Nuclear medicine tackles limits of other screening options

It's a given that breast cancer screening reduces mortality from the second leading cause of death of women in the U.S. Early detection of breast cancer requires screening techniques that can reliably detect lesions in the 5 to 15-mm range. Screening techniques have difficulty finding abnormalities of this size, however. Conventional scintimammography often has an abysmal sensitivity, said Dr. Michael O'Connor, a radiologist from Mayo Clinic in Rochester, MN. In a 2002 study of 50 women, general-purpose scintimammography had a sensitivity of 35% to 64% for lesions less than 1 cm, O'Connor reported at the 2008 SNM meeting in June (J Nucl Med 2002;43(7):909-915).

Ultrasound adds little. Ultrasound and mammography had a sensitivity of 50% in a study of 2500 women who were at high risk for breast cancer, O'Connor said (JAMA 2008;299[18];2151-2163).

While the sensitivity of MRI is impressive-around 80%-its specificity can be as low as 50%, and it is 10 times more costly than mammography, O'Connor said at the SNM meeting.

So what's the answer? Enter nuclear medicine.

Early detection of breast cancer requires imaging techniques to reliably find lesions of 5 to 15 mm. Conventional scintimammography in the 1990s admittedly was dreadful at detecting abnormalities in this range. Its sensitivity was 35% to 64% for lesions smaller than 1 cm.

But newer versions of nuclear medicine devices that are dedicated to breast imaging are finding extremely small tumors. As reported at the 2008 SNM meeting, a prototype gamma camera-based breast imaging system developed at the Mayo Clinic over the last six years has found 10 cancers in 762 high-risk patients who were monitored with the device over time. Six of the tumors were 10 mm or smaller, and one was 15 mm. Mammography, meanwhile, found only three cancers of any size.

A new PET system designed for imaging small body parts, such as the breast, has a resolution of 1.5 mm, which is about the size of the breast's network of ducts where most breast cancers arise, said Dr. Kathy Schilling, medical director of the Center for Breast Care in Boca Raton, FL. In a study of 136 patients, the PEM Flex Solo II (Naviscan PET Systems, San Diego) identified a ductal carcinoma in situ only 2 mm in size that was missed on MRI.

An experimental PET/CT device that is under development at the University of California, Davis achieves a resolution of 300 microns for CT and 2 mm for PET, which allowed investigators in the first human trial with the device to find a hot spot in the breast that was about 5 mm across. By comparison, whole-body PET/CT scans would not have been able to find a lesion smaller than 1 cm in the breast, said Dr. Ramsey D. Badawi, an assistant professor of radiology at UC Davis.

These dedicated breast imaging devices just may address the shortcomings of mammography and MRI. The breast imaging system from Mayo Clinic was significantly more sensitive than mammography in the study reported at the SNM meeting. In a 15-month follow-up period, the system identified six of seven cancers in 341 patients for a sensitivity of 85.7%. Mammography detected only two of the seven for a sensitivity of 28.6%.

The system also had a lower recall rate than mammography. Fifty-six of 762 patients were recalled for further investigation after imaging with the gamma camera (7.3%) compared with 70 (9.2%) after mammography. The biopsy rate was higher (3.4% versus 2%), and so was the positive yield at biopsy (28.6% versus 20%) for the gamma camera, O'Connor said.

The PEM system was more sensitive in detecting DCIS than MRI (91% versus 83%), and its performance was not affected by circulating hormones."MRI has a tough time with patients if they have natural circulating hormones or are on hormone replacement therapy. There are a lot of false-positive results with MRI. We do not see that same effect with PEM. Hormones don't cause things to light up that are natural in women who are in the premenopausal or per-menopausal state," Schilling said.

Nuclear medicine devices are less costly than MR scanner. Mayo's gamma camera is estimated to be one-fifth to one-third the cost of a breast MR, according to O'Connor.

The cost of the PEM machine is about half that of a whole-body MR scanner, Schilling said.

And nuclear medicine systems don't require a major facility or workflow overhaul. The Mayo and UC Davis prototypes are still under development, but the PEM is in use around the country. It is easier to get up and running than MR, according to Schilling.

"It's very difficult to set up a breast MRI program. Physicians around the country struggle with it, because there are no standardized protocols for image acquisition or even interpretation. That's not so with dedicated PET breast imaging," Schilling said. "PEM is smaller than a mammography unit. You just plug it in the wall and go."

Operators must have a nuclear license, but there isn't all the room preparation and shielding that are needed for MRI, she said. "And for image interpretation, there's a very short learning curve. So it's easy to implement in a breast practice," Schilling said.

DEVICE DIFFERENCES

The Mayo prototype is a dual-detector system that uses cadmium zinctelluride technology. The gamma camera is ideal for breast imaging because it achieves a high degree of resolution. Intrinsic resolution is 1.6 mm, and energy resolution is 4%. It also has minimal dead space. It may be preferable to mammography because it requires less compression. The compression force is about one-third that of mammography.

