Magnetic Resonance Imaging for Screening, Diagnosis, and Eligibility for Breast-conserving Surgery: Promises and Pitfalls

Magnetic resonance imaging (MRI) is able to visualize small tumor deposits that previously could only be identified on pathologic examination. MRI is most valuable in areas in which patient management has been problematic, including screening women with known or suspected BRCA 1 and 2 mutations, and identification of the primary tumor site in patients presenting with axillary adenopathy. The role of MRI in the patient with newly diagnosed breast cancer remains controversial. Success rates for patients selected for breast-conserving therapy without MRI are high, and rates of ipsilateral breast tumor recurrence are low. Future efforts to improve the local therapy for breast cancer must acknowledge the heterogeneity of the disease and tailor approaches to the biology of individual subsets. This goal can only be accomplished through a multidisciplinary approach that examines the applications of newer diagnostic modalities such as MRI.

Breast cancer mortality in the United States, as well as in other parts of the world, has decreased in recent years, a finding that is attributable in part to the use of screening mammography and in part to improved treatment, particularly the use of adjuvant endocrine therapy and chemotherapy. Although randomized trials have shown that screening mammography reduces breast cancer mortality, it fails to detect some cancer, and its application in women less than 40 years of age remains controversial. In the cancer patient, disease burden has traditionally been the major consideration in selecting local therapy. In patients treated with breast-conserving therapy (BCT) consisting of excision of the tumor and whole-breast irradiation, randomized trials have shown that failure to reduce the tumor burden in the breast to a subclinical level is associated with an increased risk of local recurrence. This failure has resulted in multicentric cancer and margins that cannot be cleared of cancer cells being accepted as indications for mastectomy. As experience with BCT has been gained, local recurrence rates have steadily decreased.

Magnetic resonance imaging (MRI) is capable of detecting small foci of cancer in the breast that were previously only evident on detailed pathology evaluation. MRI has been applied in the screening setting and in the selection of local therapy for patients with known cancer. This article considers the available data on the effect of MRI on breast cancer screening in women at high risk, as well its effect on short- and long-term outcomes of surgical treatment of operable breast cancer.

MRI for Screening

Mammography is the proven standard of care for breast cancer screening throughout the world. After the implementation of a national mammographic screening program, a greater than 1% per year decline in breast cancer mortality was observed in the Netherlands, and the uptake of screening mammography has also been credited with up to half of the observed reduction in breast cancer mortality in the United States. Although mammography is a successful screening tool, with a documented effect on patient outcomes, approximately 10% to 15% of cancers are not visible mammographically. In particular, mammography has a lower sensitivity for cancers occurring in dense breast tissue, and misses up to 22% of invasive breast cancers in women less than 50 years of age, compared with 10% in women more than 50 years of age. Mammographic sensitivity also seems to be decreased in BRCA mutation carriers, with a high percentage of cancer being identified in the interval between annual mammograms. This is likely a consequence of the more aggressive nature of BRCA1-related cancers, which have been shown to have higher mitotic counts and are more commonly estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2 negative than sporadic cancers. In addition, BRCA-related cancers frequently occur in younger women with dense breast tissue. These limitations have led to a search for alternate methods of screening in younger women at high risk.

