Benign Breast Biopsy Research Articles

Effect of previous benign breast biopsy on the interpretive performance of subsequent screening mammography.

Most breast biopsies will be negative for cancer. Benign breast biopsy can cause changes in the breast tissue, but whether such changes affect the interpretive performance of future screening mammography is not known. We prospectively evaluated whether self-reported benign breast biopsy was associated with reduced subsequent screening mammography performance using examination data from the mammography registries of the Breast Cancer Surveillance Consortium from January 2, 1996, through December 31, 2005. A positive interpretation was defined as a recommendation for any additional evaluation. Cancer was defined as any invasive breast cancer or ductal carcinoma in situ diagnosed within 1 year of mammography screening. Measures of mammography performance (sensitivity, specificity, and positive predictive value 1 [PPV1]) were compared both at woman level and breast level in the presence and absence of self-reported benign biopsy history. Referral to biopsy was considered a positive interpretation to calculate positive predictive value 2 (PPV2). Multivariable analysis of a correct interpretation on each performance measure was conducted after adjusting for registry, year of examination, patient characteristics, months since last mammogram, and availability of comparison film. Accuracy of the mammogram interpretation was measured using area under the receiver operating characteristic curve (AUC). All statistical tests were two-sided. A total of 2,007,381 screening mammograms were identified among 799,613 women, of which 14.6% mammograms were associated with self-reported previous breast biopsy. Multivariable adjusted models for mammography performance showed reduced specificity (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.73 to 0.75, P < .001), PPV2 (OR = 0.85, 95% CI = 0.79 to 0.92, P < .001), and AUC (AUC 0.892 vs 0.925, P < .001) among women with self-reported benign biopsy. There was no difference in sensitivity or PPV1 in the same adjusted models, although unadjusted differences in both were found. Specificity was lowest among women with documented fine needle aspiration-the least invasive biopsy technique (OR = 0.58, 95% CI = 0.55 to 0.61, P < .001). Repeating the analysis among women with documented biopsy history, unilateral biopsy history, or restricted to invasive cancers did not change the results. Self-reported benign breast biopsy history was associated with statistically significantly reduced mammography performance. The difference in performance was likely because of tissue characteristics rather than the biopsy itself.

Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) Model for Breast Cancer Risk Prediction in Women With Atypical Hyperplasia

Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.

Pseudoangiomatous Stromal Hyperplasia and Breast Cancer Risk

Pseudoangiomatous stromal hyperplasia (PASH) is a benign localized fibrotic lesion in which clusters of spindle cells form cleftlike spaces, resembling ectatic vessels. Its relationship to breast cancer risk has not been characterized. Histological presence of PASH was evaluated by review of archival slides in a single institution cohort of women who underwent benign excisional breast biopsy from 1967 to 1991. Relative risks for subsequent breast cancer were estimated using standardized incidence ratios (SIR), comparing the observed number of cancers with those expected based on Iowa SEER data (mean follow-up 18.5 years). PASH was identified in 579 of 9065 biopsies (6.4%). Women with PASH were younger, more likely to have a palpable mass as indication for biopsy, and had less lobular involution compared with those without PASH (all P < 0.001), while they did not differ by family history of breast cancer or degree of epithelial proliferation. Breast cancers occurred in 34 women with PASH (5.9%) and 789 without (8.8%). Women with PASH had lower risk of breast cancer (SIR 1.03, 95% confidence interval [95% CI] 0.71-1.44) than those without PASH (SIR 1.54, 95% CI 1.43-1.65), P = 0.01. Lower levels of breast cancer risk for the PASH group persisted in analyses stratified by age, family history, epithelial proliferation, and involution. The cancers in the PASH group occurred predominantly in the ipsilateral breast more than 5 years after biopsy. Despite clinical concern generated by palpable density often associated with PASH, this relatively uncommon histological finding does not connote increased risk of subsequent breast cancer.

