cells move to the surface of the cartridge where they can be imaged using the CellSpotter. The entire system provides a significant degree of automation, which helps overcome one of the major barriers to adoption of CTC testing, according to Veridex. Studies have shown that a level of less than five CTCs per sample is associated with low risk of progression, while a level of five or greater is associated with high risk.

As discussed by Howard McLeod, MD, of Washington University School of Medicine (St. Louis, Missouri), assessment of the results of therapy in breast cancer typically requires several months using conventional methods, whereas re-elevation of CTCs was detected with the Veridex system at three- to four-week follow-up. In a study using the CellSearch assay, 30% of patients were found to be in the unfavorable prognosis group at first follow-up. McLeod said he has found the CellSearch assay to be reproducible when performed at multiple different sites, with duplicate results showing a variance of one to two cells. At present, the test has been shown to have utility only for patients under treatment for diagnosed breast cancer, and not in early stage disease or for other cancer types, although studies are underway to assess such applications. The use of additional markers, such as HER2 or indicators of apoptosis, is also being explored to determine if the technology can be expanded for use in prediction of response to initial treatment. At present, the test results can be used by oncologists to decide how aggressive or palliative treatment should be, and McLeod said he believes there are selected patients who will benefit. Test turnaround time is 3.5 hours, and the CellSearch system can perform 16 tests per day. The cost-per-test for consumables will be $175. Although the CellSearch system has received de novo FDA 510(k) clearance, Veridex plans to complete beta site testing and launch the product this fall.

Veridex also is developing a line of genetic tests, under the GeneSearch label, that are intended for use in cancer diagnosis and prognosis, with a focus on breast and colorectal cancer. An initial study using a 23-marker gene expression profile, conducted by Veridex in collaboration with the Washington University School of Medicine, found that relapse in Dukes' B colorectal cancer patients could be predicted in 13 of 18 patients, and in 15 of 18 disease-free patients, for an overall accuracy of 78%. The assay could potentially be used to select patients at high risk of relapse for more aggressive therapy. Another genetic test is under development for the detection of minimal residual disease in the lymph nodes of breast cancer patients that employs PCR technology.

Another new technology for the analysis of circulating tumor cells was exhibited at the meeting by WaveSense (Irvine, California). WaveSense was founded by Robert Coleman, the former president of MediSense (Bedford, Massachusetts), now a unit of Abbott Diagnostics, and Christopher Feistel. Development of the WaveSense technology initially focused on detection of bacteria in blood. The CTC assay, EpiSEP, uses WaveSense's patented Xenographic Retention Chromatography separation platform, which integrates immunoaffinity, nucleoaffinity, magnetic density, and mobile phase chromatography into a single separation process. The EpiSEP test is configured as a magnetic strip, and employs labeling of epithelial cells expressing the EpCAM surface marker, followed by magnetic capture of the cells and immunohistochemical staining and analysis using a standard fluorescence microscope. Non-target cells are removed via an absorptive pad. Total start-up cost for the laboratory is estimated at about $1,000. In initial studies with the EpiSEP test, WaveSense has found a higher number of CTCs per sample and a higher percentage of patients with elevated CTCs as compared to results published for the Veridex system. The EpiSEP test is not yet FDA-cleared but is available for research use. In addition, WaveSense has established OncoQuest, a network of existing reference laboratories, which will provide CTC testing services.

ChromaVision (San Juan Capistrano, California) also has developed an assay system for the analysis of circulating tumor cells. ChromaVision's ACIS automated cell imaging system has been placed in over 300 sites worldwide and includes a number of FDA-cleared cancer-related tests such as HER2, ER and PR. The CTC assay, which is not FDA-cleared but is offered as a reference test by ChromaVision's ACCESS service, employs immunomagnetic enrichment and cell capture using multiple antigens including EpCAM and cytokeratin, along with immunohistochemical stains and image analysis. The test has been assessed for use in the detection of tumor cells in bone marrow. According to Klaus Pantel, MD, of the Institute of Tumor Biology (Hamburg, Germany), who has evaluated the ChromaVision assay, CTCs are detected in bone marrow in 20%-60% of patients at primary diagnosis using a broad-spectrum cytokeratin marker plus EpCAM capture. Cytokeratin-positive patients had a 20% probability of survival vs. 80% for cytokeratin-negative patients at 40 months. Significant differences (8.3% vs. 35% to 40%) also were observed in the detection of CTCs in blood for normals vs. patients with metastatic cancer. Flow cytometry analysis is also available from the ACCESS testing service for enumeration of various endothelial cell populations.

