Family History of Breast Cancer and Mammographic Breast Density in Premenopausal Women.

Importance: Family history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood. Objectives: To investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements. Design, Setting, and Participants: This single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from women in the validation set was collected between June 2010 and December 2015. Data analysis was performed between June 2018 and June 2020. Exposures: Family history of breast cancer (FHBC). Main Outcomes and Measures: The primary outcomes were mammographic breast density measured quantitatively as volumetric percent density using Volpara (discovery set) and qualitatively using BI-RADS (Breast Imaging Reporting and Data System) breast density (validation set). Multivariable regressions were performed using a log-transformed normal distribution for the discovery set and a logistic distribution for the validation set. Results: Of 14 415 premenopausal women included in the study, the discovery set and validation set had similar characteristics (discovery set with FHBC: mean [SD] age, 47.1 [5.6] years; 15 [17.2%] were Black or African American women and 64 [73.6%] were non-Hispanic White women; discovery set with no FHBC: mean [SD] age, 47.7 [4.5] years; 87 [31.6%] were Black or African American women and 178 [64.7%] were non-Hispanic White women; validation set with FHBC: mean [SD] age, 46.8 [7.3] years; 720 [33.4%] were Black or African American women and 1378 [64.0%] were non-Hispanic White women]; validation set with no FHBC: mean [SD] age, 47.5 [6.1] years; 4572 [38.5%] were Black or African American women and 6632 [55.8%] were non-Hispanic White women]). In the discovery set, participants who had FHBC were more likely to have a higher mean volumetric percent density compared with participants with no FHBC (11.1% vs 9.0%). In the multivariable-adjusted model, volumetric percent density was 25% higher (odds ratio [OR], 1.25 ;95% CI, 1.12-1.41) in women with FHBC compared with women without FHBC; and 24% higher (OR, 1.24; 95% CI, 1.10-1.40) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.40; 95% CI, 0.95-2.07) compared with women with no relatives affected. In the validation set, women with a positive FHBC were more likely to have dense breasts (BI-RADS 3-4) compared with women with no FHBC (BI-RADS 3: 41.1% vs 38.8%; BI-RADS 4: 10.5% vs 7.7%). In the multivariable-adjusted model, the odds of having dense breasts (BI-RADS 3-4) were 30% higher (OR, 1.30; 95% CI, 1.17-1.45) in women with FHBC compared with women without FHBC; and 29% higher (OR, 1.29; 95% CI, 1.14-1.45) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.38; 95% CI, 0.85-2.23) compared with women with no relatives affected. Conclusions and Relevance: In this cohort study, having an FHBC was positively associated with mammographic breast density in premenopausal women. Our findings highlight the heritable component of mammographic breast density and underscore the need to begin annual screening early in premenopausal women with a family history of breast cancer.

Breast tissue regeneration is driven by cell-matrix interactions coordinating multi-lineage stem cell differentiation through DDR1.

Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in stromal tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and function. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through a collagen receptor. Discoidin domain receptor tyrosine kinase 1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells via Notch signaling to differentiate and form lobules. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that lead to formation of a complex ductal-lobular network.

Expression of LGR5 in mammary myoepithelial cells and in triple-negative breast cancers.

Lineage tracing in mice indicates that LGR5 is an adult stem cell marker in multiple organs, such as the intestine, stomach, hair follicles, ovary, and mammary glands. Despite many studies exploring the presence of LGR5 cells in human tissues, little is known about its expression profile in either human mammary tissue or pathological lesions. In this study we aim to investigate LGR5 expression in normal, benign, and malignant lesions of the human breast using RNA in situ hybridization. LGR5 expression has not been observed in normal lactiferous ducts and terminal duct lobular units, whereas LGR5-positive cells have been specifically observed in the basal myoepithelium of ducts in the regenerative tissues, ductal carcinoma in situ, and in ducts surrounded by invasive cancer cells. These findings suggest LGR5 marks facultative stem cells that are involved in post injury regeneration instead of homeostatic stem cells. LGR5 positivity was found in 3% (9 of 278 cases) of invasive breast cancers (BC), and it showed positive associations with higher histologic grades (P = 0.001) and T stages (P < 0.001), while having negative correlations with estrogen receptor (P < 0.001) and progesterone receptor (P < 0.001) expression. Remarkably, all LGR5-positive BC, except one, belong to triple-negative BC (TNBC), representing 24% (9 of 38 cases) of all of them. LGR5 histoscores have no correlations with EGFR, CK5/6, Ki-67, or P53 expression. Additionally, no ß-catenin nuclear localization was observed in LGR5-positive BC, indicating that canonical Wnt pathway activation is less likely involved in LGR5 expression in BC. Our results demonstrate that LGR5 expression is induced in regenerative conditions in the myoepithelium of human mammary ducts and that its expression is only observed in TNBC subtype among all invasive BC. Further studies regarding the functional and prognostic impact of LGR5 in TNBC are warranted.

