U.S. Army Medical Research and Materiel Command

June 9, 2005

LIGHT & SOUND JOIN FORCES TO IMPROVE BREAST CANCER IMAGING

Points of Contact:
Lynn Rudinsky phone 212/886-2200, email lrudinsky@cooneywaters.com
In Philadelphia 6/8 - 6/11
Pennsylvania Convention Center, 215-418-2155
Gail Whitehead, Public Affairs Coordinator, phone (301) 619-7783, email gail.whitehead@amedd.army.mil

Research Results from the "Era of Hope "Department of Defense Breast Cancer Research Program Meeting

PHILADELPHIA, June 9, 2005 - Finding breast cancer early improves the odds for successful treatment. Once a suspicious mass is detected, the diagnostic gold standard remains biopsy, an invasive procedure that produces discomfort, anxiety, and an exceedingly high 80% rate of negative findings, which translates into eight benign masses for every two confirmed cancers. At the "Era of Hope" meeting, researchers funded through the Department of Defense Breast Cancer Research Program will describe an array of technologies being developed to detect tiny cancers earlier and replace biopsy with a non-invasive tool that can differentiate benign from malignant growths. These include a hand-held imager designed for at-home use, gold-wrapped bits of silica that may serve dual duty for imaging and therapy, and tandem optics-ultrasound and optoacoustic systems.

Prototype Imager Holds Promise for At-home Breast Screening
A hand-held device in development may one day allow women to screen themselves for breast cancer in the privacy of their homes. The device, tentatively named "iFind," monitors the differences in blood oxygen ratios in growing cancers and normal tissues, reported researchers from the University of Pennsylvania. If it picks up potential early signs of breast cancer, it alerts the user with either a light or a vibration.

"It's important to know that this would be part of a breast exam, not a full diagnostic device," explained Britton Chance, Ph.D., emeritus professor of physics and radiology at the University of Pennsylvania Medical School and developer of the device. "It would provide an indication of early signs of breast cancer that need to be followed up by a doctor."

The device measures oxygenation rather than blood volume to detect hypermetabolism - the speedier growth rate of cancer cells. The prototype breast cancer detector performed with a positive predictive value of about 93%, which the researchers describe as a remarkably successful test for detecting breast cancer. Reliance on near-infrared light makes it a safe technology as well; women can use it as frequently as they wish. The study was conducted over a six-year period at two sites.

"This equipment gives women an opportunity to take charge of their own health, and it only requires minimal training," said Dr. Chance. "The device also has a longitudinal memory, so if something suspicious is flagged, the woman can bring the device with her to her doctor who will have results from every time it has been used."

In an informal, online survey of 325 women of all age groups and across all income levels conducted by the developers from a group of family, friends, acquaintances and others via word of mouth, 83% of respondents said they would be interested in a screening device they could use at home. Most of the women's concerns related to the reliability and sensitivity of the device and their ability to use it by themselves.

In addition to the hand-held imager, Dr. Chance is developing an imaging tool intended for use in a clinical setting rather than at home. The clinician's device produces crisp images with the aid of an injected molecular beacon called a nanodot - a bright fluorescer that lights up tumors. Both devices would be able to detect small initial cancers as well as recurrences.

Initial studies have evaluated the hand-held device for principles of detection appropriate for breast cancer. Its developers propose to begin testing both imaging devices in a year and a half in an ongoing study of women with an identified BRCA 1 or 2 genetic defect, which places them at substantially greater risk for developing breast cancer.

Gold-shelled Nanoparticles Selectively Find and Kill Cells Associated with Invasive Breast Cancer

Researchers at Rice University sent particles called nanoshells on a successful search-and-destroy mission for a protein linked to aggressive breast cancer - the first use of a single bio-imaging tool for both diagnosis and therapy in this disease. The nanoshells lit up cells that had high levels of HER2 protein, and the illuminated cells acted as beacons for lethal doses of laser-directed heat.

"If we can develop a single safe technology that identifies and treats cancer, it would have the potential to reduce side effects for patients and reduce costs for the health care system," said Naomi J. Halas, Ph.D., Stanley C. Moore Professor in Electrical and Computer Engineering and professor of chemistry at Rice University in Houston.

