Preventive Molecular Imaging Shows Potential, Slow Progress

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Source: gastric-cancer_1335535723.jpg - Gastric Cancer
18F-FLT uptake in gastric cancer (arrow) is indicator of rapid tumor cell proliferation: companion CT image through region of stomach mass (upper left), transaxial PET image showing 18F-FLT uptake in gastric mass (arrow; upper right), coronal PET image showing 18F-FLT uptake in gastric mass adjacent to left lobe of liver (bottom right), and fusion image of PET and CT showing 18F-FLT uptake in gastric mass (arrow; bottom left).
Molecular imaging has advanced to allow clinicians to offer patients personalized medicine by using biomarkers for precise surgical mapping and experimental therapy monitoring. The most advanced biomarker research may move beyond diagnostic imaging, surgical planning and monitoring of drug therapies to include predictive medicine.

Advanced molecular imaging systems provide in-depth tumor characterization and the ability to view biological processes such as angiogenesis, hypermetabolism and the expression of growth factors in certain tumors, which, in turn can predict  the potential effectiveness of a range of therapies. The next step is to examine whether cancer biomarkers have preventive potential.

The collective prognosis of experts in radiology, molecular imaging and pathology is that preventive molecular imaging is an ambitious concept and not quite on the horizon.

Here and now

Molecular imaging biomarkers are being used to determine disease progression. Their ability to provide clinicians information about the likelihood of metastases and the aggressiveness of treatment is being expanded to offer predictive information about potential therapy response and survival during treatment planning. Cancer biomarkers provide insight about patients’ potential resistance to therapies and help determine which therapies would be most effective by revealing the presence or absence of tumor characteristics and genetic factors. Is there a turning point where predictive biomarker data can be applied for cancer prevention?

“Although several monoclonal antibodies are being used for therapy, some in combination with other [chemo]therapies, in mostly hematological malignancies, their use in molecular imaging for detection of cancer is in its infancy,” says Aram van Brussel, MD, researcher for the department of pathology at Utrecht University Medical Center in The Netherlands. “Preventing cancer with molecular imaging would imply detection of benign lesions or precursor lesions, like ductal carcinoma in situ (DCIS) in breast cancer. Tracers targeting the proteins HER2, EGFR, CAIX, VEGF to detect DCIS are under development, although no tracers exist that are specific for the pre-invasive stage only.”

The major hurdle is that there haven’t been enough molecular imaging studies to drive predictive molecular imaging into the fast lane, let alone imaging studies that explore biomarkers for precursors in precancerous growths.
“The areas where the latest research might have some preventive application is in cardiovascular disease and some neurologic diseases, but I struggle with the idea for cancer prevention,” says David A. Mankoff, MD, PhD, professor of radiology, medicine and bioengineering at the University of Washington in Seattle.

Preventive molecular imaging is showing promise in the detection of vascular inflammation and the use of biomarkers for the very early detection and prevention of atherosclerotic disease and amyloid deposition imaging for Alzheimer’s disease. In these conditions, the underlying disease processes are known and developing in the patient prior to the point of clinical significance and diagnosis.  

Preventive molecular imaging of cancer will hinge on its ability to identify precancerous processes early enough to prevent progression before they become clinically overt. However, researchers don’t quite know how to catch precancerous abnormalities.

“It is possible that there could be some applications of molecular imaging for breast cancer detection,” says Mankoff. “Researchers are starting these studies, but none have hit the mainstream yet.”

Stepping stones

More predictive studies are needed before researchers can focus on prevention, says Steven M. Larson, MD, a nuclear medicine physician at Memorial Sloan-Kettering Cancer Center in New York City.

“Biomarkers have been a part of medicine for a very long time,” he says. “Recently, there have been some examples of studies using PET imaging for the monitoring of treatment response, but these have been based on small studies. [We need] significantly larger studies. One of the things that has greatly raised the bar for biomarkers is that the FDA has now made a formal proposal for the guidance documents on how to work up a biomarker and they are saying that you must first do studies that show there is reasonable reproducibility. You have to then qualify it with some multi-center clinical trials, which should up the ante for biomarker studies.”

Whether cancer biomarkers will move into preventive medicine depends on continued research. The more scientists learn about how drugs target tumor processes, the more they will know how these processes develop in earlier stages. Some of the most advanced research in predictive molecular imaging, says Larson, involves monitoring androgen receptor expression and genetic testing to understand a given tumor’s potential response to therapy.

“Recently, there have been some reports of tyrosine kinase inhibitors binding to mutant signal transduction molecules in patients with lung cancer,” says Larson. “There will be more examples like this as time goes by.”

There also are technological limitations. Preventive cancer imaging would depend on the continued advancement of imaging technology. “In theory, lesions smaller than one millimeter could be detected, but in daily practice, the threshold is 0.5 cm to 1 cm for the best radiotracers,” says van Brussels.

Still, there appears to be some hope that this will be the eventual direction of biomarker research. “Molecular imaging could increase the detection of cancer at an earlier time point, before metastases form, which would most likely increase the chances of curative radical excision, and consequently of tumor-specific survival,” he says. “When probes now in development and clinical trials are shown to accumulate specifically in tumors, they will have to be validated as tools for screening or prevention.”

Time will tell how far cancer biomarkers can go. It could take several more years before researchers can switch their focus from cancer treatment to cancer prevention.