Breast Cancer Screening with MRI — What Are the Data for Patients at High Risk?
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《新英格兰医药杂志》
More than 275,000 women in the United States will receive a diagnosis of breast cancer this year, and 40,110 women will die of the disease.1 Randomized trials have shown that the use of screening mammography in the general population reduces mortality associated with breast cancer by at least 24 percent.2 Cancer is detected in 5 to 7 of every 1000 women on the first screening mammogram and in 2 or 3 of every 1000 women who undergo regular screening mammography. Although the average lifetime risk of breast cancer in an American woman is one in seven,1 the risk increases in women who have a history of breast cancer, atypia or lobular carcinoma in situ, mantle irradiation for Hodgkin's disease, or a strong family history of breast cancer. Women with inherited mutations of the BRCA1 or BRCA2 gene have the highest risk of breast cancer. They make up 5 to 10 percent of women with breast cancer and are also at increased risk for ovarian cancer. The cumulative risk of breast cancer in women with BRCA1 mutations is 3.2 percent by the age of 30 years, 19.1 percent by the age of 40, 50.8 percent by the age of 50, 54.2 percent by the age of 60, and 85.0 percent by the age of 70; the cumulative lifetime risk for carriers of BRCA1 or BRCA2 mutations is 50 to 85 percent.3 Breast cancers in mutation carriers often occur at a young age, have "pushing margins" and a high nuclear grade, and lack estrogen receptors.4
How can we prevent breast cancer or make an early diagnosis of the disease in women with BRCA mutations? The strategies include bilateral prophylactic mastectomy, chemoprevention, and close surveillance, including yearly mammograms beginning at 25 to 35 years of age.2,3,5 However, screening mammography detects less than half of the breast cancers in mutation carriers, perhaps owing to young age, dense breasts, or pathological features of the tumor.5,6,7,8 Cancers in mutation carriers grow rapidly; half of them appear in the interval between annual mammograms. The median size of such "interval cancers" is 1.7 cm, and half have spread to axillary lymph nodes by the time they are detected.5,6,7,8 It has been suggested that supplementing mammography with other imaging techniques, shorter screening intervals, or both may be valuable in mutation carriers.2,5,6,7,8
Magnetic resonance imaging (MRI) of the breast provides information about tissue vascularity that is not available from mammography. In many breast cancers there is neovascularity, which causes enhancement of the tumor after the injection of intravenous contrast material (gadolinium). The pattern (morphology) and time course (kinetics) of enhancement can determine the likelihood of malignancy.9 Breast MRI is highly sensitive; its disadvantages include cost, variations in technique and interpretation, imperfect specificity, variation in parenchymal enhancement during the menstrual cycle (the midcycle is optimal), exclusion criteria (e.g., the presence of pacemakers or aneurysm clips or a patient's claustrophobia), and an unproved survival benefit.10 Studies that have cumulatively evaluated breast MRI in more than 1000 high-risk patients found that the technique identified cancer that was not seen on mammography in 4 percent of cases (Table 1). 10,11,12,13,14,15
Table 1. Results of Prior Nonrandomized Studies of the Screening of High-Risk Women with Breast MRI.
In this issue of the Journal, Kriege et al.16 report a prospective, nonrandomized study of clinical breast examination, mammography, and MRI in 1909 women who had a genetic or familial predisposition to breast cancer (lifetime risk, 15 percent) in the Netherlands. Of these women, 358 (19 percent) had BRCA mutations. This work makes important contributions. Kriege et al. provide data on almost twice as many patients and twice as many mutation carriers as were included in all previously published evaluations of MRI in high-risk patients combined. Those who interpreted the MRIs and mammograms were unaware of the results of the other technique. The investigators analyzed their data in subgroups according to quantified levels of risk. Their study confirms the high sensitivity of MRI in identifying invasive breast cancer in high-risk patients.