Compared with mammography, MRI, which relies on the increased vascularity of neoplasms, has been found to have a higher sensitivity for the detection of breast cancer, and the sensitivity is not altered by breast density. Because of the high cost of the examination, initial limited availability, and early limitations in sampling lesions visible only on MRI, screening studies to date have been performed in patients at high risk. Although there have been no prospective randomized trials of MRI screening, a systematic review from Warner and colleagues in 2008 identified 11 prospective studies of MRI screening. These included a mix of single- and multi-institutional studies with varying entry criteria. For example, the proportion of known BRCA mutation carriers varied from 8% in the study by Kuhl and colleagues to 100% in the study by Warner and colleagues In addition, all but the studies of Kreige and colleagues and Leach and colleagues included women with a prior history of breast cancer. Although all studies compared the outcome of screening with MRI to that of screening with mammography, there was variation in the number of screening rounds and the use of additional studies, such as ultrasound between studies. The sensitivity of mammography varied from 14% to 59% when a positive mammogram was defined as a Breast Imaging Reporting and Data System (BI-RADS) 4 or 5 score, whereas the sensitivity of MRI ranged from 51% to 100%. Characteristics of the largest studies included in the meta-analysis are summarized in Table 1 . In the meta-analysis, the sensitivity of mammography was 32% (95% confidence interval [CI], 23–41), and that of MRI was 75% (95% CI, 62–88). Combining the 2 procedures increased the sensitivity to 84% (95% CI, 70–97). Although all studies reported a higher sensitivity for MRI for the detection of invasive cancer, results were conflicting regarding its sensitivity for the detection of ductal carcinoma in situ (DCIS). In the studies by Kreige and colleagues and Leach and colleagues, the sensitivity of mammography was superior to that of MRI for the detection of DCIS. In contrast, Kuhl and colleagues reported a high sensitivity for the detection of DCIS with MRI. In all the studies in the meta-analysis, except that by Kuhl and colleagues, the specificity of mammography was higher than the specificity of MRI. The specificity of MRI ranged from 75% to 98%, with a meta-analysis value of 96.1% (95% CI, 94.8–97.4), and increased with subsequent screens in studies that provided these data. There was a decreased specificity of MRI (81%) in the United Kingdom study compared with the other studies. This was a multi-institutional study involving 22 centers across the United Kingdom, and the results may be more reflective of outcomes of MRI screening in the community than results from single-institution studies in which high volumes of MRI are performed and read by radiologists with substantial expertise in the field.

Table 1

Studies of MRI screening in women at high risk

	Kriege et al	Leach et al	Warner et al	Kuhl et al	Hagen et al
No. of patients	1909	649	236	529	491
Risk criteria	≥15%	≥25%	BRCA carrier	≥20%	BRCA carrier
Proven mutation carriers	19%	19%	100%	8%	100%
No. of cancers	50	22	35	43	25
Sensitivity MRI	80%	77%	77%	91%	68%

The lack of specificity of MRI results in the need for additional testing. In the study by Kriege and colleagues, the recall rate for additional imaging was 10.7% compared with 3.9% for mammography, and biopsy rates were 3.1% for MRI and 1.3% for mammography. This result may be an acceptable trade-off in patients at high risk, but the additional testing and high false-positive rates are a concern in applying MRI screening to the general population. The need for additional testing has a potential negative psychological effect and may influence compliance with future screening rounds. In a subset of the United Kingdom MRI screening study, 47% reported intrusive thoughts about the MRI examination 6 weeks later, and 4% found the MRI extremely distressing.

Although MRI screening of women at high risk clearly identifies cancers not found by mammography, whether this conveys a survival advantage is uncertain. In the trials using screening MRI, lymph node involvement was present in 14% to 26% of women at diagnosis. This finding may be a reflection of the unfavorable biologic characteristics of tumors that occur in BRCA 1 mutation carriers (ER, PR, HER2 negative), but is an important point when counseling these women at high risk regarding the benefits and risks of surveillance and intervention strategies. Although it seems unlikely that a prospective randomized trial with a survival end point will be conducted, further follow-up of the studies conducted to date should provide additional information relevant to this question.

There are few data on the outcomes of MRI screening in women who are at an increased risk of breast cancer due to factors other than a family history. Patients with diagnoses of lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH) were studied retrospectively by Port and colleagues. Those patients undergoing MRI screening were younger and had stronger family histories of breast cancer. Cancer was only identified in 1% of the 478 MRI scans performed. However, of the patients undergoing MRI, 25% were recommended to have a biopsy (most solely because of MRI findings), and almost half had at least 1 MRI requiring short-term follow-up. The sensitivity and specificity of MRI was similar to that previously reported at 75% and 92%, respectively, but clear evidence of benefit for MRI screening was not found. A potential reason that the favorable results of screening with MRI in women at genetic risk may not be duplicated in other risk groups is related to the young age of onset of cancer in BRCA mutation carriers, as well as the infrequent occurrence of DCIS in this patient group, so caution should be used when extrapolating the benefits of screening known or suspected BRCA mutation carriers to other high-risk groups.

