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Breast Cancer

Breast cancer is the most common type of cancer among women, the risk of breast cancer increases with age, it is most common after the age of 50. Each breast has 15- 20 sections (lobes), each of which has many smaller sections (lobules). The lobes and lobules are connected by thin tubes (ducts). The most frequent type of breast cancer is that starting in the ducts (ductal cancer), other types include cancer beginning in the lobes or lobules (lobular carcinoma), less common is Inflammatory breast cancer which causes the breast to be red, and swollen. The incidence of breast cancer has been increasing in Western countries, the rate of increase has been faster in younger women, however, the cause of most breast cancers remains unknown. World-wide about 794,000 women are diagnosed with breast cancer each year.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Breast Cancer Organisations
Specialist Journals
Breast Cancer in Pregnancy
Breast Cancer Screening
Familial Breast Cancer
Male Breast Cancer
Paget's Disease of the Breast

Information Patients and the Public (42 links)

Information for Health Professionals / Researchers (15 links)

See also: Molecular Biology of Breast Cancer

Breast Cancer Organisations (11 links)

See also: National Cancer Organisations

Specialist Journals (12 links)

See also: Oncology Journals

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Hasan R, Gavenonis SC, Shin MC
Utilizing digital breast tomosynthesis to improve accuracy of preoperative needle localization for surgical excisional biopsy.
Del Med J. 2015; 87(4):117-20 [PubMed] Related Publications
We describe a case of an 88-year-old female who presented for needle localization to undergo excisional biopsy of a subtle asymmetry in the left breast, with successful localization achieved using digital breast tomosynthesis. Initial attempts at localization under 2D mammography were inaccurate. Subsequent digital breast tomosynthesis application for triangulation resulted in better visualization of the target, and successful localization. Specimen radiography confirmed the lesion was accurately targeted and pathology revealed ductal carcinoma in situ. Needle localization guided by mammography and inherent limitations of 2D mammography are discussed, along with a literature review of tomosynthesis guided needle localization.

Cox TR, Rumney RM, Schoof EM, et al.
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase.
Nature. 2015; 522(7554):106-10 [PubMed] Related Publications
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.

Ellis H
Amputation of the breast.
J Perioper Pract. 2015 Jan-Feb; 25(1-2):27-8 [PubMed] Related Publications
Today we take for granted the blessing of anaesthesia and it is almost impossible for us to imagine the agonies that surgical patients underwent in the past. This description of a mastectomy, performed in 1720 by Lorenz Heister, Professor of Surgery and Anatomy in Altdorf in the republic of Nurnberg, (now part of Germany), gives a vivid idea of major surgery in those days. In this much shortened abstract from his lengthy report, which appears in the 1775 English edition of his textbook entitled 'Medical, Chirurgical and Anatomical cases and Observations' he discusses the preoperative preparation, the mastectomy itself, performed as quickly as possible and the tedious postoperative dressings of the inevitably suppurating wound.

Allinson VM, Dent J
Supportive care after breast cancer surgery.
Nurs Times. 2014 Oct 8-14; 110(41):20-3 [PubMed] Related Publications
Routine follow-up after treatment for breast cancer aims to monitor for recurrence, manage late effects of treatment and give patients information, support and reassurance. However, most symptoms of local recurrence are first identified by patients so time spent following up women who are essentially well may not be clinically beneficial or cost effective. To better use its resources, Calderdale and Huddersfield Foundation Trust developed a follow-up education programme for patients at low-to-moderate risk; after two years an audit showed it reduced overall patient anxiety and routine hospital appointments, maintained standards of care and provided patient with an effective support network.

Arora S, Kumar R, Kaur H, et al.
Translocation and toxicity of docetaxel multi-walled carbon nanotube conjugates in mammalian breast cancer cells.
J Biomed Nanotechnol. 2014; 10(12):3601-9 [PubMed] Related Publications
Multi-walled-carbon nanotubes (MWNTs) are widely explored as carriers for drug delivery due to their facile transport through cellular membranes and are reportedly found to be effective against cancer. In the present study, we have evaluated cellular uptake of Docetaxel (DTX) conjugated MWNTs from human breast cancer cells (MCF-7 and MDA-mb-231) and have provided primary results on cytotoxicity of the same. Efficient internalization of the drug conjugate (DTX-MWNTs) inside the cell was corroborated with the help of confocal microscopy, transmission electron microscopy and flow cytometry. The comparison of cytotoxicity of the conjugate and DTX was done by MTT assay. Results of the study indicated increased efficacy of the conjugates over the drug in terms of their cytotoxicity. It was observed that such conjugation of drug to MWNTs can be explored as a strategy to improve therapeutic index of cytotoxic drugs such as DTX and thereby enriching cancer therapies of coming time.