A novel new microarray-based cellular analysis technology that may have important applications in cancer diagnosis and monitoring was described by Daniel Chen of Stanford University (Palo Alto, California). The microarrays can employ antibodies, extracellular matrix components or proteins to capture intact, live cells expressing specific surface markers (e.g., HER2 in breast cancer specimens). The cells can then be analyzed using a variety of methods, including molecular probes as well as effector molecules on the surface of the microarray to stimulate the captured cells so that a characteristic response is observed. The assay is very rapid, with cell absorption requiring only about five minutes. The researchers are initially evaluating the technology for the profiling of lymphocyte malignancies. Other potential applications include assessment of chemotherapy drug response.

InterGenetics (Oklahoma City, Oklahoma) is developing a genetic profiling test for assessment of the risk of development of breast cancer that employs bucchal cells collected by a mouthwash technique and a panel of 10 single nucleotide polymorphisms (SNPs) analyzed using the Luminex 100 platform from Luminex (Austin, Texas). The SNPs in the panel were selected via an extensive discovery program that required candidate genes to have known involvement in cancer-related pathways (as evidenced by the existence of at least one published study), as well as a bioinformatics analysis that assessed the degree of interaction between the identified SNPs in breast cancer risk prediction. A study using 1,050 cancer cases and 1,845 controls identified a number of interacting combinations of SNPs that identify groups of patients at high risk for developing breast cancer, with one group showing an odds ratio of 5.2, i.e., a five-fold+ increase in risk. The company's goal is to develop a multi-gene screening test that will detect elevated risk for the majority of breast cancers, not just the 5% to 10% that are currently detected using genetic tests such as the BRCA 1/2 assay.

New generation of image-based technologies

Other important modalities used for the early detection of cancer include diagnostic imaging techniques such as computed tomography (CT), MRI, ultrasound, mammography, radioimmunoscintigraphy and, increasingly, positron emission tomography (PET) scans. Those modalities are continuing to improve in terms of sensitivity and specificity, and new developments in targeted imaging agents, as well as emerging approaches that combine various modalities are expected to enable even more sensitive detection of tumors in the future. For example, Laura Liberman, MD, of Memorial Sloan-Kettering Cancer Center (New York) described studies using MRI to improve the ability to detect breast tumors in cases wherein mammography does not provide definitive results. While the use of mammography screening has been shown to provide a reduction in breast cancer mortality, the technique has lower sensitivity in women with dense breasts, dropping as low as 69% according to Liberman. MRI provides information on vascularity, unlike mammography, and development of new features such as double breast coils has resulted in enhanced MR imaging capabilities.

Liberman described studies performed at Memorial Sloan-Kettering in which women diagnosed with cancer in one breast, but believed to be tumor-free in the contralateral breast, were tested with MRI. In about 30% of the patients, the MR procedure resulted in a recommendation for a biopsy due to suspicious findings, and 30% of those patients proved to have a positive biopsy. Those results correlate with findings of other studies that have reported a 5% to 10% rate of cancer in women who had follow-up MRI. MRI also has been shown to detect additional tumors in the breast in which the primary tumor was found (in 27% of those scanned in one study), and similar studies have reported positivity rates ranging from 20% to 63%. Importantly, the rates of recurrence for breast cancer in women receiving prophylactic radiotherapy following surgical resection versus those not having radiotherapy differ by a quite similar proportion (~34%), indicating that the additional tumors detected only by MRI are clinically important.

