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Screening of Women with Hereditary Risk of Breast Cancer
commentary Screening of Women with Hereditary Risk of Breast Cancer Christiane K. Kuhl, MD Department of Radiology University of Bonn Germany
The adequate management of individuals who carry a high lifetime risk for breast cancer is still an unsettled issue. This holds especially true for subjects with documented or suspected germline mutation of a breast cancer susceptibility gene. These women face a lifetime risk of breast cancer as high as 80%, which is of course significant. But this still means that about one fifth of these women will never develop the disease. Also, it is impossible to predict at which time in a woman’s life the threat comes true, from her thirties to many years after menopause. This, together with the perceived mutilating effects of mastectomy, makes the decision for surgical prevention very difficult for most women. Understandably, in their search for alternatives to surgical measures, patients urge their health care providers to offer screening for familial breast cancer, with the underlying assumption that early diagnosis is a synonym for (or ensures) an excellent prognosis. However, this concept is debatable in many aspects.
Breast Screening It is important to realize that there is only very limited evidence regarding the effectiveness of screening programs in women at high genetic risk. As Robson correctly summarizes in his review in this issue of Clinical Breast Cancer, there are a number of thoroughly conducted clinical screening trials under way that investigate the efficacy of imaging studies for screening women with familial breast cancer.1 Although there is some evidence to suggest that intensified screening allows an early diagnosis of familial breast cancer, the long-term efficacy of all screening efforts are unclear in terms of actual patient outcome. There may be some evidence suggesting that screening, particularly with breast
magnetic resonance imaging (MRI), may allow diagnosis of tumors in their early stages, but whether or this will translate into reduced mortality remains to be seen. The positive predictive value (PPV), number of detected cancers, or tumor stage at diagnosis are only surrogate markers for the efficacy of screening. It is important to communicate this lack of long-term outcome data to the patient and to explain that the only intervention for which an effect on mortality has been documented so far is preventive mastectomy.2,3 In this context, another problematic issue needs to be discussed: today, breast cancer awareness is high, in particular among families with several affected individuals. Probably more than in the past, today, women tend to actively seek independent information resources, such as via the media or the Internet. The very limited published evidence regarding screening MRI has been closely followed by many of these women, and this seems sufficient to make a prospective randomized clinical trial virtually impossible. Already, based on the limited evidence that exists today on the use of MRI for screening familial breast cancer, it would be difficult to withhold MRI from women at increased risk for study purposes. Accordingly, it will be increasingly difficult to set up a randomized screening trial that would be needed to investigate the efficacy of intensified screening in terms of mortality.
Figure 1 Images from a Patient with Hereditary Risk of Breast Cancer A
B
C
D
E
Imaging Techniques Robson carefully explains that there is uncertainty as to which of the available imaging techniques (mammography, high-frequency breast ultrasonography [US], and MRI) should be used for screening (Figure 1). Even if cost-effectiveness issues are disregarded, the question that remains is which technique is most suitable for this task. Surprisingly, and despite the obvious lack of scientific evidence, a number of guidelines already exist for the surveillance of women at high genetic risk of breast cancer.4-7 Yet these
Images from a 32-year-old patient with a strong family history of early-onset breast cancer and documented BRCA1 mutation. Screening mammogram and screening US were negative. MRI reveals a suspicious lesion in the lower outer quadrant of her right breast. MRI-guided localization and excisional biopsy confirmed presence of a 5-mm duct-invasive breast cancer, G3. Patient underwent breast-conserving therapy and uneventful follow-up for 6 years. A. Mammogram, mediolateral view. B. Mammogram, CC view. C: Non-enhanced MRI of the breast. D. Contrast material–enhanced MRI of the breast. E. Contrast material–enhanced subtracted MRI. Note that the mammogram is normal and that the breast parenchyma is only intermediately dense (ACR 3). Note the small enhancing lesion in the MRI.
