The Role of hBRCA2 in the Repair of Spontaneous and UV DNA Damage in Saccharomyces cerevisiae.

Women with mutations in the human BRCA2 gene ( hBRCA2 ) have an increased risk of developing breast and ovarian cancer throughout their lifetime. hBRCA2 transcribes proteins necessary for gene repair through homologous recombination (HR). In order to better understand the role of hBRCA2 in response to specific types of DNA damage, the present study evaluated HR in the budding yeast, Saccharomyces cerevisiae , using wildtype (WT) and rad52Δ mutant cells subject to spontaneous and UV damage in the presence or absence of hBRCA2. As expected, rad52Δ genotypes yielded lower recombination frequencies compared to WT in both spontaneous and UV exposure experiments. However, there was no significant difference between rad52Δ mutants with or without hBRCA2. Interestingly, higher UV exposure resulted in a relative increase in HR for only the rad52Δ mutant genotypes. The results demonstrate that hBRCA2 complementation may not be as substantial in spontaneous or UV DNA damage compared to double-strand break DNA damage, as previous work has shown.

Potential Role of Glyphosate, Glyphosate-Based Herbicides, and AMPA in Breast Cancer Development: A Review of Human and Human Cell-Based Studies.

The potential connection between exposure to glyphosate and glyphosate-based herbicides (GBHs) and breast cancer risk is a topic of research that is rapidly gaining the public's attention due to the conflicting reports surrounding glyphosate's potential carcinogenicity. In this review, we synthesize the current published biomedical literature works that have explored associations of glyphosate, its metabolite, aminomethylphosphonic acid (AMPA), and GBHs with breast cancer risk in humans and human cell-based models. Using PubMed as our search engine, we identified a total of 14 articles that were included in this review. In the four human studies, urinary glyphosate and/or AMPA were associated with breast cancer risk, endocrine disruption, oxidative stress biomarkers, and changes in DNA methylation patterns. Among most of the 10 human cell-based studies, glyphosate exhibited endocrine disruption, induced altered gene expression, increased DNA damage, and altered cell viability, while GBHs were more cytotoxic than glyphosate alone. In summary, numerous studies have shown glyphosate, AMPA, and GBHs to have potential carcinogenic, cytotoxic, or endocrine-disruptive properties. However, more human studies need to be conducted in order for more definitive and supported conclusions to be made on their potential effects on breast cancer risk.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Mechanism underlying and prevention of electrode migration in cochlear implants.

PURPOSE: We investigate the clinical manifestations, mechanisms, and methods of preventing electrode migration in Cochlear Implantation (CI) patients, based on our practical experience with this problem. STUDY DESIGN: This is a retrospective study in a single center. METHODS: We retrospectively reviewed electrode migration in 4 (0.75%) of 532 patients who underwent CI at our tertiary institution from January 2002 to December 2022. Pre- and post-operative pure-tone audiometry, word recognition score, aided functional gain test, and sound field speech intelligibility test were evaluated. RESULTS: All four patients underwent CIs with the straight electrode type. The following events or symptoms were observed in the patients before confirming electrode migration: an increase in high-frequency thresholds during the post-operative aided functional gain test and a decline in scores on the sound field speech intelligibility test. Electrode migration was confirmed through transocular view X-ray or temporal bone computer tomography. Two patients showed coiled electrodes within the mastoid cavity; while in the others, the electrodes were observed to be floating inside the cavity. To prevent migration of electrodes due to these issues, we mixed bone paste collected during the drilling of the mastoid cavity with glue and used it to secure the electrodes in place. CONCLUSION: Electrode migration can result in a decrease in hearing ability and may necessitate a revision surgery to adjust the electrode placement. The main factors affecting electrode placement include the position of electrode within the mastoid cavity and the elasticity of straight electrodes. It is important for surgeons to recognize the factors that increase the risk of electrode migration and to take preventative measures to reduce this risk.

Expression of human BRCA2 in Saccharomyces cerevisiae complements the loss of RAD52 in double-strand break repair.