Kriege et al. found that the breast-cancer detection rate was 9.5 per 1000 woman-years of follow-up overall: 7.8 per 1000 for women with a 15 to 29 percent lifetime risk, 5.4 per 1000 for those with a 30 to 49 percent lifetime risk, and 26.5 per 1000 for carriers of BRCA1 or BRCA2 mutations. Among 45 cancers, 22 (49 percent) were identified by MRI but not mammography, 10 (22 percent) were identified by both MRI and mammography, and 8 (18 percent) were identified by mammography but not MRI. Of these 45 tumors, 4 were interval cancers, and 1 was identified by clinical examination only. Certain features appeared in more than half of cancers in mutation carriers: they were diagnosed in women between the ages of 30 and 39 years; they were invasive cancers; and the tumors were of high nuclear grade, estrogen receptor–negative, and node-negative. Only 17 percent of cancers in mutation carriers were interval cancers. In their analyses, MRI, as compared with mammography, had higher sensitivity (71 percent vs. 40 percent) but lower specificity (90 percent vs. 95 percent).
Kriege et al. report that short-term follow-up MRI was recommended in 7 percent of examinations, as compared with 10 to 25 percent in prior reports.11,17 MRI had limited sensitivity (17 percent) in detecting ductal carcinoma in situ; in prior studies, the sensitivity of MRI for this type of lesion ranged from 0 percent13 to 100 percent.11,14 Kriege et al. also report that MRI had lower specificity than mammography, but Kuhl et al.11 found that MRI had higher sensitivity and specificity than mammography. Refinement and standardization of MRI technique and interpretation may improve specificity while retaining high sensitivity. Not addressed by Kriege et al. is the potential role of ultrasonography in screening high-risk women. In studies that supplemented mammography with both MRI and ultrasonography, MRI had higher sensitivity and specificity than ultrasonography and was superior in detecting ductal carcinoma in situ (Table 2).11,13,14
Table 2. Sensitivity and Specificity of Mammography, MRI, and Ultrasonography for Detecting Tumors in High-Risk Women.
The report by Kriege et al. highlights an important issue: How do we evaluate the efficacy of a screening test, and what is the desirable balance between sensitivity and specificity? Any method of breast-cancer screening has the potential for benefit (lifesaving cancer detection) and for harm (cost, anxiety, follow-up imaging, or benign biopsy). The prognosis is better for small, early cancers, but detecting small cancers at an early stage does not guarantee improved survival rates; detecting nonlethal cancers or cancers that have already metastasized will not decrease mortality. Only a randomized, controlled trial with death as the end point can definitively prove that any screening intervention improves survival.18
Without information provided by randomized, controlled trials, the management of breast cancer may be guided by other reports, such as observational studies, data extrapolation, and expert opinion.19 Whereas breast cancer develops in only a minority of women in the general population, the disease develops in most women who are BRCA mutation carriers (50 to 85 percent). For mutation carriers, the benefit of high sensitivity may outweigh the effects of imperfect specificity. The Blue Cross–Blue Shield Association's Technology Evaluation Center has adopted criteria for technology assessment, including that the technology improve the net health outcome; a recent report concluded that using MRI to screen women at high genetic risk for breast cancer meets this criterion.20 The new data reported by Kriege et al. provide further evidence of a benefit.
MRI can detect otherwise occult breast cancer in high-risk patients and is probably most beneficial to those at highest risk. Data are accumulating in support of supplementing mammography with MRI to detect cancer in carriers of BRCA mutations. MRI may also be valuable in screening women with an increased risk due to nongenetic factors (e.g., prior breast cancer), but more work is needed to substantiate this possibility, including analysis of the contribution of MRI in subgroups with defined risk factors and quantified levels of risk. No data support the use of MRI in screening women at normal risk. Ideally, breast MRI should be performed at facilities that follow technical and interpretive guidelines9 and that can perform biopsies of lesions detected by MRI alone.21 Whether the excellent results reported in the literature can be achieved in practice remains to be determined. Further outcomes research is essential to develop evidence-based recommendations for methods of breast-cancer screening that are tailored to the specific needs of women at various levels of risk.
