Spotting Breast Cancer Sooner

A new contrast agent could help those for whom mammography is ineffective.

Harvard University researchers have developed an imaging contrast agent that targets a compound found in cancerous breast tissue. The researchers hope that the agent will help doctors identify breast cancer at an earlier stage, when treatment is easier, and that it will provide a better alternative for patients for whom mammography is not very effective. A test that uses the agent could also cut down on false positives.

Warning sign: A new contrast agent developed by Harvard researchers targets this compound, hydroxyapatite, which builds up in breast-cancer tissue.

The imaging agent emits a particular wavelength of near-infrared light when it binds to a compound called hydroxyapatite, a calcium salt that builds up in breast tissue as milk-producing cells die. These so-called microcalcifications are one of the things radiologists look for in mammograms to diagnose breast cancer.

Among women in the United States, breast cancer is the most common cancer and the second leading cause of cancer death. The U.S. Preventive Services Task Force recommends that women between the ages of 40 and 75 have mammograms every one or two years. Mammography is not recommended for younger women, whose breast tissue is denser and therefore yields images that are more difficult to interpret. Mammograms in younger women find fewer cancers and save fewer lives. Doctors also suspect that they are missing tumors in older women with denser breasts.

Screening with mammography has been very effective: breast-cancer death rates have been steadily declining since the 1990s. But John Frangioni, a physician and associate professor at Harvard Medical School, who led the research, thinks that targeted imaging agents could do better.

With agents like Frangioni’s, “You know when you see it binding it’s because of an accumulation of calcium,” says A. Dean Sherry, a professor in the Advanced Imaging Research Center at the University of Texas Southwest Medical Center. “It tells you something specific about the biology.”

The wavelength of light needed to activate the agent and the wavelength of light the agent emits fall within what researchers call the near-infrared window, an area of the spectrum where light is very good at passing through biological tissues.

The hydroxyapatite-targeting molecule is one of many near-infrared imaging agents being developed by Frangioni for breast-cancer screening. The advantage of near-infrared imaging is that “you can use different flavors for different processes,” says Bruce Tromberg, professor of biomedical engineering and director of the Beckman Laser Institute at the University of California, Irvine. The idea is to use imaging to provide a molecular profile of a patient’s cancer. Tromberg and Frangioni are developing imaging molecules that fluoresce in different areas of the spectrum, and each targets different cancer-associated compounds.

Zhen Cheng, assistant professor of radiology and a member of the Molecular Imaging Program at Stanford University, says that he is impressed by the specificity of Frangioni’s agent for hydroxyapatite: the agent binds to the molecule but not to other calcium-containing compounds. Frangioni has tested the agent in bones and soft tissue in pigs but has not done tests in a breast-cancer model. “The in vivo images [he] acquired are quite impressive,” says Cheng. The Harvard group’s next goal is to validate its work in human clinical trials.

Other researchers and oncologists are skeptical of the usefulness of the hydroxyapatite-targeting agent. “In theory, it sounds like an interesting idea,” says Elizabeth Steiner, assistant professor of family medicine at the Oregon Health and Sciences University. “But you can have benign calcifications.” That is, the presence or absence of hydroxyapatite is not enough to distinguish between cancerous and healthy breast tissue.

But the imaging researchers say that detecting cancer at the molecular level does not depend on the total absence of the targeted molecule from healthy tissue. Tromberg points to the example of herceptin, a drug that targets cell receptors present in normal tissue as well as breast-cancer tissue. “All the normal cells have it, but maybe there’s 10 percent more on tumor cells,” he says. A 10 percent difference in the levels of hydroxyapatite in cancerous and normal breast tissue would be more than enough to provide imaging contrast, he says.

However, Tromberg acknowledges that the technology faces many hurdles. It’s unlikely that patients will accept fluorescent dyes as a part of routine screening. “From a practical point of view, people don’t want to be injected with probes to do screening,” he says. The agents may be more tolerable to some groups of patients, such as women at high risk for breast cancer who are considered too young for mammography. The agents could also be used as follow-up testing for patients with suspicious mammograms or magnetic resonance imaging scans.

“The bottom line is, mammography is not a great test,” says Steiner, and any improvement in breast-cancer screening would be welcome.

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