BRCA2 is a tumor-suppressor gene that is normally expressed in the breast and ovarian tissue of mammals. The BRCA2 protein mediates the repair of double-strand breaks (DSBs) using homologous recombination, which is a conserved pathway in eukaryotes. Women who express missense mutations in the BRCA2 gene are predisposed to an elevated lifetime risk for both breast cancer and ovarian cancer. In the present study, the efficiency of human BRCA2 (hBRCA2) in DSB repair was investigated in the budding yeast Saccharomyces cerevisiae. While budding yeast does not possess a true BRCA2 homolog, they have a potential functional homolog known as Rad52, which is an essential repair protein involved in mediating homologous recombination using the same mechanism as BRCA2 in humans. Therefore, to examine the functional overlap between Rad52 in yeast and hBRCA2, we expressed the wild-type hBRCA2 gene in budding yeast with or without Rad52 and monitored ionizing radiation resistance and DSB repair efficiency. We found that the expression of hBRCA2 in rad52 mutants increases both radiation resistance and DSB repair frequency compared to cells not expressing BRCA2. Specifically, BRCA2 improved the protection against ionizing radiation by at least 1.93-fold and the repair frequency by 6.1-fold. In addition, our results show that homology length influences repair efficiency in rad52 mutant cells, which impacts BRCA2 mediated repair of DSBs. This study provides evidence that S. cerevisiae could be used to monitor BRCA2 function, which can help in understanding the genetic consequences of BRCA2 variants and how they may contribute to cancer progression.

Factors Associated with Longitudinal Changes in Mammographic Density in a Multiethnic Breast Screening Cohort of Postmenopausal Women.

Background: Breast density is an important risk factor for breast cancer and is known to be associated with characteristics such as age, race, and hormone levels; however, it is unclear what factors contribute to changes in breast density in postmenopausal women over time. Understanding factors associated with density changes may enable a better understanding of breast cancer risk and facilitate potential strategies for prevention. Methods: This study investigated potential associations between personal factors and changes in mammographic density in a cohort of 3,392 postmenopausal women with no personal history of breast cancer between 2011 and 2017. Self-reported information on demographics, breast and reproductive history, and lifestyle factors, including body mass index (BMI), alcohol intake, smoking, and physical activity, was collected by an electronic intake form, and breast imaging reporting and database system (BI-RADS) mammographic density scores were obtained from electronic medical records. Factors associated with a longitudinal increase or decrease in mammographic density were identified using Fisher's exact test and multivariate conditional logistic regression. Results: 7.9% of women exhibited a longitudinal decrease in mammographic density, 6.7% exhibited an increase, and 85.4% exhibited no change. Longitudinal changes in mammographic density were correlated with age, race/ethnicity, and age at menopause in the univariate analysis. In the multivariate analysis, Asian women were more likely to exhibit a longitudinal increase in mammographic density and less likely to exhibit a decrease compared to White women. On the other hand, obese women were less likely to exhibit an increase and more likely to exhibit a decrease compared to normal weight women. Women who underwent menopause at age 55 years or older were less likely to exhibit a decrease in mammographic density compared to women who underwent menopause at a younger age. Besides obesity, lifestyle factors (alcohol intake, smoking, and physical activity) were not associated with longitudinal changes in mammographic density. Conclusions: The associations we observed between Asian race/obesity and longitudinal changes in BI-RADS density in postmenopausal women are paradoxical in that breast cancer risk is lower in Asian women and higher in obese women. However, the association between later age at menopause and a decreased likelihood of decreasing in BI-RADS density over time is consistent with later age at menopause being a risk factor for breast cancer and suggests a potential relationship between greater cumulative lifetime estrogen exposure and relative stability in breast density after menopause. Our findings support the complexity of the relationships between breast density, BMI, hormone exposure, and breast cancer risk.

Early Ascertainment of Breast Cancer Diagnoses Comparing Self-Reported Questionnaires and Electronic Health Record Data Warehouse: The WISDOM Study.