Guo LS, Li HX, Li CY, et al.
Synergistic antitumor activity of vitamin D3 combined with metformin in human breast carcinoma MDA-MB-231 cells involves m-TOR related signaling pathways.
Pharmazie. 2015; 70(2):117-22 [PubMed] Related Publications
Metformin is usually used for the treatment of type 2 diabetes. Recently, many studies suggest that metformin and vitamin D have broad-spectrum antitumor activities. Our aim in this research was to study the effects of vitamin D3 combined with metformin on the apoptosis induction and its mechanisms in the human breast cancer cell line MDA-MB-231. Cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. The morphology of cell apoptosis was observed after Hoechst 33342 staining. Here we show that vitamin D3 280 μg/ml or vitamin D3 300 μg/ml or vitamin D3 320 μg/ml seperately combined with metformin 15000 μg/ml exhibited synergistic effects on cell proliferation and apoptosis. The underlying anti-tumor mechanisms may involve m-TOR related pathways, which are related to activating expression of cleaved caspase-3, Bax and p-AMPK, as well as inhibiting expressions of p-Bcl-2, c-Myc, p-IGF-IR, p-mTOR, p-P70S6K, p-S6.

Milroy MJ
Breast cancer screening.
S D Med. 2015; Spec No:69-73 [PubMed] Related Publications
Decreasing breast cancer mortality represents a high priority for patients and their health care providers. Assessment of individual risk combined with discussion of risks and benefits of screening is essential in assisting patients in making their screening decisions. This article reviews the literature in order to provide primary care providers information regarding risk assessment, controversies regarding screening including age to start screening, best interval for screening, age to stop screening and methods to perform screening. Providers are encouraged to initiate this conversation with their patients.

Zacarias-Fluck MF, Morancho B, Vicario R, et al.
Effect of cellular senescence on the growth of HER2-positive breast cancers.
J Natl Cancer Inst. 2015; 107(5) [PubMed] Related Publications
BACKGROUND: Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors.
METHODS: Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided.
RESULTS: We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005).
CONCLUSIONS: Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.

Socolov D, Anghelache I, Ilea C, et al.
Benign breast disease and the risk of breast cancer in the next 15 years.
Rev Med Chir Soc Med Nat Iasi. 2015 Jan-Mar; 119(1):135-40 [PubMed] Related Publications
AIM: Fibrocystic mastosis (FCM) is defined by the totality of dystrophic changes of the mammary tissue, the grouping in the form of fibrosis of epithelial, cystic, metaplastic and hyperplastic alterations. A very good estimation of the cancer risk is related specifically to the microscopic aspect. Other factors, the family history as well as the presence of an inherited gene determining the increase in the risk of breast cancer are also considered. But, if a woman known with fibrocystic mastosis has not undergone any biopsy, then it is impossible to calculate the specific individual risk of developing cancer.
MATERIAL AND METHODS: The data collected as a study material and considered refer to: the total num- ber of cases investigated and diagnosed with fibrocystic mastosis, the annual distribution of this disease cases, the distribution of the cases according to age groups, admission reasons, clinical examination, personal pathologic history clinically significant for the basic disease (the main diagnosis), the family medical history significant for the basic disease, the anatomopathological diagnosis.
RESULTS: Between 2004 and 2006, at "Cuza Vodă" Obstetrics and Gynecology Hospital of Iaşi, a maximum number of cases is noticed in 2006, when there were 147 cases, and the lowest number of cases was in 2005. There was high frequency of the anatomopathological examinations that highlighted the presence of fibrocystic lesions (both proliferative and non-proliferative), and the second most often diagnosis is fibroadenoma. Though fibrocystic mastosis is not clearly defined, it is still admitted that in order to support this diagnosis it is first compulsory to exclude malignant tumours.
CONCLUSIONS: Only in 5% of the women with fibrocystic mastosis cellular changes can be revealed in the form of atypical hyperplasia, which are a risk factor for cancer. The lesion that delimits cancer from non-cancer is ductal carcinoma in situ. An incidence of over 20% is present in the countries that use mammographic screening programmes, mammographic surveillance programmes and programmes for the guided localization of nonpalpable lesions of the mammary gland.

