Mdp051v1

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Mdp051v1

  1. 1. Annals of Oncology doi:10.1093/annonc/mdp051original article Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups B. G. Haffty1  *, D. H. Choi2  , S. Goyal1 , A. Silber3 , K. Ranieri4 , E. Matloff5 , M. H. Lee6 , M. Nissenblatt7 , D. Toppmeyer7 & M. S. Moran8 1 Department of Radiation Oncology, UMDNJ-RWJMS and Cancer Institute of New Jersey, New Brunswick, NJ, USA; 2 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3 Section of Medical Oncology, Department of Medicine, Yale University School of Medicine; 4 Section of Medical Genetics, Cancer Institute of New Jersey; 5 Department of Medical Genetics, Yale University School of Medicine; 6 Department of Surgery, Soonchunhyang University College of Medicine, Seoul, South Korea; 7 Section of Medical Oncology, Department of Medicine, UMDNJ-RWJMS and Cancer Institute of New Jersey and 8 Department of Therapeutic Radiology, Yale University School of Medicine Received 6 December 2008; revised 26 January 2009; accepted 9 February 2009 Background: Despite significant differences in age of onset and incidence of breast cancer between Caucasian (CA), African-American (AA) and Korean (KO) women, little is known about differences in BRCA1/2 mutations in these populations. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations and the association between BRCA1/2 mutation status and secondary malignancies among young women with breast cancer in these three racially diverse groups. Methods: Patients presenting to our breast cancer follow-up clinics selected solely on having a known breast cancer diagnosis at a young age (YBC defined as age <45 years at diagnosis) were invited to participate in this study. A total of 333 eligible women, 166 CA, 66 AA and 101 KO underwent complete sequencing of BRCA1/2 genes. Family history (FH) was classified as negative, moderate or strong. BRCA1/2 status was classified as wild type (WT), variant of uncertain significance (VUS) or deleterious (DEL). Results: DEL across these three racially diverse populations of YBC were nearly identical: CA 17%, AA 14% and KO 14%. The type of DEL differed with AA having more frequent mutations in BRCA2, compared with CA and KO. VUS were predominantly in BRCA2 and AA had markedly higher frequency of VUS (38%) compared with CA (10%) and KO (12%). At 10-year follow-up from the time of initial diagnosis of breast cancer, the risk of secondary malignancies was similar among WT (14%) and VUS (16%), but markedly higher among DEL (39%). Conclusions: In these YBC, the frequency of DEL in BRCA1/2 is remarkably similar among the racially diverse groups at 14%–17%. VUS is more common in AA, but aligns closely with WT in risk of second cancers, age of onset and FH. Key words: BRCA1, BRCA2, breast cancer, genetics, race introduction The incidence of breast cancer varies widely across geographic regions and racial groups, with the highest incidence in Caucasian (CA) women and lower incidences among African- American (AA) and Korean (KO) women. In addition, there are known and marked differences in the age of onset of breast cancer among racial groups, with CA having an average age of onset in their 50s, AA in the late 40s and KO even younger [1–3]. There are likely multiple environmental, biological and genetic factors that contribute to the variability in incidence and age of onset of disease [4]. Despite these marked differences, little is known about the racial diversity in BRCA1 and BRCA2 and the contribution of these mutations to breast cancer and secondary malignancies in younger women (YBC) among racially diverse groups [5–14]. While there is no clearly established age cutoff for young women, we have chosen in this study to use 45 years of age as a cutoff, as the vast majority of women affected at this age are in the premenopausal years and a majority of families with BRCA1/2 mutations have breast cancers presenting at or below this age. Although BRCA1 and BRCA2 mutations represent a relatively small component of breast cancers overall, YBC present with a higher frequency of BRCA1 and BRCA2 mutations. It remains unclear whether there is variability original article *Correspondence to: Dr B. G. Haffty, Department of Radiation Oncology, Cancer Institute of New Jersey, Robert Wood Johnson Medical School-UMDNJ, 195 Little Albany Street, New Brunswick, NJ 08901, USA. Tel: +1-732-235-5203; E-mail: hafftybg@umdnj.edu   These authors contributed equally to this work. ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org Annals of Oncology Advance Access published June 2, 2009
  2. 2. among racially diverse populations in the prevalence and spectrum of BRCA1/2 mutations. Such data may be useful in clinical decision making regarding genetic testing in YBC. The purpose of the current study was twofold. First, we sought to determine the prevalence and spectrum of mutations in BRCA1/2 among racially diverse populations of YBC from a general breast cancer clinic population, and secondly, we sought to evaluate the association of wild-type (WT), deleterious (DEL) mutations and variants of uncertain significance (VUS) in BRCA1/2 on secondary malignancies and family history (FH) among these populations of YBC. While there are inherent selection biases in any study of this nature, we sought to minimize selection bias by recruiting YBC who were presenting for routine evaluation or follow-up in our breast cancer clinics and not selected from high-risk familial breast cancer clinics. methods and materials For the CA and AA cohorts, YBC under age 45 from breast cancer clinics at Yale (New Haven, CT) and Cancer Institute of New Jersey (New Brunswick, NJ) were recruited for the study from January 2000 to December 2007. Patients were recruited during routine follow-up who met the eligibility criteria of age <45 years, with a known previous diagnosis of breast cancer. Many of the women seen had been treated >10 years before enrollment, which allowed for a median follow-up of >10 years after initial diagnosis. Women were classified as AA by self-description. The KO were all recruited from the Soonchunhyang University Hospital (Seoul, Korea). There were no specific exclusion or inclusion criteria other than diagnosis of breast cancer at a young age. Other racial groups were excluded from this analysis as they represented a very small proportion of patients seen at these clinics. Since AA in the two US locations represented a smaller proportion of breast cancers, accrual among AA was expectedly lower than CA. In order to increase accrual, recruitment was limited to AA in the final 3 years of the study at the two US locations. While there always inherent selection biases in recruitment of patients to these studies, the proportion of patients enrolling in the studies represented 40% of patients meeting the eligibility criteria at the two US locations for both the CA and AA groups and nearly 100% of patients approached at the KO location, as these patients were recruited during a fixed time interval from a single clinic by their treating physician. Of note, patients who had no FH or predisposing factors for familial breast cancer were routinely included in the study. Therefore, the cohorts were felt to reasonably reflect a representative sample of young women diagnosed with breast cancer from these racially diverse populations. After informed consent was obtained, complete FHs through three generations as well as details of demographic, staging, histology, pathology and treatment data was entered into a computerized database. Blood samples were drawn and patients underwent complete sequencing of genomic DNA for BRCA1 and BRCA2 through standard commercial testing [15, 16]. For this study, samples underwent routine sequencing through the Myriad Genetics Laboratories. More recent technologies, including the BRACAnalysisÒ Rearrangement Test, which detects rare, large cancer-associated rearrangements of the DNA in the BRCA1 and BRCA2 genes, which were previously undetected by standard genetic testing, were not carried out in this study. The funding agencies had no role in the design of the study or the analysis of the data. BRCA1 and BRCA2 mutations were classified in accordance with the breast cancer information core (BIC) database [17]. Patients with known DEL in BRCA1 or BRCA2 were classified as having hereditary breast cancer. Patients with genetic changes in BRCA1 or BRCA2 that are not known to be DEL were classified as VUS, in accordance with the BIC database. These changes may contribute to disease risk or may be polymorphisms that are not associated with disease risk. Patients with known polymorphisms or no mutations detected on complete sequencing of BRCA1 and BRCA2 were classified as sporadic or WT. FH was classified as none, moderate (one or more second-degree relatives with a FH of breast cancer) or strong (one or more first-degree relatives with a FH of breast cancer). At the time of entry into the study and at the time of data analysis, the details of second malignancies diagnosed before or following the diagnosis of breast cancer were entered into the database. Only biopsy-documented second malignancies as reflected in the medical record and/or the tumor registry were entered. Time to second malignancy was calculated from the date of the initial breast cancer diagnosis to the date of biopsy of the second malignancy. All demographic, clinical, pathological treatment and outcome data were entered into a computerized database. results As of December 2007, a total of 333 patients were recruited in these three populations. Characteristics of the overall patient population are summarized by group in Table 1. All patients in the study were younger than age 45 years at the time of initial diagnosis of breast cancer and the majority of patients had stage Table 1. Patient characteristics by racial group Caucasian African-American Korean P value Age (mean) 37 39 35 0.001 Family history (%) 0.001 None 46 48 69 Moderate 32 25 10 Strong 22 27 21 AJCC (%) 0.001 0 (DCIS) 11 8 2 I 55 28 36 II 34 61 58 III 0 3 4 Nodal status (%) 0.06 Negative 74 62 60 Positive 26 38 40 ER status (%) 0.21 Negative 49 59 59 Positive 51 41 41 PR status (%) 0.29 Negative 51 63 52 Positive 49 37 48 Her2/neu (%) 0.49 Negative 66 76 72 Positive 34 24 27 Triple negative 29 58 26 0.008 Histology (%) 0.04 Intraductal 13 14 3 Invasive ductal 75 76 91 Medullary 7 3 4 Other invasive 5 6 2 AJCC, American Joint Commission on Cancer; DCIS, ductal carcinoma in situ; ER, estrogen receptor; PR, progesterone receptor. original article Annals of Oncology 2 | Haffty et al.
  3. 3. I or stage II. Median age at diagnosis was 37 years in this population of YBC. There are several differences of note between the three racially diverse populations of YBC. Although all women were by definition in a younger age group, the KO were of a slightly younger age (mean 35 versus 37 years in CA and 39 years in AA) consistent with the known younger age of onset of disease in KO women with breast cancer [3]. Despite the younger age of KO, a FH of breast cancer was less frequent among this group (no FH 69%), compared with CA (no FH 47%) or AA (no FH 44%). Although the majority of patients in all three cohorts presented with stage I or stage II disease, there were less patients with ductal carcinoma in situ presenting in KO and more patients with stages II and III disease in the KO and AA compared with CA. Although there were no significant differences in individual variables of estrogen receptor, progesterone receptor or Her2/neu status among the three populations, AA had a higher proportion of triple-negative cancers, consistent with previous studies which report a high frequency of triple-negative cancers in AA [18–20]. Table 2 summarizes the results of the genetic testing in the three racial groups. Of note, the frequency of DEL in BRCA1 or BRCA2 was remarkably similar in these three racially diverse populations, varying between 14% and 17%. The high frequency of DEL mutations among YBC of Jewish ancestry is well documented. Our data are consistent with this where the frequency of DEL was 50% among 24 women classified as of Jewish ancestry (all Jewish women were in the CA cohort). Among the non-Jewish Caucasian YBC, DEL mutations were observed in 13%, as shown in Table 2. As demonstrated in Table 2 and Figure 1, there were significant differences in the spectrum of mutations, with a greater proportion of DEL BRCA2 mutations in the AA cohort (4% BRCA1 versus 8% BRCA2), whereas the distribution of mutations in CA was 12% BRCA1 versus 4% BRCA2 and KO was 8% BRCA1 and 6% BRCA2. Of particular note, there were substantially higher rates of VUS in AA, where 38% of AA were found to have VUS compared with only 10% of CA and 12% of KO. Specific mutations detected in the entire cohort are summarized in Table 3. As demonstrated in Table 4 and as anticipated, DEL were more prevalent among patients with a positive FH than in patients with no FH and were more prevalent among the youngest patients in the cohorts. Among patients with a strong FH, DEL were observed in 28% of the patients, whereas DEL were observed in 7% of patients with no FH. However, in this group of YBC, even for those with no known FH of breast cancer, the frequency of DEL varied between 6% and 10% in all three racial groups. The strong correlation between FH and DEL held across all the racial groups. Specifically, DEL were found in patients with strong FHs in 37%, 23% and 22% of the CA, AA and KO, respectively, while DEL were observed in patients with no FH in 7%, 6% and 10% in the CA, AA and KO groups, respectively. Across all three racial groups, the prevalence of DEL was higher among the younger cohorts with DEL ranging from 28% of women under the age of 30 to 11% of women over age 35. Although numbers get smaller when the results are broken down by BRCA1 and BRCA2, it appears that the relationship between DEL BRCA status, young age and FH are stronger in the BRCA1, compared with the BRCA2 patients. The AA group had a much higher incidence of VUS than the CA or KO. These VUS are nontruncating mutations, but until further data are obtained regarding their linkage with familial patterns of disease, and/or functional assays, their clinical significance with respect to cancer susceptibility remains unclear. While it is likely that many of these variants are not DEL or associated with breast cancer risk, it can be unsettling for the patient faced with the VUS as a test result. A secondary aim of this study was to assess the association of WT, DEL and VUS BRCA mutation status with age, FH and risk of secondary cancers among these racially diverse populations. With a median follow-up from original breast cancer diagnosis of over 10 years, there were a total of 65 biopsy-documented second malignancies recorded. The vast majority of these were contralateral breast cancers, followed by gynecological malignancies and a variety of gastrointestinal, lung and other malignancies. As demonstrated in Table 5, at 10 years the risk of second malignancy in the DEL group was over twice that of the WT and VUS. Figure 2 demonstrates the risk of second malignancies as a function of testing results over 15 years in this patient population. It is evident that the VUS track much more closely with the WT than the DEL, which suggests that a majority of these VUS are less likely to be functional with respect to risk of secondary cancers and less likely to be associated with strong familial history. These data are important for the large portion (38%) of AA, as well as the smaller portion of CA and KO (10%–12%), who are faced with the result of a VUS. discussion BRCA1/2 DEL appear to be present in 1% of the general population and it is estimated that DEL in BRCA1 and BRCA2 contribute to 5% of breast cancers in the general population Table 2. Results of genetic testing by racial group Caucasian African-American Korean P value Deleterious mutation 17% (28)a 14% (9) 14% (14) 0.73 Jewish 50% NA NA Non-Jewish 13% NA NA Non-deleterious mutation 83% (138) 86% (57) 86% (87) Subclassification of BRCA status 0.001 Wild type 73% (121) 48% (32) 74% (75) Deleterious mutation 17% (28) 14% (9) 14% (14) BRCA1 (21) (3) (8) BRCA2 (7) (6) (6) Variant of uncertain significance 10% (17) 38% (25) 12% (12) BRCA1 (5) (7) (4) BRCA2 (12) (18) (8) a Number of mutations in parenthesis. Annals of Oncology original article doi:10.1093/annonc/mdp051 | 3
  4. 4. and 10%–20% of YBC [21–30]. There are inherent biases in estimating the prevalence of BRCA1/2 mutations in YBC since testing is often based on screening for familial patterns of breast cancer and/or data from patients presenting to high-risk familial breast cancer clinics. However, available data suggest that between 10% and 20% of YBC may be BRCA1/2 associated, which is in agreement with the overall frequency of DEL in 14% of our young breast cancer population [10, 11,21–24]. In our study, the frequency of mutations in YBC exceeds 10% and increases with earlier age of onset and increasingly positive FH, and this association was evident among all three racially diverse populations. Our results are consistent with the population-based study from the Breast Cancer Family Registry by John et al. [10] which reported in women diagnosed with breast cancer under age 35 a mutation frequency of 16.7% in 30 AA, 8.9% in 56 Hispanic women, 2.4% in 41 KO and 9.3% in 86 non-Hispanic Whites. Nanda et al. [11] reported DEL from families presenting to a high-risk clinic in 12 of 43 (27%) AA families and 36 of 78 (46%) white families. Given that this was a high-risk clinic, the higher mutation rate compared with our study is expected. The frequency of VUS was remarkably similar to our study with 44% of AA and 11% of CA with VUS [11]. In a population-based study of breast cancer cases and controls, which was not based out of high-risk clinics, Malone et al. [7] reported DEL of 10.3% (6% BRCA1 and 4.3% BRCA2) in women aged 35–44 years, which is similar to the rate reported in our study. Their report is also consistent with our studies and others in reporting a higher rate of BRCA2 mutations in AA, though they did not report on VUS [5–8]. In our study even in patients with no FH of breast cancer, the frequency of DEL disease-associated mutations was between 6% and 10%. While we acknowledge the possibility of selection biases, patients presenting to our follow-up breast clinics were offered testing solely based on a diagnosis of breast cancer at a young age. While there is no clearly defined threshold, genetic testing has been proposed for patients whose mutation risk is 10% and certainly would be strongly considered for those with a risk of between 6% and 10% [31]. These data indicate that even in women without a strongly suggestive FH, genetic testing could be considered based on presentation with breast cancer at a young age. This would be particularly true if treatment decisions or prevention strategies may be dependent on the results of genetic testing [31–38]. In addition, since the frequency of DEL among these three racially distinct groups was nearly identical, our results suggest that when counseling patients with YBC regarding genetic testing, racial background may not be a contributing factor in the decision-making process. While our study was limited to three specific racial groups and we cannot necessarily extrapolate these results to other racial groups, there is no reason to assume that other populations would differ. Indeed a study of Hispanic women from a high-risk clinics at MD Anderson reported by Vogel et al. [39] demonstrated DEL mutations in 17% of 78 tested women and John et al. [10] reported mutations in 8.9% of 56 tested Hispanic women under age 35 and 3.2% of tested Hispanic women aged 35–49 years. Figure 1. (A–D) Frequency of mutations in population and among racial groups: overall population (A), Caucasian population (B), African-American population (C) and Korean Population (D). original article Annals of Oncology 4 | Haffty et al.
  5. 5. Although the frequency of DEL mutations was nearly identical across the racial groups, AA had a much higher frequency of VUS. The high frequency of VUS among AA women has previously been reported, and the incidence of 38% in our population is similar to the 44.2% reported by Nanda et al. [11]. While these are nontruncating mutations that may have no functional implications, their clinical significance remains to be elucidated as data accumulate from linkage to familial patterns of disease. Functional studies and other biological, mathematical and epidemiologic methods are likely to further refine our understanding of the clinical significance of these VUS [40–42]. Over time, these VUS may be reclassified as polymorphism or perhaps DEL. Our analysis of VUS Table 4. Age and family history among deleterious mutation patients Deleterious mutations overall BRCA1 BRCA2 Age group 30 7/25 = 28%a 6/25 = 20% 2/25 = 8% 30–35 17/74 = 23% 13/74 = 18% 4/74 = 5% 35 27/234 = 11% 14/234 = 6% 13/234 = 5% Family history None 14/177 = 8% 9/177 = 5% 5/177 = 3% Moderate 14/78 = 18% 7/78 = 9% 7/78 = 9% Strong 23/76 = 30%a 18/76 = 24% 6/76 = 8% a One patient in this group had deleterious mutations in both BRCA1 and BRCA2. Table 5. Comparison of variants with wild-type and deleterious mutation Variant of uncertain significance Wild type Deleterious Median age 38.5 37 35 Family history (%) None 62 57 27 Moderate 19 24 27 Strong 19 19 46 Risk of second malignancy at 10 years (%) 16 14 39 Table 3. List of mutations detected BRCA1 BRCA2 Deleterious 3875del4 (C·2) 1222delA (CA) IVS8 + 2TA (C·2) 984delCA (CA) IVS+1GA (CA) 6626delA (CA) 185delAG (C·8) 6174delT (CA · 2) C61G (CA) 1417ins4 (CA) 187delAG (C·3) 984delCA (CA) 6174delT (CA) 9017delA (AA) 5438insC (CA) Q3037X (AA) 3825del8 (CA) R3128X (AA) 1294del40 (CA) 6828delTT(AA) IVS23 + 1GA (AA) 6174delT(AA) R71G (AA) IVS13-2AG (AA) S1796X (AA) 1775delT (KO) 1041del3insT (KO) L2080X (KO) 5589del8 (KO) R2494X (KO) IVS17 + 1GT (KO) 3026delCA (KO) IVS12 + 1GT (KO) K467X (KO) Y130X (Kx2) K1533N (KO) E1661X (KO) 1623del5 (KO) Variantsa R496H (CA) K2950N (CA · 2) R1347K (CA) K3392T (CA) R1443G (CA) S2247G (CA) R1347G (CA) S1172L (CA · 2) P568L (CA) S1424C (CA) V191I (CA) A1170V (CA) M1137T(CA) F1524V (CA) V772A (AA) M192T (CA) R1645S (AA) C1365Y (CA) T37R (AA) A2466V (CA) V191I (AA) A2466V (AA) IVS23 + 1GA (AA) Q2384K (AA) S1140G (AA) V3079I (AA) D1739G (AA) I1364L (AA) S645Y (AA) H114R(AA) Q1395R (AA) E462G(AA) M1775R (AA) Q713L (AA) L1780P (KO) V2010G (AA) S1577P (K·2) N1880K (AA) G275D (KO) I379M (AA) P1150S (KO) D935H (AA) M1628T (KO) E2571G (AA) IVS19 + 8GA (AA) 21-4 AC (AA) N1880K (AA) G3212R (AA) Q713L (AA) S442L (AA) K2013E (AA) 214AC (AA) L2936F (AA) V3079I (AA) Q2384K (AA) K2339N (AA) H2440R (AA) V3244I (AA) I3412V (AA) Table 3. (Continued) BRCA1 BRCA2 V2109I (KO) E2029G (KO · 2) T27221 (KO) T582P (KO · 2) I1929V (KO · 2) G2044V (KO) a Number of variants exceeds number of patients reported as several patients had multiple variants CA, Caucasian; AA, African-American; KO, Korean. Annals of Oncology original article doi:10.1093/annonc/mdp051 | 5
  6. 6. indicated that the risk of second malignancies, familial history and age of onset was more closely aligned with the WT than with the DEL, which suggests that a majority of these VUS are less likely to be associated with hereditary breast cancer. These data may be helpful to clinicians in guiding their patients in interpreting the implications of a VUS result. The data presented here have several implications. First, it would appear that in YBC the indications for BRCA1/2 testing should be approached without regard to racial group. It appears that YBC whether of CA, AA or KO background have similar rates of DEL mutations in BRCA1/2. Furthermore, and as expected, even among this cohort of YBC, the younger the patient, and the stronger the FH, the more likely the patient is to have DEL, and this relationship holds across all the racial groups. It is also notable that the frequency of mutations even among patients with no FH was between 6% and 10%, which itself may be a high enough frequency to warrant genetic testing. It is notable that the frequency of DEL was as high in KO as it was in CA and AA, despite the fact that KO women tended to have lower rates of breast cancer in their families. This is consistent with previous observations that Asian women with BRCA mutations are less likely associated with strong FHs [14, 43]. Furthermore, as recently reported by Kurian et al. [44], modeling programs such as BRACAPRO, a BRCA mutation carrier prediction model, may not be as reliable in predicting for BRCA1 mutations in Asian women. Although all patients tested in this study carried a diagnosis of breast cancer, even in those KO women with DEL, the FHs were notably low in breast and ovarian cancers. We acknowledge, however, that underreporting of FHs or less informative families may potentially influence this result. Since other family members are likely to be carrying the DEL, it is possible that other genetic and/or environmental factors contribute to the lower penetrance of breast cancer in these families. As previously discussed, these three racially diverse populations have unique epidemiologic profiles with respect to breast cancer. The highest incidence of breast cancer is in CA whereas they have the latest age of onset of disease. AA have a slightly lower incidence of breast cancer, with a younger average age of onset, while KO have the lowest incidence of the three groups, with an even lower average age of onset. In our study, all the women selected had early-onset disease, and the frequency of DEL was nearly identical. Several studies estimate the underlying prevalence of combined BRCA1 and BRCA2 DEL mutations to be between 0.4% and 0.6%, with selected populations such as Ashkenazi Jewish populations having prevalence rates of 1.2% [7, 45, 46]. While it is difficult to extrapolate our results in this selected population of YBC to overall population genetics, our data indicate that the underlying frequency of DEL in all three of these racially distinct groups is similar and contributes equally to early-onset breast cancer in these populations. funding Susan B. Komen Foundation (POP0403085); Ethel F. Donaghue Women’s Health Investigator Program at Yale; Patterson Trust and Breast Cancer Alliance. acknowledgements The funding agencies had no role in the design of the study, evaluation, presentation of the data or review or writing of the manuscript. The authors have nothing to disclose. references 1. El-Tamer MB, Wait RB. Age at presentation of African-American and Caucasian breast cancer patients. J Am Coll Surg 1999; 188: 237–240. 2. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130. 3. Ahn SH. Clinical characteristics of breast cancer patients in Korea in 2000. 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