PURPOSE: The goal of this study was to use real-world data sources that may be faster and more complete than self-reported data alone, and timelier than cancer registries, to ascertain breast cancer cases in the ongoing screening trial, the WISDOM Study. METHODS: We developed a data warehouse procedural process (DWPP) to identify breast cancer cases from a subgroup of WISDOM participants (n = 11,314) who received breast-related care from a University of California Health Center in the period 2012-2021 by searching electronic health records (EHRs) in the University of California Data Warehouse (UCDW). Incident breast cancer diagnoses identified by the DWPP were compared with those identified by self-report via annual follow-up online questionnaires. RESULTS: Our study identified 172 participants with confirmed breast cancer diagnoses in the period 2016-2021 by the following sources: 129 (75%) by both self-report and DWPP, 23 (13%) by DWPP alone, and 20 (12%) by self-report only. Among those with International Classification of Diseases 10th revision cancer diagnostic codes, no diagnosis was confirmed in 18% of participants. CONCLUSION: For diagnoses that occurred ≥20 months before the January 1, 2022, UCDW data pull, WISDOM self-reported data via annual questionnaire achieved high accuracy (96%), as confirmed by the cancer registry. More rapid cancer ascertainment can be achieved by combining self-reported data with EHR data from a health system data warehouse registry, particularly to address self-reported questionnaire issues such as timing delays (ie, time lag between participant diagnoses and the submission of their self-reported questionnaire typically ranges from a month to a year) and lack of response. Although cancer registry reporting often is not as timely, it does not require verification as does the DWPP or self-report from annual questionnaires.

Assessment of Radiologic Extranodal Extension Using Combinatorial Analysis of Nodal Margin Breakdown and Metastatic Burden in Oropharyngeal Cancer.

The importance of risk stratification in the management of oropharyngeal squamous cell carcinoma (OPSCC) is becoming increasingly obvious with the growing evidence of its variable prognosis. We identified and evaluated imaging characteristics predictive of extranodal extension (ENE) in OPSCC. Preoperative computed tomography and histopathologic results of 108 OPSCC patients who underwent neck dissection as primary treatment were analyzed. Imaging characteristics were reassessed for factors associated with nodal margin breakdown and metastatic burden. Moreover, the predictability of pathological ENE (pENE) was analyzed. Univariate and multivariate binomial logistic regression analyses were performed to examine the predictive power of ENE-related radiologic features. Imaging-based characteristics showed variable degrees of association with pENE. Factors associated with nodal margin breakdown (indistinct capsular contour, irregular margin, and perinodal fat stranding) and factors associated with nodal burden (nodal matting, lower neck metastasis, and presence of >4 lymph node metastases) were significantly predictive of ENE (odds ratio (OR) = 11.170 and 12.121, respectively). The combined utilization of the nodal margin and burden factors further increased the predictive ability (OR = 14.710). Factors associated with nodal margin breakdown and nodal burden were associated with pENE, demonstrating the use of combinatorial analysis for more accurate ENE prediction.

Which is Better for Ossiculoplasty Following Tympanomastoidectomy: Polycel® or Titanium?

OBJECTIVES: The purpose of this study was to compare the surgical outcomes of Polycel® and titanium in ossiculoplasty following tympanomastoidectomy (TM). METHODS: A total of 221 patients underwent ossiculoplasty following TM by a single surgeon using either Polycel® or titanium as prosthesis. Hearing was tested preoperatively and postoperatively at 6 months by pure-tone audiometry. Successful surgery was defined if postoperative air-bone gap (ABG) was <20 dB, the gain in air conduction (AC) hearing was >15 dB HL, or postoperative AC was <30 dB HL. Multiple linear regression was conducted to identify the factors associated with the surgical outcomes. RESULTS: In canal wall up mastoidectomy (CWUM), both Polycel® and titanium showed favorable successful rates if partial ossicular replacement prosthesis (PORP) was used (64.3% of Polycel® and 67.6% in titanium). If total ossicular replacement prosthesis (TORP) was used, both represented similar outcomes (54.5% of Polycel® and 75.0% in titanium). In canal wall down mastoidectomy (CWDM), significant ABG reductions were observed only in the titanium group (5.2 ± 14.7 dB of Polycel® [P = .083] and 7.0 ± 14.2 dB of titanium [P = .002] in PORP; 4.6 ± 13.5 dB of Polycel® [P = .097] and 9.5 ± 11.2 dB of titanium [P < .001] in TORP). In multivariate analysis, titanium had a positive effect on the reduction of postoperative AC thresholds (B: -4.772; 95% CI: -8.706--0.838). CONCLUSIONS: Both Polycel® and titanium showed favorable surgical outcomes for ossiculoplasty following CWUM. Titanium prosthesis is recommended for surgery after CWDM.