Expression of leukemia/lymphoma-related factor (LRF/POKEMON) in human breast carcinoma and other cancers

The POK family of proteins plays an important role in not only embryonic development and cell differentiation, but also in oncogenesis. Leukemia/lymphoma-related factor (LRF) belongs to the POK family of transcriptional repressors and is also known as POK erythroid myeloid ontogenic factor (POKEMON), which binds to short transcripts of HIV-1 (FBI-1) and TTF-1 interacting peptide (TIP21). Its oncogenic role is known only in lymphoma, non-small cell lung carcinoma, and malignant gliomas. The functional expression of LRF in human breast carcinoma has not yet been confirmed. The aim of this study was to investigate and compare the expression of LRF in human breast cancer tissues and other human tumors. The expression of LRF mRNA transcripts and protein was observed in twenty human benign and malignant breast biopsy tissues. Expression of LRF was observed in several formalin-fixed tissues by immunohistochemistry and immunofluorescence. All malignant breast tissues expressed mRNA transcripts and protein for LRF. However, 40% and 15% benign breast biopsy tissues expressed LRF mRNA transcripts and protein, respectively. The overall expression of LRF mRNA transcripts and total protein was significantly more in malignant breast tissues than the benign breast tissues. LRF expression was also observed in the nuclei of human colon, renal, lung, hepatocellular carcinomas and thymoma tumor cells. In general, a significantly higher expression of LRF was seen in malignant tissues than in the corresponding benign or normal tissue. Further studies are warranted to determine the malignant role of LRF in human breast carcinoma.

Abstract 2782: Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer

Abstract The growth hormone and insulin-like growth factor (IGF) axis plays an essential role in the growth and development of the mammary gland. More recently it has become evident that IGF1 and IGF1 receptor (IGF1R) may play a role in the early transformation of mammary cells. Using a nested case-control design, we examined the association between IGF1R expression in normal breast tissue from benign biopsies and subsequent risk of breast cancer within the Nurses' Health Study. We constructed tissue microarrays (TMAs) containing normal terminal ductal lobular units (TDLUs) from benign breast biopsies. Immunostains for IGF1R were performed on sections cut from the TMAs. A total of 312 women had both normal TDLUs included in the TMAs and evaluable IGF1R staining; 75 subsequently developed breast cancer (cases) and 237 did not (controls). The epithelial cells in the normal TDLUs were scored for both cytoplasmic and membranous staining for IGF1R. Membranous IGF1R expression in normal TDLU epithelial cells was inversely associated with subsequent breast cancer risk (OR= 0.49; 95%CI 0.26-0.93) independent of type of benign breast disease (BBD). In contrast, the presence of cytoplasmic IGF1R expression was positively associated with subsequent risk of breast cancer (OR=2.88, 95% CI 1.60-5.19). Women in which TDLU epithelial cells showed little or no membrane expression of IGF1R but high levels of cytoplasmic IGF1R were at the highest breast cancer risk and were 15 times more likely to develop subsequent breast cancer when compared with women who had little or no membranous or cytoplasmic IGF1R expression in their TDLU epithelium (OR=15.1, 95% CI 3.2-70.2). It has been demonstrated that stimulation of cells with IGF1 results in altered localization of IGF1R expression. Upon stimulation, IGF1R levels on the cell membrane decrease while internalized levels increase. Studies of other receptor tyrosine kinases indicate that chronic stimulation by the ligand results in increased internalization of the receptor. In this study, IGF1R expression patterns in the epithelial cells of normal TDLUs were associated with an increased risk of subsequent breast cancer. The results of this study support the hypothesis that the IGF1 pathway plays an important role in the early development of breast cancer and suggest that there may be opportunities for breast cancer chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2782.

Abstract LB-413: A multi-stage association study in breast cancer identifies a protective allele at NCOA7

Abstract Estrogen metabolism and growth factor signaling pathway genes play a potential role in breast cancer predisposition. We evaluated pathway genes in a nested case-control investigation of women within the Nashville Breast Cohort, using germline DNA obtained from archival benign breast biopsies (formalin-fixed paraffin embedded). We applied methods enabling large-scale candidate gene investigation in the archival DNA (2 to 6 decades old). The study included 447 women who progressed to breast cancer (cases), and 838 women who did not (controls, matched on age and year of biopsy to cases in a ∼ 2:1 ratio). Single allele- and haplotype-based tests of association were explored among 115 tagged pathway genes, and results were compared to those of the CGEMS GWAS (1,145 cases, 1,142 controls). Findings across the two study populations were concordant in 8 genes. Further replication of results was sought in the Collaborative Breast Cancer Study (1,552 cases, 1,185 controls). FGFR2 and NCOA7 associations were concordant across all three studies. FGFR2 carries known susceptibility variants confirmed in prior GWAS, whereas the association at NCOA7 on 6q22.32 is novel. NCOA7 encodes a nuclear receptor co-activator that directly interacts with estrogen receptor to modulate its activity. A haplotype of NCOA7 had a significant inverse association with breast cancer in each of the three studies (odds ratios of 0.67, 0.77, and 0.78 (respectively) for haplotype carriers relative to non-carriers), with a combined odds ratio of 0.77 (95% CI 0.65-0.89), P = 5.1 × 10-4. These observations provide credible evidence that this NCOA7 variant has a protective effect on breast cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-413.

Declines in ductal hyperplasia may be linked to hormone therapy reduction

Researchers are beginning to observe a possible link between the decline of atypical ductal hyperplasia—a known risk for breast cancer—and the reduced use of postmenopausal hormone therapy. Hormone therapy use is associated with more benign breast biopsies, as well as the development of early and late-stage breast cancer. As hormone therapy use has declined over the years, so has the incidence of atypical ductal hyperplasia, according to Tehillah Menes, MD, chief of the breast service in the department of surgery at Elmhurst Hospital Center in NewYork. Previous research has indicated that women with atypical ductal hyperplasia have a 3-fold to 5-fold increased risk of breast cancer. Using data from the Breast Cancer Surveillance Consortium, Dr. Menes and colleagues examined the rates and risks of atypical ductal hyperplasia in more than 2.4 million mammograms. They found that between 1996 and 2005, post- menopausal hormone therapy use decreased from 35% to 11%, while the incidence of atypical ductal hyperplasia decreased from 5.5 per 10,000 mammograms in 1999 to 2.4 per 10,000 mammograms in 2005. The researchers note that they did not expect to observe this decline because of the increased use of mammography to discover abnormal lesions. They also found that atypical ductal hyperplasia is usually associated with low-grade cancers or early stage cancers, which may support the idea of separate pathways for the development of low-grade and high-grade breast cancers, Dr. Menes says. She and her colleagues conclude that future research should focus on the influence of exogenous hormone therapy on benign proliferative lesions of the breast. Decreased use of hormone replacement therapy may be linked to fewer cases of a typical ductal hyperplasia.

Risk factors for breast cancer in postmenopausal Caucasian and Chinese-Canadian women

IntroductionStriking differences exist between countries in the incidence of breast cancer. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The goal of this cross-sectional study was to examine breast cancer risk factors in populations with different risks for breast cancer.MethodsWe compared breast cancer risk factors among three groups of postmenopausal Canadian women at substantially different risk of developing breast cancer - Caucasians (N = 413), Chinese women born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants (N = 421). Information on risk factors and dietary acculturation were collected by telephone interviews using questionnaires, and anthropometric measurements were taken at a home visit.ResultsCompared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, less often had a family history of breast cancer or a benign breast biopsy, a higher Chinese dietary score, and a lower Western dietary score. For most of these variables, Western born Chinese and early Chinese migrants had values intermediate between those of Caucasians and recent Chinese migrants. We estimated five-year absolute risks for breast cancer using the Gail Model and found that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the risk factors in the Gail Model.ConclusionsOur results suggest that in addition to the risk factors in the Gail Model, there likely are other factors that also contribute to the large difference in breast cancer risk between Canada and China.

Breast self-examination and adherence to mammographic follow-up: an intriguing diptych after benign breast biopsy