Clinical Breast Cancer October 2004 • 269
guidelines in the majority of cases are based on “expert opinion” alone. First, systematic comparative screening trials suggested that mammography is of limited value in the young patient at high risk.8-16 Nevertheless, virtually all the existing guidelines recommend yearly bilateral 2-view mammographic screening to start at age 30 or even younger. However, the dense parenchyma in young women tends to cause diagnostic difficulties. This leads to additional mammographic burden caused by short-term follow-up studies; additional views and spot magnification views can be predicted to occur. It is important to realize that the long-term effects of such an intensified mammographic screening are unknown, particularly in BRCA mutation carriers. BRCA-regulated gene products have been implicated directly or indirectly in cell cycle regulation and DNA repair.17-19 Thus, there is evidence to suggest that carriers of pathogenic mutations of the BRCA1 or BRCA2 genes may be more susceptible to mutagenic effects of even low-dose irradiation, such as that used for mammography. So although the potentially increased radiation sensitivity should caution us to use as little ionizing radiation as possible, current guidelines recommend that we expose mutation carriers to a cumulative lifetime organ dose that will be substantially higher than that recommended for a woman at average risk. These guidelines are justifiable in view of the very high lifetime risk of breast cancer in mutation carriers, and it should be well understood that, even in the worst-case scenario, the attributable risk induced by mammographic screening will be slight. Still, if there were imaging studies at hand that offered a diagnostic accuracy equivalent to a mammogram, but without ionizing radiation, the possibly increased radiation sensitivity would be a good reason to prefer these imaging studies over mammography in this specific subset of patients. The results of several multimodality screening studies are impressively concordant in that MRI seems to be not only equivalent to mammography, but even substantially more accurate for di-
270 • Clinical Breast Cancer October 2004
agnosing early familial breast cancer. Still, MRI is only rarely offered for screening women at high genetic risk. Apart from cost, the most important reason why MRI is only reluctantly accepted for screening is probably its reported low specificity and PPV. Particularly in young women, hormonal stimulation and proliferative changes (ie, adenosis) are notorious causes of falsepositive diagnoses on MRI. These are even more problematic than false-positive mammographic or sonographic diagnoses, because any MRI-only suspicious finding would require an MRIguided intervention for clarification, or at least an additional MRI study for follow-up. Given the very low number of institutions that offer MRI-guided interventions at this time, the issue of mere availability of this type of patient care becomes a major concern. So despite the well-recognized and unprecedented sensitivity, the allegedly low PPV (high rate of false-positive MRI diagnoses) seems to outweigh the benefits. However, it is important to note that this reported low PPV is not an inherent feature of breast MRI. Rather, it is a side effect of the relative underuse of this technique compared with mammography. It is well established that the accuracy of any diagnostic imaging modality depends heavily on the experience of the interpreting radiologist. Specifically regarding mammographic screening, this has led to the recommendation to require a certain number of mammograms to be read each year by radiologists who wish to participate in screening (the current guidelines of the European Union require a minimum of 5000 mammograms to be read per year). There is no reason to assume that reading screening breast MRI or breast US would require less expertise with these imaging modalities. However, although > 40,000,000 screening mammograms are read each year in the United States, the total number of breast MRI studies is estimated to range between 6000 and 9000 per year; ie, 0.02% of the number of mammograms.20 This wide gap between the presumed average expertise in reading mammograms compared with the respective expertise in reading breast MRI studies is probably the single most im-
portant reason for the reported low PPV for breast MRI. One may even speculate that if mammograms were read with the same level of expertise as the average breast MRI study is read, the PPV of mammographic screening would in turn be considered inappropriate. Evidence suggests that with increasing practical experience, screening MRI has not only equivalent, but in fact higher, PPV compared with mammographic or US screening. Our own department sees approximately 5000 breast MRI studies per year; this translated into a PPV of 57% for MRI screening in women at high risk, compared with PPVs of 38% for mammography and only 16% for breast US in the same patients.8 So it seems that the allegedly low PPV of breast MRI is simultaneously a cause and an effect of the continued underuse of this technique, thus perpetuating the current situation. It is certainly true that false-positive diagnoses may still occur even with the most experienced readers and may impair the quality of life (QOL) of women undergoing screening. Yet the majority of women still appreciate having access to screening with MRI, because QOL is certainly worse with a diagnosis of advanced-stage breast cancer. If our screening efforts proved effective in terms of survival, then another important contribution of screening to QOL would be the fact that screening may allow women to avoid mastectomy and live their lives with their body image untouched. Our current concept is to offer yearly breast MRI together with single-view (mediolateral oblique) mammography to offer maximum sensitivity for intraductal and invasive cancer and still reduce radiation dose. Breast US is then performed between screening rounds to ensure timely surveillance of women at high risk. With this it is hoped, but not yet proven, that we do more good than harm. 1. Robson M. Breast cancer surveillance in women with hereditary risk of breast cancer with BRCA1 or BRCA2 mutations. Clin Breast Cancer 2004; 5:260-268. 2. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999; 340:77-84.
3. Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001; 345:159-164. 4. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277:997-1003. 5. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9:939-950. 6. Pichert G, Bolliger B, Buser K, et al. Evidence-based management options for women at increased breast/ovarian cancer risk. Ann Oncol 2003; 14:9-19. 7. Vasen HF, Haites NE, Evans DG, et al. Current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. European Familial Breast Cancer Collaborative Group. Eur J Cancer 1998; 34:1922-1926. 8. 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: prelimi-
nary results. Radiology 2000; 215:267-279. 9. 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. 10. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al. First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000; 63:53-60. 11. Tilanus-Linthorst MM, Bartels CC, Obdeijn AI, et al. Earlier detection of breast cancer by surveillance of women at familial risk. Eur J Cancer 2000; 36:514-519. 12. Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al. A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 2002; 102:91-95. 13. 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. 14. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast cancer screening in women with a familial and genetic predisposition. N Engl J
Med 2004; 351:427-437. 15. 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. Proc Am Soc Clin Oncol 2003; 22:2 (Abstract #4). 16. 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(3 suppl):115-124. 17. Zhou C, Smith JL, Liu J. Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1. Oncogene 2003; 22:2396-2404. 18. Somasundaram K. Breast cancer gene 1 (BRCA1): Role in cell cycle regulation and DNA repair-perhaps through transcription. J Cell Biochem 2003; 88:1084-1091. 19. Deng CX, Wang RH. Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum Mol Genet 2003; 12(suppl 1):R113-R123. 20. United States General Accounting Office, Report to the Chairman of the Special Committee on Aging, US Senate; GAO-02-532 Mammography, Capacity Generally Exists to Deliver Services; April 2002.
Clinical Breast Cancer October 2004 • 271
The adequate management of individuals who carry a high lifetime risk for breast cancer is still an unsettled issue. This holds especially true for subjects with documented or suspected germline mutation of a breast cancer susceptibility gene. These women face a lifetime risk of breast cancer as high as 80%, which is of course significant. But this still means that about one fifth of these women will never develop the disease. Also, it is impossible to predict at which time in a woman’s life the threat comes true, from her thirties to many years after menopause. This, together with the perceived mutilating effects of mastectomy, makes the decision for surgical prevention very difficult for most women. Understandably, in their search for alternatives to surgical measures, patients urge their health care providers to offer screening for familial breast cancer, with the underlying assumption that early diagnosis is a synonym for (or ensures) an excellent prognosis. However, this concept is debatable in many aspects.
Breast Screening It is important to realize that there is only very limited evidence regarding the effectiveness of screening programs in women at high genetic risk. As Robson correctly summarizes in his review in this issue of Clinical Breast Cancer, there are a number of thoroughly conducted clinical screening trials under way that investigate the efficacy of imaging studies for screening women with familial breast cancer.1 Although there is some evidence to suggest that intensified screening allows an early diagnosis of familial breast cancer, the long-term efficacy of all screening efforts are unclear in terms of actual patient outcome. There may be some evidence suggesting that screening, particularly with breast
magnetic resonance imaging (MRI), may allow diagnosis of tumors in their early stages, but whether or this will translate into reduced mortality remains to be seen. The positive predictive value (PPV), number of detected cancers, or tumor stage at diagnosis are only surrogate markers for the efficacy of screening. It is important to communicate this lack of long-term outcome data to the patient and to explain that the only intervention for which an effect on mortality has been documented so far is preventive mastectomy.2,3 In this context, another problematic issue needs to be discussed: today, breast cancer awareness is high, in particular among families with several affected individuals. Probably more than in the past, today, women tend to actively seek independent information resources, such as via the media or the Internet. The very limited published evidence regarding screening MRI has been closely followed by many of these women, and this seems sufficient to make a prospective randomized clinical trial virtually impossible. Already, based on the limited evidence that exists today on the use of MRI for screening familial breast cancer, it would be difficult to withhold MRI from women at increased risk for study purposes. Accordingly, it will be increasingly difficult to set up a randomized screening trial that would be needed to investigate the efficacy of intensified screening in terms of mortality.
