Cell-based breast cancer risk stratification based on DNA methylation in fine needle aspiration samples

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1508-1508
Author(s):  
D. Euhus ◽  
D. Bu ◽  
S. Milchgrub ◽  
A. M. Leitch ◽  
C. M. Lewis
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Lower Risk ◽  
Breast Tissue ◽  
Needle Aspiration ◽  
Gail Model ◽  
Rassf1a Methylation ◽  
Risk Patients

1508 Background: Tumor suppressor gene (TSG) methylation is identified in nearly all breast cancers, but rarely in histologically normal breast tissue from wonen unaffected with breast cancer. Its occurrence in high risk preneoplasia and in benign breast tissue adjacent to breast cancer suggests that it may represent a high risk field change that could be exploited for cell-based breast cancer risk stratification. Methods: TSG methylation was measured by quantitative methylation-specific real time PCR in 53 breast tumor fine needle aspiration (FNA) biopsies, 84 cellular random periareolar FNAs (RP-FNA) ipsilateral or contralateral to these cancers, 36 cellular RP- FNAs from unaffected women at high risk for breast cancer by the Gail model, and 95 cellular RP-FNAs from unaffected women at lower risk by the Gail model. Results: The breast tumors showed a high frequency of TSG methylation: RASSF1A 80%, HIN-1 65%, Cyclin D2 60%, RAR-β2 53%, and APC 47%. In general, RP-FNA samples from cancer patients and Gail high risk patients showed a greater frequency of methylation than samples from Gail lower risk patients: RASSF1A 43% vs. 21%, P = 0.001, HIN-1 32% vs. 20%, P = 0.05; Cyclin D2 18% vs. 9%, P = 0.10; RAR-β2 21% vs. 18%, P = 0.68; and APC 25% vs. 16%, P = 0.17. Twelve of 215 RP-FNA samples (5%) showed very high levels of methylation (>10% methylation for two or more genes). Only two of these samples were from women classified as lower risk by the Gail model. Methylation frequencies were entirely independent of cell yields but the frequency of RASSF1A methylation increased with increasing Masood scores (P = 0.05). Methylation of RASSF1A in one breast was highly predictive of RASSF1A methylation in the opposite breast (P < 0.0001). Conclusions: TSG methylation appears to be a breast cancer risk-associated field change that can be quantified in RP-FNA samples. RASSF1A methylation occurs frequently in benign breast epithelium, provides reasonable discrimination between high and lower risk breasts (O.R. = 2.0), is related to cytological atypia, and may be an early marker of a methylator phenotype. Quantification of TSG methylation in RP-FNA samples may provide a valuable surrogate endpoint biomarker for Phase II prevention trials. No significant financial relationships to disclose.

Assessment of tumor suppressor gene methylation for breast cancer risk screening

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1004-1004
Author(s):  
D. Euhus ◽  
R. Ashfaq ◽  
D. Bu ◽  
A. M. Leitch ◽  
C. Lewis
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Tumor Suppressor ◽  
Cancer Risk ◽  
Tumor Suppressor Gene ◽  
Lower Risk ◽  
Suppressor Gene ◽  
Gene Copies ◽  
Wide Range

