Reduction in Ki-67 in benign breast tissue of high-risk premenopausal women with the SERM acolbifene.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 520-520
Author(s):  
Carol J. Fabian ◽  
Bruce F. Kimler ◽  
Carola M. Zalles ◽  
Brian K. Petroff ◽  
Trina Metheny ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Adverse Events ◽  
Breast Density ◽  
Premenopausal Women ◽  
Wilcoxon Test ◽  
Mammographic Breast Density ◽  
Relative Reduction ◽  
Marginal Effect ◽  
Ki 67

520 Background: Selective Estrogen Receptor Modulators (SERMs) are approved for reduction of risk for breast cancer; however, uptake and use is limited. We conducted a pilot study of a 4th generation SERM to determine tolerability and effect on tissue biomarkers in healthy women at high risk for development of breast cancer. Methods: Premenopausal women at elevated risk for breast cancer were screened by random periareolar fine needle aspiration (RPFNA) performed during the follicular phase of the menstrual cycle. Women were eligible if breast epithelial cells exhibited evidence of cytologic hyperplasia with or without atypia, as well as Ki-67 ≥2% by immunocytochemistry. Following 6-8 months of open-label acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was modulation of the proportion of cells that expressed Ki-67. Body composition (DEXA), pelvic sonography, mammographic breast density, and serum levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed pre and post intervention. Results: 76 women were screened by RPFNA, with 25 eligible and enrolled in the intervention over a 9 month period. All 25 (7 on oral contraceptives) subjects completed the study, had a second RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range 2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a reduction of 3.0% (range -20.2% to +2.8%; decreased in 23, increased in 2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly less than baseline (p<0.001, 2-tailed Wilcoxon test). There were no statistically significant changes in cytomorphology over this short intervention period. There was a marginal effect on breast density (16 decreased; 8 increased; p=0.067). Adverse events were minimal with greatest grade of 3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11 subjects. No serious adverse event was reported and no subject discontinued the study due to an AE. Conclusions: Based on preliminary evaluation showing favorable modulation of proliferation and minimal adverse events, further investigation of acolbifene, a fourth generation SERM, as a breast cancer chemoprevention agent for premenopausal women appears warranted. Supported by NO1-CN-35135.

Correlation of mammographic breast density with Ki-67 expression in benign breast epithelial cells obtained by random periareolar fine needle aspiration of high risk women

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1011-1011
Author(s):  
Q. J. Khan ◽  
B. F. Kimler ◽  
E. J. Smith ◽  
A. P. O’Dea ◽  
P. Sharma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Mammographic Density ◽  
Breast Density ◽  
Fine Needle Aspiration ◽  
Needle Aspiration ◽  
Mammographic Breast Density ◽  
Ki 67 ◽  
Fine Needle ◽  
Cytologic Atypia

1011 
 >Background: Known risk factors for breast cancer development include elements incorporated into the Gail risk model, mammographic breast density and cytologic atypia detected by Random Periareolar Fine Needle Aspiration (RPFNA). Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. We have previously shown that Ki-67 expression is higher in RPFNA specimens of benign breast cells exhibiting cytologic atypia. It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA. Methods: 344 women at high risk of developing breast cancer (based on personal or family history) seen at The University of Kansas Medical Center high risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment, plus a mammogram were included in the study. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by Chi-square test and continuous variables were analyzed by non-parametric test and linear regression. Results: 40% of women were premenopausal, 7% perimenopausal and 53% were postmenopausal. Median age was 49 years, median 5 year Gail Risk was 2.2%, and median Ki-67 was 1.9%. Median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality and number of cells collected, but was unrelated to Gail risk (as observed previously). Breast density was higher in pre-menopausal women (p=0.001), those with lower BMI (p< 0.001), and lower 5-year Gail risk (p=0.012); Breast density showed no correlation with Ki-67 expression or cytomorphology. Conclusion: Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers for breast cancer chemoprevention trials. No significant financial relationships to disclose.