This study evaluates the effect of palpability upon breast self-examination (BSE) and adherence to annual mammogram after benign breast biopsy (BBB). Seven hundred and fifty-two women with palpable (WP, n = 359) or nonpalpable (WNP, n = 393) lesions were evaluated 2 years before and after BBB. BSE was considered adequate when it was performed at least once per month, and inadequate when it was performed with a frequency of less than once per month. Prebiopsy/postbiopsy adherence was characterized as inadequate when at least one session of mammographic examination was lost within the 2-prebiopsy/postbiopsy (including the last visit) years, respectively. The prebiopsy frequency of adequate BSE was higher in WP [49 (176 of 359) vs. 38.9% (153 of 393) for WNP; Pearson's chi2 (1) = 7.77, P = 0.005]. However, the opposite happened regarding the prebiopsy adherence to mammogram, as the frequency of adequate adherence was 64.1% (252 of 393) in WNP, but only 46.0% (165 of 359) in WP. After BBB, adherence to mammogram significantly increased in both groups, reaching 76.1% (299 of 393) for WNP and 65.2% (234 of 359) for WP. However, BSE increased significantly only in WNP. Regarding the WP group, the postBBB BSE did not exhibit any significant change. Noticeably, the aforementioned increase in BSE among WNP resulted in the disappearance of the initial WP-WNP discrepancy regarding BSE; the postBBB BSE did not differ between WP and WNP. However, concerning adherence to mammogram, the superiority of WNP versus WP persisted (76.1 vs. 65.2%, respectively). In conclusion WP and WNP may perceive BBB differently, as reflected upon the differentially modified patterns.

Effect of Previous Benign Breast Biopsy on the Interpretive Performance of Subsequent Screening Mammography

Effect of Previous Benign Breast Biopsy on the Interpretive Performance of Subsequent Screening Mammography

Lobular Involution and Mammographic Density: Independent Contributors to Breast Cancer Risk.

Abstract Background: Women with benign breast disease are at elevated breast cancer risk. In order to accurately predict a woman's individual risk of breast cancer, a breast cancer risk-prediction model is needed that incorporates significant breast cancer risk factors. This report describes two factors: tissue based assessment of lobular involution, and radiological marker- mammographic density (MD). Lobular involution, or physiologic atrophy of the breast glandular epithelium, is inversely associated with breast cancer risk. MD is a strong positive risk factor for breast cancer. With increasing age, the extent of lobular involution increases while MD decreases. However, it is unclear whether involution and MD represent independent breast cancer risk factors. We examined breast cancer risk associated with lobular involution and MD in women with benign breast disease (BBD) to determine whether these features are independently associated with breast cancer risk.Methods: Using the Mayo Clinic Surgical and Pathology Indices, 9376 women ages 18 to 85 with benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified and formed the Mayo BBD cohort. We studied a sub-cohort of women diagnosed with BBD between 1985 and 1991 (when MD was clinically assessed and recorded) who had a mammogram within 6 months of the BBD diagnosis. Breast cancer outcomes were determined through the Mayo medical records and a study-specific questionnaire. Lobular involution extent was assessed in background tissue as 'none' (0% lobules involuted), 'partial' (1-74% lobules involuted) or 'complete' (≥75% lobules involuted). MD was classified as Wolfe's parenchymal pattern (PP) as N1/ fatty; P1; P2; and DY/ homogenously dense. Hazard ratios and confidence intervals were calculated using Cox regression analyses, adjusting for confounders: age, parity, BMI, BBD histology, menopausal status, family history, PP and involution extent.Results: A total of 2666 women in the Mayo BBD cohort, with biopsies between 1985 and 1991, had a mammogram within 6 months of the breast biopsy. The mean age at biopsy was 54.6 years. After a mean follow-up of 13.3 years, 172 (6.5%) women developed breast cancer. After adjustment for PP and other confounders, women with no or partial involution had elevated risk compared to women with complete involution (HR 2.62 [95% CI 1.39, 4.94] for no involution and 1.61 [95% CI 1.03, 2.53] for partial involution; complete involution as reference group; p for trend 0.003). Moreover, women with dense breasts were at greater risk compared to women with nondense breasts (HR 1.67 [95% CI 1.0, 2.73] for DY pattern, 1.96 [95% CI 1.2 – 3.21] for P2, 1.23 [95% CI 0.67, 2.26] for P1; N1 category as reference group; p for trend 0.02). Multivariate analyses also showed that women with the combination of no involution and dense breasts had greater risk compared to those with complete involution and nondense breasts (HR 4.08 [95% CI 1.72, 9.68]).Conclusion: Lobular involution and MD are both risk factors for breast cancer; this report is the first to demonstrate that each provides unique information about breast cancer risk. These findings emphasize the potential for inclusion of both these factors in future breast cancer risk-prediction models. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6064.