Dr. Halas designed nanoshells in the 1990s. These gold-wrapped bits of silica, roughly 20 times smaller than a red blood cell, naturally accumulate inside malignant tumors. For this dual-purpose application, nanoshells were tailored for photothermal therapy, a process in which they convert near-infrared light (NIR) into heat that kills cancer cells without harming nearby healthy tissue.

The Rice team used two breast cancer cell lines: one that overexpressed HER2 and one that did not. One set of nanoshells was joined to HER2 so that it would seek out this biomarker. After incubating the cells with nanoshells, the researchers conducted the imaging portion of the study with NIR to illuminate cells showing high HER2 levels.

"At that point, all we have to do for treatment is turn up the laser power, shine the light for a few minutes, then do viability stains that show different colors for live and dead cells," Dr. Halas explained. Nanoshells can be manipulated to scatter or absorb light, and in this case, it was both. Researchers employed a scatter signal for the imaging and an absorption signal for the photothermal therapy.

The results of this experiment, demonstrating that a single particle can be designed for sequential imaging and therapy, appeared in April 2005 issue of Nano Letters, a publication of the American Chemical Society. As a next step, Dr. Halas and her colleagues plan to follow a similar procedure in a mouse model. These nanoshell functions should be applicable to most soft tissue cancers.

Marriage of Near-Infrared Light and Sound Waves May Help Detect Very Early Breast Cancer
By combining features of near-infrared light and sound waves, a new imaging technology demonstrates the potential to find breast cancers when they are very small - an early stage when the cells are genetically altered but the malignant changes are not detectable by other methods. The Laser Optoacoustic Imaging System (LOIS) uses sound waves to sharpen the resolution of optical images and give clinicians a better view of subtle contrasts in subsurface structures that indicate cancer.

"Contrast and resolution are interrelated issues," explained Alexander Oraevsky, Ph.D., vice president for research and development at Fairway Medical Technologies, Inc. in Houston, TX. "Near-infrared light penetrates tissue deep enough to show the difference between cancer and benign areas, but image resolution is limited because light scatters strongly in tissue. This can smear the contrast, making a small tumor look large, featureless and faint, or even invisible. We solve this problem by converting the light into acoustic waves, so it's the sound waves that are detected, not photons from light."

In this process, light penetrates tissue to a significant depth and is absorbed preferentially by tumors. As the light warms the tumors slightly, the heat builds pressure, which the tumor cannot contain. This pressure becomes an acoustic wave that propagates out as ultrasound, where it is picked up with only minimal scattering. Most detectors discern only a narrow range of frequencies. The LOIS ultrawide band transducers detect acoustic pulses at all frequencies simultaneously.

To demonstrate feasibility, Fairway scientists have been testing LOIS in three systems. In the first, they used a "phantom," a collagen gel structure that resembles breast tissue. Embedded in the phantom was an object with greater absorption capability to approximate a tumor. Phantoms allow scientists to predict system response and calibrate the equipment. Next, they studied LOIS in mastectomy tissues to confirm that real tissues and the phantom provided similar optoacoustic responses. Now they are conducting clinical studies with women already known to have suspicious breast lesions.

"Our goals are to prove that LOIS can detect the same tumors found with other imaging modalities but with greater contrast; and then to see whether it can distinguish cancer from benign masses non-invasively, from imaging alone," said Dr. Oraevsky.

Of the 24 patients examined to date, LOIS detected more than 95% of the tumors. The researchers are still working on the differential diagnosis aspect of the technology. Eventually, they hope to conduct a large clinical trial to define the technology's false-positive and false-negative rates for both detection and diagnosis.

"We think we can refine LOIS to be not only a more sensitive technology for early detection of breast cancer but one that provides a true differential diagnosis. If we could reduce the number of benign biopsies, that would be a significant breakthrough," Dr. Oraevsky said.

In a related project, Fairway scientists are exploring gold nanorods as a contrast agent to further clarify images of very early tumors. "Every imaging technology uses a contrast agent for a variety of applications, though not necessarily for breast imaging, and gold nanorods have the potential to be a good agent for X-ray as well as for LOIS," Dr. Oraevsky commented.

The nanorods are similar to gold nanoshells, but have a greater optical absorption coefficient, which means they deliver a stronger signal. For example, 10 nanoshells and one nanorod of equal volume have equal absorption and signaling capability. This matters, because of the limited number of nanoparticles that can be delivered to a tumor. Consequently, the more signal they can produce, the better. Using a mouse model of human breast cancer, the researchers plan to determine optimal ways to deliver the nanorods to the tumors and then to visualize them with LOIS.