BRCA1 and BRCA2 germline mutation carriers have a lower breast density compared to high risk women without such mutations

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1517-1517
Author(s):  
P. Sharma ◽  
J. R. Klemp ◽  
B. F. Kimler ◽  
Q. J. Khan ◽  
E. J. Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
High Risk ◽  
Breast Density ◽  
Genetic Factors ◽  
Mammographic Breast Density ◽  
Mutation Status ◽  
High Risk Women ◽  
Mutation Carriers ◽  
Chi Square Analysis

1517 Background: High mammographic breast density, a known risk factor for breast cancer is influenced by both genetic and non genetic factors. It is not clear if there are differences in breast densities between BRCA1/2 mutation carriers and high-risk non carriers. The aim of this study was to compare breast density in high-risk women with and without BRCA1/2 mutation. Methods: Women at high risk for development of breast cancer (based on family history, prior precancerous disease or prior breast cancer) who underwent genetic testing at the University of Kansas Breast Cancer Prevention Center between 1998 and 2005 were identified under an IRB approved protocol. BRCA1/2 full sequencing was performed at Myriad Genetic Laboratories. The earliest digitized mammogram of these subjects was identified from a preexisting mammogram database. All mammograms had to be prior to/at least one year from any chemoprevention intervention. For subjects with prior breast cancer, mammogram of the uninvolved breast was used. Breast density was assessed on the left craniocaudal mammographic view by computer assisted method, Cumulus. Frequencies of categorical variables were assessed using chi-square analysis. Continuous variables were assessed using Mann-Whitney non parametric test. Multiple regression analysis was used to investigate whether differences are due to variables other than mutation status. Results: The study population consisted of 284 high-risk women who underwent BRCA1/2 testing and for whom a mammogram was available. 30 (11%) had BRCA1 and/or 2 deleterious mutation. There was no difference between mutation carriers and non-carriers for BMI, 5 year Gail risk, parity, menopausal status and HRT use. Mutation carriers were younger (median age 42 vs. 46, p=0.020) and more likely to have a positive family history (100% vs. 85%, p=0.020). Older age (p<0.001), higher BMI (p<0.001) and having a BRCA1/2 mutation (p=0.025) were significantly associated with a lower breast density. Conclusion: Among high risk women, possession of a deleterious BRCA1/2 mutation is associated with lower breast density after adjusting for factors known to affect breast density. This suggests that breast density may be governed by genetic factors other than BRCA1/2 mutation status. No significant financial relationships to disclose.

scholarly journals Evaluation of Quantra Hologic Volumetric Computerized Breast Density Software in Comparison With Manual Interpretation in a Diverse Population

2018 ◽  
Vol 12 ◽  
pp. 117822341875929
Author(s):  
Gloria Richard-Davis ◽  
Brianna Whittemore ◽  
Anthony Disher ◽  
Valerie Montgomery Rice ◽  
Rathinasamy B Lenin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Risk Stratification ◽  
Breast Density ◽  
Gold Standard ◽  
Assessment Tool ◽  
Low Risk ◽  
Mammographic Breast Density ◽  
Cutoff Value ◽  
Density Assessment

Objective: Increased mammographic breast density is a well-established risk factor for breast cancer development, regardless of age or ethnic background. The current gold standard for categorizing breast density consists of a radiologist estimation of percent density according to the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) criteria. This study compares paired qualitative interpretations of breast density on digital mammograms with quantitative measurement of density using Hologic’s Food and Drug Administration–approved R2 Quantra volumetric breast density assessment tool. Our goal was to find the best cutoff value of Quantra-calculated breast density for stratifying patients accurately into high-risk and low-risk breast density categories. Methods: Screening digital mammograms from 385 subjects, aged 18 to 64 years, were evaluated. These mammograms were interpreted by a radiologist using the ACR’s BI-RADS density method, and had quantitative density measured using the R2 Quantra breast density assessment tool. The appropriate cutoff for breast density–based risk stratification using Quantra software was calculated using manually determined BI-RADS scores as a gold standard, in which scores of D3/D4 denoted high-risk densities and D1/D2 denoted low-risk densities. Results: The best cutoff value for risk stratification using Quantra-calculated breast density was found to be 14.0%, yielding a sensitivity of 65%, specificity of 77%, and positive and negative predictive values of 75% and 69%, respectively. Under bootstrap analysis, the best cutoff value had a mean ± SD of 13.70% ± 0.89%. Conclusions: Our study is the first to publish on a North American population that assesses the accuracy of the R2 Quantra system at breast density stratification. Quantitative breast density measures will improve accuracy and reliability of density determination, assisting future researchers to accurately calculate breast cancer risks associated with density increase.

Effect of the third generation selective estrogen receptor modulator arzoxifene on mammographic breast density

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 562-562
Author(s):  
B. F. Kimler ◽  
G. Ursin ◽  
C. J. Fabian ◽  
J. R. Anderson ◽  
C. Chamberlain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
High Risk ◽  
Phase Ii ◽  
Breast Density ◽  
Receptor Expression ◽  
Mammographic Breast Density ◽  
Computer Assisted ◽  
Breast Cancer Patients ◽  
Dense Area

562 Background: Arzoxifene (ARZ) is currently being studied for treatment of breast cancer patients in a Phase II trial because of tamoxifen-like efficacy but lack of uterine agonist effect. We conducted a Phase II chemoprevention trial in women at high risk for development of breast cancer on the basis of personal or family history. Methods: Potential subjects had multiple biomarkers assessed, including random periareolar fine needle aspiration (RPFNA) with breast epithelial cells processed for cytomorphology and immunocytochemistry. Women who exhibited cytologic hyperplasia ± atypia were eligible for enrollment. Subjects were stratified on the basis of atypia, estrogen receptor expression, menopause status, germline BrCa1/2 mutation status, and accrual site. Subjects were randomized (double-blind) between placebo and ARZ (LY353381.HCI, 20 mg daily) for 6 mo, with an option to continue on study for another 6 mo while receiving open-label ARZ. Assessments conducted at baseline, 6 mo, and 12 mo included mammographic breast density. Mammograms were digitized to image files which were cropped to remove labels and dates, and then identified by a study subject ID number and a random coding for baseline, 6 or 12 mo. This allowed the reader (GU) to view the three files for a subject, but to remain blinded as to the sequence of the films or the study agent. The files were assessed for mammographic density using the Madena computer-assisted system. Results: Of 199 subjects enrolled on the study, 52% were pre-menopausal; with 101 women randomized to placebo and 98 to ARZ. At baseline, mean values were comparable for placebo and ARZ groups for breast area (∼244 cm2), total dense area (∼100 cm2), and the percent of the breast at increased density (41.3% vs 46.2%). After 6 mo, there were minimal changes in total breast area (P=0.13); but statistically significant decreases (P<0.001) for the comparison of placebo vs ARZ (2-sided T-test) for change in both dense area (+3.8 vs −12.9 cm2) and percent breast density (+0.8% vs −4.6%). Conclusions: The 3rd generation SERM arzoxifene administered for 6 mo produces statistically significant decreases in mammographic breast density relative to placebo in women at high risk for development of breast cancer. No significant financial relationships to disclose.

Evaluation of Ki-67 measured in benign breast tissue acquired from premenopausal women treated with a flaxseed derivative

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1507-1507
Author(s):  
C. J. Fabian ◽  
Q. J. Khan ◽  
P. Sharma ◽  
S. Baxa ◽  
T. Metheny ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Tissue ◽  
Premenopausal Women ◽  
Needle Aspiration ◽  
Relative Reduction ◽  
Aromatase Activity ◽  
Ki 67 ◽  
Increased Risk ◽  
Benign Breast Tissue ◽  
Risk Biomarkers

1507 Background: The lignans enterolactone and enterodiol are derived from the action of gut bacteria on ingested secoisolariciresinol diglycoside (SDG) which is commonly found in flaxseed. Enterolactone and enterodiol are thought to impair mammary carcinogenesis via reduction in aromatase activity and the mid-cycle surge of luteinizing hormone. We assessed the modulatory activity of 1 year of SDG on a number of risk biomarkers for breast cancer in a prospective phase II pilot study. We report the effect of SDG on the primary endpoint, proliferation in benign breast tissue as measured by Ki-67 immunocytochemistry, in the first 35 women completing study. Methods: Premenopausal women age 21 to 55 at increased risk for breast cancer underwent a baseline random periareolar fine needle aspiration (RPFNA) between the first and tenth days of their menstrual cycle. Those with RPFNA evidence of hyperplasia and Ki-67 greater than or equal to 2% were invited to participate. Women taking flaxseed or oral contraceptives were ineligible. All women took one Brevail (lignan research) capsule containing 50 mg of SDG daily. Ki-67 staining was performed with DAKO M7240 antibody on hematoxylin counterstained slides and the number of cells staining positive in 500 cells within hyperplastic clusters was counted. Results: Forty-nine women were enrolled on study between February 2006 and June 2008. Of these, four stopped prematurely, 10 women have not completed, and 35 have completed study and undergone follow-up RPFNA. Baseline characteristics of the 35 women completing study are as follows: median age 44 (range 29–50), median baseline 5-year Gail model risk 1.6% (range 0.1%-5.7%), median Ki-67 4.2% (range 2.0%-16.8%). Thirty seven percent had hyperplasia without atypia, and 63% had atypia. At repeat RPFNA, Ki-67 expression was reduced (median value of 2.0%, range 0%-15.2%); with 29 of the 35 women demonstrating a decrease (median relative reduction of 0.70). Conclusions: Based upon reduction in Ki-67 expression in hyperplastic benign breast tissue after 12 months, 50 mg of SDG administered daily as Brevail appears promising as a preventive. Supported in part by grant R21 CA117847 from the National Cancer Institute. No significant financial relationships to disclose.

Gene methylation in random FNA samples as biomarkers for breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 518-518
Author(s):  
Vered Stearns ◽  
Seema Ahsan Khan ◽  
Mary Jo Fackler ◽  
Robert T. Chatterton ◽  
Lisa K. Jacobs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Density ◽  
Menopausal Status ◽  
Life Time ◽  
Wilcoxon Test ◽  
Mammographic Breast Density ◽  
Gene Methylation ◽  
Cytologic Atypia

518 Background: Current methods to determine breast cancer risk are insufficiently sensitive to select women most likely to benefit from preventive strategies. We hypothesized that candidate gene promoter hypermethylation may provide an individualized risk profile. We performed a prospective study to determine whether DNA cumulative methylation index (CMI) varies by menstrual phase or menopausal status, and to correlate CMI with established risk factors. Methods: We obtained random fine needle aspiration (rFNA) samples from healthy women age 35-60 and determined their menopausal and menstrual status, lifetime Gail risk, mammographic breast density, and cytologic atypia assessed as the Masood score. We evaluated CMI of 11 candidate genes in rFNA cells using the Quantitative Multiplex Methylation-Specific PCR (QM-MSP) technique. We used Wilcoxon test and ANOVA model to compare CMI across menopausal and menstrual (follicular, mid-cycle, luteal) categories, respectively. We used linear regression model to adjust for age and BMI. Methylation scores were log-transformed in the analysis. Results: We enrolled 390 women at the Avon Breast Centers at Johns Hopkins and Northwestern, the majority through the Love/Avon Army of Women, and 380 completed study procedures. Median age 50 (36-60), mean BMI 28 (18.7-50.8), 52% were postmenopausal. Mean life-time Gail risk 14.6 (5.6-54.1), mean percent mammographic density 19.6 (2.5-72.8), and mean Masood score (N=354) 13.6 (7-18). QM-MSP analysis was completed on 229 samples. We did not observe differences in CMI among menopausal (P=0.4895) or menstrual categories (P=0.2333). There was no association between CMI and life-time Gail risk (P=0.706) or breast density (P=0.4116). We observed a significant correlation between CMI and Masood score (P=0.0167). Conclusions: CMI correlates with degree of cytologic atypia and is potentially a robust indicator of breast cancer risk since it does not vary with menstrual or menopausal status. Next, we will select genes that best reflect changes in the clinical parameters to create a gene methylation signature that will be validated in other studies and correlated with breast cancer risk.

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