Effects of Arzoxifene on Breast Cancer Incidence in Postmenopausal Women with Osteoporosis or with Low Bone Mass.

Abstract Precinical and early clinical data indicate that arzoxifene, a third generation SERM, is more potent and bioavailable than raloxifene. Here we report the results of the phase 3, multicenter, placebo-controlled, double-blind GENERATIONS trial of 9354 postmenopausal women with osteoporosis (N=5252) or low bone mineral density (BMD) (N=4102), randomly assigned to arzoxifene 20mg/d (N=4676) or placebo (N=4678). The primary endpoints were the incidences of radiographic vertebral fracture in the osteoporotic population (at 36 months) and invasive breast cancer in all study participants (after all participants had completed 48 months of treatment). Breast cancers were detected by annual mammograms and/or clinical breast examination and adjudicated centrally by an independent committee. The primary analysis compared the incidence of adjudicated invasive breast cancer between treatment groups using a log-rank test. Both treatment groups were evenly balanced for risk of breast cancer including age, previous benign breast biopsies, family history of breast cancer, estimated Gail risk and BMD. The trial met both primary endpoints with a 41% reduction in the incidence of vertebral fractures (p&amp;lt;0.001) and 56% percent reduction in incidence of invasive breast cancer (p=0.002). Table 1 summarizes the breast cancer findings after the 48 month follow-up. The incidence of invasive breast cancer in the placebo group was higher in the women who had a Gail score &amp;gt; 1.66 compared to ≤ 1.66 (1.5% vs. 0.6%) and in those with low bone mass versus osteoporosis (1.2% vs. 0.7%), but the risk reduction with arzoxifene was similar between Gail risk groups (HR 0.32 vs 0.57. p-value for interaction=0.31) and between low bone mass and osteoporosis groups (HR 0.34 vs 0.57. p-value for interaction=0.35). Other findings included no significant reduction in non-vertebral fractures or cardiovascular events. Generally, arzoxifene was well tolerated, although there was a significant increase in venous thromboembolism, gall bladder disease, pulmonary obstructive/infective disorders, hot flushes, muscle cramps and gynecological-related events in the arzoxifene group. We conclude that arzoxifene reduces the incidence of invasive breast cancer as well as vertebral fracture. The results of the GENERATIONS trial provide further support for a significant risk reduction of invasive breast cancer by SERMs in post menopausal women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 51.

Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk

Protein phosphatase 2A (PP2A) is a major cellular phosphatase and plays key regulatory roles in growth, differentiation, and apoptosis. Women who are diagnosed with benign proliferative breast disease are at increased risk for the subsequent development of breast cancer. The authors evaluated genetic variation of PP2A holoenzyme subunits for their potential contribution to breast cancer risk. A nested case-control investigation was performed on a cohort of women who had a history of benign breast disease. The women were followed for an average of 18 years, and DNA prepared from the original archival benign breast biopsy (1954-1995) was available for 450 women who were diagnosed with breast cancer on follow-up and for 890 of 900 women in a control group who were matched on race, age, and year of entry biopsy. Single allele-based and haplotype-based tests of association were conducted with assessment of significance by permutation testing. Significant risk and protective haplotypes of the PP2A structural/regulatory subunit A alpha isoform (PPP2R1A) were identified and had odds ratios of 1.63 (95% confidence interval [CI], 1.3-2.1) and 0.55 (95% CI, 0.41-0.76), respectively. These odds ratios remained significant after the analysis was adjusted for multiple comparisons. Women who had both the PPP2R1A risk haplotype and a history of proliferative breast disease had an odds ratio of 2.44 (95% CI, 1.7-3.5) for the subsequent development of breast cancer. The effects of haplotypes for 2 PP2A regulatory subunit genes, PP2 regulatory subunit B alpha isoform (PPP2R2A) and PP2A regulatory subunit B' epsilon isoform (PPP2R5E) on breast cancer risk were nominally significant but did not remain significant after the analysis was adjusted for multiple comparisons. The current findings supported the previously hypothesized role of PP2A as a tumor suppressor gene in breast cancer.