Beaber EF, Kim JJ, Schapira MM, et al.
Unifying screening processes within the PROSPR consortium: a conceptual model for breast, cervical, and colorectal cancer screening.
J Natl Cancer Inst. 2015; 107(6):djv120 [PubMed] Related Publications
General frameworks of the cancer screening process are available, but none directly compare the process in detail across different organ sites. This limits the ability of medical and public health professionals to develop and evaluate coordinated screening programs that apply resources and population management strategies available for one cancer site to other sites. We present a trans-organ conceptual model that incorporates a single screening episode for breast, cervical, and colorectal cancers into a unified framework based on clinical guidelines and protocols; the model concepts could be expanded to other organ sites. The model covers four types of care in the screening process: risk assessment, detection, diagnosis, and treatment. Interfaces between different provider teams (eg, primary care and specialty care), including communication and transfer of responsibility, may occur when transitioning between types of care. Our model highlights across each organ site similarities and differences in steps, interfaces, and transitions in the screening process and documents the conclusion of a screening episode. This model was developed within the National Cancer Institute-funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR). PROSPR aims to optimize the screening process for breast, cervical, and colorectal cancer and includes seven research centers and a statistical coordinating center. Given current health care reform initiatives in the United States, this conceptual model can facilitate the development of comprehensive quality metrics for cancer screening and promote trans-organ comparative cancer screening research. PROSPR findings will support the design of interventions that improve screening outcomes across multiple cancer sites.

Shah M, Denlinger CS
Optimal post-treatment surveillance in cancer survivors: is more really better?
Oncology (Williston Park). 2015; 29(4):230-40 [PubMed] Related Publications
A substantial rise in the number of cancer survivors has led to management questions regarding effective post-treatment surveillance strategies. Although a number of professional societies have proposed surveillance guidelines, clinical practice varies; the general trend is toward more intensive strategies. The evidence supporting intensive surveillance is relatively lacking, with most studies showing that more intense surveillance regimens have minimal, if any, impact on outcomes in terms of survival, quality of life, or overall cost-effectiveness. This has been demonstrated in breast cancer, and data supporting a similar conclusion may be evolving in colorectal cancer, where large prospective studies call into question the utility of intensive surveillance; in prostate cancer, retrospective data suggest a similar trend. In this review, we discuss the established guidelines and current evidence regarding post-treatment surveillance, and we propose general management strategies in prostate, colorectal, and breast cancers.

Gęgotek A, Cyuńczyk M, Łuczaj W, et al.
The redox status of human breast cancer cell lines (MCF-7 and MDA-MB231) treated with novel dinuclear berenil-platinum(II) complexes.
Pharmazie. 2014; 69(12):923-8 [PubMed] Related Publications
This study compared the effects of cisplatinum and novel berenil-platinum(ll) complexes on the redox status of breast cancer cells that were estrogen receptor-positive (MCF-7) or estrogen receptor-negative (MDA-MB231). Both cell lines were treated with cisplatinum or the following berenil-platinum(ll) complexes: Pt2(isopropylamine)4(berenil)2, Pt2(piperidine)4(berenil)2, Pt2(2-picoline)4(berenil)2, Pt2(3-picoline)4(berenil)2, and Pt2(4-picoline)4(berenil)2. Changes in levels of reactive oxygen species, levels and activities of antioxidants, and lipid peroxidation products levels were measured. All investigated compounds enhanced ROS generation, reduced the activity of antioxidant enzymes (e.g., glutathione peroxidase and glutathione reductase), and decreased levels of small-molecule antioxidants (GSH, vitamins E and A). Such conditions are conducive to generating oxidative stress and phospholipids peroxidation. Cellular phospholipids in MCF-7 cells were most sensitive to the Pt2(isopropylamine)4(berenil)2 complex, whereas MDA-MB231 cells were not particularly sensitive to any berenil-platinum(ll) complex. These findings will facilitate future anticancer drug design strategy for breast cancer pharmacotherapy.

Illouz YG
Breast cancer treatment by adipose-derived stem cells: an experimental study.
J Stem Cells. 2014; 9(4):211-7 [PubMed] Related Publications
Breast cancer is a leading cause of deaths in humans. Mesenchymal stem cells (MSC) have been identified to possess powerful therapeutic properties in humans. The capability of MSC to migrate toward injured tissue suggests their potential in new clinical applications. The aim of this study was to investigate the potential role of adipose stem cells (ADSCs) for recovering cellular potential and delaying or treating breast cancer in an animals model of human breast cancer. Cellular adoptive immunotherapy using adipose derived mesenchymal stem cells tailored made for Breast Cancer patients would offer a new effective less invasive treatment method. ADSCs injected into the cancer tumor did not affect tumor growth and the cancer kept growing. ADSCs injected so that they surrounded the tumor decreased growth and the tumor had disappeared after 3 to 8 weeks and total recovery was maintained throughout the 6 months of study. The adipose stem cells are the "active" and "regenerative" part of fat. ADSCs may appear promising for their use as "secretor" of the supernatant substance against breast cancer cells.