Source Information
From the Memorial Sloan-Kettering Cancer Center, New York.
References
Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29.
Smith RA, Saslow D, Sawyer KA, et al. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin 2003;53:141-169.
Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BCRA1 and BRCA2. JAMA 1997;277:997-1003.
Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310-2318.
Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164.
Brekelmans CTM, Seynaeve C, Bartels CCMM, et al. Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 2001;19:924-930.
Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002;20:1260-1268.
Komenaka IK, Ditkoff BA, Joseph KA, et al. The development of interval breast malignancies in patients with BRCA mutations. Cancer 2004;100:2079-2083.
ACR breast imaging reporting and data system atlas. Reston, Va.: American College of Radiology, 2003.
Morris EA, Liberman L, Ballon DJ, et al. MRI of occult breast carcinoma in a high-risk population. AJR Am J Roentgenol 2003;181:619-626.
Kuhl CK, Schmutzler RK, Leutner 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 2000;215:267-279. [Abstract/Full Text]
Tilanus-Linthorst MMA, Obdeijn IMM, Bartels KCM, de Koning HJ, Oudkerk M. First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000;63:53-60.
Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 2001;19:3524-3531.
Podo F, Sardanelli F, Canese R, et al. The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk. J Exp Clin Cancer Res 2002;21:Suppl:115-124.
Stoutjesdijk MJ, Boetes C, Jager GJ, et al. Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 2001;93:1095-1102.
Kriege M, Brekelmans CTM, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004;351:427-437.
Liberman L, Morris EA, Benton CL, Abramson AF, Dershaw DD. Probably benign lesions at breast magnetic resonance imaging: preliminary experience in high-risk women. Cancer 2003;98:377-388.
Kopans DB, Monsees B, Feig SA. Screening for cancer: when is it valid? Lessons from the mammography experience. Radiology 2003;229:319-327.
Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process, 2004. (Accessed July 9, 2004, at http://www.ahrq.gov/clinic/ajpmsuppl/harris3.htm.)
Blue Cross Blue Shield. Magnetic resonance imaging of the breast in screening women considered to be at high genetic risk of breast cancer, December 2003. (Accessed July 9, 2004, at http://www.bluecares.com/tec/vol18/18_15.html.)
Liberman L, Morris EA, Dershaw DD, Thornton CM, Van Zee KJ, Tan LK. Fast MRI-guided vacuum-assisted breast biopsy: initial experience. AJR Am J Roentgenol 2003;181:1283-1293.(Laura Liberman, M.D.)
How can we prevent breast cancer or make an early diagnosis of the disease in women with BRCA mutations? The strategies include bilateral prophylactic mastectomy, chemoprevention, and close surveillance, including yearly mammograms beginning at 25 to 35 years of age.2,3,5 However, screening mammography detects less than half of the breast cancers in mutation carriers, perhaps owing to young age, dense breasts, or pathological features of the tumor.5,6,7,8 Cancers in mutation carriers grow rapidly; half of them appear in the interval between annual mammograms. The median size of such "interval cancers" is 1.7 cm, and half have spread to axillary lymph nodes by the time they are detected.5,6,7,8 It has been suggested that supplementing mammography with other imaging techniques, shorter screening intervals, or both may be valuable in mutation carriers.2,5,6,7,8
Magnetic resonance imaging (MRI) of the breast provides information about tissue vascularity that is not available from mammography. In many breast cancers there is neovascularity, which causes enhancement of the tumor after the injection of intravenous contrast material (gadolinium). The pattern (morphology) and time course (kinetics) of enhancement can determine the likelihood of malignancy.9 Breast MRI is highly sensitive; its disadvantages include cost, variations in technique and interpretation, imperfect specificity, variation in parenchymal enhancement during the menstrual cycle (the midcycle is optimal), exclusion criteria (e.g., the presence of pacemakers or aneurysm clips or a patient's claustrophobia), and an unproved survival benefit.10 Studies that have cumulatively evaluated breast MRI in more than 1000 high-risk patients found that the technique identified cancer that was not seen on mammography in 4 percent of cases (Table 1). 10,11,12,13,14,15
Table 1. Results of Prior Nonrandomized Studies of the Screening of High-Risk Women with Breast MRI.
