Commentary (Esserman/Hylton): The Application of Breast MRI in Staging and Screening for Breast Cancer

In this excellent review of breast magnetic resonance imaging (MRI), Gundry discusses the potential advantages and disadvantages of magnetic resonance in breast cancer screening and management and gives recommendations for how it should be applied.

One of the most important points that should be drawn from this comprehensive review is that all MRI exams are not alike. There is a great deal of variability in technique, sequence, interpretation, and capability for follow-up and biopsy. Although the ability to order MRIs has proliferated rapidly, the standards have not. Clinicians ordering breast MRIs should be aware that technique, time of menses (the midcycle is optimal), and skill in interpretation have an enormous impact on the reported results. Interpreting images from one institution to another can also be challenging. The optimal way to interpret MRIs is on a picture archiving and communication system (PACS), which is rarely available for use between different hospital systems, posing an additional barrier to interpretation.

Role in Screening

Gundry suggests that there is a rather limited role for MRI in breast cancer screening. This is true, although the role for MRI in the imaging of extremely high-risk younger women (eg, BRCA mutation carriers) is gaining acceptance. MRI will continue to be actively pursued by both patients and clinicians as a screening method because the need for an effective screening tool is so great in this group. MRI is a very expensive, sensitive test not suitable for general screening and thus should be reserved for those situations where there is a high prior probability of identifying a cancer and where other less expensive, robust screening tools (eg, mammography) are known to be less sensitive.[1]

Women with an inherited predisposition for breast cancer on the basis of a mutation in BRCA1 or BRCA2 have as high as an 85% lifetime risk of developing breast cancer, and the majority of this risk is found between the ages of 30 and 50. While the average 35-year-old woman would have a 1 in 10,000 chance of having a cancer, a mutation carrier would have a risk in the range of 1 to 5 in 100, and MRI would be much more sensitive than mammography in this population. Women with a very high 5-year Gail risk and very dense breast tissue may also fall into this category.

Dutch Study

The true measure of a screening test is not whether it finds more cancers but whether finding the cancers decreases mortality and morbidity from breast cancer. No study has yet shown that cancers found by MRI decrease mortality from breast cancer. However, the MRI screening study from the Netherlands[1] provided detail on tumor size and lymph node involvement in the cohort of 1,909 women screened with mammography and MRI who were found to have cancers. Although the patients were not randomized, the investigators compared the results to two appropriate control groups of mutation carriers and high-risk patients, none of whom had access to MRI screening.

The study population divided women into mutation carriers (lifetime risk: 40%-85%), high risk (30%- 50%), and moderate risk (15%-30%). Among mutation carriers, 63% (or 78% if isolated cells are counted as negative) with screened cancers had negative nodes in the screening study compared to 47% of controls who did not receive MRI screening. Interestingly, in the moderate-risk group, only 12% had lymph node involvement and 87% had negative nodes (compared to 52%-56% positive nodes and 44%- 48% negative nodes in the control groups). Not suprisingly, the mutation carriers had a high proportion of grade 3 (63%), estrogen receptor (ER)-negative (67%) tumors compared to high-risk (25% high-grade and 27% ER-negative) and moderate-risk women (0% grade 3 and 12% ER-negative). Finally, one-third of the mutation carriers with screened cancers had tumors over 2 cm in diameter, compared to 13% and 19% of the high-and moderate- risk groups, respectively.

Another large study from Canada has confirmed that MRI is more sensitive than either mammography or ultrasound, with MRI sensitivity in the range of 77% to 79% compared to 30% and 33% for ultrasound and mammography, respectively.[2] The rate of detection of cancer was 26.5, 5.4, and 7.8 per 1,000 women-years for the mutation carriers, high-risk, and moderate-risk groups, respectively. The message is that the biology of the tumors in the highest-risk group is different from the lowest-risk group. The mutation carriers have high-grade tumors and a higher chance of nodal involvement and perhaps should be screened at different intervals. Many fewer cancers were detected in the high- and moderate-risk groups (less than one-quarter of the rate of the mutation carriers). There did not appear to be a difference in the rate of cancers between the moderate- and high-risk groups, but the biology was not the same.

Tailored Strategies

As we go forward, it is critical that we develop tools to improve our ability to predict which cancers women are susceptible to and tailor screening strategies accordingly. For example, BRCA2 carriers may be able to have annual screening, whereas BRCA1 carriers might be better served with more frequent screening. Interestingly, while MRI found many more cancers (20 of 45) that were not seen by mammography, 8 cancers were seen by mammography alone, and 1 was found by clinical exam alone. Thus, mammography and MRI should be staggered at 6-month intervals if ordered for women who are mutation carriers, and an exam should be performed.

Screening comes at a price, both financial and psychological. A total of 1,200 extra procedures were performed over the period of the study from the Netherlands. In the process of finding the 45 cancers, MRI led to twice as many unneeded extra procedures (420) compared to mammography (207), and three times as many unnecessary biopsies (24 vs 7 for MRI and mammography, respectively). Mammography is much less sensitive than MRI in this setting, but the falsepositive rate is double with MRI.[1]

The Dutch[1] and Canadian[2] studies demonstrate that MRI should be applied very judiciously as a screening tool and with rigorous criteria, so that we do not misapply resources and inadvertently cause women anguish over false-positives, which are both more likely and more difficult to follow and resolve because MRI-directed biopsy tools are not readily available.[1] It is common to recommend 3- or 6-month follow-up studies after an abnormal imaging test, but MRI exams cost $1,000 to $2000; it is clearly inappropriate to order these tests unless the likelihood of finding an abnormality is much higher than in the general population, and mammography is unlikely to be effective.