Stemless Hemiarthroplasty and Anterior Capsular Reconstruction in the Setting of a Residual Humeral Limb: A Case Report.

CASE: We present a 58-year-old left hand-dominant woman with right glenohumeral osteoarthritis and anterior instability in the setting of a congenital residual limb at the level of the mid-humerus. She had persistent pain and dysfunction despite trying conservative treatments and elected for a stemless or "canal-sparing" hemiarthroplasty with anterior capsular reconstruction. At the 2-year follow-up, there was significant improvement in her pain, motion, and function without signs of radiographic loosening. CONCLUSION: A stemless humeral implant is a versatile component that can be used in the face of humeral dysplasia, such as this patient with a congenital residual limb.

Stakeholder perceptions affecting the implementation of teleophthalmology.

PURPOSE: Teleophthalmology has become the subject of heightened interest and scrutiny in the wake of the SARS-CoV-2 global pandemic. A streamlined implementation framework becomes increasingly important as demand grows. This study identified obstacles to teleophthalmology implementation through summative content analysis of key stakeholders' perceptions. DESIGN: Summative content analysis of transcribed interviews with key stakeholders (including patients, technicians, ophthalmic readers, staff, nurses, and administrators at two teleophthalmology clinic sites). METHODS: Keyword Were counted and compared to examine underlying meaning. Two analysts coded text independently using MAXQDA for summative qualitative content analysis to derive themes and hierarchical relationships as a basis for future refinement of TECS implementation. xMind ZEN was used to map conceptual relationships and overarching themes that emerged to identify perceived facilitators and barriers to implementation RESULTS: Analysis revealed two themes common to perceptions: (1) benefits of care, and (2) ease of implementation. Perceived benefits included efficiency, accessibility, and earlier intervention in disease course. The quality and quantity of training was heavily weighted in its influence on stakeholders' commitment to and confidence in the program, as were transparent organizational structure, clear bidirectional communication, and the availability of support staff. CONCLUSION: Using a determinant framework of implementation science, this report highlighted potential hindrances to teleophthalmology implementation and offered solutions in order to increase access to screening, improve the quality of care provided, and facilitate sustainability of the innovation.

Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women.

BACKGROUND: Glyphosate is the most commonly used herbicide in the world and is purported to have a variety of health effects, including endocrine disruption and an elevated risk of several types of cancer. Blood DNA methylation has been shown to be associated with many other environmental exposures, but to our knowledge, no studies to date have examined the association between blood DNA methylation and glyphosate exposure. OBJECTIVE: We conducted an epigenome-wide association study to identify DNA methylation loci associated with urinary glyphosate and its metabolite aminomethylphosphonic acid (AMPA) levels. Secondary goals were to determine the association of epigenetic age acceleration with glyphosate and AMPA and develop blood DNA methylation indices to predict urinary glyphosate and AMPA levels. METHODS: For 392 postmenopausal women, white blood cell DNA methylation was measured using the Illumina Infinium MethylationEPIC BeadChip array. Glyphosate and AMPA were measured in two urine samples per participant using liquid chromatography-tandem mass spectrometry. Methylation differences at the probe and regional level associated with glyphosate and AMPA levels were assessed using a resampling-based approach. Probes and regions that had an false discovery rate q<0.1 in ≥90% of 1,000 subsamples of the study population were considered differentially methylated. Differentially methylated sites from the probe-specific analysis were combined into a methylation index. Epigenetic age acceleration from three epigenetic clocks and an epigenetic measure of pace of aging were examined for associations with glyphosate and AMPA. RESULTS: We identified 24 CpG sites whose methylation level was associated with urinary glyphosate concentration and two associated with AMPA. Four regions, within the promoters of the MSH4, KCNA6, ABAT, and NDUFAF2/ERCC8 genes, were associated with glyphosate levels, along with an association between ESR1 promoter hypomethylation and AMPA. The methylation index accurately predicted glyphosate levels in an internal validation cohort. AMPA, but not glyphosate, was associated with greater epigenetic age acceleration. DISCUSSION: Glyphosate and AMPA exposure were associated with DNA methylation differences that could promote the development of cancer and other diseases. Further studies are warranted to replicate our results, determine the functional impact of glyphosate- and AMPA-associated differential DNA methylation, and further explore whether DNA methylation could serve as a biomarker of glyphosate exposure. https://doi.org/10.1289/EHP10174.