Vitamin D as a Potential Preventive Agent For Young Women's Breast Cancer.

Clinical studies backed by research in animal models suggest that vitamin D may protect against the development of breast cancer, implicating vitamin D as a promising candidate for breast cancer prevention. However, despite clear preclinical evidence showing protective roles for vitamin D, broadly targeted clinical trials of vitamin D supplementation have yielded conflicting findings, highlighting the complexity of translating preclinical data to efficacy in humans. While vitamin D supplementation targeted to high-risk populations is a strategy anticipated to increase prevention efficacy, a complimentary approach is to target transient, developmental windows of elevated breast cancer risk. Postpartum mammary gland involution represents a developmental window of increased breast cancer promotion that may be poised for vitamin D supplementation. Targeting the window of involution with short-term vitamin D intervention may offer a simple, cost-effective approach for the prevention of breast cancers that develop postpartum. In this review, we highlight epidemiologic and preclinical studies linking vitamin D deficiency with breast cancer development. We discuss the underlying mechanisms through which vitamin D deficiency contributes to cancer development, with an emphasis on the anti-inflammatory activity of vitamin D. We also discuss current evidence for vitamin D as an immunotherapeutic agent and the potential for vitamin D as a preventative strategy for young woman's breast cancer.

The 10-Year Experience with Volume Distribution Mastopexy: A Novel, Safe, and Efficient Method for Breast Rejuvenation.

BACKGROUND: Recurrent ptosis may occur after mastopexy procedures over time. The volume distribution mastopexy technique provides breast lifting with projection enhancement and maintains breast suspension. METHOD: Since 2010, 50 patients underwent volume distribution mastopexy procedures. The technique consists of a superior or superomedial pedicle, dissection of a Würinger-septum-based chest wall flap, suspension of the flap to the pectoralis major muscle using a prosthetic mesh, gland suture to the mesh, and fat grafting if required. A prospective study was conducted. Nipple position and length of the lower pole distance of the breast were noted. Patient satisfaction and results evaluation were reported using a Likert scale. RESULTS: A Vicryl mesh was used in the first 23 patients and a mixed polyester/Vicryl mesh was used in the following 27 patients. Wound dehiscence occurred in one patient. At an average follow-up of 3 years, nipple position remained stable in position, but lower pole distance elongation was observed in five patients (20 percent) and in one patient (3 percent) who had Vicryl mesh and mixed mesh respectively (p < 0.05). Only four breasts (4.7 percent) demonstrated significant lower pole elongation over time (>15 percent), all in the Vicryl mesh group. Worth noting, both the patients and the independent evaluators provided high ratings of the result of 4.7 and 4.6, respectively, on a Likert scale. CONCLUSIONS: The volume distribution mastopexy technique repositions the ptotic gland with a mesh to suspend the breast gland and to maintain the lifting effect. However, the synthetic mixed mesh proved to be significantly more effective in achieving this goal. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Micronized progesterone, progestins, and menopause hormone therapy.

Treatment with estrogens alone in women without a uterus or in combination with progestins (PG) in women with a uterus is the most effective treatment for vasomotor symptoms in the peri or postmenopausal period. However, PGs differ by their biological activities, and it is likely that not all PGs will display a class effect. The type of PG is important regarding tolerance and cardiovascular and breast cancer risk. Some studies indicate that micronized progesterone (P) is safer than synthetic PGs with an acceptable metabolic profile. For that purpose, we conducted a narrative review on the balance between benefit/risk using P versus PGs in menopause hormone therapy (MHT) to aid clinician to choose the best regimens, specifically the PG component of hormone therapy, for women with bothersome menopausal symptoms and with a uterus.