Mammographic breast cancer screening. Part II. Non-randomised comparisons: results similar to those of randomised trials.
Prescrire Int. 2015; 24(159):99-102 [PubMed] Related Publications
Screening practices in the early 21st century may not have the same impact on breast cancer mortality than the small reduction seen in some randomised controlled trials. To determine whether non-randomised comparative studies can help to estimate the possible benefits of mass screening for breast cancer, we conducted a review of the literature using the standard Prescrire methodology. The most reliable non-randomised studies are those that combine historical and geographic comparisons, include follow-up data recorded for at least 10 years after the introduction of screening, and take into account the date of cancer diagnosis in mortality calculations. We identified eight such studies, all conducted in Scandinavian countries, in regions where screening was generally introduced during the 1980s and 1990s. Three studies conducted in Sweden showed no statistically significant reduction in all-cause mortality among women with breast cancer after the introduction of screening. One of the two Finnish studies (statistically the most powerful) and a Danish study showed a statistically significant decrease in breast cancer mortality after the introduction of screening. A study conducted in four Norwegian counties showed no significant reduction in breast cancer mortality after the introduction of screening. A meta-analysis of five of these studies, corresponding to a total of about 4.7 million woman-years, showed that the introduction of organised breast cancer screening among women aged 50 to 69 years was associated with about a one-sixth reduction in breast cancer mortality. Another study, published after this meta-analysis, was conducted throughout Norway and spanned more than 15 million woman-years. It showed that the introduction of organised screening was associated with about a one-quarter reduction in mortality attributed to breast cancer, equivalent to about 20 to 30 fewer breast cancer deaths per 10 000 women invited for screening. Overall, the results of these different studies are consistent with the small decrease in breast cancer mortality observed in randomised trials and their least stringent meta-analyses. This rather modest benefit must be weighed against the adverse effects of screening and treatment, which will be examined in a future issue.

Arcand SL, Akbari MR, Mes-Masson AM, et al.
Germline TP53 mutational spectrum in French Canadians with breast cancer.
BMC Med Genet. 2015; 16:24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer.
METHODS: TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer.
RESULTS: Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age.
CONCLUSIONS: In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.

Weichman KE, Urbinelli L, Disa JJ, Mehrara BJ
Breast reduction in patients with prior breast irradiation: outcomes using a central mound technique.
Plast Reconstr Surg. 2015; 135(5):1276-82 [PubMed] Related Publications
BACKGROUND: Breast reduction in patients with a history of lumpectomy and irradiation is controversial because of a heightened risk of infection and wound healing complications. Persistent macromastia or asymmetry remains a problem in this patient population that is commonly not addressed. The authors studied the safety and efficacy of a central mound technique with minimal dissection for breast reduction or mastopexy in patients with a history of breast irradiation.
METHODS: A case-control study of all patients undergoing bilateral breast reduction mammaplasty between 2008 and 2013 at Memorial Sloan Kettering Cancer Center was conducted. Patients who had unilateral breast irradiation and bilateral reduction using the central mound technique were included. Each patient had a control breast and an irradiated breast. Complications and outcomes were analyzed.
RESULTS: Thirteen patients were included for analysis. Their average age was 50.23 ± 9.9 years, and average time from irradiation to breast reduction mammaplasty was 41.3 ± 48.5 months (range, 9 to 132 months). The average specimen weight of irradiated breasts was less than that of control breasts; however, this failed to reach statistical significance (254.2 ± 173.5 g versus 386.9 ± 218.5 g; p = 0.099). One patient developed fat necrosis in the previously irradiated breast and underwent biopsy. There was no incidence of nipple necrosis or breast cancer in either irradiated or nonirradiated breasts.
CONCLUSIONS: Breast reduction mammaplasty in patients who have had irradiation is feasible and can be performed safely in select cases. The central mound technique provides reliable and reproducible results and should be considered in patients with macromastia/asymmetry and a history of irradiation.

