PET Technique Could Aid in Targeted Breast Cancer Treatment

New research showing that PET scans in mice can be used to detect and monitor a protein often associated with aggressive breast cancer could facilitate the development of new, targeted therapies for breast, ovarian, prostate and lung cancers.

Jacek Capala, Ph.D. National Cancer Institute’s Center for Cancer Research

Gary J. Whitman, M.D. University of Texas M.D. Anderson Cancer Center

In a study published in the July issue of the Journal of Nuclear Medicine, researchers at the National Institutes of Health (NIH) used PET and a specially developed radioactive compound (fluorine-18) attached to an Affibody® molecule to image human epidermal growth factor receptor type 2 (HER2), a well-established tumor biomarker that is overexpressed in a wide variety of carcinomas. Affibody molecules are small and robust high affinity protein molecules that can be engineered to bind specifically to a large number of target proteins.

While HER2 expression is currently measured in biopsy specimens, senior author Jacek Capala, Ph.D., of the National Cancer Institute's Center for Cancer Research, said the NIH research indicates that PET can provide rapid, reproducible and noninvasive in vivo assessment of the receptor expression.

"Our work shows that PET imaging using Affibody molecules was sufficiently sensitive to detect a two- to threefold decrease in HER2 expression," said Dr. Capala. "Therefore, PET imaging may provide a considerable advantage over other current methods. Our technique would allow a better selection of patients for HER2-targeted therapies and also early detection of tumors that either do not respond to or acquire resistance to these therapies."

The breakthrough lies not only in the ability of the technique to detect HER2 expression, but also to monitor the patient's immediate response to therapeutic interventions, allowing the physician to adjust the dose and treatment schedule based on the actual status of HER2 receptors, said Dr. Capala.

Although stressing that the NIH research needs further validation in mice and in human trials, Gary J. Whitman, M.D., a professor in the Department of Diagnostic Radiology at the University of Texas M.D. Anderson Cancer Center in Houston, said the study represents an advance in the role of imaging in targeting receptors. "This research moves us more toward thinking in terms of pathways, receptors and quantitative analysis rather than just assessing morphology," said Dr. Whitman, a member of the RSNA News Editorial Board. (Listen in as Dr. Whitman discusses the role of imaging in the NIH study)

PET Detects HER2 Expression

Researchers at the National Institutes of Health (NIH) used PET and a specially developed radioactive compound (fluorine-18) attached to an Affibody® molecule to image human epidermal growth factor receptor type 2 (HER2), a well-established tumor biomarker that is overexpressed in a wide variety of carcinomas. (shown) Affibody molecules are much smaller than antibodies or antibody fragments, but the size of their binding surfaces is comparable. Image courtesy of the National Institutes of Health

In the NIH study, researchers injected mice with human breast cancer cells varying in their level of HER2 expression. After three to five weeks, when tumors had formed, the mice were injected with the Affibody molecule and PET images were recorded. The levels of HER2 expression as determined by PET were consistent with the levels measured in surgically removed samples of the same tumors using established laboratory techniques, Dr. Capala said.

To gauge possible changes in HER2 expression in response to treatment, the team injected the Affibody molecule into mice with tumors that expressed high or very high levels of HER2 and then treated them with the drug 17-DMAG, a type of heat shock protein 90 (Hsp90) inhibitor that is known to decrease HER2 expression. PET scans were performed before and after 17-DMAG treatment.

Researchers found that HER2 levels were reduced by 71 percent in mice with tumors that expressed very high levels of HER2 and by 33 percent in mice with tumors that expressed high levels of HER2 compared with mice that did not receive 17-DMAG.

"Our approach using PET for in vivo assessment of HER2 expression may aid diagnosis of breast cancer and improve the outcome of HER2-targeted therapies," said Dr. Capala. "Several molecular probes based on antibodies have recently been tested in experimental animal tumor models, but a PET tracer for routine clinical use has not yet been developed."

Invasive Method Has Drawbacks

Although invasive tissue sampling is currently the gold standard for investigating HER2 tumor levels, the method has a number of obvious drawbacks including restricting analysis to only the sampled cells at a single time, according to Peter M. Smith-Jones, Ph.D., associate attending radiochemist at Memorial Sloan-Kettering Cancer Center in New York and creator of a probe developed to study the pharmacodynamics of the therapeutic 17-AAG, another Hsp90 inhibitor, on HER2.

"This PET technique allows you to scan the whole patient for multiple sites and can be repeated within 24 hours so you can quickly monitor the drug effects on the tumor," said Dr. Smith-Jones.

Along with facilitating the selection of patients for HER2-targeted therapy and providing information on the immediate response to therapeutic intervention, the PET imaging technique would reduce the number of biopsies and cut back on the number of false-negative or false-positive results associated with invasive methods, said Dr. Whitman. (Listen In as Dr. Whitman discusses the drawbacks to invasive biopsy)

He stresses that the technique's monitoring capability would be especially advantageous in terms of administering the best treatments as early as possible. "Sometimes our ability to monitor response to therapy seems primitive and often not that precise or sensitive," said Dr. Whitman.

"Using conventional response criteria, it can take months until the physician can definitively say that the patient is responding to a drug regime," added Dr. Smith-Jones. "This scan should quickly help find the right drug for the right patient."

PET Research Continues

While using PET and MR imaging with tracers that target receptors is still in the early stages, the technique "will make tremendous progress in the next five to 10 years," said Dr. Whitman, who said it is part of a general trend toward personalized medicine. "Parallel to that, we're discovering various pathways and receptors and there may be more entities such as HER2 that we will discover in the future." (Listen in as Dr. Whitman discusses the future role of imaging in targeting receptors)

In continuing his research on the technique, Dr. Capala and colleagues are studying whether it can be used to target HER2 and epidermal growth factor receptor for diagnoses and therapy of metastatic lesions in the brain and brain tumors.

Ultimately, he said, "PET may provide a considerable advantage and become an attractive alternative for assessing HER2 expression quantitatively, objectively yet noninvasively, allowing several scans to be performed over the course of therapy."