Relationships between Breast Feeding and Breast Cancer Subtypes: Lessons Learned from Studies in Humans and in Mice.

There are differential risk relationships between parity and breast cancer according to estrogen receptor (ER) status, with an increased risk of ER- disease reduced by breastfeeding. This may be particularly relevant for understanding the higher incidence of ER- tumors in Black women, who are more likely to be parous and less likely to breastfeed than other U.S. groups. Potential mechanisms for these relationships may include effects of disordered breast involution on inflammatory milieu in the breast as well as epigenetic reprogramming in the mammary gland, which can affect cell fate decisions in progenitor cell pools. In normal breast tissue, parity has been associated with hypermethylation of FOXA1, a pioneer transcription factor that promotes the luminal phenotype in luminal progenitors, while repressing the basal phenotype. In breast tumors, relationships between FOXA1 methylation and parity were strongest among women who did not breastfeed. Here, we summarize the epidemiologic literature regarding parity, breastfeeding, and breast cancer subtypes, and review potential mechanisms whereby these factors may influence breast carcinogenesis, with a focus on effects on progenitor cell pools in the mammary gland.

Anatomy and Physiology of the Breast during Pregnancy and Lactation.

The mature breast is located within the anterior thoracic wall, lying atop the pectoralis major muscle. Pubertal changes lead to incomplete development of the breast , a process which is only completed during pregnancy . The incomplete breast consists mostly of adipose tissue but also lactiferous units called lobes. These eventually drain into the lactiferous ducts and then into the lactiferous sinus and then to the nipple-areolar complex. During pregnancy , the breast undergoes both anatomic and physiologic changes to prepare for lactation. During the first trimester, the ductal system expands and branches out into the adipose tissue in response to the increase of estrogen. Elevated levels of estrogen also cause a decrease in adipose tissue and ductal proliferation and elongation. Estrogen also stimulates the pituitary gland which leads to elevated levels of prolactin. By the twentieth week of gestation, mammary glands are sufficiently developed to produce components of milk due to prolactin stimulation. Milk production is inhibited by high estrogen and progesterone levels and colostrum is produced during this time. In the third trimester and then rapidly after birth, these levels decrease, allowing for milk production and eventual let-down to allow for breastfeeding. Most pregnancies cause the areola to darken, the breast to increase in size, and the Montgomery glands to become more prominent. Post-lactational involution occurs at the cessation of milk production caused by a decline in prolactin.

Physical Breast Examination in Pregnancy and Lactation.

Physical exam of the breast is a very important part of breast assessment both for breast cancer screening, and when approaching breast lesions. Examination during pregnancy and breastfeeding follows exactly the same method as non-pregnancy periods. However, physical changes that occur in the breast during these times due to hormonal effects cause alterations that can on one hand conceal some pathologic disorders, and may on the other hand appear as pathologic findings while being purely physiologic. This chapter focuses first on some key points for an accurate breast examination, and then reviews some challenging controversial findings that may be noticed during breast exam in a pregnant or lactating woman.

Comparison of sonoelastographic values of breast tissue with mammographically and ultrasonically assessed density: a cross-sectional study.

AIM: To determine the relationship between breast stiffness assessed with sonoelastography (elasticity) and breast tissue density assessed with mammography (MG) and ultrasound (US). METHODS: This cross-sectional study involved 100 women who underwent MG, gray-scale US, and shear-wave sonoelastography during 2013. Mammographic density was categorized into four groups and sonographic density into three groups according to Breast Imaging-Reporting and Data System criteria. The stiffness of breast parenchymal and adipose tissue in all breast quadrants was quantified by shear-wave sonoelastography. Mean elastographic estimates were compared with MG- and US-derived density estimates. RESULTS: Parenchymal and adipose tissue elasticity positively correlated with MG- and US-derived breast density (for parenchyma: for MG Kendall's tau b 0.522; Jonckheere-Terpstra test P<0.001 and for US Kendall's tau b 0.533; Jonckheere-Terpstra test P<0.001); the higher was the breast density on MG and US, the higher was the elastographic stiffness. CONCLUSION: Sonoelastographic breast stiffness strongly positively correlated with breast density. Thus, sonoelastography may have a potential for estimating the breast cancer risk, which allows a novel application of this technique in routine clinical practice.