Gale KL, Rakha EA, Ball G, et al.
A case-controlled study of the oncologic safety of fat grafting.
Plast Reconstr Surg. 2015; 135(5):1263-75 [PubMed] Related Publications
BACKGROUND: Currently, there is no clinical evidence of oncologic risk associated with fat grafting, although its safety has been questioned. The authors investigated the risk of relapse associated with fat grafting in women with a history of breast cancer.
METHODS: Of 328 women with previously treated malignant breast disease who underwent fat grafting at the Nottingham Breast Institute, complete data were available for 211 (invasive carcinoma, n = 184; ductal carcinoma in situ, n = 27). Mean follow-up was 88 months after primary cancer surgery and 32 months after fat grafting. Control subjects were matched 2:1 for date of primary cancer operation (within 2 years), age (within 5 years), type of surgery, tumor histology, estrogen receptor status, and disease-free status by time equivalent to that of fat grafting. Final endpoints were tumor recurrence and death. Outcome results were compared with a systematic review of all patients undergoing fat grafting with adequate follow-up reported in the literature.
RESULTS: No significant excess oncologic events were observed in patients who had fat grafting compared to controls with regard to local (0.95 percent versus 1.90 percent; p = 0.33), regional (0.95 percent versus 0 percent; p = 0.16), and distant recurrences (3.32 percent versus 2.61 percent; p = 0.65). A systematic review identified case series with a total of 1573 women who had fat grafting after primary oncologic breast surgery. The locoregional relapse rate for these patients was 2.92 percent (0.95 percent per year).
CONCLUSION: This study has found no evidence of increased oncologic risk associated with fat grafting in women previously treated for breast cancer.

Wang HC, Tseng YH, Wu HR, et al.
Anti-proliferation effect on human breast cancer cells via inhibition of pRb phosphorylation by taiwanin E isolated from Eleutherococcus trifoliatus.
Nat Prod Commun. 2014; 9(9):1303-6 [PubMed] Related Publications
Eleutherococcus trifoliatus has been used as a folk medicine since ancient times, especially as refreshing qi medicines. In our current study, taiwanin E, which possesses strong cytotoxicity, was isolated from the branches of E. trifoliatus by using a bioactivity guided fractionation procedure. Taiwanin E presented a potent anti-proliferation activity on the growth of a human breast adenocarcinoma cell line (MCF-7), with an IC50 value for cytotoxicity of 1.47 μM. Cell cycle analysis revealed that the proportion of cells in the G0/G1 phase increased in a dose-dependent manner (from 79.4% to 90.2%) after 48 h exposure to taiwanin E at a dosage range from 0.5 to 4μM. After treatment with taiwanin E, phosphorylation of retinoblastoma protein (pRb) in MCF-7 cells was inhibited, accompanied by a decrease in the levels of cyclin D1, cyclin D3 and cyclin-dependent kinase 4 (cdk4) and cdk6; in addition, there was an increase in the expression of cyclin-dependent kinase inhibitors p21(WAF-1/Cip) and p27(Kip1). The results suggest that taiwanin E inhibits cell cycle progression of MCF-7 at the G0/G1 transition.

Ghodsi Z, Hojjatoleslami S
Breast self examination and mammography in cancer screening: women health protective behavior.
J Prev Med Hyg. 2014; 55(2):46-9 [PubMed] Related Publications
BACKGROUND: Breast cancer (BC) is one of the leading causes of death among women. Secondary prevention may enable early detection, but this is suboptimal among all Iranian women.
METHODS: This was a descriptive, analytic cross sectional study on 385 women 35 years old or more with no history of BC. Participants were selected by simple randomized method and were assessed through a two-part self-administered questionnaire and a self-examination checklist with content validity and test-re-test reliability.
RESULTS: 14.8% of women carried out breast self examination (BSE). Among them 5.7% was done in adequate timing and 9.4% performed it on a regular basis. The average age of BSE onset was 20.1 ± 7.6 and mean of Score was 6.25 ± 2.26 (2-11). 2.3% of participants performed BSE poorly, 7.5% fairly and 1.6% performed it well. 25.84% of samples had a history of mammography that 13% of whom received it as a result of prescription. The average age for mammography was 36 ± 7.2 (20-50) years and the frequency of mammography was 1.8 ± 1.4 (1-8) of times. Due to the low percentage of breast cancer preventive behaviors, in this study knowledge towards breast cancer was also measured because they are factors that are crucial in performance.
CONCLUSION: The results highlight the need to educate Iranian women to recognize the risk factors to promote early detection of breast cancer. Creation of health behavioral by focused educational programs might cause decrease of breast cancer prevalence.

Leduc O, Fumière E, Banse S, et al.
Identification and description of the axillary web syndrome (AWS) by clinical signs, MRI and US imaging.
Lymphology. 2014; 47(4):164-76 [PubMed] Related Publications
The Axillary Web Syndrome (AWS) follows surgery for breast neoplasia and consists of one, or more frequently two or three, cords of subcutaneous tissue. Cords originate from the axilla, spread to the antero-medial surface of the arm down to the elbow and then move into the antero-medial aspect of the forearm and sometimes into the root of the thumb. The purpose of this study was to compare two techniques, ultrasound (US) and Magnetic Resonance Imaging (MRI) for their sensitivity and accuracy in identifying AWS cords and to provide insights to the origin of this pathology. US examinations were performed on fifteen patients using a high frequency probe (17 MHz). We first palpated and marked the cord with location aided by maximum abduction. To identify the cord with MRI (1.5 Tesla), a catheter filled with a gel detectable under MRI was placed on the skin at the site of the cord. We found that in some US cases, the dynamic abduction maneuver was essential to facilitate detection of the cord. This dynamic method on ultrasound confirmed the precise location of the cord even if it was located deeper in the hypodermis fascia junction. US and MRI images revealed features of the cords and surrounding tissues. Imaging the cords was difficult with either of the imaging modalities. However, US seemed to be more efficient than MRI and allowed dynamic evaluation. Overall analysis of our study results supports a lymphatic origin of the AWS cord.

