Magnetic Resonance Imaging in Breast Cancer: Title and subTitle BreakOne Step Forward, Two Steps Back?

The use of magnetic resonance imaging (MRI) of the breast is being examined in 2 distinct settings: as a screening test in women at high risk for breast cancer development such as those with mutations of the BRCA1 and BRCA2 genes; and as an adjunct to mammography for the selection of local therapy in women with known or suspected breast cancer. The rationale for these 2 approaches is quite different. In women with predisposition mutations, breast cancer often occurs at an early age when dense breast tissue decreases the sensitivity of mammographic screening^{1 - 2} and interval cancers are common² due to the histological features and rapid growth rates of cancerous tumors occurring in mutation carriers.^{3 - 5} These observations provide a strong biological rationale for examining alternative screening methods, particularly those not influenced by breast density. Two recent prospective trials^{6 - 7} suggest that MRI screening in this high-risk population is a promising approach.

In contrast, the role of MRI in the evaluation of women with a clinical or mammographic abnormality is less clear. The possible utility of MRI in this circumstance includes avoidance of biopsy by reliably distinguishing between benign and malignant lesions, or improving the outcome of breast conserving surgery by better definition of the extent of carcinoma in the breast. In this issue of JAMA, the report of Bluemke et al,⁸ involving 821 patients referred for breast biopsy because of suspicious mammographic or clinical findings, documented a negative predictive value for MRI of 85.4%, which is not sufficiently high to avoid a breast biopsy, and does not provide justification for the routine use of MRI. In this study, significant numbers of invasive cancers of all sizes were not detected by MRI, including 13 of 141 T1c tumors and 8 of 138 tumors greater than or equal to 2.1 cm. As in other studies, the sensitivity of MRI for the detection of intraductal carcinoma was significantly lower than for the detection of invasive carcinoma.^{6 ,9}

If MRI does not preclude the need for surgical biopsy, what accounts for the dramatic increase in its use? The answer appears to be the perception that MRI improves the selection of patients for breast conserving therapy. Contraindications to the use of breast conserving therapy include first or second trimester pregnancy, a history of prior irradiation to the breast region, the inability to obtain margins that are histologically free of tumor, and multicentric carcinoma.¹⁰ Single institution studies using MRI to evaluate clinically and mammographically localized breast cancer indicate that MRI identifies additional foci of malignancy in 15% to 34% of cases.^{11 - 12}

In the International Breast Magnetic Resonance Consortium cohort reported on by Bluemke et al,⁸ 103 of the 428 women with cancer (24%) were noted to have additional suspicious abnormalities on MRI.¹³ Of these 103 women, 78 had biopsies and 56 were found to have carcinoma. The impact of the identification of these additional foci of carcinoma on the choice of local therapy (breast conservation vs mastectomy) was not addressed in the multi-institutional study. However in the article by Bedrosian et al,¹¹ the most common change in the surgical procedure was conversion from lumpectomy to mastectomy.

The ability of MRI to identify additional carcinoma in such a large proportion of patients would suggest that MRI is an indispensable part of the preoperative evaluation, but this idea is not supported by clinical experience. Morrow et al¹⁴ demonstrated that failure of breast conserving therapy due to inability to obtain a negative margin in patients selected on the basis of a history, physical examination, and diagnostic mammography occurs in fewer than 5% of patients, and is no more frequent in patients with mammographically occult tumors than in those with mammographically evident tumors of the same size.¹⁵ Early randomized trials that documented rates of 14% to 20% for ipsilateral breast tumor recurrence at 10 to 20 years after lumpectomy and radiotherapy^{16 - 17} raised the possibility that significant numbers of patients might have undetected multicentric or multifocal disease resulting in local failure. However, more recent studies indicate that among patients with negative surgical margins, local failure rates at 10 years are less than 10%, and less than 5% in many cases.^{18 - 20}

Is it possible to reconcile the fact that MRI detects additional carcinoma in as many as a third of patients, yet clinical outcomes for patients undergoing breast-conserving therapy on the basis of clinical and mammographic selection are excellent? At this point, some clinicians may be experiencing a sense of déjà vu. In the 1970s when the prospective randomized trials of breast conserving therapy were being initiated, pathological studies demonstrating multicentric foci of carcinoma separate from the primary tumor site in 38% to 54% of patients^{21 - 22} were used to argue that even early stage breast carcinoma was a disease of the entire breast, and treatment with less than complete mastectomy was inappropriate. Extensive clinical experience has shown that the majority of these tumor foci are controlled with breast irradiation^{16 - 20} and these deposits of microscopic cancer have largely been forgotten for the past 20 years. Now, MRI technology is capable of identifying some of these occult tumor foci. Is this an appropriate reason to start doing more mastectomies? The answer is no. Prior to adopting MRI as a routine part of the evaluation of the patient with breast cancer, there should be evidence of benefit to the patient in the form of a reduced rate of ipsilateral breast tumor recurrence. This reduction in breast recurrences will need to be weighed against the number of extra biopsies resulting from the routine use of MRI, the cost, and the delay in surgical treatment.

Whether MRI will result in a meaningful clinical benefit is an open question, and one that should have been answered prior to its widespread adoption. Even the performance of mastectomy does not eliminate the problem of local tumor recurrence,^{16 - 17} so it is unrealistic to believe that an additional imaging study will do so. Evidence of clinical benefit in terms of overall survival, disease-free survival, or quality of life is the established standard for new therapeutic modalities in breast cancer. When imaging studies are used to select therapy, the same rigorous standards must be applied. But determining whether MRI reduces local recurrence in the breast from 6% to 4% at 10 years is not really the most important question to ask. The need for radiotherapy remains a major drawback to breast conserving therapy for many patients. Perhaps a more important issue is whether MRI will allow identification of a subset of patients who require no breast irradiation, or perhaps only partial breast irradiation. Only a clinical trial can definitely resolve these issues. In the absence of trials with a clinical end point, breast cancer patients undergoing MRI should be advised that this step forward in technology may take them right back to the 1970s and result in a mastectomy for disease that can be controlled with radiation.