Diametric Comparison between the Thoracodorsal Vessel and Deep Inferior Epigastric Vessel in Breast Reconstruction.

BACKGROUND: In microvascular anastomosis, size discrepancy is common and can increase thrombotic complications. If size differences can be predicted, then vessels of the appropriate size can be selected. This study documented the difference in diameter between the thoracodorsal (TD) vessel and deep inferior epigastric perforator (DIEP) pedicle in each patient who underwent breast reconstruction using free tissue transfer. Patients and Methods. This retrospective study included 32 anastomoses (27 breasts including five cases of supercharged anastomosis) of breast reconstruction with the free DIEP flap and TD recipient between August 2018 and June 2019. In the microscopic view, the caliber of the TD vessel, the largest branch to the serratus anterior muscle, the descending branch, the largest and the second largest branches to the latissimus dorsi muscle, and the DIEP pedicle were measured. RESULTS: The diameter of the deep inferior epigastric artery was similar to that of the descending branch, and their anastomosing rate was 56.3%. The diameter of the deep inferior epigastric vein was similar to the branch to the serratus anterior muscle and the descending branch, and their anastomosing rates were 29.3% and 29.3%, respectively. All flaps were survived; however, in one case, a reoperation was needed to remove the hematoma, in which case fat necrosis occurred as the only complication. CONCLUSION: TD branches of similar size to the DIEP pedicle were prioritized in anastomosis. The descending branch and the branch to the serratus anterior muscle are expected to be good candidates as recipients in breast reconstruction with DIEP free flap. Moreover, supercharged anastomosis of DIEP pedicles can be achieved within TD branches.

Age-associated genes in human mammary gland drive human breast cancer progression.

BACKGROUND: Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. METHOD: We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. RESULTS: We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. CONCLUSION: Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.

Background Parenchymal Enhancement on Contrast-Enhanced Spectral Mammography: Influence of Age, Breast Density, Menstruation Status, and Menstrual Cycle Timing.

To evaluate the relationship of the extent and quantitative intensity of background parenchymal enhancement (BPE) on contrast-enhanced spectral mammography (CESM) with age, breast density, menstruation status, and menstrual cycle timing. This retrospective study included women who underwent CESM from July 2017 to March 2019 and who had menstruation status records. BPE category assessment was performed subjectively. BPE intensity was quantitatively measured using regions-of-interest. 208 subjects were included (150 were regular menstrual cycle and 58 were postmenopausal). The breast density was classified as category B in 11 subjects, category C in 231 subjects, and category D in 23 subjects. Subjects based on menstrual cycle timing, 24 at days 1-7, 55 at days 8-14, 48 at days 15-21, and 23 at days 22-28. Both quantitative and categorical analyses show a weak negative correlation between BPE and age in all subjects, but there was no significant correlation in premenopausal patients. Both the BPE pixel intensity value and BPE category was significantly lower in postmenopausal patients than in premenopausal patients, and there was no significant difference in breast density according to BPE. The minimum and maximum pixel values of BPE on days 8-14 of the menstrual cycle was significantly lower than those on days 15-21. There was no correlation between BPE level and menstrual cycle timing. Breast density with category D was more likely to have a lower BPE level than category C. We show here that BPE level is affected by menstruation status and menstrual cycle timing. We suggest that CESM should not be performed on days 15-21 of the menstrual cycle, but on days 8-14.

Biomechanics of Breast Support for Active Women.

More systematic breast biomechanics research and better translation of the research outcomes are necessary to provide information upon which to design better sports bras and to develop effective evidence-based strategies to alleviate exercise-induced breast pain for women who want to participate in physical activity in comfort.

In Vivo Dielectric Properties of Healthy and Benign Rat Mammary Tissues from 500 MHz to 18 GHz.