Koehler LA, Hunter DW, Haddad TC, et al.
Characterizing axillary web syndrome: ultrasonographic efficacy.
Lymphology. 2014; 47(4):156-63 [PubMed] Related Publications
The aim of this study was to determine if ultrasound could successfully characterize axillary web syndrome (AWS) and clarify the pathophysiologic basis of AWS as a vascular or lymphatic abnormality, or an abnormal tissue structure. This prospective study evaluated women who developed AWS following breast cancer surgery. Using an 18 MHz ultrasound transducer, images were taken of the AWS cord and compared to mirror images on the contralateral side. A blinded radiologist assessed the ultrasound characteristics of and structural changes in the skin and subcutaneous tissue and formulated an opinion as to the side in which AWS was located. Seventeen subjects participated in the study. No structure or abnormality consistent with AWS could be identified by ultrasound. There were no statistical differences between the ipsilateral and contralateral side in skin thickness; subcutaneous reflector thickness, number or disorganization; or subcutaneous tissue echodensity (p>0.05). The radiologist correctly identified the side with AWS in 12 of 17 subjects (=0.41). A distinct ultrasonographic structure or abnormality could not be identified in subjects with AWS using 18 MHz ultrasound. The inability to identify a specific structure excludes the possibility that AWS is associated with vein thrombosis or a fascial abnormality, and supports the theory that AWS may be pathology that is not visible with 18 MHz ultrasound, such as microlymphatic stasis or binding of fibrin or other proteins in the interstitial space.

Rößler AC, Wenkel E, Althoff F, Kalender W
The Influence of Patient Positioning in Breast CT on Breast Tissue Coverage and Patient Comfort.
Rofo. 2015; 36(2):115-22 [PubMed] Related Publications
PURPOSE: The presented study aimed at optimizing a patient table design for breast CT (BCT) systems with respect to breast tissue coverage and patient comfort. Additionally, the benefits and acceptance of an immobilization device for BCT using underpressure were evaluated.
MATERIALS AND METHODS: Three different study parts were carried out. In a positioning study women were investigated on an MRI tabletop with exchangeable inserts (flat and cone-shaped with different opening diameters) to evaluate their influence on breast coverage and patient comfort in various positioning alternatives. Breast length and volume were calculated to compare positioning modalities including various opening diameters and forms. In the second study part, an underpressure system was tested for its functionality and comfort on a stereotactic biopsy table mimicking a future CT scanner table. In the last study part, this system was tested regarding breast tissue coverage.
RESULTS: Best results for breast tissue coverage were shown for cone-shaped table inserts with an opening of 180 mm. Flat inserts did not provide complete coverage of breast tissue. The underpressure system showed robust function and tended to pull more breast tissue into the field of view. Patient comfort was rated good for all table inserts, with highest ratings for cone-shaped inserts.
CONCLUSION: Cone-shaped tabletops appeared to be adequate for BCT systems and to allow imaging of almost the complete breast. An underpressure system proved promising for the fixation of the breast during imaging and increased coverage. Patient comfort appears to be adequate.
KEY POINTS: Tissue coverage in breast CT is highly dependent on patient table design. An underpressure fixation system shows potential to increase breast coverage. The proposed breast CT patient table design combines good coverage and patient comfort.

Ma CX, Reinert T, Chmielewska I, Ellis MJ
Mechanisms of aromatase inhibitor resistance.
Nat Rev Cancer. 2015; 15(5):261-75 [PubMed] Related Publications
Oestrogen receptor-positive (ER(+)) breast cancer is a major cause of cancer death in women. Although aromatase inhibitors suppress the function of ER and reduce the risk of recurrence, therapeutic resistance is common and essentially inevitable in advanced disease. This Review considers both genomic and cell biological explanations as to why ER(+) breast cancer cells persist, progress and cause an incurable, lethal, systemic disease. The design and outcomes of clinical trials are considered with the perspective that resistance mechanisms are heterogeneous, and therefore biomarker and somatic mutation-based stratification and eligibility will be essential for improvements in patient outcomes.