The American Cancer Society convened a group of experts to develop guidelines for annual MRI screening that were published in 2007. The only groups for which sufficient evidence to justify the use of MRI screening was felt to be present were women proven to be BRCA mutation carriers, untested first-degree relatives of mutation carriers, and women with a lifetime risk of breast cancer development of 20% or greater as determined by models based on a family history of breast cancer. The committee considered that MRI screening was justified based on expert consensus in women at high risk due to radiation exposure at a young age and less common genetic syndromes associated with an increased risk of breast cancer. For a larger group of women at increased risk of breast cancer development, including those with a personal history of breast cancer, dense breasts, atypical hyperplasia, or LCIS, the committee considered that there was insufficient evidence to recommend for or against MRI screening ( Table 2 ). When screening with MRI was indicated, the committee recommended that mammographic screening also be performed.

Table 2

American Cancer Society screening guidelines

Recommend annual MRI screening (based on evidence ^a)	• BRCA mutation • Untested first-degree relative of BRCA carrier • Lifetime breast cancer risk ∼20%–25% or greater, as defined by models that are largely dependent on family history
Recommend annual MRI screening (based on expert consensus opinion ^b)	• Radiation to chest between age 10 and 30 years • Li-Fraumeni syndrome and first-degree relatives • Cowden syndrome and first-degree relatives
Insufficient evidence to recommend for or against MRI screening	• Lifetime risk 15%–20%, as defined by models that are largely dependent on family history • LCIS or atypical lobular hyperplasia (ALH) • ADH • Heterogeneously or extremely dense breast on mammography • Women with a personal history of breast cancer, including DCIS
Recommend against MRI screening (based on expert consensus opinion)	• Women at <15% lifetime risk

a Evidence from nonrandomized screening trials and observational studies.

b Based on evidence of lifetime risk for breast cancer.

MRI for Treatment Selection

Current guidelines for the use of BCT cite multicentric cancer as an indication for mastectomy. Clinically and radiographically, breast cancer is usually a unicentric lesion, with multicentric carcinoma identified by physical examination or mammography in fewer than 10% of cases. However, pathology studies using serial subgross sectioning of mastectomy specimens have documented that additional tumor foci are present in 21% to 63% of cases, in the same quadrant (multifocal) or other quadrants (multicentric), of a breast with what seems to be a clinically unicentric tumor. In 1 such study, Holland and colleagues evaluated mastectomy specimens of 282 patients with unicentric cancers 5 cm or smaller in size and found additional tumor foci in 63%. In 20% of cases, the additional tumor was identified within 2 cm of the index tumor, and, in the remaining 43%, at a greater distance from the primary site, although usually within 4 cm. The likelihood of identifying additional tumor foci was not related to the size of the primary tumor, and a 44% incidence of additional tumor was seen in patients with mammographically detected lesions. Such studies were initially used to argue that the treatment of breast cancer with approaches that did not remove the entire breast was inappropriate and would result in high rates of local recurrence. Extensive clinical experience, including multiple prospective randomized trials, has since shown that survival after BCT is equal to survival after mastectomy. In the current era of the routine use of adjuvant systemic therapy, 10-year rates of local recurrence after BCT are less than 10%, which is considerably lower than the incidence of multifocality/multicentricity seen in pathology studies. These findings indicate that, although subclinical tumor foci are present in significant numbers of women with clinically localized breast cancer, most of these subclinical tumor foci are controlled with radiotherapy (RT), and this paradox lies at the heart of the debate about the benefit of MRI for cancer staging and treatment selection.

In women with breast cancer, MRI identifies additional cancer foci that are not evident on clinical examination, mammogram, or ultrasound. In a meta-analysis of 19 studies, including 2610 breast cancer patients, Houssami and colleagues reported that additional cancer was identified by MRI in 16% of patients (with a range of 6%–34%). In a meta-analysis of MRI restricted to patients with lobular carcinoma reported by Mann and colleagues, which included 18 studies and 450 cancers, additional disease was detected with MRI in 32% of cases (95% CI, 22%–44%). The usefulness of MRI in DCIS is unclear. Sardanelli and colleagues observed a sensitivity of only 40% for the detection of DCIS by MRI when the results of serial subgross sectioning were used as the standard. In contrast, Kuhl and colleagues reported that MRI was significantly more sensitive than mammography for the detection of DCIS using conventional pathologic evaluation as the comparator. Of 167 women with DCIS who had undergone mammography and MRI preoperatively, DCIS was diagnosed by mammography in 56% of cases, and by MRI in 98%, with the superior performance of MRI particularly evident in high-grade DCIS.