"A big drawback, however, is radiation dose," O'Connor said.

Patients are injected with 740 MBq of technetium-99m sestamibi five minutes before being imaged with the gamma camera. The 6.7-mSv total dose of radiation for gamma camera imaging is therefore markedly higher than the minimal 1 mSv or less for mammography. But investigators at Mayo Clinic are working on techniques that will lower the dose of sestamibi to 70 to 100 MBq.

The PEM system is a commercially available high-resolution functional tool for breast imaging. Unlike MRI, which identifies cancers by looking for new blood vessel formation, the PEM looks for differences in metabolic uptake of sugar in normal and abnormal cells. And unlike whole-body PET, for which high detection rates of breast cancers are hampered by the arrangement of the detectors and their distance from the target organ, the PEM can see cancers when they are still confined to ductal structures because its detectors are in intimate contact with the breast, Schilling said.

The experimental dedicated PET/ CT breast imaging machine at UC Davis is capable of high-resolution anatomic as well as functional imaging because it is not imaging the chest, where both PET and CT signals are badly attenuated and signal is lost during whole-body imaging. The scanner consists of flat-panel detectors, which have been used for high-resolution PET/CT imaging before. But it also includes very small scintillating crystal arrays, which were pioneered in small animal imaging and have not been used in humans until now.

In its first test in humans, the PET/CT scanner found three areas of ductal carcinoma in situ, including one with intralymphatic cancer in a 49-year-old woman who had pathologically confirmed breast cancer.

CLINICAL APPLICATIONS

Findings from the studies presented at the SNM meeting are carving out several paths for dedicated nuclear medicine breast imaging.Because of its high sensitivity and low cost, Mayo's gamma camera may be an alternative to MRI for screening women with a personal or family history of breast cancer or mutated BRCA1 or BRCA 2 genes. The technique is two times more sensitive than mammography and just as sensitive as MRI in finding breast cancers among high-risk women, O'Connor said.

Breast imaging with the gamma camera also has a higher specificity than mammography or MRI. In the study reported at the SNM meeting, the technique had a specificity of nearly 94% while mammography had a specificity of 91%. The specificity in this study bested that of MRI, which, in the best of circumstances, tops out at around 80%.

If the PEM proves to compare well in a direct one-on-one match up with MRI, it may replace MRI in small, cost-conscious breast imaging centers. Schilling is currently leading a multicenter trial of the PEM and MRI in 400 women with newly diagnosed breast cancer. The results of that trial, which are expected early next year, may open the door to more wide-scale adoption of the technique in women's health practices that can't afford or don't have access to MRI.

"Instead of just waiting until tumors get so big we can see them and feel them, we're trying to identify the earliest changes down at the cellular level and the changes that make cancer cells different from normal cells. We are looking for a tool that will not be redundant and find the same cancers as breast MRI," Schilling said. "We are able to find additional cancers and even precancerous pathology with PEM, with improvement in our specificity and accuracy."

In a comprehensive breast center, she said, an exam with the PEM would complement mammography.

"It would be one of multiple tools that you can tailor for specific patients. In a smaller center, or one that does not have breast MRI, this can serve as a functional imaging tool to look for breast cancer in high-risk women." Schilling said.

Dedicated breast PET/CT is not for everyone. It takes more than an hour for the radioactive tracer necessary for the PET portion of the exam to circulate into the breast. PET/CT, therefore, is probably not going to be practical for screening large numbers of women, Badawi said.But it may have a role if a mammogram is suspicious for breast cancer and a woman is destined for biopsy.

"Our technology may be able to reduce the number of negative biopsies that these women have. If we can see lesions at a high resolution and determine if they are cancer or scar tissue-or even a cyst-then there would be no need to do the biopsy," Badawi said.PET/CT may also be helpful in surgical planning to depict the full extent of disease so the surgeon has a better chance of removing all of the involved areas at the first surgery.

Another emerging role for breast PET/CT is as a chemotherapy treatment monitor.

"There has been a lot of interest in giving chemotherapy before surgery to shrink the tumor so it is small enough to cut out completely. But how do we know which chemotherapy is going to work?" Badawi said.

It may take several months of monitoring with CT to see whether the tumor shrinks.

"But with PET scans, we can see that the uptake of sugar goes down quite quickly if the chemotherapy is working-even in a day or two. On that basis, you could give the drug, do the PET/CT scan, and see if the cancer is changing or responding. Then you have the answer right away," Badawi said.

The new breast imaging techniques are giving clinicians and radiologists more options for deciding how to image the patient, not just the disease.

"Medicine is becoming much more personalized today, not only in treatment but also in diagnosis," Schilling said. "So we are really looking at the patient and her age, breast density, and risk for developing cancer, and we are beginning to tailor the screening to fit her needs."

Ms. Sandrick is a freelance writer and frequent contributor to Diagnostic Imaging.