1004 Background: Tumor suppressor gene (TSG) methylation is frequently detected in benign proliferative breast tissue suggesting that it occurs early in breast carcinogenesis. If it can be screen-detected and is associated with breast cancer risk it could be exploited for breast cancer prevention. Methods: Nipple duct lavage (NDL) samples, obtained from 150 women selected to represent a wide range of breast cancer risk, were evaluated by quantitative methylation-specific real time PCR. High risk breasts were defined as those contralateral to a breast cancer (N = 63) and those of women with a 5-year Gail risk ≥ twice the age- and race-matched general population risk (N = 64). The prevelence of TSG methylation and marked atypia was compared for high risk and lower risk breasts using Chi-square. Data for breasts ipsilateral to a breast cancer are shown for comparison, but not included in the calculations for the high risk category. Results: Samples with adequate cellularity were obtained for 219 breasts (76%). The proportion of healthy breasts with ≥ 1% of the gene copies methylated was 13% for Cyclin D2, 19% for APC, 19% for HIN-1, 16% for RASSF1A, and 9% for RAR-beta. RAR-beta provided the best risk discrimination as 15% of high risk breasts were methylated at a level that exceeded the 95th percentile of the lower risk breasts (0.9% of gene copies methylated, P = 0.05). For the table , methylation fractions for all five genes were summed and the threshold for classifying a breast as positive was set to the 95th percentile of the lower risk breasts (methylation sum = 25.0%). Both methylation and marked atypia provide some discrimination between high and lower risk breasts; the combination, however, provides the best discrimination (24% marker positive for high risk versus 9% for lower risk, P = 0.02). Conclusions: TSG methylation in NDL samples is a marker of breast cancer risk that is complementary to cytology. [Table: see text] [Table: see text]

scholarly journals Aberrant epigenetic and transcriptional events associated with breast cancer risk

2021 ◽  
Author(s):  
Natascia Marino ◽  
Rana German ◽  
Ram Podicheti ◽  
Douglas B. Rush ◽  
Pam Rockey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Epithelial Cells ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Normal Breast ◽  
Breast Tissues

ABSTRACTBackgroundGenome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina’s HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation.ResultsTranscriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change≥2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures and correlated with transcriptional changes (p<0.05, r≤0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified.ConclusionsNormal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

scholarly journals Assessment of breast cancer risk among Iraqi women in 2019

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hashim Talib Hashim ◽  
Mustafa Ahmed Ramadhan ◽  
Kabas Monther Theban ◽  
John Bchara ◽  
Ahed El-Abed-El-Rassoul ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Low Risk ◽  
Lifetime Risk ◽  
Gail Model ◽  
Breast Cancer Risk Assessment ◽  
Iraqi Women ◽  
The Mean

Abstract Background Breast cancer is one of the most common cancers among women worldwide and the leading cause of death among Iraqi women. Breast cancer cases in Iraq were found to have increased from 26.6/100,000 in 2000 to 31.5/100,000 in 2009. The present study aims to assess the established risk factors of breast cancer among Iraqi women and to highlight strategies that can aid in reducing the incidence. Methods 1093 Iraqi females were enrolled in this cross-sectional study by purposive sampling methods. Data collection occurred from July 2019 to September 2019. 1500 women participated in the study, and 407 women were ultimately excluded. The questionnaire was conducted as a self-administrated form in an online survey. Ethical approval was obtained from the College of Medicine in the University of Baghdad. The Gail Model risk was calculated for each woman by the Breast Cancer Risk Assessment Tool (BCRAT), an interactive model developed by Mitchell Gail that was designed to estimate a woman’s absolute risk of developing breast cancer in the upcoming five years of her life and in her lifetime. Results The ages of the participants ranged from 35 to 84 years old. The mean 5–year risk of breast cancer was found to be 1.3, with 75.3% of women at low risk and 24.7% of women at high risk. The mean lifetime risk of breast cancer was found to be 13.4, with 64.7% of women at low risk, 30.3% at moderate risk, and 5.0% at high risk. The results show that geographically Baghdad presented the highest 5-year risk, followed by Dhi Qar, Maysan, and Nineveh. However, the highest lifetime risk was found in Najaf, followed by Dhi Qar, Baghdad, and Nineveh, successively. Conclusion Breast cancer is a wide-spreading problem in the world and particularly in Iraq, with Gail Model estimations of high risk in several governorates. Prevention programs need to be implemented and awareness campaigns organized in order to highlight the importance of early detection and treatment.