Association of mammographic density with blood DNA methylation.

BACKGROUND: Altered DNA methylation may be an intermediate phenotype between breast cancer risk factors and disease. Mammographic density is a strong risk factor for breast cancer. However, no studies to date have identified an epigenetic signature of mammographic density. We performed an epigenome-wide association study of mammographic density. METHODS: White blood cell DNA methylation was measured for 385 postmenopausal women using the Illumina Infinium MethylationEPIC BeadChip array. Differential methylation was assessed using genome-wide, probe-level, and regional analyses. We implemented a resampling-based approach to improve the stability of our findings. RESULTS: On average, women with elevated mammographic density exhibited DNA hypermethylation within CpG islands and gene promoters compared to women with lower mammographic density. We identified 250 CpG sites for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, including HDLBP, TGFB2, CCT4, and PAX8, and were more likely to be located in regulatory regions of the genome. We also identified differential DNA methylation in 37 regions, including within the promoters of PAX8 and PF4, a gene involved in the regulation of angiogenesis. Overall, our results paint a picture of epigenetic dysregulation associated with mammographic density. CONCLUSION: Mammographic density is associated with differential DNA methylation throughout the genome, including within genes associated with cancer. Our results suggest the potential involvement of several genes in the biological mechanisms behind differences in breast density between women. Further studies are warranted to explore these potential mechanisms and potential links to breast cancer risk.

Mammography screening and mortality by risk status in the California teachers study.

BACKGROUND: The debate continues among medical professionals regarding the frequency, starting age, and stopping age for mammography screening. Some experts suggest tailoring recommendations based on individuals' personal breast cancer risk. Previous studies have not compared the impact of annual versus biennial mammography stratified by age group and risk category. The purpose of this study was to examine the relationship between mammography frequency and mortality by age group and risk category in the California Teachers Study. METHODS: Using data from study questionnaires from 93,438 women between the ages of 40 and 85 and linkages to the California Cancer Registry and other indices, overall and breast cancer-specific mortality by mammography frequency were estimated using multivariable Cox proportional hazards models, stratified by age group and risk category at baseline as determined by the Gail breast cancer risk model. RESULTS: During the follow-up period of 20 years, overall mortality risk was lower in women who had annual or biennial mammography compared to less frequent or no mammography in all age groups. Annual mammography was associated with lower overall mortality risk compared to biennial mammography among women age 50-85. This difference was especially apparent in women age 60-74, regardless of estimated Gail risk category at baseline. Breast cancer-specific mortality was lower among women who had annual mammography compared to biennial or less frequent mammography among women age 60-74, regardless of their baseline risk. CONCLUSIONS: Our findings suggest that at least biennial mammography is beneficial to most women age 40-85 and that annual mammography is more beneficial than biennial mammography to most women age 50-85 in terms of overall mortality.

Factors Associated with Women's Unwillingness to Decrease Alcohol Intake to Decrease Breast Cancer Risk.

