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© 2001 American Society for Clinical Oncology Comparison of Breast Magnetic Resonance Imaging, Mammography, and Ultrasound for Surveillance of Women at High Risk for Hereditary Breast CancerByFrom the Divisions of Medical and Preventive Oncology, Departments of Medical Biophysics, Medical Imaging, Pathology, and Surgery, and Centre for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Centre; Department of Clinical Biochemistry, Toronto Hospital; and Department of Health Administration, University of Toronto, Toronto, Ontario, Canada. Address reprint requests to Ellen Warner, MD, Division of Medical Oncology, Toronto Sunnybrook Regional Cancer Centre, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada; email: ellen.warner{at}tsrcc.on.ca
PURPOSE: Recommended surveillance for BRCA1 and BRCA2 mutation carriers includes regular mammography and clinical breast examination, although the effectiveness of these screening techniques in mutation carriers has not been established. The purpose of the present study was to compare breast magnetic resonance imaging (MRI) with ultrasound, mammography, and physical examination in women at high risk for hereditary breast cancer. PATIENTS AND METHODS: A total of 196 women, aged 26 to 59 years, with proven BRCA1 or BRCA2 mutations or strong family histories of breast or ovarian cancer underwent mammography, ultrasound, MRI, and clinical breast examination on a single day. A biopsy was performed when any of the four investigations was judged to be suspicious for malignancy. RESULTS: Six invasive breast cancers and one noninvasive breast cancer were detected among the 196 high-risk women. Five of the invasive cancers occurred in mutation carriers, and the sixth occurred in a woman with a previous history of breast cancer. The prevalence of invasive or noninvasive breast cancer in the 96 mutation carriers was 6.2%. All six invasive cancers were detected by MRI, all were 1.0 cm or less in diameter, and all were node-negative. In contrast, only three invasive cancers were detected by ultrasound, two by mammography, and two by physical examination. The addition of MRI to the more commonly available triad of mammography, ultrasound, and breast examination identified two additional invasive breast cancers that would otherwise have been missed. CONCLUSION: Breast MRI may be superior to mammography and ultrasound for the screening of women at high risk for hereditary breast cancer.
WOMEN WHO CARRY a constitutional mutation of the BRCA1 gene or the BRCA2 gene face a high lifetime risk of breast cancer. The cancer risk is significant in these women at age 25, and by the age of 70, approximately 80% of mutation carriers will have developed invasive breast cancer.1 After breast cancer is diagnosed in one breast, there is a 30% risk of developing cancer in the contralateral breast within 5 years.2 Although there is evidence that breast cancer risk can be reduced by prophylactic mastectomy,3 oophorectomy,4 and tamoxifen,5 few women choose these interventions, and no preventive measure will eliminate the risk of breast cancer completely. Current recommendations for the management of high-risk women include semi-annual clinical breast examination and annual mammography beginning between the ages of 25 and 35.6 Despite widespread endorsement of mammographic screening for high-risk women, no evidence to date has shown that routine mammography reduces cancer mortality in BRCA1 or BRCA2 carriers. Most hereditary breast cancers occur in premenopausal women, and the value of screening mammography is significantly lower for women below age 50.7-9 If breast cancer screening is to be successful, the majority of cancers among screened women must be detected when tumors are small and before the occurrence of distant or nodal metastases. It may be that a combination of imaging modalities will be superior to any single screening technique. Magnetic resonance imaging (MRI) is a new breast imaging technique that is gaining popularity.10,11 With the use of gadolinium-DTPA as an intravenous contrast agent, breast MRI has been shown to be capable of detecting early breast cancer12 with 94% to 100% sensitivity.13,14 The enhancement of the breast lesion reflects local tissue changes in blood flow, capillary permeability, and extracellular volume.15,16 These changes are thought to be characteristic of tumor-related angiogenesis and help to distinguish tumors from surrounding stromal and fatty tissues. MRI quality is not influenced by breast density, which is believed to limit the effectiveness of mammography in young women. The use of MRI as a screening method for the general population is not practical at present because of its high cost and inadequate specificity17,18; however, it may be an appropriate screening tool for high-risk populations. In the general population, ultrasound is not in use as a breast cancer screening tool but is commonly used to evaluate breast abnormalities found at mammography or on physical examination. However, among high-risk women, ultrasound in combination with other methods may have a role in breast cancer screening. To determine whether MRI increases the ability to detect small breast cancers in high-risk women, beyond that of mammography, clinical breast examination, and ultrasound, we screened a series of 196 high-risk women using all four modalities.