In this issue of the Journal, Kriege et al.16 report a prospective, nonrandomized study of clinical breast examination, mammography, and MRI in 1909 women who had a genetic or familial predisposition to breast cancer (lifetime risk, 15 percent) in the Netherlands. Of these women, 358 (19 percent) had BRCA mutations. This work makes important contributions. Kriege et al. provide data on almost twice as many patients and twice as many mutation carriers as were included in all previously published evaluations of MRI in high-risk patients combined. Those who interpreted the MRIs and mammograms were unaware of the results of the other technique. The investigators analyzed their data in subgroups according to quantified levels of risk. Their study confirms the high sensitivity of MRI in identifying invasive breast cancer in high-risk patients.
Kriege et al. found that the breast-cancer detection rate was 9.5 per 1000 woman-years of follow-up overall: 7.8 per 1000 for women with a 15 to 29 percent lifetime risk, 5.4 per 1000 for those with a 30 to 49 percent lifetime risk, and 26.5 per 1000 for carriers of BRCA1 or BRCA2 mutations. Among 45 cancers, 22 (49 percent) were identified by MRI but not mammography, 10 (22 percent) were identified by both MRI and mammography, and 8 (18 percent) were identified by mammography but not MRI. Of these 45 tumors, 4 were interval cancers, and 1 was identified by clinical examination only. Certain features appeared in more than half of cancers in mutation carriers: they were diagnosed in women between the ages of 30 and 39 years; they were invasive cancers; and the tumors were of high nuclear grade, estrogen receptor–negative, and node-negative. Only 17 percent of cancers in mutation carriers were interval cancers. In their analyses, MRI, as compared with mammography, had higher sensitivity (71 percent vs. 40 percent) but lower specificity (90 percent vs. 95 percent).
Kriege et al. report that short-term follow-up MRI was recommended in 7 percent of examinations, as compared with 10 to 25 percent in prior reports.11,17 MRI had limited sensitivity (17 percent) in detecting ductal carcinoma in situ; in prior studies, the sensitivity of MRI for this type of lesion ranged from 0 percent13 to 100 percent.11,14 Kriege et al. also report that MRI had lower specificity than mammography, but Kuhl et al.11 found that MRI had higher sensitivity and specificity than mammography. Refinement and standardization of MRI technique and interpretation may improve specificity while retaining high sensitivity. Not addressed by Kriege et al. is the potential role of ultrasonography in screening high-risk women. In studies that supplemented mammography with both MRI and ultrasonography, MRI had higher sensitivity and specificity than ultrasonography and was superior in detecting ductal carcinoma in situ (Table 2).11,13,14
Table 2. Sensitivity and Specificity of Mammography, MRI, and Ultrasonography for Detecting Tumors in High-Risk Women.
The report by Kriege et al. highlights an important issue: How do we evaluate the efficacy of a screening test, and what is the desirable balance between sensitivity and specificity? Any method of breast-cancer screening has the potential for benefit (lifesaving cancer detection) and for harm (cost, anxiety, follow-up imaging, or benign biopsy). The prognosis is better for small, early cancers, but detecting small cancers at an early stage does not guarantee improved survival rates; detecting nonlethal cancers or cancers that have already metastasized will not decrease mortality. Only a randomized, controlled trial with death as the end point can definitively prove that any screening intervention improves survival.18
Without information provided by randomized, controlled trials, the management of breast cancer may be guided by other reports, such as observational studies, data extrapolation, and expert opinion.19 Whereas breast cancer develops in only a minority of women in the general population, the disease develops in most women who are BRCA mutation carriers (50 to 85 percent). For mutation carriers, the benefit of high sensitivity may outweigh the effects of imperfect specificity. The Blue Cross–Blue Shield Association's Technology Evaluation Center has adopted criteria for technology assessment, including that the technology improve the net health outcome; a recent report concluded that using MRI to screen women at high genetic risk for breast cancer meets this criterion.20 The new data reported by Kriege et al. provide further evidence of a benefit.