Mango VL, Kaplan J, Sung JS, et al.
Breast carcinoma in augmented breasts: MRI findings.
AJR Am J Roentgenol. 2015; 204(5):W599-604 [PubMed] Related Publications
OBJECTIVE: The objective of our study was to characterize the MRI features of breast carcinomas detected in augmented breasts.
MATERIALS AND METHODS: A review of the MRI database identified 54 patients with biopsy-proven breast carcinoma in augmented breasts. The images were reviewed for the type and location of the implant and for the characteristics of the carcinoma. The cases included 46 (85%) invasive cancers (invasive ductal carcinoma, n = 35; invasive lobular carcinoma, n = 7; and mixed features, n = 4) and eight (15%) ductal carcinomas in situ.
RESULTS: The median age of the patients at diagnosis was 49 years (range, 28-72 years). Thirty-eight of the 54 cancers (70%) were palpable. The mean tumor size was 2.8 cm (range, 0.6-9.6 cm). Of the 54 cancers, 34 (63%) presented as masses and 20 (37%) as nonmass enhancement on MRI. There was no detectable difference between implant position and lesion morphology (p = 0.55) or tumor size (p = 1.00). Twenty of 54 (37%) carcinomas abutted the implant, 13 (24%) abutted the pectoralis major muscle, and two (4%) invaded the pectoralis major muscle. Of the tumors abutting the implant, 18 of 20 (90%) spread along the implant capsule for more than 0.5 cm. This pattern of tumor spread was more common in breasts with retroglandular implants (9/16, 56%) than in those with retropectoral implants (9/38, 24%) (p = 0.03). MRI detected the index carcinoma in 16 of 54 (30%) cases, showed a greater extent of disease than was visible on mammography or ultrasound in 21 of 52 (40%) cases, and detected an unsuspected contralateral carcinoma in three of 54 (6%) cases.
CONCLUSION: In augmented breasts, breast cancer often contacts either the implant or the pectoralis major muscle. Tumor spread along the implant contour is more often seen with retroglandular implants than with retropectoral implants. MRI should be considered to assess disease extent in women with augmented breasts before surgery.

Hartman M, Drotman M, Arleo EK
Annual screening mammography for breast cancer in women 75 years old or older: to screen or not to screen.
AJR Am J Roentgenol. 2015; 204(5):1132-6 [PubMed] Related Publications
OBJECTIVE: The purpose of the study was to review screening mammography examinations at our institution from 2007 through 2013 with the primary endpoint of determining the incidence of breast cancer and the associated histologic and prognostic features in women 75 years old or older.
MATERIALS AND METHODS: Patients who presented for screening mammography who ultimately received a BI-RADS assessment of category 4 or 5 for a suspicious abnormality were followed retrospectively through completion of care and were analyzed with respect to pathology results, treatment, and family history.
RESULTS: From 2007 through 2013, 68,694 screening mammography examinations were performed. Of these screening examinations, 4424 (6.4%) were performed of patients 75 years old or older. On the basis of these examinations, 64 biopsies were recommended. Sixty biopsies were performed, and these biopsies detected 26 breast cancers. These results correspond to a breast cancer detection rate of 5.9 per 1000 screening examinations and a positive predictive value 2 (PPV2), defined as the probability of breast cancer after a BI-RADS assessment category of 4 (suspicious abnormality) or 5 (highly suggestive of malignancy), of 40.6%. Approximately 85% (22/26) of the screening-detected cancers in the women in this age group were invasive. For those with known genetic status (18 of 26), 33% had a first-degree relative with breast cancer.
CONCLUSION: Although women 75 years or older accounted for less than 10% of the total screening population during the study time period, the breast cancer detection rate in this cohort was 5.9 per 1000 screening examinations, which is compatible with the American College of Radiology's recommendations, and most of these breast cancers were invasive. These results are relevant when considering appropriate age ranges for annual screening mammography.