Breast Screening and Evaluation, High Risk Patients

2019 ◽  
Author(s):  
Helen Cappuccino ◽  
Ermelinda Bonaccio
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Reduction ◽  
Breast Density ◽  
Breast Screening ◽  
High Risk Patients ◽  
Risk Patients

The fundamental tasks facing surgeons evaluating patients’ breasts are to rule out malignancy, ameliorate breast symptoms, and manage premalignant breast conditions and risk factors to minimize a patient’s chances of developing cancer. Woman presenting to a surgeon should receive thorough and appropriate breast evaluation, breast cancer risk assessment, and treatment, which minimizes risks going forward. In this review, we focus on screening recommendations for (both average and high-risk) patients for breast cancer, Breast Imaging, Reporting and Data System categories, the performance of a thorough breast history and physical examination. We also discuss various breasts imaging modalities and their strengths and weaknesses. We review breast density as a confounding factor and increased risk factor, and the grading of breast density. Finally, different ways of performing breast biopsies are discussed as well as the evaluation of risk for breast cancer with interventions for enhanced screening and risk reduction. This review contains 12 figures, 7 tables, and 35 references.  Key Words: BI-RADs, breast cancer risk factors, breast cancer risk reduction, breast core biopsy, breast screening, enhanced screening, BRCA, chemoprevention, mammography

Global tissue stiffness on breast MR elastography: High-risk dense breast patients have higher stiffness compared to average-risk dense breast patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10541-10541
Author(s):  
Bhavika K. Patel ◽  
Kay Pepin ◽  
Kathy R Brandt ◽  
Gina L. Mazza ◽  
Barbara A. Pockaj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Cancer Risk ◽  
Menopausal Status ◽  
Risk Groups ◽  
Average Risk ◽  
Tissue Stiffness ◽  
Tissue Properties ◽  
Dense Breasts ◽  
Risk Patients

10541 Background: Biomechanical tissue properties may vary in the breasts of patients at elevated risk for breast cancer. We aim to quantify in vivo biomechanical tissue properties in various breast densities and in both normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association of biomechanical properties of the breast with cancer risk. Methods: In this IRB–approved prospective single-institution study, we recruited two groups of women differing by breast cancer risk to undergo a 3.0 T dynamic contrast enhanced MRI/MRE of the breast. Low-average risk women were defined as having no personal or significant family history of breast cancer, no prior high risk breast biopsies and a negative mammography within 12 months. High-risk breast cancer patients were recruited from those patients who underwent standard of care breast MR. Within each breast density group (non-dense versus dense), two-sample t-tests were used to compare breast stiffness, elasticity, and viscosity across risk groups (low-average vs high). Results: There were 50 low-average risk and 86 high-risk patients recruited to the study. The risk groups were similar on age (mean age = 55.6 and 53.6 years), density (68% vs. 64% dense breasts) and menopausal status (66.0% vs. 69.8%). Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients ( N = 55) compared to low-average risk patients ( N = 34; all p < 0.001). In the multivariate logistic regression model, breast stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, MRI BPE, age, and menopausal status. Similar results were seen for breast elasticity (OR=4.88, 95% CI [2.08, 11.43]) and viscosity (OR=11.49, 95% CI [1.15, 114.89]). Conclusions: Structurally-based, quantitative biomarker of tissue stiffness obtained from global 3D breast MRE is associated with differences in breast cancer risk in dense breasts. As such, tissue stiffness could provide a novel prognostic marker to help identify the subset of high-risk women with dense breasts who would benefit from increased surveillance.[Table: see text]

scholarly journals A streamlined model for use in clinical breast cancer risk assessment maintains predictive power and is further improved with inclusion of a polygenic risk score

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245375
Author(s):  
Richard Allman ◽  
Erika Spaeth ◽  
John Lai ◽  
Susan J. Gross ◽  
John L. Hopper
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
African American ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Score ◽  
Clinical Risk Factors ◽  
Polygenic Risk Score ◽  
Gail Model ◽  
Clinical Risk