Dual Role for Optical Tomography in Advanced Disease: Diagnose Early-Stage Breast Cancer, Predict Treatment Response
Combining optical tomography (OT) with commonly used imaging overcomes important limitations of both technologies and shows both diagnostic and prognostic potential in breast cancer, according to a University of Connecticut study. In more than 100 women with small breast lesions located precisely by ultrasound after a mammogram, OT distinguished benign from malignant masses with a high degree of accuracy. Preliminary results also suggest that once another type of imaging has pinpointed a tumor, OT may predict response to chemotherapy in advanced-stage disease.

"Researchers in the optical community have been trying to use OT for cancer detection and diagnosis, but infrared light scatters when it passes through soft tissue, making it difficult to spot a small tumor. Using other imaging techniques to find lesions and OT to characterize them has great potential to improve diagnosis in early-stage breast cancer," said Quing Zhu, Ph.D., an associate professor of bioengineering at the University of Connecticut in Storrs.

In the diagnostic component of the study, images created via OT were able to distinguish early-stage cancers from benign lesions by showing which ones featured high hemoglobin concentrations, which indicate the formation of new blood vessels that feed malignancies. To create these images, researchers took multiple measurements of light transmitted through the target site, which produced massive data sets that were then translated into images by computer software developed by Dr. Zhu's team.

Dr. Zhu acknowledges that this new approach, which she calls "optical tomography with ultrasound guidance," will not replace mammograms. Instead, she hopes it can improve the ability to characterize a suspicious breast mass detected by mammography and thus spare many women the distress and discomfort of a biopsy that turns out to be negative.

The researchers also are investigating how OT can monitor changes in the body after chemotherapy to predict treatment response in women with advanced breast cancer. This part of the study focuses on two parameters: blood volume as a marker of angiogenesis (formation of tumor-supplying new blood vessels) and blood oxygenation. Other investigators have reported that resistance to cancer drugs is related to local deoxygenation of blood.

"In the small group of patients monitored so far, the technology appears to predict response during the early treatment cycles," Dr. Zhu reported. "This could help clinicians know pretty quickly whether or not a tumor is shrinking, so they can switch to another therapy in a timeframe that might make a difference. Palpation and non-functional imaging tools like mammography and ultrasound can't do that."

Because it relies on non-ionizing infrared light, OT can be repeated frequently for monitoring purposes without the potential health risks of medical imaging methods that involve radiation or contrast dyes. Dr. Zhu cautions, however, that her group has monitored only eight patients. Larger studies are needed to confirm the value of OT in predicting response to treatment and thus to improve clinicians' ability to tailor breast cancer therapies to individual patients.

"Era of Hope" is a forum for the presentation of research supported by the U.S. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of many congressional research programs managed by the U.S. Army Medical Research and Materiel Command, the BCRP has received more than $1.8 billion to date from Congress for innovative breast cancer research.

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"A New Approach to Early Detection for Women's Medicine"
B Chance, B Onaral, K Pour, M Herr
Concurrent Symposia Session I, Symposia 4: Thursday, June 9, 2:00 p.m. - 4:00 p.m., Room 204A

"Nanoshells for Integrated Cancer Imaging and Therapy"
N Halas, R Drezek, C Loo, A Lowery, J West Innovator Session: Saturday, June 11, 12:45 a.m. - 12:15 p.m., Ballroom A

"LOIS - Novel Imaging Modality for Early Diagnosis of Breast Cancer in Situ"
A Oraevsky, P Henrichs, K Mehta, T Miller, A Yee, J Copland, N Kotov, V Popov, M Eghtedari, M Motamedi, T Khamapirad
Concurrent Symposia Session V, Symposia 28: Saturday, June 11, 3:00 p.m. - 5:00 p.m., Room 201C

"Imaging Tumor Angiogenesis Using Optical Tomography with Ultrasound Guidance"
Q Zhu, S Kurtzman, E Cronin, S Tannenbaum, M Huang, C Xu, B Yuan, N Chen, D Piao, P Hegde, M Kane
Concurrent Symposia Session V, Symposia 28: Saturday, June 11, 6: