Performance measures of 8,169,869 examinations in the National Breast Cancer Screening Program in Taiwan, 2004-2020.

BACKGROUND: The benefits of mammographic screening have been shown to include a decrease in mortality due to breast cancer. Taiwan's Breast Cancer Screening Program is a national screening program that has offered biennial mammographic breast cancer screening for women aged 50-69 years since 2004 and for those aged 45-69 years since 2009, with the implementation of mobile units in 2010. The purpose of this study was to compare the performance results of the program with changes in the previous (2004-2009) and latter (2010-2020) periods. METHODS: A cohort of 3,665,078 women who underwent biennial breast cancer mammography screenings from 2004 to 2020 was conducted, and data were obtained from the Health Promotion Administration, Ministry of Health and Welfare of Taiwan. We compared the participation of screened women and survival rates from breast cancer in the earlier and latter periods across national breast cancer screening programs. RESULTS: Among 3,665,078 women who underwent 8,169,869 examinations in the study population, the screened population increased from 3.9% in 2004 to 40% in 2019. The mean cancer detection rate was 4.76 and 4.08 cancers per 1000 screening mammograms in the earlier (2004-2009) and latter (2010-2020) periods, respectively. The 10-year survival rate increased from 89.68% in the early period to 97.33% in the latter period. The mean recall rate was 9.90% (95% CI: 9.83-9.97%) in the early period and decreased to 8.15% (95%CI, 8.13-8.17%) in the latter period. CONCLUSIONS: The evolution of breast cancer screening in Taiwan has yielded favorable outcomes by increasing the screening population, increasing the 10-year survival rate, and reducing the recall rate through the participation of young women, the implementation of a mobile unit service and quality assurance program, thereby providing historical evidence to policy makers to plan future needs.

Breast Nonmass Enhancement Detected with MRI: Uility and Lesion Characterization with Second-Look Ultrasonography.

The purpose of this study was to verify the utility of second-look ultrasonography (US) in evaluating nonmass enhancement (NME) lesions detected on breast magnetic resonance imaging (MRI) by analysing its correlation and imaging features. From July 2008 to June 2012, 102 consecutive MRI-detected NME lesions were subsequently evaluated with US. Lesions were evaluated according to the established Breast Imaging Reporting and Data System (BI-RADS) lexicon. The correlation between MRI-detected NME lesion characteristics, lesion size, histopathological findings and features at second-look US were analysed. Second-look US identified 44/102 (43%) of the NME lesions revealed by MRI. A US correlate was seen in 34/45 (76%) malignant lesions compared with 10/57 (18%) benign lesions (p < 0.0001). The likelihood of malignancy was significantly higher for NME lesions with a US correlate than lesions without: 34/44 (77%) versus 11/58 (19%) (p < 0.0001). The malignancy of the 44 (43%) MRI-detected NME lesions with a US correlate was significantly associated with US lesion margins and BI-RADS categories (p = 0.001 and 0.002 respectively). Second-look US of MRI-detected NME lesions is useful for decision-making as part of the diagnostic workup. Familiarity with the US features associated with malignancy improves the utility of US in the workup of these NME abnormalities.

Effects of quality assurance regulatory enforcement on performance of mammography systems: evidence from large-scale surveys in Taiwan.

OBJECTIVE: The Standards for Medical Exposure Quality Assurance in mammography systems were enacted on July 1, 2008, in Taiwan. This study aimed to evaluate the trends in performance of mammography units before and after the regulation started on the basis of annual on-site surveys from 2008 to 2010. MATERIALS AND METHODS: On-site measurements were conducted on 215, 205, and 209 mammography units in 2008, 2009, and 2010, respectively, which accounted for more than 95% of all units in Taiwan. Phantom image quality, average glandular dose (AGD), and half-value layer were evaluated on all systems. Processor conditions, compression conditions, radiation output, and computed radiography exposure indicators were assessed on units participating in mammography screening in 2008 and on all units in the later years. Evaluations of maximum compression force and automatic exposure control reproducibility were added into the protocol from 2009 onward. RESULTS: Mean phantom scores were improved significantly from 2008 to 2009 (11.63 ± 1.30 vs 12.31 ± 0.94, p < 0.05) and remained stable for 2010 (12.35 ± 0.87). Mean AGDs were 1.48 ± 0.47, 1.38 ± 0.41, and 1.37 ± 0.42 mGy over the 3 years, with a significant reduction from 2008 to 2009 (p < 0.05). For film-screen mammography systems, variations of sensitometric curves were greatly reduced in 2009 and 2010 when compared with 2008. Passing rates were increased after the regulation took effect in almost all aspects. CONCLUSION: Results from large-scale on-site surveys showed an overall improvement in performance after quality assurance in mammography was enforced in Taiwan.

Genetic variation in the genome-wide predicted estrogen response element-related sequences is associated with breast cancer development.

INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the promoter region of estrogen-responsive genes, regulates their transcription, and consequently mediates physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect the estrogen-ER-ERE interaction. In this study, we examined the hypothesis that genetic variations of EREs are associated with breast cancer development. METHODS: This case-control study involved 815 patients of Asian descent with incident breast cancer and 821 healthy female controls. A total of 13,737 ERE sites in the whole genome predicted by a genome-wide computational algorithm were blasted with single-nucleotide polymorphism (SNP) sequences. Twenty-one SNPs located within 2,000 bp upstream or within introns 1 and 2 of putative genes and with a minor allele frequency greater than 5% were identified and genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility. RESULTS: A significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for ER, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of lifetime estrogen exposure, supporting a hormonal etiology of this SNP in breast tumorigenesis. CONCLUSIONS: Our findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development.

Joint effect of peroxisome proliferator-activated receptor γ genetic polymorphisms and estrogen-related risk factors on breast cancer risk: results from a case-control study in Taiwan.

Peroxisome proliferator-activated receptor γ (PPARγ) has been linked with possible antineoplastic effects in colorectal carcinogenesis. However, data for the possible link between PPARγ and breast cancer risk are sparse. We assessed the association of three polymorphisms in PPARγ (rs10865710 [C-681T], rs1805192 [Pro12Ala], and rs3856806 [C1431T]) with the risk of breast cancer in an ethnic Chinese female population in Taiwan. In addition, interactions with estrogen exposures were also explored. Genotypes for the PPARγ polymorphisms were determined on 291 incident breast cancer cases and 589 matched controls by fluorogenic 5'-nuclease assay. The at-risk haplotypes were defined according to the three polymorphisms in the following order: C-681T, Pro12Ala, and C1431T, which include CCT, GGT, and GGC. In addition, a critical period of estrogen exposure was estimated by the interval between age at menarche and age at first full-term pregnancy. Overall, there was no evidence of a significant impact of individual polymorphisms of PPARγ on breast cancer risk. However, the haplotype analysis revealed that women harboring at-risk haplotypes showed a significant 67% increase in breast cancer risk [adjusted odds ratio (OR) 1.67; 95% confidence interval (CI) 1.11-2.52]. Furthermore, there was a significant joint effect of estrogen exposure-related factors and at-risk haplotypes of PPARγ on breast cancer risk (adjusted OR 4.04; 95% CI 1.89-8.65), particularly in premenopausal women. The present study implicates a role for PPARγ in breast cancer risk. Mechanistic studies to fully elucidate the mechanisms underlying PPARγ's effects should be pursued in future investigations.

Dietary intake of vitamin B(6) and risk of breast cancer in Taiwanese women.

BACKGROUND: B vitamins, including vitamin B(6), are coenzymes that are important for DNA integrity and stability. Deficiencies in B vitamins may promote tumor carcinogenesis. METHODS: We examined the association of dietary vitamin B(6) intake with overall breast cancer risk and breast cancers stratified by hormone receptor status. This case-control study included 391 breast cancer cases and 782 control subjects enrolled at the Tri-Service General Hospital in Taipei, Taiwan. Energy-adjusted intake of vitamin B(6) was derived from a food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: As compared with women in the lowest tertile, the multivariate-adjusted ORs for breast cancer among women in the second and highest tertiles of vitamin B(6) intake were 0.78 (95% CI, 0.64-2.52) and 0.64 (0.26-0.92), respectively. In addition, higher vitamin B(6) intake was associated with a significantly lower risk of developing ER-negative breast tumors. CONCLUSIONS: Our findings suggest that higher intake of vitamin B(6) is associated with a reduction in breast cancer risk, particularly ER-negative tumors.