Study Population Study subjects were recruited between November 1997 and May 2000 from the following six familial cancer clinics in southern Ontario: Toronto-Sunnybrook Regional Cancer Centre, Women’s College Hospital, North York General Hospital, University Health Network, Mt Sinai Hospital, and London Regional Cancer Centre. Eligible women were age 25 to 60 and at high risk for breast cancer because of either (1) a germline BRCA1 or a BRCA2 mutation, (2) a first-degree relative with a BRCA1 or BRCA2 mutation (but an unknown personal mutation status), or (3) three or more relatives on the same side of the family with breast cancer diagnosed before age 50 or ovarian cancer. A woman with a past history of unilateral breast cancer who satisfied the criteria was also eligible if her contralateral breast had not been removed. In this case, she could be included among the affected relatives under (3) above. Pregnant or lactating women were asked to defer their participation. Women with metallic foreign objects in their bodies, a history of bilateral breast cancer, or known metastatic disease were excluded. Participation in the study was offered to eligible women (and to their eligible first-degree relatives) in the context of genetic counseling. These women were invited to contact the study coordinator directly if they wished to participate.
Study Protocol
Physical Examination
Mammography The mammographic density of the breast tissue was evaluated from the screening mammogram. The total percentage of dense breast was calculated as the ratio of the area of dense breast compared with the total breast area using a standard protocol.20,21 In addition, the density of the breast tissue surrounding the breast cancer was compared to the overall breast density. In these cases, the location of the breast cancer was estimated by reference to the MRI image.
MRI In cases where a potentially suspicious area of enhancement (anything other than an obvious benign structure such as a blood vessel or scar) was detected, an additional set of dynamic, unilateral MRI scans of the suspicious breast was conducted. This scan involved a series of nine adjacent, two-dimensional images (SPGR, TR/TE/flip angle = 150 msec/4.2 msec/50°), which allowed dynamic monitoring of tissue enhancement with a temporal resolution of 20 seconds. These images were used to further track tracer kinetics and to help characterize the lesion for clinical management. MRI results were scored in a pattern similar to the BI-RADS classification using a combination of morphology and enhancement kinetics.22 Criteria that were considered included overall lesion configuration, lesion margins, internal architecture (eg, internal septations or central clearing), and the time course of signal intensity changes.
Ultrasound
Breast Biopsies Core and excisional biopsies were performed under ultrasound or stereotactic guidance, with the exception of two women in whom the abnormality was visualized by MRI but was not seen with directed ultrasound or mammography. In these cases, an excisional biopsy was performed using an MRI-guided wire localization device.18 This consisted of a needle guide plate that provided medial-lateral compression of the breast and contained an array of 4,000 holes drilled on 2.5 mm centers as well as MR-visible fiducial markings to allow accurate definition of the location of the tumor. The appropriate hole was used to guide the needle into the tumor for final wire localization.
Pathologic Analysis
The characteristics of the 196 study subjects are listed in Table 1. Their mean age at the time of screening was 43.3 years (range, 26 to 59 years). Ninety-six of the patients (49%) had a BRCA1 or BRCA2 mutation. Seventeen patients had unknown mutation status but had a first-degree relative with a mutation. Eighty-three patients had a strong family history of breast or ovarian cancer, but no mutation had been identified. In this category, there were 66 women for whom testing had been performed for the family, but a mutation had not yet been identified. There were 17 women for whom testing had not been performed. This group included six women who had no living affected relative available for testing and 11 women who chose not to undergo testing for other reasons. Fifty-five of the patients (28%) had a past history of breast cancer, including 34 of those with a BRCA1 or BRCA2 mutation. The majority (71%) of the women had a screening mammogram within the previous 15 months, but none had a previous MRI. Sixty-four percent performed regular breast self-examination.