Biopsy Method: A Major Predictor of Adherence After Benign Breast Biopsy?

Adopting a longitudinal approach to assess women after breast biopsy with a benign result, this study aimed to comparatively evaluate the effect of the biopsy method on compliance with clinical recommendations for follow-up. For this study, 410 patients who underwent biopsy of a breast lesion were included: fine-needle aspiration biopsy, n = 95 patients; core biopsy, n = 84; local excision under local anesthesia, n = 72; vacuum-assisted breast biopsy, n = 100; and hookwire localization, n = 59. Information about patient age, place of residence, whether complications occurred, and type of lesion was collected. Compliance was higher among women who had undergone vacuum-assisted breast biopsy than those who had undergone one of the other biopsy methods. The superiority (carryover effect) of vacuum-assisted breast biopsy persisted for 18 months after the biopsy procedure. Patient compliance for all of the other biopsy methods followed an M pattern, with the peaks corresponding to the follow-up mammography sessions. In patients who had undergone vacuum-assisted breast biopsy, a gradual decrease in compliance over time was observed. Older women were more compliant than younger women with follow-up recommendations regardless of biopsy method. A subanalysis of the vacuum-assisted breast biopsy group indicated that complications are associated with better compliance. Women more often adhere to clinical recommendations for follow-up sessions comprising mammography. Patient age and whether biopsy complications occurred also seem to modify compliance. Further studies should assess whether superior compliance after vacuum-assisted breast biopsy persists in other settings, such as with stereotactic or ultrasound guidance, different numbers of cores, and procedures of various durations.

Novel breast tissue feature strongly associated with risk of breast cancer.

Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women. We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women. There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic. Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.

Potential Role of Tissue Microarrays for the Study of Biomarker Expression in Benign Breast Disease and Normal Breast Tissue

Tissue microarrays (TMAs) are commonly used to study biomarker expression in invasive breast cancers. Whether or not TMAs may also be a potentially useful platform for assessing biomarkers in benign proliferative breast lesions (BPBL) and normal breast tissue has not been previously studied in detail. We evaluated the success of capturing the targeted areas in TMAs constructed from benign breast biopsy blocks of 368 Nurses' Health Study and Nurses' Health Study II participants. Areas targeted included 214 BPBL and 361 normal terminal duct lobular units (TDLUs). At least three 0.6 mm cores were obtained from the areas of interest from each donor paraffin block and arrayed into a recipient block. Sections cut from TMA blocks were stained with hematoxylin and eosin. Each TMA slide was examined to determine the number of cores per case in which the targeted area was represented. Overall, the targeted area was present in 776 of 1800 TMA cores (43%). At least 1 of the cores contained the area of interest for 401 of the 575 targeted foci (70%), including 76%, 66%, 60%, and 40% of cases in which the targeted areas were normal TDLUs, usual ductal hyperplasia, atypical lobular hyperplasia, and atypical ductal hyperplasia, respectively. In TMAs constructed from BPBL and normal TDLUs, the targeted area was present on at least 1 core in 70% of cases. Our findings indicate that it is feasible to construct TMAs from donor tissue blocks consisting of BPBLs and normal breast tissue with a relatively high rate of capture of the targeted area.

Breast Cancer Risk Assessments Comparing Gail and CARE Models in African-American Women

The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African-American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African-American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5-year breast cancer risk was 0.88% (Range: 0.18-6.60%) for the Gail model and 1.29% (Range: 0.20-4.50%) for the CARE model. Using the usual cutoff-point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar's test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African-Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African-Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk.

Clinicopathological characteristics of subsequent breast cancers in patients with benign breast disease