Figure 1 Images from a Patient with Hereditary Risk of Breast Cancer A
B
C
D
E
Imaging Techniques Robson carefully explains that there is uncertainty as to which of the available imaging techniques (mammography, high-frequency breast ultrasonography [US], and MRI) should be used for screening (Figure 1). Even if cost-effectiveness issues are disregarded, the question that remains is which technique is most suitable for this task. Surprisingly, and despite the obvious lack of scientific evidence, a number of guidelines already exist for the surveillance of women at high genetic risk of breast cancer.4-7 Yet these
Images from a 32-year-old patient with a strong family history of early-onset breast cancer and documented BRCA1 mutation. Screening mammogram and screening US were negative. MRI reveals a suspicious lesion in the lower outer quadrant of her right breast. MRI-guided localization and excisional biopsy confirmed presence of a 5-mm duct-invasive breast cancer, G3. Patient underwent breast-conserving therapy and uneventful follow-up for 6 years. A. Mammogram, mediolateral view. B. Mammogram, CC view. C: Non-enhanced MRI of the breast. D. Contrast material–enhanced MRI of the breast. E. Contrast material–enhanced subtracted MRI. Note that the mammogram is normal and that the breast parenchyma is only intermediately dense (ACR 3). Note the small enhancing lesion in the MRI.
Clinical Breast Cancer October 2004 • 269
guidelines in the majority of cases are based on “expert opinion” alone. First, systematic comparative screening trials suggested that mammography is of limited value in the young patient at high risk.8-16 Nevertheless, virtually all the existing guidelines recommend yearly bilateral 2-view mammographic screening to start at age 30 or even younger. However, the dense parenchyma in young women tends to cause diagnostic difficulties. This leads to additional mammographic burden caused by short-term follow-up studies; additional views and spot magnification views can be predicted to occur. It is important to realize that the long-term effects of such an intensified mammographic screening are unknown, particularly in BRCA mutation carriers. BRCA-regulated gene products have been implicated directly or indirectly in cell cycle regulation and DNA repair.17-19 Thus, there is evidence to suggest that carriers of pathogenic mutations of the BRCA1 or BRCA2 genes may be more susceptible to mutagenic effects of even low-dose irradiation, such as that used for mammography. So although the potentially increased radiation sensitivity should caution us to use as little ionizing radiation as possible, current guidelines recommend that we expose mutation carriers to a cumulative lifetime organ dose that will be substantially higher than that recommended for a woman at average risk. These guidelines are justifiable in view of the very high lifetime risk of breast cancer in mutation carriers, and it should be well understood that, even in the worst-case scenario, the attributable risk induced by mammographic screening will be slight. Still, if there were imaging studies at hand that offered a diagnostic accuracy equivalent to a mammogram, but without ionizing radiation, the possibly increased radiation sensitivity would be a good reason to prefer these imaging studies over mammography in this specific subset of patients. The results of several multimodality screening studies are impressively concordant in that MRI seems to be not only equivalent to mammography, but even substantially more accurate for di-
270 • Clinical Breast Cancer October 2004
agnosing early familial breast cancer. Still, MRI is only rarely offered for screening women at high genetic risk. Apart from cost, the most important reason why MRI is only reluctantly accepted for screening is probably its reported low specificity and PPV. Particularly in young women, hormonal stimulation and proliferative changes (ie, adenosis) are notorious causes of falsepositive diagnoses on MRI. These are even more problematic than false-positive mammographic or sonographic diagnoses, because any MRI-only suspicious finding would require an MRIguided intervention for clarification, or at least an additional MRI study for follow-up. Given the very low number of institutions that offer MRI-guided interventions at this time, the issue of mere availability of this type of patient care becomes a major concern. So despite the well-recognized and unprecedented sensitivity, the allegedly low PPV (high rate of false-positive MRI diagnoses) seems to outweigh the benefits. However, it is important to note that this reported low PPV is not an inherent feature of breast MRI. Rather, it is a side effect of the relative underuse of this technique compared with mammography. It is well established that the accuracy of any diagnostic imaging modality depends heavily on the experience of the interpreting radiologist. Specifically regarding mammographic screening, this has led to the recommendation to require a certain number of mammograms to be read each year by radiologists who wish to participate in screening (the current guidelines of the European Union require a minimum of 5000 mammograms to be read per year). There is no reason to assume that reading screening breast MRI or breast US would require less expertise with these imaging modalities. However, although > 40,000,000 screening mammograms are read each year in the United States, the total number of breast MRI studies is estimated to range between 6000 and 9000 per year; ie, 0.02% of the number of mammograms.20 This wide gap between the presumed average expertise in reading mammograms compared with the respective expertise in reading breast MRI studies is probably the single most im-