This work investigates the in vivo dielectric properties of healthy and benign rat mammary tissues in an attempt to expand the dielectric property knowledge of animal models. The outcomes of this study can enable testing of microwave medical technologies on animal models and interpretation of tissue alteration-dependent in vivo dielectric properties of mammary tissues. Towards this end, in vivo dielectric properties of healthy rat mammary tissues and chemically induced benign rat mammary tumors including low-grade adenosis, sclerosing adenosis, and adenosis were collected with open-ended coaxial probes from 500 MHz to 18 GHz. The in vivo measurements revealed that the dielectric properties of benign rat mammary tumors are higher than the healthy rat mammary tissues by 9.3% to 35.5% and 19.6% to 48.7% for relative permittivity and conductivity, respectively. Furthermore, to our surprise, we found that the grade of the benign tissue affects the dielectric properties for this study. Finally, a comparison with ex vivo healthy human mammary tissue dielectric properties revealed that the healthy rat mammary tissues best replicate the dielectric properties of healthy medium density human samples.

"Three-dimensional evaluation of breast volume changes following autologous free flap breast reconstruction over six months".

OBJECTIVES: To date, little is known about postoperative changes in breast volume after autologous breast reconstruction. The purpose of this retrospective study was to investigate breast volume changes following autologous free flap reconstruction and the factors affecting flap volume. MATERIALS AND METHODS: Patients who underwent deep inferior epigastric perforator, superficial inferior epigastric artery and profunda artery perforator flaps between December 2016 and January 2019 were included. Exclusion criteria were breast complications requiring surgical debridement, and the absence of at least two suitable three-dimensional images postoperatively. Three-dimensional stereophotogrammetry volume measurements were performed at the time of standard surgical check-ups. Changes in breast volume were modeled using a quartic polynomial curve function in a nested mixed effects model. RESULTS: 136 breasts in 101 patients were included. An average decrease of predicted breast volume was found from 637.8 cc (95%-CI [624.4, 651.1]) at two weeks to 566.6 cc (95%-CI [535.1, 598.0]) after three and 567.6 cc (95%-CI [515.9, 617.6]) after six months postoperatively. Reconstruction timing and first postoperatively measured breast volume showed a statistically significant difference in initial reconstructed breast volume and in the shape of the relationship between time and breast volume, whereas autologous technique and BMI only showed a statistically significant difference in initial reconstructed volume and mastectomy indication in the shape of the relationship. CONCLUSION: The final overall flap volume decreased to 88.9% of its original volume after six months. Gaining more insight into the factors influencing flap volume is of crucial importance to facilitate predictable surgical outcomes.

Theoretical and practical knowledge curriculum for European Breast Surgeons.

The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the knowledge and skills expected of a fully trained breast surgeon practicing in the European Union and European Economic Area (EEA). It forms part of a range of factors that contribute to the delivery of high quality cancer care. It has been developed by a panel of experts from across Europe and has been validated by professional breast surgery societies in Europe. The curriculum maps closely to the syllabus of the Union of European Medical Specialists (UEMS) Breast Surgery Exam, the UK FRCS (breast specialist interest) curriculum and other professional standards across Europe and globally (USA Society of Surgical Oncology, SSO). It is envisioned that this will serve as the basis for breast surgery training, examination and accreditation across Europe to harmonise and raise standards as breast surgery develops as a separate discipline from its parent specialties (general surgery, gynaecology, surgical oncology and plastic surgery). The curriculum is not static but will be revised and updated by the curriculum development group of the European Breast Surgical Oncology Certification group (BRESO) every 2 years.

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.

The Role of Butch versus Femme Identity in Body Image and Breast Health Among Lesbians in Taiwan: Results of an Online Survey.

PURPOSE: The views of butch- and femme-identified lesbians toward their own breasts, breast cancer, breast cancer screenings, and their behavior and intentions toward breast health care were examined and compared in this study. METHODS: A total of 208 Taiwanese lesbians (134 butch-identified lesbians and 78 femme-identified lesbians) completed an online survey. RESULTS: Butch-identified lesbians were more likely to hold negative views regarding their own breasts, which were found to be significantly and negatively associated with their actions in performing breast self-examinations when compared with femme-identified lesbians. CONCLUSIONS: Healthcare providers should be aware of and provide culturally competent care to lesbians with different identities. CLINICAL RELEVANCE: The results can be employed as evidence for promoting lesbians' breast health, particularly butch-identified lesbians. Healthcare providers should provide a supportive environment in order to promote a positive body image and improve breast health among lesbians.