1061 Background: Benign breast disease (BBD) is a significant risk factor for breast cancer (BC); however little is known about the aggressiveness of the BCs these patients develop. Shared features between select atypias and low-grade DCIS have led some to speculate that a history of BBD portends the development of well-differentiated BCs. Methods: The Mayo BBD cohort includes 9,376 women who had benign breast biopsies from 1967–1991. Data on BC events were obtained from medical records and questionnaires. Tissue from the BCs was reviewed by a single breast pathologist (DWV). Results: Our cohort included 6,244 patients with nonproliferative disease (NP), 2,801 women with proliferative disease without atypia (PDWA), and 331 with atypical hyperplasias (AH). With a median of 18 years of follow-up, 799 patients with BBD have developed breast cancer, 416 initially had NP, 313 had PDWA, and 70 AH. BC tissue was available for 703 of the women. The cancers were invasive ductal in 76.1% (n = 535), invasive lobular in 9.4% (n = 66), and DCIS alone in 14.5% (n = 102) patients. Grade is currently available for 500 women, and is well differentiated in 29.4% (n = 150), moderately differentiated in 42.7% (n = 218) and poorly differentiated in 27.8% (n = 142). In 537 cases the malignant tissue had a concurrent benign component consisting of NP in 24% (n = 129), PDWA in 25.1% (n = 135), and AH in 50.8% (n = 273). In regards to tumor size, 69.6% had T1 tumors, 24.9% T2 tumors, and 5.5% T3 disease. Metastasis to lymph nodes occurred in 25% of patients. Median time to BC was 12.3 years and did not differ across the different benign entities. Breast cancer developed within 5 years from the initial BBD in 163 women (20%). In this group, tumor size was greater (p = 0.02), and there were more poorly differentiated tumors (p = 0.006) than in those who later developed BC. Conclusions: In the BCs that have developed in our BBD cohort, we do not see a preponderance of well-differentiated, good-risk BCs. Patients diagnosed within 5 years of BBD appear to have BCs with more aggressive features. No significant financial relationships to disclose.

Ceramide synthases and ceramide levels are increased in breast cancer tissue

Several in vitro studies have correlated dysfunction of the sphingolipid-signaling pathway with promotion of tumor cell growth as well as progression and resistance of tumors to chemotherapeutic agents. As ceramides (Cer) constitute the structural backbones of all sphingolipids, we investigated the endogenous ceramide levels in 43 malignant breast tumors and 21 benign breast biopsies and compared them with those of normal tissues using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The total ceramide levels in malignant tumor tissue samples were statistically significantly elevated when compared with normal tissue samples. Upregulation of the total ceramide level averaged 12-fold and 4-fold higher than normal tissue samples, for malignant tumors and benign tissues, respectively. Specifically, the levels of C(16:0)-Cer, C(24:1)-Cer and C(24:0)-Cer were significantly raised in malignant tumors as compared with benign and normal tissue. The augmentation of the various ceramides could be assigned to an increase of the messenger RNA levels of ceramide synthases (CerS) LASS2 (longevity assurance), LASS4 and LASS6. Notably, elevated levels of C(16:0)-Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. Moreover, the levels of C(18:0)-Cer and C(20:0)-Cer were significantly higher in estrogen receptor (ER) positive tumor tissues as compared with ER negative tumor tissues. In conclusion, progression in breast cancer is associated with increased ceramide levels due to an upregulation of specific LASS genes.

Weighing the Benefits and Burdens of Mammography Screening Among Women Age 80 Years or Older

To examine outcomes of mammography screening among women > or = 80 years to inform decision making. We conducted a cohort study of 2,011 women without a history of breast cancer who were age > or = 80 years between 1994 and 2004 and who received care at one academic primary care clinic or two community health centers in Boston, MA. Medical record data were abstracted on all screening and diagnostic mammograms, breast ultrasounds and biopsies performed, all breast cancers diagnosed through December 31, 2006, and on sociodemographics. Date and cause of death were confirmed using the National Death Index. The majority of patients (78.6%) were non-Hispanic white and 51.4% (n = 1,034) had been screened with mammography since age 80 years. Among women who were screened, eight were diagnosed with ductal carcinoma in situ, 16 with early stage disease (1.5%), two with late stage disease, and one died as a result of breast cancer. Many (110; 11%) experienced a false-positive screening mammogram that led to 19 benign breast biopsies, eight refused work-up, and three experienced a false-negative screening mammogram; 97 were screened within 2 years of their death from other causes. There were no significant differences in the rate, stage, recurrence rate, or deaths due to breast cancer between women who were screened and those who were not screened. The majority of women > or = 80 years are screened with mammography yet few benefit. Meanwhile, 12.5% experience a burden from screening. The data from this study can be used to inform elderly women's decision making and potentially lead to more rational use of screening.