Breast MRI for women with hereditary cancer risk.

Abstract

APPROXIMATELY A DECADE AGO, GERMLINE MUTAtions in BRCA1 and BRCA2 were identified as the most common detectable causes of a hereditary predisposition to breast (and ovarian) cancer. A recent meta-analysis of 22 studies indicated that the average risk of breast cancer by 70 years is 65% for women with BRCA1 mutations and 45% for BRCA2 mutations, although the risk may be substantially higher in some families. Women with BRCA1 mutations in their fourth and fifth decade of life have on average approximately a 30-fold higher risk of breast cancer than women without mutations, and BRCA2 mutation carriers are at 10-fold to 16-fold higher risk. Confronted by breast cancer risks of this magnitude, it is not surprising that a significant fraction of mutation carriers elect to undergo prophylactic mastectomy, a procedure that has been shown to reduce breast cancer risk by 90% or more. However, for many women, the physical and psychological morbidity of risk-reducing surgery is unacceptable. Although adjuvant therapy with tamoxifen appears to reduce contralateral breast cancer risk in affected mutation carriers, its value as primary prevention in unaffected women remains uncertain. While our group and other researchers have described a significant reduction in breast cancer risk among women with mutations who enter premature menopause as the result of a risk-reducing oophorectomy, protection is clearly incomplete. Women at hereditary risk who choose not to undergo preventive mastectomy have been advised to undergo breast self-examination, clinical breast examination (CBE), and annual mammography beginning at an early age (25-30 years). However, in large cohorts of BRCA mutation carriers undergoing such surveillance in New York and the Netherlands, nearly 50% of breast cancers identified were diagnosed in the interval between screening studies and nearly half of the invasive breast cancers had metastasized to axillary nodes at the time of diagnosis. The relative insensitivity of mammography among women at hereditary risk results from several factors, including the underlying breast density of these young women, the benign mammographic appearance of some BRCA-associated breast cancers, and the rapid growth rate of these frequently high-grade tumors. Magnetic resonance imaging (MRI) has emerged as an extremely powerful tool in breast cancer management. The use of the contrast agent gadolinium, in combination with sophisticated imaging protocols, allows the identification of tumor neovascularity, which cannot be detected by conventional mammography. In this issue of JAMA, the article by Warner and colleagues from a large singleinstitution study using this new technology provides important new information for women at hereditary risk regarding their surveillance options. In the study by Warner et al, 236 women with germline BRCA1 or BRCA2 mutations underwent annual multimodality screening with CBE, mammography, screening ultrasound, and breast MRI, all performed on the same day. An interval CBE was performed 6 months later. Systematic imaging and follow-up protocols were followed to minimize unnecessary biopsies generated by nonmalignant enhancement on MRI. Consistent with previous surveillance studies in women at hereditary risk, only 45% of the identified cancers would have been detected by “conventional” screening (mammography and CBE). However, of the 22 cancers diagnosed, 77% were detected by MRI, and 32% were identified by MRI alone. MRI identified a significantly greater proportion of breast cancers than either mammography (36%) or ultrasound (33%). These results are similar to those of a recently reported, multi-institutional study performed in the Netherlands by Kriege et al, in which 1909 women at a 15% or more lifetime breast cancer risk (including 358 BRCA mutation carriers) were screened annually with concurrent mammography and MRI. Of the 45 cancers diagnosed in the Netherlands cohort, 22 (49%) were detected by MRI alone, with an overall sensitivity of 71% for MRI vs 40% for mammography. Comparison of the positive predictive value (PPV) of an abnormal MRI in these and other studies is hampered by differences in the definitions used, but 17 (46%) of 37 “positive screens” in the study by Warner et al were as-