Fourteen eligible women contacted the study coordinator to discuss participation but did not complete the study protocol. Seven patients declined after the study protocol was described to them in detail. Three women agreed to participate initially but could not be reached to schedule an appointment. Two women presented for an MRI examination but experienced claustrophobia and withdrew before the examination was completed. One patient became pregnant after enrolling, and her participation has been deferred. One patient discovered a lump in her breast shortly after her examination was scheduled and withdrew from the study.
Breast Cancers
MRI MRI tests were completed for 196 women. Follow-up sequence studies were performed for 32 cases (16%). One hundred seventy-three women had a result that was judged to be normal or of low suspicion, and 23 women had a result that was suspicious for cancer (BI-RADS categories 4 and 5) and have had a biopsy. For 15 of these women, the MRI was the only abnormal screening test, and for eight women, at least one additional screening test was suspicious. Cancer was detected in six (26%) of the 23 women who had a biopsy. For two of the six women with cancer, the MRI was the only abnormal screening test. The women who underwent biopsy but did not have cancer were found to have fibroadenoma (seven patients), stromal fibrosis (five), proliferative fibrocystic changes (three), fat necrosis (one), and an intramammary lymph node (one).
Mammography
Physical Examination
Ultrasound
Comparison of Screening Modalities
Pathologic Features All six invasive tumors detected were node-negative and were 1 cm or less in size (range, 0.5 to 1.0 cm). All had high-grade histologic features. Four patients had tumors with medullary features, evidenced by pushing margins, syncytial arrangement of tumor cells, and a loose fibrovascular stroma containing a lymphoplasmacytic infiltrate. These patients had documented BRCA1 or BRCA2 mutations. The tumors of the other two women showed histologic features typical of invasive breast cancer, not otherwise specified. One of these women was a BRCA1 carrier and the other had a personal and family history of breast cancer. There was no evidence of lymphatic invasion, and none of the cases showed a detectable in situ component. All tumors were estrogen and progesterone receptor–negative, all had low p27 levels, and none showed evidence of Her-2/neu overexpression or stable p53 protein. Microvessel density was high in all tumors. The range of values extended from 17 to 22 vessels per high-power field (mean, 18.5 vessels). The seven fibroadenomas detected on MRI showed values from 12 to 14 vessels per high-power field (mean, 13 vessels).
Breast Density
The objective of the present study was to compare breast MRI with mammography, screening ultrasound, and physical examination in women at high risk for hereditary breast cancer. We identified six stage I invasive cancers and one noninvasive breast cancer in our population of 196 women. All six invasive cancers were detected by MRI. In contrast, only three invasive cancers were detected by ultrasound, two by mammography, and two by physical examination. Two cancers were missed by all screening modalities other than MRI. Our estimates of sensitivity of the four screening modalities (Table 3) were based on only six tumors that were detected at the first round of screening. It is possible that we missed some cancers that will become clinically apparent over the next few years. As a result, our estimate of 100% sensitivity for MRI is likely to be high. However, no interval cancer was reported in this cohort of women to date, after a mean follow-up period of 18 months. We expect that the cancers detected in future screening rounds will be smaller on average than the mean size of 0.8 cm for cancers detected by this prevalence screen. Our results suggest that mammography is less sensitive than MRI for surveillance of BRCA1 and BRCA2 mutation carriers. Only two of six invasive tumors were identified by mammography. The poor sensitivity of mammography in this population may have been related both to the young age of the women and to the characteristics of hereditary breast cancer. The majority of hereditary breast cancers are diagnosed in premenopausal women in whom breast density is on average higher than in older women.31 Several groups of investigators have reported lower sensitivity of screening mammography and higher rates of interval cancers in women with dense breasts compared with those with fatty breasts, after adjustment for age, menopausal status, and other possible confounding factors.32-34 Interestingly, the two tumors that were detected by mammography