Critical Points

The two key messages are that we need to find ways of stratifying risk to appropriately tailor the use of technology, and MRI screening should be undertaken only in facilities that have the capability of investigating MRI abnormalities-with both ultrasound and MRI-guided biopsy, if necessary. The Blue Shield technology assessment concluded that MRI screening was justified in women who carry an inherited predisposition to breast cancer.[ 3] The Dutch[1] and Canadian[2] studies only strengthen this conclusion. Moderate- and high-risk women probably gain less overall because their risk is not as great, suggesting that MRI must become more specific and follow- up of abnormalities easier before we implement widespread screening of women at intermediate risk. Again, the goal of the scientific community should be to find better ways to discriminate risk so that screening tools can be tailored more judiciously.

Another setting in which current modalities are suboptimal includes the staging of a lobular cancer. Lobular cancers comprise only 10% of all breast cancers and are frequently more diffuse than can be appreciated clinically. The value of MRI is greatest if it is performed preoperatively, because there will be less interference with false-positive enhancement at the edge of the surgical biopsy cavity, and the target lesion can be used to help interpret other lesions that enhance.

Impact on Management

Extreme caution should be used to change operative management to mastectomy.[ 4] Because there are many false-positives, it is best to start with reexcision rather than mastectomy in a patient who strongly prefers breast conservation. Confirmation of multicentric disease should be obtained with a needle biopsy prior to making any decision to perform a mastectomy. Not only are false-positives common, but the significance of tiny lesions distant from the primary may or may not be responsible for recurrence after radiation. In the first 10 years after breast conservation, 90% of all recurrences are in the same quadrant as the original tumor, but MRI studies are finding 15% to 25% multifocal lesions.[5]

A trial conducted by the International Breast MRI Consortium showed that MRI found additional foci of cancer separate from the index lesion in 17%, whereas, in those same women, mammography found only 7.3% additional cancers.[5] The additional cases identified on MRI may represent women who would eventually require mastectomy, or those with lesions elsewhere in the breast that would not otherwise come to clinical attention. It is important to remember that no studies have been performed to help us distinguish between these two possible scenarios. The randomized trials of partial breast irradiation may help us to better answer this question, particularly if MRI were to be added as a blind clinical study. Another way to solve the problem of multicentric disease or the presence of more tumor than was originally expected is to use the neoadjuvant approach, with either chemotherapy or hormonal therapy for women over age 50 who have ER-positive disease.

Assessing Treatment Response

Assessing the response to neoadjuvant therapy is an important use of MRI. MRI is effective not only for staging the initial extent of disease[6] (to decide between treatment options), but can also be used to measure the degree and rate of response with sufficient accuracy to guide individual treatment. Nonresponsive patients can potentially be identified early in the course of treatment, allowing therapy to be modified. In responders, MRIbased measurements of tumor response may be able to stratify response levels, leading to more tailored treatment approaches, which could include extended courses of treatment or alternative chemotherapeutic agents for patients with poorer tumor responses.

As Gundry points out, in patients with a good response, residual disease can be underestimated if radiologic criteria normally used for nontreated tumors are applied. Residual disease assessment after neoadjuvant chemotherapy should only be made if a baseline MRI is available for comparison. Residual disease can then be estimated using less stringent criteria for enhancement in areas of the breast where tumor was present at baseline.[7]

The accuracy of measuring response and extent of disease after chemotherapy is being tested in a multicenter trial using a standard staging MRI protocol (ACRIN 6657). In this trial, MRI-based measurements of size-both diameter and volume-as well as measurements related to tumor perfusion will be assessed for their ability to identify nonresponsive tumors and to stratify patient outcomes based on primary tumor response. Importantly, the radiologic findings will be correlated with genomic and protein expression studies, in the hopes of linking MRI patterns to underlying biology. In the future, MRI may provide a basis for stratifying treatment.

Conclusions

MRI is a powerful tool that will improve our ability to screen and treat women with breast cancer and provide insight that will catalyze change in management, particularly in the adjuvant setting. As with any new tool, it must be judiciously applied in a setting where there is expertise in performing and interpreting the studies.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Kriege M, Brekelmans CT, Boetes C, et al: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427-437, 2004.
2. Warner E, Plewes DB, Hill KA, et al: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292:1317-1325, 2004.
3. Magnetic resonance imaging of the breast in screening women considered to be at high genetic risk of breast cancer. Blue Cross/Blue Shield, December 2003.
4. Esserman L, Hylton N, Yassa L, et al: Utility of magnetic resonance imaging in the management of breast cancer: Evidence for improved preoperative staging. J Clin Oncol 17:110-119, 1999.
5. Bluemke DA, Gatsonis CA, Chen MH, et al: Magnetic resonance imaging of the breast prior to biopsy. JAMA 292:2735-2742, 2004.
6. Esserman L, Kaplan E, Partridge S, et al: MRI phenotype is associated with response to doxorubicin and cyclophosphamide neoadjuvant chemotherapy in stage III breast cancer. Ann Surg Oncol 8:549-559, 2001.
7. Partridge SC, Gibbs JE, Lu Y, et al: Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol 179:1193-1199, 2002.