MRI can detect otherwise occult breast cancer in high-risk patients and is probably most beneficial to those at highest risk. Data are accumulating in support of supplementing mammography with MRI to detect cancer in carriers of BRCA mutations. MRI may also be valuable in screening women with an increased risk due to nongenetic factors (e.g., prior breast cancer), but more work is needed to substantiate this possibility, including analysis of the contribution of MRI in subgroups with defined risk factors and quantified levels of risk. No data support the use of MRI in screening women at normal risk. Ideally, breast MRI should be performed at facilities that follow technical and interpretive guidelines9 and that can perform biopsies of lesions detected by MRI alone.21 Whether the excellent results reported in the literature can be achieved in practice remains to be determined. Further outcomes research is essential to develop evidence-based recommendations for methods of breast-cancer screening that are tailored to the specific needs of women at various levels of risk.
Source Information
From the Memorial Sloan-Kettering Cancer Center, New York.
References
Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29.
Smith RA, Saslow D, Sawyer KA, et al. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin 2003;53:141-169.
Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BCRA1 and BRCA2. JAMA 1997;277:997-1003.
Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310-2318.
Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164.
Brekelmans CTM, Seynaeve C, Bartels CCMM, et al. Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 2001;19:924-930.
Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002;20:1260-1268.
Komenaka IK, Ditkoff BA, Joseph KA, et al. The development of interval breast malignancies in patients with BRCA mutations. Cancer 2004;100:2079-2083.
ACR breast imaging reporting and data system atlas. Reston, Va.: American College of Radiology, 2003.
Morris EA, Liberman L, Ballon DJ, et al. MRI of occult breast carcinoma in a high-risk population. AJR Am J Roentgenol 2003;181:619-626.
Kuhl CK, Schmutzler RK, Leutner 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 2000;215:267-279. [Abstract/Full Text]
Tilanus-Linthorst MMA, Obdeijn IMM, Bartels KCM, de Koning HJ, Oudkerk M. First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000;63:53-60.
Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 2001;19:3524-3531.
Podo F, Sardanelli F, Canese R, et al. The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk. J Exp Clin Cancer Res 2002;21:Suppl:115-124.
Stoutjesdijk MJ, Boetes C, Jager GJ, et al. Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 2001;93:1095-1102.
Kriege M, Brekelmans CTM, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004;351:427-437.
Liberman L, Morris EA, Benton CL, Abramson AF, Dershaw DD. Probably benign lesions at breast magnetic resonance imaging: preliminary experience in high-risk women. Cancer 2003;98:377-388.
Kopans DB, Monsees B, Feig SA. Screening for cancer: when is it valid? Lessons from the mammography experience. Radiology 2003;229:319-327.
Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process, 2004. (Accessed July 9, 2004, at http://www.ahrq.gov/clinic/ajpmsuppl/harris3.htm.)
Blue Cross Blue Shield. Magnetic resonance imaging of the breast in screening women considered to be at high genetic risk of breast cancer, December 2003. (Accessed July 9, 2004, at http://www.bluecares.com/tec/vol18/18_15.html.)
Liberman L, Morris EA, Dershaw DD, Thornton CM, Van Zee KJ, Tan LK. Fast MRI-guided vacuum-assisted breast biopsy: initial experience. AJR Am J Roentgenol 2003;181:1283-1293.(Laura Liberman, M.D.)