It seems that MRI identifies some, but not all, of the tumor foci identified by pathologists using serial subgross sectioning. This question was most directly addressed by Sardanelli and colleagues, who performed MRI on 90 patients before mastectomy, then processed the mastectomy specimens with serial subgross sectioning and correlated the pathologic tumor location with the findings of the preoperative MRI. The overall sensitivity of MRI for the detection of tumor was 81%: 89% for invasive carcinoma and 40% for DCIS. In the 90 breasts studied, MRI failed to identify microscopic multifocal or multicentric disease in 19, and incorrectly indicated additional disease in 30, whereas it correctly identified the extent of tumor in 50. The mean diameter of malignant lesions not seen by MRI was 5 mm, and ranged from 0.5 mm to 15 mm.

Indirect evidence also suggests that the same tumor is identified with both techniques. Berg and colleagues observed that in 40 of 46 breasts with additional tumor foci detected with MRI, the tumor foci were within 4 cm of the index lesion. Liberman and colleagues also noted that most of the additional tumors detected were in the same quadrant as the index lesion. These findings correspond well with the observations of Holland and colleagues that 96% of pathologically detected tumor foci were within 4 cm of the index tumor.

Until recently, it has been assumed that the finding of additional cancer on MRI was clearly of benefit to the patient. In the meta-analyses by Houssami and colleagues, the results of the MRI examination changed surgical therapy in 7.8% to 33.3% of cases in individual studies, and virtually always in the direction of more extensive surgery, such as a wider excision or a mastectomy that would not otherwise have been performed. In a study of 5405 patients treated at the Mayo Clinic, Rochester, Minnesota, the use of MRI increased from 10% of newly diagnosed breast cancers in 2003 to 26% in 2006. A significant increase in the mastectomy rate was also observed during this period, and, after adjustment for age, stage, and the presence of contralateral carcinoma, women who had MRI were 1.7 times more likely to undergo mastectomy than their counterparts who did not have the examination. If the more extensive surgery that occurs as a result of MRI findings is truly beneficial to patients, it should result in improvement in short-term outcomes of surgery, such as the improved ability to identify patients requiring a mastectomy preoperatively, or an increased likelihood of achieving negative margins with a single operative procedure. Alternatively, the benefit of MRI may be to improve long-term outcomes by decreasing the incidence of local recurrence after BCT or allowing the synchronous detection of contralateral breast cancer.

The Effect of MRI on Short-term Surgical Outcomes

The identification of patients who are appropriate candidates for BCT is not a major problem. Contraindications to the procedure are reliably identified with a history, physical examination, and diagnostic mammography. Morrow and colleagues reported that of 263 consecutive patients selected for BCT between 1989 and 1993 using a history, physical examination, and diagnostic mammography, conversion to mastectomy was necessary in only 2.9%. In a population-based sample of 800 women from the Los Angeles and Detroit Surveillance Epidemiology and End Results (SEER) registry sites attempting BCT between June 2005 and May 2006, 12% required conversion to mastectomy, although in 8% mastectomy occurred after a single attempt at BCT. Two retrospective studies and 1 prospective randomized trial have examined whether the use of MRI reduces the need for mastectomy in patients attempting BCT. Bleicher and colleagues retrospectively reviewed 290 patients attempting BCT between July 2004 and December 2006 after multidisciplinary preoperative evaluation and found no significant difference in the likelihood of requiring conversion from BCT to mastectomy on the basis of a preoperative MRI. Pengel and colleagues compared outcomes with and without MRI among 355 women treated at a single institution. Those who had MRI were part of a study evaluating the procedure, and the control group consisted of patients who declined to enter the study. Again, no significant differences in the rate of unanticipated conversion to mastectomy were noted ( Table 3 ).

Table 3

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