portant reason for the reported low PPV for breast MRI. One may even speculate that if mammograms were read with the same level of expertise as the average breast MRI study is read, the PPV of mammographic screening would in turn be considered inappropriate. Evidence suggests that with increasing practical experience, screening MRI has not only equivalent, but in fact higher, PPV compared with mammographic or US screening. Our own department sees approximately 5000 breast MRI studies per year; this translated into a PPV of 57% for MRI screening in women at high risk, compared with PPVs of 38% for mammography and only 16% for breast US in the same patients.8 So it seems that the allegedly low PPV of breast MRI is simultaneously a cause and an effect of the continued underuse of this technique, thus perpetuating the current situation. It is certainly true that false-positive diagnoses may still occur even with the most experienced readers and may impair the quality of life (QOL) of women undergoing screening. Yet the majority of women still appreciate having access to screening with MRI, because QOL is certainly worse with a diagnosis of advanced-stage breast cancer. If our screening efforts proved effective in terms of survival, then another important contribution of screening to QOL would be the fact that screening may allow women to avoid mastectomy and live their lives with their body image untouched. Our current concept is to offer yearly breast MRI together with single-view (mediolateral oblique) mammography to offer maximum sensitivity for intraductal and invasive cancer and still reduce radiation dose. Breast US is then performed between screening rounds to ensure timely surveillance of women at high risk. With this it is hoped, but not yet proven, that we do more good than harm. 1. Robson M. Breast cancer surveillance in women with hereditary risk of breast cancer with BRCA1 or BRCA2 mutations. Clin Breast Cancer 2004; 5:260-268. 2. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999; 340:77-84.
3. Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001; 345:159-164. 4. Burke W, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277:997-1003. 5. Eisinger F, Alby N, Bremond A, et al. Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee. Ann Oncol 1998; 9:939-950. 6. Pichert G, Bolliger B, Buser K, et al. Evidence-based management options for women at increased breast/ovarian cancer risk. Ann Oncol 2003; 14:9-19. 7. Vasen HF, Haites NE, Evans DG, et al. Current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. European Familial Breast Cancer Collaborative Group. Eur J Cancer 1998; 34:1922-1926. 8. 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: prelimi-
nary results. Radiology 2000; 215:267-279. 9. 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. 10. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al. First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 2000; 63:53-60. 11. Tilanus-Linthorst MM, Bartels CC, Obdeijn AI, et al. Earlier detection of breast cancer by surveillance of women at familial risk. Eur J Cancer 2000; 36:514-519. 12. Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al. A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 2002; 102:91-95. 13. 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. 14. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast cancer screening in women with a familial and genetic predisposition. N Engl J
Med 2004; 351:427-437. 15. 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. Proc Am Soc Clin Oncol 2003; 22:2 (Abstract #4). 16. 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(3 suppl):115-124. 17. Zhou C, Smith JL, Liu J. Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1. Oncogene 2003; 22:2396-2404. 18. Somasundaram K. Breast cancer gene 1 (BRCA1): Role in cell cycle regulation and DNA repair-perhaps through transcription. J Cell Biochem 2003; 88:1084-1091. 19. Deng CX, Wang RH. Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum Mol Genet 2003; 12(suppl 1):R113-R123. 20. United States General Accounting Office, Report to the Chairman of the Special Committee on Aging, US Senate; GAO-02-532 Mammography, Capacity Generally Exists to Deliver Services; April 2002.
Clinical Breast Cancer October 2004 • 271