Relationships between critical period of estrogen exposure and circulating levels of insulin-like growth factor-I (IGF-I) in breast cancer: evidence from a case-control study.

Epidemiological observations suggest that insulin-like growth factor-I (IGF-I), a potent mitogenic and anti-apoptotic peptide, plays a role in the etiology of breast cancer. Estrogen, which is crucial in breast carcinogenesis, both regulates and is influenced by IGF-I family. A case-control study was conducted to assess the role of IGF-I as a biomarker for breast cancer and to evaluate the potential joint effect of circulating IGF-I and critical period of estrogen exposure, as estimated by the interval between age at menarche and age at first full-term pregnancy on the risk of breast cancer. Questionnaire information and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2006. Plasma levels of IGF-I and IGFBP-3 were measured by immunoradiometric assay. Conditional logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Our case-control data indicate that breast cancer risk related to IGF-I differs according to menopausal status. High circulating levels of IGF-I increased risk of pre- but not postmenopausal breast cancer (top vs. bottom tertile, adjusted OR, 1.86; 95% CI, 1.01-3.44). Furthermore, elevated IGF-I concentrations in conjunction with prolonged interval of critical period of estrogen exposure were associated with significantly increased risk of breast cancer, particularly among estrogen-positive cases (adjusted OR, 2.42, 95% CI, 1.33-4.38). These results suggest that the joint effect of IGF-I and estrogens may provide novel methods of breast cancer risk reduction among women.

Adipocytokine resistin and breast cancer risk.

Adipocytokine resistin is a member of the newly discovered family of cysteine-rich protein. Recent data suggest that macrophages are a major source of human resistin. Given the obesity-breast cancer link and convergence of adipocyte and macrophage function, resistin may provide unique insight into links between obesity, inflammation, and breast cancer risk in humans. We conducted a hospital-based case-control study to evaluate whether plasma resistin levels were associated with breast cancer risk in women. We also examined the modification effect of estrogen exposures on the resistin-breast cancer link. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 380 incident cases with breast cancer and 760 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2008. Plasma levels of resistin were measured by enzyme immunoassay. Cumulative exposure to estrogens were estimated according to the age at menarche and age at enrollment for premenopausal women and age at menarche and age at menopause for postmenopausal women. Cases with breast cancer had significantly elevated resistin concentrations as compared with control subjects. Compared with those in the lowest quartile, the adjusted odds ratios of breast cancer for women in the second, third, and highest quartiles were 1.48 [95% confidence interval (CI) = 0.65-3.38], 1.76 (95% CI = 1.00-4.73), and 2.08 (95% CI = 1.04-3.85), respectively. Furthermore, the biological gradient of breast cancer risk by plasma resistin levels remained after adjustment for measures of adiposity. The dose-dependent relationship of resistin levels with breast cancer risk was notably pronounced among women with excess exposure to estrogens. Adipocytokine resistin may have an adiposity-independent role in breast carcinogenesis. Mechanistic studies to fully elucidate the mechanisms underlying resistin's effects should be pursued in future investigations.

Ultrasonographic alterations associated with the dilatation of mammary ducts: feature analysis and BI-RADS assessment.

OBJECTIVE: The purpose of this study was to analyse the lesion characteristics and the patterns of dilated ducts on ultrasonography (US) to determine the appropriateness of the Breast Imaging Reporting and Data System (BI-RADS) categories. MATERIALS AND METHODS: From July 2001 to June 2006, 172 consecutive pathologically proved lesions with dilated ducts on US were reviewed retrospectively. All the lesions were classified into four types according to their US features, and in combination with the size, location, margins and number of lesions, the corresponding positive predictive values (PPVs) were obtained. RESULTS: Of the 172 lesions, 55 (32%) were classified as type I, 68 (40%) as type II, 14 (8%) as type III and 35 (20%) as type IV. The PPVs for malignancy were 9% for type I, 13% for type II, 43% for type III and 17% for type IV. There was a significantly higher frequency of malignancy among type III lesions than among type I (43% vs 9%, respectively, P = 0.002; chi (2) test) or type II lesions (43% vs 13%, respectively, P = 0.009; chi (2) test). Lesions with a nonsubareolar location and noncircumscribed margins had a high probability of malignancy (P < 0.001 and P = 0.03, respectively). CONCLUSION: The four types of US classifications used in our study establish reliable references for the dilated duct patterns when stratified according to BI-RADS categories, and they clarify the indications for biopsy of these lesions.

Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility.

The role of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, in the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair suggests that the mechanisms involved in HR and DNA DSB repair are of etiological importance during breast tumorigenesis. Bloom (BLM) helicase directly interacts with RAD51 recombinase, which is involved in regulating HR, and it is thus of particular interest to examine whether this interaction is associated with breast cancer susceptibility. This single-nucleotide polymorphism (SNP)-based case-control study was performed to examine this hypothesis using specimens from 933 patients with breast cancer and 1539 healthy controls. The results showed that one SNP (rs2380165) in BLM and two (rs2412546 and rs4417527) in RAD51 were associated with breast cancer risk. Furthermore, haplotype and diplotype analyses based on combinations of five SNPs in RAD51 revealed a strong association between RAD51 polymorphisms and breast cancer risk (P < 0.05). Support for the interaction between BLM and RAD51 in determining breast cancer risk came from the finding that the association between cancer risk and at-risk genotypes/haplotype pairs of RAD51 was stronger and more significant in women harboring homozygous variant alleles of BLM (P for interaction < 0.05). Interestingly, not only the intronic SNP located within the region encoding the helicase domain of BLM but also those within the RAD51-interaction domain-encoding region showed an interaction with RAD51 polymorphisms in determining breast cancer susceptibility. Our results suggest a contribution of BLM and RAD51 to breast cancer development and provide support for the tumorigenic significance of the functional interaction between these two HR proteins.

Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes.

Tumor levels of the cell cycle regulators cyclin E and p27 correlate strongly with survival in breast cancer patients and are specifically regulated by the ubiquitin ligases hCDC4 and SKP2. This study was to explore whether genetic susceptibility to breast cancer is associated with polymorphism of these genes and whether gene-gene and gene-risk factor [i.e. full-term pregnancy (FTP)] interactions are important in determining cancer risk. A two-stage case-control study based on single-nucleotide polymorphisms was performed. The first study (560 cases and 1122 controls) was to define the contribution of cell cycle and ubiquitin ligase genes to cancer susceptibility. The second study (926 cases and 923 controls) was to confirm the association identified in the first stage and to map the variant alleles. Increased breast cancer risk was associated with both polymorphism of hCDC4 and a joint effect of cyclin E and hCDC4. These associations were more significant in nulliparous women, and cancer risk associated with a lower number of FTPs was only seen in women with a higher number of high-risk genotypes, providing support for an effect of gene-risk factor interaction in determining susceptibility. Sequence variants of intron 2 in hCDC4 were found to be the most significant polymorphism and high-stage estrogen receptor (ER)-negative patients carrying the homozygous variant genotype manifested significantly poorer survival. This study concludes that polymorphism of hCDC4 is a risk factor for breast cancer development by interacting with either cyclin E or FTP and may also prove useful in predicting progression of patients with high-stage and ER-negative breast cancers.

Value of sonographically guided needle sampling of cystic versus solid components in the diagnosis of complex cystic breast masses.

BACKGROUND: The common practice for diagnosis of complex cystic breast masses (CCBM) may be imaging-guided aspiration or biopsy of cystic or solid components. PURPOSE: To assess the diagnostic value of sonographically guided needle sampling of cystic and solid components for CCBM. MATERIAL AND METHODS: Twenty patients with 20 CCBM underwent sonographically guided fine-needle aspiration biopsy (FNAB) for cystic components, followed by core needle biopsy (CNB) for residual solid components. The diagnostic results of each were evaluated. Excisional biopsy or mastectomy served as a reference standard. RESULTS: Fourteen (70%) masses were malignant. Needle sampling for cystic components of the 14 malignant tumors showed malignancy in one (7%), atypia in four (29%), benign findings in four (29%), and insufficient samples in five (36%). Needle sampling for residual solid components showed malignancy in 11 (79%), atypia in two (14%), and insufficient sample in one (7%). The diagnostic yield of needle sampling of solid components was significantly higher than that of cystic components for malignant CCBM (P<0.05). Sixteen (80%) of 20 CCBMs showed bloody fine-needle aspirates. There was no significant difference between the rates of bloody aspirates of malignant and benign CCBM (86% vs. 67%, P=0.55). CONCLUSION: Sonographically guided needle sampling of solid components may help to identify most malignant CCBMs, and the aspirated fluid may be discarded due to low diagnostic value.

A late complication of augmentation mammoplasty by polyacrylamide hydrogel injection: ultrasound and magnetic resonance imaging findings of huge galactocele formation in a puerperal woman with pathological correlation.

Polyacrylamide hydrogel (PAAG) was widely used for injection augmentation mammoplasty in Eastern Europe and China although uncommon in the western countries. However, the safety of this procedure remained controversial. Herein, we report a 30-year-old woman with a history of augmentation mammoplasty by PAAG injection developed galactoceles during her pregnancy. Ultrasound and magnetic resonance imaging showed huge cystic lesions in bilateral breasts; as a result, the normal breast tissue was almost completely replaced. On the basis of the imaging findings, the patient underwent mastectomy as well as immediate breast reconstruction with satisfactory outcome. It is important to be familiar with the imaging findings of this rare yet severe complication after augmentation mammoplasty in order to make an accurate diagnosis and a proper management.

Therapeutic strategies for pancreatic pseudocysts: experience in Taiwan.

BACKGROUND/AIMS: A retrospective study of Chinese patients with pancreatic pseudocysts to compare the results between non-conservative and conservative treatments, and the use of serial serum amylase and imaging in monitoring treatment success. METHODOLOGY: One hundred and sixty-two pseudocyst patients, treated between 1974 and 2003, were divided into two groups, conservative treatment and interventions (percutaneous needle drainage, internal drainage, or resection), and treatment results for these groups compared. RESULTS: Ninety-one cases (56%) showed spontaneous pseudocyst resolution (mean duration to resolution, 33.4 days). Pseudocyst size was less than 5cm in 86 of these cases (94.5%). Excellent symptomatic responses after aggressive treatment were noted in 68 of 71 patients (93.1%) with pseudocysts larger than 5 cm. All percutaneous tube drainage patients had pseudocyst resolution when the pseudocyst size was less than 5 cm. Hyperamylasemia was noted in 114 cases (70.4%) at diagnosis and returned to normal range in those patients whose cysts underwent spontaneous resolution or who had successful operations. CONCLUSIONS: Pancreatic pseudocysts smaller than 5 cm should have conservative treatment or percutaneous needle drainage. Larger pseudocysts should be treated aggressively. Serum amylase and ultrasound examinations are important to evaluate the occurrence of spontaneous resolution or the need for surgical intervention.

Breast cancer screening with digital breast tomosynthesis - 4 year experience and comparison with national data.

BACKGROUND: To determine if mammography combined with digital breast tomosynthesis (DBT), leads to superior performance in screening for breast cancer compared to digital mammography (DM) alone. METHODS: We retrospectively collected data from A) the results of population-based mammography-screening provided by the National Cancer Registry in Taiwan, and B) the results from all screening mammography performed with DBT from 2012 through 2015 at Kaohsiung Veterans General Hospital (VGHKS) since the institution of DBT at the end of 2011. This was compared data from 3 years with DM performed prior to DBT implementation. We calculated the results of medical audit of VGHKS and compared this with national data. Fisher's exact test is applied. RESULTS: VGHKS data demonstrated a higher cancer detection rate (CDR) and positive predictive value 1 (PPV 1) than the national average. Most prominently in the year 2014, our CDR was 120% better than that of the national average. CDR ranged from 6.3 to 8.1‰ prior to the introduction of DBT, and following DBT implementation this improved to 8.5-11.4‰, reflecting a mean increase of 32.2%. Early cancer detection was 50% higher and node negative rate was 25% higher than the national average of latest year. A 17.8% reduction in recall rate (RR) was achieved due to a decrease in unnecessary recall. CONCLUSION: There was a 32.2% increase in CDR and a 17.8% decrease in RR when DBT was used as an adjunct to DM, as compared to DM alone. CDRs were approximately twofold better than national average data. DBT was more effective at detecting cancer in ductal carcinoma in situ and stage 1.

Anthropometric measures, plasma adiponectin, and breast cancer risk.

Adiponectin is a peptide hormone secreted exclusively by adipocytes, and obesity is an established risk factor for breast cancer. We have, thus, evaluated the associations of anthropometric measures of adiposity and adiponectin with the development of breast cancer in a case-control study. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 244 incident cases with breast cancer, including 141 premenopausal and 103 postmenopausal cases, and 244 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2005. Plasma levels of adiponectin were measured by RIA. The relationship between anthropometric measures of adiposity and breast cancer risk was modified by menopausal status, with a significant increase in risk observed in postmenopausal but not premenopausal women. Moreover, a fairly robust inverse association of adiponectin with the risk was observed only in postmenopausal women (adjusted odds ratio (OR), 0.55; 95% confidence interval (CI), 0.23-0.97), but not in premenopausal women. Additionally, the plasma adiponectin levels tended to be inversely associated with estrogen receptor (ER)-positive (adjusted OR, 0.53; 95% CI, 0.27-0.98) but not ER-negative breast tumors. Furthermore, the associations of adiponectin with breast cancer risk overall and by menopausal and ER status remained after adjustment for obesity indices. These results suggest that adiponectin may have an independent role in breast carcinogenesis, particularly in the postmenopausal and ER-positive breast cancer risk.

Genetic variation in the premature aging gene WRN: a case-control study on breast cancer susceptibility.

The high risk of developing cancer seen in human genetic diseases that resemble accelerated aging provides support for a tumorigenic contribution of the mechanisms and genes responsible for regulating life span and aging. We therefore speculated that the WRN gene (encoding RECQL2, a DNA helicase), the germline mutation of which causes the progeroid disorder Werner syndrome, may be associated with breast tumorigenesis. This hypothesis was tested in this case-control study of 935 primary breast cancer patients and 1,545 healthy controls by examining single-nucleotide polymorphisms (SNPs) in WRN. We were also interested in knowing whether any identified association between WRN and breast cancer was modified by reproductive risk factors reflecting susceptibility to estrogen exposure. Our hypothesis is that because estrogen is known to promote breast cancer development via its mitogenic effect leading to cell proliferation, and because WRN is an essential gene, as its suboptimal function leads to a severe decrease in proliferation, estrogen stimulation may have a protective effect on cells harboring variant WRN, allowing them to survive and proliferate for the prolonged period needed for tumor formation. Support for this hypothesis came from the following observations: (a) one SNP in WRN was significantly associated with breast cancer risk (P = 0.002); (b) haplotype and diplotype analyses, based on different combinations of multiple SNPs in WRN, revealed a strong association with breast cancer risk; (c) this association between risk and putative high-risk genotypes was stronger and more significant in women with a longer interval between menarche and first full-term pregnancy; and (d) the protective effect conferred by having a higher number of full-term pregnancy was only significant in women with homozygous or heterozygous wild-type WRN genotypes. This study provides support for the tumorigenic role of WRN in breast cancer development, suggesting that breast cancer can be driven by the aging associated with variant WRN, the tumorigenic contribution of which might be enhanced as a result of increased cell growth due to estrogen exposure.

Breast cancer risk is associated with the genes encoding the DNA double-strand break repair Mre11/Rad50/Nbs1 complex.

The evolutionarily conserved Mre11-Rad50-Nbs1 (MRN) complex, consisting of proteins encoded by the genes Mre11, Rad50, and Nbs1, was recently shown to play a crucial role in DNA double-strand break (DSB) repair by recruiting the nuclear protein kinase ataxia telangiectasia mutated to DSB sites, leading to activation of this DNA repair network. Given the fact that carriers of defective mutation and polymorphic variants of ataxia telangiectasia mutated are at higher risk of developing breast cancer, we hypothesized a role of the MRN genes in determining breast cancer susceptibility. This hypothesis was examined both in a case control study of 559 breast cancer patients and 1,125 healthy women of single-nucleotide polymorphisms in Mre11, Rad50, and Nbs1 and by the in vivo detection of binding between Mre11 and BRCA1, encoded by the breast cancer susceptibility gene BRCA1. We were also interested in defining whether any association between MRN genes and breast cancer was modified by reproductive risk factors reflecting the level of estrogen exposure or susceptibility to estrogen exposure, as estrogen is known to initiate breast cancer development due to its metabolites causing DSB formation. Support for the hypothesis came from the observations that (a) one single-nucleotide polymorphism in Nbs1 was significantly associated with breast cancer risk, and a trend toward an increased risk of developing breast cancer was found in women harboring a greater number of putative high-risk genotypes of MRN genes (an adjusted odds ratio of 1.25 for each additional putative high-risk genotype; 95% confidence interval, 1.10-1.44); (b) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with no history of full-term pregnancy, those older (>or=26 years of age) at first full-term pregnancy, or those having had fewer (<2) full-term pregnancies; the risk effect conferred by harboring a higher number of high-risk genotypes of MRN genes was more significant in women without a history of breast feeding; and (c) Mre11 and BRCA1 were shown to form a complex in vivo, and this interaction was increased by irradiation. This study supports the role of the MRN pathway in breast cancer development, further strengthening the suggestion that mechanisms regulating DSB repair may play a mutator role driving breast cancer pathogenesis.

Application of intraoperative ultrasound to nonsentinel node assessment in primary breast cancer.

PURPOSE: To evaluate whether intraoperative ultrasonography can help surgeons to identify patients with breast cancer and metastases confined to the sentinel node. EXPERIMENTAL DESIGN: We used blue dye to identify sentinel node during 512 procedures done on 509 patients with breast cancers of <3 cm. After sentinel node biopsy, we used intraoperative ultrasonography to explore the whole axilla followed by at least level II axillary dissection. All sentinel nodes were evaluated histologically and immunohistochemically using anti-cytokeratin antibody. All nonsentinel nodes were examined by routine histology. Multiple logistic regression was used to assess the associations of interest and to adjust for potential confounders. Receiver operating characteristic curves were used to calculate the areas under the curves of interest and for comparisons. RESULTS: Sentinel nodes were identified in 506 of 512 (98.8%) procedures and sentinel node metastases were found in 161 of these (31.8%). Subsequent axillary dissection revealed tumor involvement in nonsentinel nodes in 93 of 161 (57.8%) procedures. Multivariate analysis showed that tumor size, number of positive sentinel nodes, and metastatic size in sentinel nodes were independent factors predicting the presence of tumor-positive nonsentinel nodes. The validity of using either node size or cortical thickness ascertained by intraoperative ultrasound to predict nonsentinel node metastases was highly significant (P < 0.0001). Intraoperative ultrasound not only detected metastatic nonsentinel nodes in 89 of 93 (95.7%) cases but also detected metastatic nonsentinel nodes in patients with false-negative sentinel node mapping. CONCLUSION: Sentinel node biopsy combined with intraoperative ultrasonography can help breast surgeons decide whether to perform a subsequent nonsentinel node dissection after identification of a positive sentinel node.