While MRI for breast cancer is not a perfect technique, with a 20% false negative rate reported for detection of residual cancer after surgical biopsy, Liberman said she believes its use is justified in women diagnosed with breast cancer via mammography. In addition, its use is justified in initial screening of women who are at high risk for development of breast cancer, such as women who are BRCA 1/2 positive, those with prior breast cancer, those with a prior atypical mammogram and women who have had prior radiation therapy for conditions such as Hodgkin's disease. In order to employ MR imaging for breast cancer effectively, however, it is necessary to acquire specialized equipment for performing MR-guided biopsy, since lesions detected via MR are visible on ultrasound imaging only about 25% of the time. Ultrasound is the primary modality used to guide needle biopsy procedures. Equipment for performing MR-guided biopsy is available from companies including Suros Surgical Systems (Indianapolis, Indiana) and Artemis Medical (Hayward, California). The market for MRI systems is continuing to expand, as indicated by the data in Table 3.

Mukesh Harisinghani, MD, of Massachusetts General Hospital (Boston, Massachusetts), described recent studies with a new type of contrast agent that shows promise for further enhancing the ability of MRI to accurately detect breast tumors. The studies have employed a nanoparticle-based contrast agent under development by Advanced Magnetics (Cambridge, Massachusetts) called Combidex. The agent is being evaluated for use in assessment of lymph nodes of patients with diagnosed breast cancer, as a supplement to sentinel node biopsy. The nanoparticles are injected into the region of the node, and target macrophages in the tissue. If a tumor is present, migration of the nanoparticles into the node is prevented, making it easy to distinguish positive vs. negative nodes.

A pilot study using the technique in 20 patients found a sensitivity of 90.3% and specificity of 96.7% for detection of positive nodes. In one patient, sentinel node biopsy missed a cancer that was picked up by nanoparticle MRI. Although the new nanoparticle agent appears promising, some issues remain, such as a limit of about 2 mm on the minimum tumor size that can be detected, and interference from nodal fibrosis. However, Harisinghani believes the technique will be widely available in the near future. Although Advanced Magnetics received an approvable letter from the FDA for Combidex in June 2000, subject to certain conditions, the company is still working with the agency in an effort to resolve outstanding issues cited in the letter and bring the product to market.

Improvements in mammography technology also are being pursued. One promising approach, under development by GE Healthcare and Lorad (Danbury, Connecticut), a unit of Hologic (Bedford, Massachusetts), uses tomographic techniques to improve the discrimination capability of mammography. The technique, know as breast tomosynthesis, addresses the drawbacks of conventional 2-D mammography resulting from overlap of structures in the image. As a result of those shortcomings, up to 25% of women who are recalled for additional mammography testing are found not to have cancer. Tomosynthesis is a 3-D technique that eliminates structural overlap, increasing lesion visibility and facilitating analysis of tumor margins. A pilot study has shown a threefold improvement in the ability to detect lesions compared to conventional mammography, and also indicates that the method may allow determination of lesion type (benign vs. malignant) by providing a more well-defined morphology. An 83% reduction in the false positive callback rate was observed. The basic imaging technology for breast tomosynthesis has been available for a number of years, but became practical only with the development of the full field digital detector. According to Elizabeth Rafferty, MD, of Massachusetts General Hospital, the GE breast tomosynthesis system is about 18 months away from market introduction, while the Lorad system should be available in about 12 months.

The imaging modality attracting the most attention within the oncology community at present, however, is positron imaging tomography, along with PET/CT imaging that combines the metabolic information from PET with the anatomical accuracy of CT. The use of PET is expanding rapidly, as indicated by the data in Table 3. According to representatives from CTI Molecular Imaging (Knoxville, Tennessee), the leading supplier of PET imaging equipment and services, the PET market is just beginning to enter a new growth phase. Referring physicians are just now beginning to understand PET technology and to appreciate its ability to image metabolic changes.

The company is developing more targeted agents that it believes will expand the range of applications beyond those available with fluorodeoxyglucose, the standard agent used now. Even with FDG-PET, however, studies have shown that treatment plans are changed in 45% of cases as a result of PET imaging. Another barrier to market growth is the limited number of cyclotrons, since the half-life of positron-emitting agents is only about two hours. Molecular Imaging has begun to address that barrier with the establishment of the PETnet distribution network, allowing a wider range of hospitals to adopt PET.

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