in our study were situated in areas of low breast density, whereas those tumors not detected by mammography occurred in areas with high breast density and were either partially or completely surrounded by stromal fibrosis. In a small study of Asian women, it was found that the breast density was higher in women with BRCA1 mutations than in age-matched controls,35 but this finding has not been replicated in the North American population. In addition, BRCA1-associated tumors are less likely than sporadic tumors to have associated DCIS,36 which often presents with microcalcifications that lead to detection by mammography. Detection by MRI depends on the visualization of intravascular contrast media and is proportionate to the density of blood vessels at a given site.37 In this study, 13 false-positive results were obtained using MRI. Seven of these resulted from the detection of fibroadenomas, which were shown to have microvessel densities approaching that of the tumors. Vascular benign lesions can often but not always be distinguished from cancers on the basis of enhancement kinetics.22 Although the positive predictive value of MRI was low (26%), we chose to biopsy all lesions for which there was even a fairly low suspicion of malignancy. The majority of these patients underwent core biopsy by directed ultrasound. We are currently evaluating new techniques that we hope will help distinguish benign from malignant areas of enhancement on MRI in order to reduce the number of biopsies. It is expected that the biopsy rate on MRI screens subsequent to the initial screen will be lower. One previous study from Germany reported results similar to ours. Kuhl et al38 performed screening MRI examinations on 192 asymptomatic, high-risk women. They found invasive or in situ cancers in six (3.1%) of 192 women at the first MRI screening round and in three (3.0%) of 101 women at the second screening round. Genetic testing was not done on all patients, but of the nine women with cancer, six were carriers of a BRCA1 mutation, and one carried a BRCA2 mutation. Of the nine MRI-detected cancers, only three were apparent on mammography. It is not yet possible to establish which high-risk women would benefit from MRI surveillance, but it seems that priority should be given to women who are known to carry a BRCA1 or BRCA2 mutation. In our study, six of seven cancers were detected in women who were mutation-positive. In the German study, seven of nine women with cancer had a BRCA1 or BRCA2 mutation.38 It remains to be seen whether or not women without an identified mutation but with a significant family history of cancer are at sufficiently high risk to warrant intensive surveillance. Future studies should explore whether breast density can be helpful in selecting other groups of high-risk women most likely to benefit from MRI screening in addition to mammography. Our results suggest that MRI may be superior to mammography, ultrasound, and physical examination of the breasts for the surveillance of women at high risk for hereditary breast cancer. The invasive tumors we detected were node-negative and 1 cm or less in maximum dimension. These preliminary findings are encouraging but need to be confirmed on larger samples and with longer follow-up. Furthermore, it is not yet known what proportion of MRI-detected tumors will ultimately be cured. Large trials similar to ours are now underway in the United States and Europe.39 In the absence of a randomized screening study, the best test of the utility of MRI screening will be to document long-term survival of a cohort of the BRCA1 and BRCA2 mutation carriers with MRI-detected tumors, using combined data from all MRI screening trials.
Supported by grant no. 8410 from the Canadian Breast Cancer Research Initiative. We are indebted to radiologists P. Hamilton, B. Wright, and R. Jong; to W. Meschino, MD, B. Rosen, MD, K.J. Murphy, MD, S. Messner, MD, P.E. Goss, MD, A. Hunter, MD, and P. Goodwin, MD, for referring patients; to Edmee Franssen for help with data analysis; to Chana Weinstock for data entry; to Raymond Boyer at Sunnybrook Studios for assistance with Fig 1; and to all the women who participated in this study.
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Kuhl KC, Schmutzler RK, Luetner CC, et al: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: Preliminary results. Radiology 215: 267-279, 2000 39. Brown J, Coulthard A, Dixon AK, et al: Rationale for a national multi-centre study of magnetic resonance imaging screening in women at genetic risk of breast cancer. Breast 9: 72-77, 2000[Medline] Submitted September 18, 2000; accepted April 26, 2001. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
