Commentary (Ghosh et al): Advising Women at High Risk of Breast Cancer
Commentary (Ghosh et al): Advising Women at High Risk of Breast Cancer
Dr. Wood has provided an excellent review of the issues facing women at high risk for developing breast cancer. In addition to emphasizing the significance of accurate risk assessment, he describes surveillance techniques that enable early detection of the disease and has provided a comprehensive review of risk-reduction options for women at high risk.
Close surveillance remains the preferred option for most high-risk women. To assess the value of an early detection strategy, we would ideally like to know the stage at diagnosis for women pursuing this strategy, the sensitivity and specificity of the tests, and the risks of the tests. Some recent data with regard to the advantages as well as potential drawbacks of using magnetic resonance imaging (MRI) of the breast as a screening tool for high-risk women are now available, and we will review these here.
Large Studies of High-Risk Women
Morris et al reported a large retrospective study of 367 asymptomatic high-risk women (defined as women with a personal history of breast cancer, lobular carcinoma in situ, atypia, or family history of breast cancer) with a normal mammogram who underwent screening breast MRI. The median age of the subjects was 50 years (range: 23 to 82 years). Biopsy was recommended in 64 women (17%). For lesions with sonographic correlates, an ultrasound-guided core needle biopsy was performed, whereas lesions without sonographic correlates underwent surgical excision following MRI-guided needle localization.
Cancer was detected in 14 of the 59 women who had a biopsy (24%), with ductal carcinoma in situ accounting for 57% of the cancers. Interestingly, the positive-predictive value of the test was greatest in the subgroups of women with a family history of breast cancer and those with both a family history and personal history of breast cancer (32% and 50%, respectively), suggesting that the test may be more useful when applied to women at the greatest risk.
In another study by Brekelmans et al, 1,198 women with high familial risk were assessed with 6-monthly clinical breast examination (CBE) and yearly mammography. MRI of the breast was added during the course of the study for women with dense breast tissue and/or BRCA1/2 mutations. There were three subsets of women in the overall cohort based on risk level: 128 BRCA1/2 carriers, 621 high-risk women defined as having an estimated lifetime breast cancer risk of 30% to 50%, and 449 women at moderate risk with an estimated lifetime risk of 15% to 30%.
With a mean follow-up of 3 years, 26 breast cancers occurred in the 1,198 women, either detected by the screening strategy or becoming clinically apparent in the interval between screenings. Overall, the sensitivity of the screening strategy was 74%. The sensitivity of the screening method was 56% for the BRCA1/2 mutation carriers, 77% for women at high risk, and 100% for women at moderate risk. Breast cancer detection rates (per 1,000 person-years) were 33, 8.4, and 3.3 for BRCA1/2 mutation carriers, high-risk, and moderate-risk groups, respectively. With regard to stage at diagnosis, 35% of all invasive tumors were node-positive, as were 56% of invasive tumors in the mutation carriers and 62% of tumors in women under age 40.
These data show that intensive screening is warranted in BRCA1/2 mutation carriers and in women under age 40, for whom newer, highly sensitive screening modalities such as breast MRI would be of greatest benefit and most cost-effective.
Additional Screening Studies
Recently available data also show promise in the use of breast MRI as a screening tool in high-risk women. In a study by Kuhl et al of 462 women with proven or suspected familial/ hereditary breast cancer risk who underwent annual screening with CBE, mammography, ultrasound, and MRI, 51 breast cancers were identified in 45 patients, with a node-negative rate of 64.7%. Of the tests studied, MRI was found to be the most sensitive (96% compared to 43% for mammography and 47% for ultrasound) and most specific (95% compared to 94% for mammography and 88% for ultrasound).
In the Dutch MRI screening study presented at the American Society of Clinical Oncology meeting in 2003, women with > 15% familial or genetic cumulative lifetime risk of breast cancer underwent 6-monthly CBE and yearly mammography and breast MRI. In the 33 months of follow-up, 30 breast cancers were detected (6 were DCIS), and the node-negative rate was 77%. The overall sensitivity was 71% for breast MRI, 36% for mammography, and 16% for CBE. The specificity was 88% for MRI, 95% for mammography, and 97% for CBE.
Limitations of MRI
While breast MRI shows definite promise for detecting early cancers in women at high risk, it is crucial that patients and participants of the screening trials are informed of the current limitations of this screening modality. The lower specificity of breast MRI results in falsepositive findings that require further investigation. In screening studies of high-risk women, recall rates from 12% to 25% have been reported.
Unfortunately, however, MRI-guided biopsy techniques are not yet optimized, nor are they widely available. Thus, when an area of concern is found on MRI, most centers turn to ultrasound to try to localize it for biopsy. Difficulty localizing these lesions can pose additional clinical challenges. Equally challenging is the follow-up of such incidentally detected abnormalities. In addition, the cost of breast MRI is approximately six times that of mammography, and the cost for a screening MRI may not be covered by insurance agencies. False-positive findings on breast MRI are also associated with significant anxiety, especially in a woman at high-risk of breast cancer.
Clearly, effective screening in young women with dense breast tissue represents a major challenge. At this time, many breast specialists are still not recommending routine screening breast MRI, even for high-risk women, due to the relatively low specificity, high cost, and difficulty in obtaining a tissue diagnosis for a lesion detected solely on MRI. Breast MRI is potentially a valuable tool in screening high-risk women for breast cancer, but further research and experience are required to lower the false-positive rate. Moreover, the availability of MRIdirected biopsies will be critical to the accurate assessment of detected abnormalities.
2. Brekelmans CTM, Seynaeve C, Bartels CCM, et al: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19:924-930, 2001.
3. Kuhl CK, Schrading S, Leutner CC, et al: Surveillance of “high risk” women with proven or suspected familial (hereditary) breast cancer: First mid-term results of a multi-modality clinical screening trial (abstract 4). Proc Am Soc Clin Oncol 22:2, 2003.
4. Kriege M, Brekelmans CTM, Boetes C, et al: MRI screening for breast cancer in women with high familial and genetic risk: First results of the Dutch MRI screening study (MRISC) (abstract 5). Proc Am Soc Clin Oncol 22:2, 2003.
5. Morris EA: Screening for breast cancer with MRI. Semin Ultrasound CT MR 24(1): 45-54, 2003.