OBJECTIVE: Alcohol intake is a known risk factor for breast cancer. National organizations recommend that women consume no more than one serving of alcohol per day, if at all; however, many women exceed this recommendation, and some are unwilling to decrease consumption. Our study sought to identify factors associated with women's unwillingness to decrease their alcohol intake to decrease their breast cancer risk. METHODS: 942 women in a screening mammography cohort were asked questions about their demographics, personal and family health history, lifestyle factors, and willingness/unwillingness to decrease alcohol intake to decrease their breast cancer risk. Univariate and multivariate analyzes of their responses were performed. RESULTS: 13.2% of women in our cohort indicated they were unwilling to decrease their alcohol intake to reduce their breast cancer risk. After adjusting for potential confounders, women who were 60 years and older were more than twice as unwilling to decrease their alcohol intake compared to their younger counterparts (P = .0002). Women who had an annual household income of more than $200,000 were 1.75 times more unwilling to decrease their alcohol intake compared to their less affluent counterparts (P = .033). Unwillingness was not significantly associated with race/ethnicity, education, having a first-degree family member with cancer, health perception, breast cancer risk perception, or BMI. CONCLUSIONS: Levels of unwillingness to decrease alcohol intake differed by age and household income. An opportunity is present to potentially decrease breast cancer risk in the community by educating women, especially older and more affluent women, about alcohol as a risk factor for breast cancer and the importance of limiting one's alcohol intake.

Breast Cancer Risk Prediction in Korean Women: Review and Perspectives on Personalized Breast Cancer Screening.

Due to an increasing proportion of older individuals and the adoption of a westernized lifestyle, the incidence rate of breast cancer is expected to rapidly increase within the next 10 years in Korea. The National Cancer Screening Program (NCSP) of Korea recommends biennial breast cancer screening through mammography for women aged 40-69 years old and according to individual risk and preference for women above 70 years old. There is an ongoing debate on how to most effectively screen for breast cancer, with many proponents of personalized screening, or screening according to individual risk, for women under 70 years old as well. However, to accurately stratify women into risk categories, further study using more refined personalized characteristics, including potentially incorporating a polygenic risk score (PRS), may be needed. While most breast cancer risk prediction models were developed in Western countries, the Korean Breast Cancer Risk Assessment Tool (KoBCRAT) was developed in 2013, and several other risk models have been developed for Asian women specifically. This paper reviews these models compared to commonly used models developed using primarily Caucasian women, namely, the modified Gail, Breast Cancer Surveillance Consortium, Rosner and Colditz, and Tyrer-Cuzick models. In addition, this paper reviews studies in which PRS is included in risk prediction in Asian women. Finally, this paper discusses and explores strategies toward development and implementation of personalized screening for breast cancer in Korea.

Organophosphate Pesticide Exposure and Breast Cancer Risk: A Rapid Review of Human, Animal, and Cell-Based Studies.

BACKGROUND: Organophosphate pesticides (OPs) are one of the most commonly used classes of insecticides in the U.S., and metabolites of OPs have been detected in the urine of >75% of the U.S. POPULATION: While studies have shown that OP exposure is associated with risk of neurological diseases and some cancers, the relationship between OP exposure and breast cancer risk is not well understood. METHODS: The aim of this rapid review was to systematically evaluate published literature on the relationship between OP exposure and breast cancer risk, including both epidemiologic and laboratory studies. Twenty-seven full-text articles were reviewed by searching on Pubmed, EMBASE, and Cochrane databases. RESULTS: Some human studies showed that malathion, terbufos, and chlorpyrifos were positively associated with human breast cancer risk, and some laboratory studies demonstrated that malathion and chlorpyrifos have estrogenic potential and other cancer-promoting properties. However, the human studies were limited in number, mostly included agricultural settings in several geographical areas in the U.S., and did not address cumulative exposure. CONCLUSIONS: Given the mixed results found in both human and laboratory studies, more research is needed to further examine the relationship between OP exposure and breast cancer risk, especially in humans in non-agricultural settings.

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention.

Environmental and lifestyle factors are believed to account for >80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies.

Expression of the BAD pathway is a marker of triple-negative status and poor outcome.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.