Grimm LJ, Anderson AL, Baker JA, et al.
Interobserver Variability Between Breast Imagers Using the Fifth Edition of the BI-RADS MRI Lexicon.
AJR Am J Roentgenol. 2015; 204(5):1120-4 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to assess the interobserver variability of users of the MRI lexicon in the fifth edition of the BI-RADS atlas.
MATERIALS AND METHODS: Three breast imaging specialists reviewed 280 routine clinical breast MRI findings reported as BI-RADS category 3. Lesions reported as BI-RADS 3 were chosen because variability in the use of BI-RADS descriptors may influence which lesions are classified as probably benign. Each blinded reader reviewed every study and recorded breast features (background parenchymal enhancement) and lesion features (lesion morphology, mass shape, mass margin, mass internal enhancement, nonmass enhancement distribution, nonmass enhancement internal enhancement, enhancement kinetics) according to the fifth edition of the BI-RADS lexicon and provided a final BI-RADS assessment. Interobserver variability was calculated for each breast and lesion feature and for the final BI-RADS assessment.
RESULTS: Interobserver variability for background parenchymal enhancement was fair (ĸ = 0.28). There was moderate agreement on lesion morphology (ĸ = 0.53). For masses, there was substantial agreement on shape (ĸ = 0.72), margin (ĸ = 0.78), and internal enhancement (ĸ = 0.69). For nonmass enhancement, there was substantial agreement on distribution (ĸ = 0.69) and internal enhancement (ĸ = 0.62). There was slight agreement on lesion kinetics (ĸ = 0.19) and final BI-RADS assessment (ĸ = 0.11).
CONCLUSION: There is moderate to substantial agreement on most MRI BI-RADS lesion morphology descriptors, particularly mass and nonmass enhancement features, which are important predictors of malignancy. Considerable disagreement remains, however, among experienced readers whether to follow particular findings.

Poplack SP, Levine GM, Henry L, et al.
A Pilot Study of Ultrasound-Guided Cryoablation of Invasive Ductal Carcinomas up to 15 mm With MRI Follow-Up and Subsequent Surgical Resection.
AJR Am J Roentgenol. 2015; 204(5):1100-8 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to evaluate the effectiveness of ultrasound-guided cryoablation in treating small invasive ductal carcinoma and to assess the role of contrast-enhanced (CE) MRI in determining the outcome of cryoablation.
SUBJECTS AND METHODS: Twenty consecutive participants with invasive ductal carcinomas up to 15 mm, with limited or no ductal carcinoma in situ (DCIS), underwent ultrasound-guided cryoablation. Preablation mammography, ultrasound, and CE-MRI were performed to assess eligibility. Clinical status was evaluated at 1 day, 7-10 days, and 2 weeks after ablation. CE-MRI was performed 25-40 days after ablation, followed by surgical resection within 5 days.
RESULTS: Ultrasound-guided cryoablation was uniformly technically successful, and postablation clinical status was good to excellent in all participants. Cryoablation was not clinically successful in 15% (three of 20 patients). Three participants had residual cancer at the periphery of the cryoablation site. Two participants had viable nonmalignant tissue within the central zone of cryoablation-induced necrosis. Postablation CE-MRI had a sensitivity of 0% (0/3) and specificity of 88% (15/17). The predictive value of negative findings on CE-MRI was 83% (15/18). Correlations between cancer characteristics, cryoablation procedural variables, postablation CE-MRI findings, and surgical specimen features were not statistically significant. There were also no significant differences in participants with or without residual cancer.
CONCLUSION: In our pilot experience, ultrasound-guided cryoablation of invasive ductal carcinomas up to 15 mm has a clinical failure rate of 15% but is technically feasible and well tolerated by patients. The majority of cryoablation failures are manifest as DCIS outside the cryoablation field. Postablation CE-MRI does not reliably predict cryoablation outcome.

Guo Q, Schmidt MK, Kraft P, et al.
Identification of novel genetic markers of breast cancer survival.
J Natl Cancer Inst. 2015; 107(5) [PubMed] Related Publications
BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival.
METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.
RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.
CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

Menendez JA, Schroeder B, Peirce SK, et al.
Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling.
J Natl Cancer Inst. 2015; 107(6):djv090 [PubMed] Related Publications
BACKGROUND: Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2's extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective.
METHODS: To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student's t test were used to analyze differences. All statistical tests were two-sided.
RESULTS: The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451-466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451-466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested.
CONCLUSIONS: These findings reveal that an essential "activating" sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas.

Terrenato I, Pennacchia I, Buglioni S, et al.
HER2 status determination: analyzing the problems to find the solutions.
Medicine (Baltimore). 2015; 94(15):e645 [PubMed] Related Publications
Misdiagnosis in the evaluation of HER2 status in breast cancer may have consequent negative impact on clinical decision-making. Therefore, it has become ever more important to share procedures and interpretation criteria for HER2 testing among laboratories. Herein, we report an interlaboratory survey among 9 hospitals located in the central-south regions of Italy. The centers sent a series of 36 slides, 4 for each HER2 score, to the revising centers. We found a good concordance in HER2 scoring for 0 and 3+ score, but a very low concordance for 1+ and 2+ scores. To focus on factors that may lead to discordant results, we report 4 cases which summarized the most common source of discrepancy in HER2 testing. This methodological approach will help the individual laboratory to minimize technical variables and to reduce the percentage of erroneous interpretations of HER2 status.

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