Five-year absolute breast cancer risk prediction models are required to comply with national guidelines regarding risk reduction regimens. Models including the Gail model are under-utilized in the general population for various reasons, including difficulty in accurately completing some clinical fields. The purpose of this study was to determine if a streamlined risk model could be designed without substantial loss in performance. Only the clinical risk factors that were easily answered by women will be retained and combined with an objective validated polygenic risk score (PRS) to ultimately improve overall compliance with professional recommendations. We first undertook a review of a series of 2,339 Caucasian, African American and Hispanic women from the USA who underwent clinical testing. We first used deidentified test request forms to identify the clinical risk factors that were best answered by women in a clinical setting and then compared the 5-year risks for the full model and the streamlined model in this clinical series. We used OPERA analysis on previously published case-control data from 11,924 Gail model samples to determine clinical risk factors to include in a streamlined model: first degree family history and age that could then be combined with the PRS. Next, to ensure that the addition of PRS to the streamlined model was indeed beneficial, we compared risk stratification using the Streamlined model with and without PRS for the existing case-control datasets comprising 1,313 cases and 10,611 controls of African-American (n = 7421), Caucasian (n = 1155) and Hispanic (n = 3348) women, using the area under the curve to determine model performance. The improvement in risk discrimination from adding the PRS risk score to the Streamlined model was 52%, 46% and 62% for African-American, Caucasian and Hispanic women, respectively, based on changes in log OPERA. There was no statistically significant difference in mean risk scores between the Gail model plus risk PRS compared to the Streamlined model plus PRS. This study demonstrates that validated PRS can be used to streamline a clinical test for primary care practice without diminishing test performance. Importantly, by eliminating risk factors that women find hard to recall or that require obtaining medical records, this model may facilitate increased clinical adoption of 5-year risk breast cancer risk prediction test in keeping with national standards and guidelines for breast cancer risk reduction.

scholarly journals Addressing Barriers to Uptake of Breast Cancer Chemoprevention for Patients and Providers

2015 ◽  
pp. e50-e58 ◽  
Author(s):  
Katherine D. Crew
Keyword(s):  
Breast Cancer ◽  
Primary Prevention ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Chemoprevention ◽  
The United States ◽  
Cancer Risk Assessment ◽  
Breast Cancer Risk Assessment ◽  
Breast Cancer Chemoprevention

Breast cancer is the most common malignancy among women in the United States, and the primary prevention of this disease is a major public health issue. Because there are relatively few modifiable breast cancer risk factors, pharmacologic interventions with antiestrogens have the potential to significantly affect the primary prevention setting. Breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene, and with aromatase inhibitors (AIs) exemestane and anastrozole, is underutilized despite several randomized controlled trials demonstrating up to a 50% to 65% relative risk reduction in breast cancer incidence among women at high risk. An estimated 10 million women in the United States meet high-risk criteria for breast cancer and are potentially eligible for chemoprevention, but less than 5% of women at high risk who are offered antiestrogens for primary prevention agree to take it. Reasons for low chemoprevention uptake include lack of routine breast cancer risk assessment in primary care, inadequate time for counseling, insufficient knowledge about antiestrogens among patients and providers, and concerns about side effects. Interventions designed to increase chemoprevention uptake, such as decision aids and incorporating breast cancer risk assessment into clinical practice, have met with limited success. Clinicians can help women make informed decisions about chemoprevention by effectively communicating breast cancer risk and enhancing knowledge about the risks and benefits of antiestrogens. Widespread adoption of chemoprevention will require a major paradigm shift in clinical practice for primary care providers (PCPs). However, enhancing uptake and adherence to breast cancer chemoprevention holds promise for reducing the public health burden of this disease.

scholarly journals Validation of the Gail model for predicting individual breast cancer risk in a prospective nationwide study of 28,104 Singapore women

2012 ◽  
Vol 14 (1) ◽  
Author(s):  
Wen Yee Chay ◽  
Whee Sze Ong ◽  
Puay Hoon Tan ◽  
Nicholas Qi Jie Leo ◽  
Gay Hui Ho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Gail Model ◽  
Nationwide Study
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