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October 17, 2005

MR Spectroscopy Helps Improve Breast Cancer Diagnosis
By Beth W. Orenstein
Radiology Today
Vol. 6 No. 21 P. 22

MRI has been able to detect breast lesions that are not visible by clinical examination, mammography, or ultrasound. Contrast-enhanced MRI has high sensitivity—94% to 100%.

“It’s overwhelmingly clear that the diagnostic accuracy of MRI is very high,” says Robert Lenkinski, PhD, head of MRI research at Beth Israel Deaconess Medical Center in Boston.

However, MRI of the breast is far less reliable for determining whether the lesions it finds are malignant. Breast MRI specificity varies from 37% to 97%.

Researchers are now finding that adding spectroscopy to the standard breast MRI exam can greatly improve a radiologist’s ability to distinguish benign breast lesions from cancerous ones. Studies have also shown that magnetic resonance spectroscopy (MRS) holds promise as an early indicator of response to drug therapy in women with locally advanced breast cancer.

Same Hardware
MRS uses the same magnet and hardware as MRI, but with specialized sequences to produce a “spectrum” of different biochemical compounds in tissue.

“We use the same machine that does the MRI, but instead of scanning the patient and getting a picture, we scan the patient and get a graph,” explains Lia Bartella, MD, a radiologist at Memorial Sloan-Kettering Cancer Center in New York, who specializes in breast imaging.

Radiologists are looking for elevated concentrations of choline, a product of membrane synthesis that rises in rapidly reproducing cancer cells. “We can look at a specific area of the breast and it will tell us if there is any choline there,” Bartella says. “Choline is a marker for cancer.”

Over the past decade or so, spectroscopy has been used mostly in the brain to help identify various disorders, including tumors and Alzheimer’s disease.

Spectroscopy of the breast has been slower to develop because it is more technically challenging. The composition of breast tissues differs from that of brain tissue. The irregular distribution of fatty and glandular tissue in the breast makes it more difficult to establish reference points to compare with measured choline levels.

“So far, with the breast, we have only been able to do one voxel or one part at a time, which is usually one lesion at a time or one area at a time,” says Bartella, the principal investigator on a study involving MR breast spectroscopy at Sloan-Kettering.

Performing spectroscopy on one area adds approximately 10 minutes to the time the patient lies in the scanner. The MRI alone can take approximately 30 to 45 minutes. “We cannot ask the patient to lie there for much longer,’’ Bartella says.

However, Bartella suspects that as the technology and techniques advance, it will be possible to perform MRS on the whole breast within a time frame acceptable to women and physicians.

Researchers are optimistic that MRS eventually could reduce the number of benign biopsies recommended by MRI.

“In the general population, 70% of the time lumps that light up on MRI are benign,” says Michael Garwood, PhD, associate director of the Center for Magnetic Resonance Research and professor of radiology at the University of Minnesota in Minneapolis. “If you don’t do spectroscopy to say those are benign, then what happens is there are extra procedures—biopsies and surgeries—and all the anxiety and other factors that come into it. Spectroscopy adds another measure to improve the overall accuracy of MR scanning of the breast.”

Therapy Response
MRS also has the potential to predict clinical response to chemotherapy in patients with locally advanced breast cancer. “It gives us quick feedback,” says Patrick J. Bolan, PhD, an assistant professor of radiology at the University of Minnesota’s Center for Magnetic Resonance Research. Choline in the tumor can be measured before and again within 24 hours after treatment; patients who will respond to the chemotherapy will have decreased choline levels almost immediately. Measuring for choline is far better than having to wait weeks before scanning the patient again to see whether the tumor has shrunk, Bolan says.

Researchers at the Center for Magnetic Resonance Research had some promising results with their study of MRS of the breast. The study, published in the August issue of Radiology, evaluated 55 breast MRI cases with findings confirmed through earlier biopsies.

Four radiologists—two from academic institutions and two from private institutions—were asked to read breast exams done with and without MRS, says Sina Meisamy, MD, who was a postdoctoral fellow at the center when the research was conducted. Meisamy is now completing his radiology residency at State University of New York Downstate/King’s County Medical Center in Brooklyn, N.Y.

When spectroscopy was added, the radiologists detected more cancerous tumors—from 87% to 94%. Researchers also found that the radiologists had a higher success rate for distinguishing benign from malignant tumors—from 51% to 57%.

Radiologist Agreement
There was also greater agreement among the radiologists in their interpretations and recommendations for treatment. The radiologists had been asked to categorize each case using the American College of Radiology’s (ACR) Breast Imaging Reporting and Data System (BI-RADS), which ranges from 0, for needs no additional evaluation, to 5, for highly suggestive of malignant and appropriate action should be taken. Their BI-RADS were in closer agreement when they had information from the spectroscopy.

“A lot of people have published data that shows we can detect choline in cancers,” Meisamy says. “What we did was something that no one has done before and that is to do an observer performance study to see whether detecting and quantifying this choline made a difference in radiologists’ ability to distinguish benign from malignant tumors, and we found that it does. Sensitivity and specificity improved for all four radiologists.”

The Minneapolis researchers also developed a quantitative technique telling the radiologists how reliable the given choline measurements were. “When you make a measurement, you want to know if it’s reliable, if it’s a good measurement or not, and we were able to provide that with our quantitative technique,” Garwood says. The researchers told the readers when the error associated with the measurement was small and could be considered reliable and when it was large and should be discounted.

Earlier, researchers at the Minneapolis center were able to show the change in choline concentration 24 hours after the first treatment could predict whether the patient would respond to it. Their study, reported in the November 2004 issue of Radiology, followed 14 patients with locally advanced breast cancer who completed the protocol. In one patient, the level of choline was not measurable because the lesion was in an unfavorable location for MRS voxel placement.

Of the remaining 13 patients, four had inflammatory breast cancer, six had invasive ductal carcinoma, two had invasive lobular carcinoma, and one had mixed invasive ductal and lobular carcinoma. Spectroscopy was done before treatment and 24 hours after the first treatment was administered.

Eight of 13 patients had an objective response and five had no response. The change in choline concentration within 24 hours after the first dose was significantly different between patients with objective response and those with no response. “The results suggest that the change in choline concentration between baseline and 24 hours after the first dose can serve as an indicator for predicting clinical response to doxorubicin-based chemotherapy in locally advanced breast cancer,” Bolan says.

High Field, For Now
Meisamy points out, however, that all the Center for Magnetic Resonance Research’s MRI and spectroscopy studies were acquired on its high-field MR scanner. Few clinical facilities have such high-field magnets.

“We are doing our work on a 4-Tesla [4T] research MR scanner. We have some different tools, different coils, and our own unique method of acquiring the spectra,” he says. “There are currently no commercial 1.5-Tesla clinical MR scanners that have the technique to perform breast MR spectroscopy that is similar to ours at high field.” However, Meisamy is confident that their techniques can be transferred and reproduced on the current 3T clinical MR scanners. Meisamy cautions that larger studies at multiple centers need to be done before the imaging technique becomes widely practiced.

Researchers at Sloan-Kettering are also evaluating the benefits of MRS of the breast and they are predominantly using a 1.5T magnet.

At RSNA last November, Bartella reported on Sloan-Kettering’s study, which at the time involved 45 women between the ages of 20 and 77 who underwent MRS.

“We had a sensitivity of spectroscopy of 100% in the 45 patients, meaning that it did not miss any of the cancers. It picked up every single cancer,” she says. “Our specificity was 89%, which is much higher than with MRI alone.”

Bartella’s group also concluded that the positive predictive value (PPV) of the MRI improved with the addition of spectroscopy. “The positive predictive value of MRI alone was 42%. Once we added spectroscopy, it went up to 88%, which is huge,” she says.

Reducing Biopsies
Many women in the study would have been spared biopsies had spectroscopy been done in addition to the MRI study, the researchers concluded. “Biopsies would have been spared in 52% of the lesions because they showed no choline and were benign,” she says.

The cancers involved in the Sloan-Kettering study were invasive ductal cancers and invasive lobular cancers. The study included only one ductal carcinoma in situ (DCIS), where the cells lining the milk ducts are cancerous but stay contained within the ducts.

“In general, we don’t have a lot of data about spectroscopy of DCIS. There are very few cases reported in the literature,” Bartella says.

Also, because the utilized magnet was not very powerful, they could not do spectroscopy on very small lesions. “One centimeter was the smallest lesion that we did. You couldn’t do less than that because you don’t get meaningful data,” Bartella says. Also, doing more than one lesion at a time would have taken too long.

The study at Sloan-Kettering is ongoing; the number of patients included has nearly doubled since Bartella presented the results at RSNA last year, and the results continue to be promising, she says. Her goal is to enroll more than 150 patients.

Most agree that MRI is too costly to be used in place of mammograms for routine breast cancer screening of the general population. However, it is becoming standard for women who are at high risk for breast cancer to have MR screenings. High-risk women include those who have a family history of the disease and those who have inherited gene mutations (BRCA1 and BRCA2). Women who are at high risk for breast cancer are more likely to develop the disease before the age of 40, when their breasts are denser, making the images on the mammograms harder to read. For women aged 40 to 55, breast cancer is the leading cause of death.

Robert Lenkinski, of Beth Israel Deaconess, sees MRS becoming a routine part of breast MRI, especially when manufacturers make it easier to do on 1.5T scanners. “If it were easy and didn’t take a lot of time, why wouldn’t you do it every time?” he says. Spectroscopy has no known risks, he adds. Also, MRS does not require any new inventions or a leap of faith, he says. “You just have to do it.”

Broadening Use
Even though a number of premier academic centers are doing breast spectroscopy at 3T and 4T, and some of these centers are using specialized techniques, Lenkinski is very optimistic “that this can be moved into clinical practice at 1.5T.”

While Bolan, of Minnesota, believes “there still needs to be some technical developments before it’s ready to go on all clinical sites,” he “thinks it will be there … in a year or so.”

A sizable percentage of new MRI systems are 3T, he says. “That makes breast MRS—and other MRS applications—more clinically relevant,” Bolan says.

For a diagnosis of breast cancer, “I think radiologists are going to want to get as much information as they can,” Bolan says. “And spectroscopy does add valuable information. Our group and others have pretty well established that.”

The two main applications of MRS of the breast will be in distinguishing between benign and malignant tumors and predicting response to chemotherapy, Bolan says. “But there could be others as well, including determining the recurrence of cancer and staging.”

— Beth W. Orenstein writes frequently for Radiology Today from her home in Northampton, Pa.

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