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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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  • PubMed search for publications about Breast Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Breast Cancer
    MeSH term: Breast Neoplasms
    International US National Library of Medicine
    qualityPubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.

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).

Ács B, Zámbó V, Vízkeleti L, et al.
Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy.
Diagn Pathol. 2017; 12(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain.
METHODS: One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival).
RESULTS: Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS.
CONCLUSIONS: NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker.

Moghaddaskho F, Eyvani H, Ghadami M, et al.
Demethylation and alterations in the expression level of the cell cycle-related genes as possible mechanisms in arsenic trioxide-induced cell cycle arrest in human breast cancer cells.
Tumour Biol. 2017; 39(2):1010428317692255 [PubMed] Related Publications
Arsenic trioxide (As2O3) has been used clinically as an anti-tumor agent. Its mechanisms are mostly considered to be the induction of apoptosis and cell cycle arrest. However, the detailed molecular mechanisms of its anti-cancer action through cell cycle arrest are poorly known. Furthermore, As2O3 has been shown to be a potential DNA methylation inhibitor, inducing DNA hypomethylation. We hypothesize that As2O3 may affect the expression of cell cycle regulatory genes by interfering with DNA methylation patterns. To explore this, we examined promoter methylation status of 24 cell cycle genes in breast cancer cell lines and in a normal breast tissue sample by methylation-specific polymerase chain reaction and/or restriction enzyme-based methods. Gene expression level and cell cycle distribution were quantified by real-time polymerase chain reaction and flow cytometric analyses, respectively. Our methylation analysis indicates that only promoters of RBL1 (p107), RASSF1A, and cyclin D2 were aberrantly methylated in studied breast cancer cell lines. As2O3 induced CpG island demethylation in promoter regions of these genes and restores their expression correlated with DNA methyltransferase inhibition. As2O3 also induced alterations in messenger RNA expression of several cell cycle-related genes independent of demethylation. Flow cytometric analysis revealed that the cell cycle arrest induced by As2O3 varied depending on cell lines, MCF-7 at G1 phase and both MDA-MB-231 and MDA-MB-468 cells at G2/M phase. These changes at transcriptional level of the cell cycle genes by the molecular mechanisms dependent and independent of demethylation are likely to represent the mechanisms of cell cycle redistribution in breast cancer cells, in response to As2O3 treatment.

Tong D, Liang YN, Stepanova AA, et al.
Increased Eps15 homology domain 1 and RAB11FIP3 expression regulate breast cancer progression via promoting epithelial growth factor receptor recycling.
Tumour Biol. 2017; 39(2):1010428317691010 [PubMed] Related Publications
Recent research indicates that the C-terminal Eps15 homology domain 1 is associated with epithelial growth factor receptor-mediated endocytosis recycling in non-small-cell lung cancer. The aim of this study was to determine the clinical significance of Eps15 homology domain 1 gene expression in relation to phosphorylation of epithelial growth factor receptor expression in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Eps15 homology domain 1, RAB11FIP3, and phosphorylation of epithelial growth factor receptor expression via immunohistochemistry. The clinical significance was assessed via a multivariate Cox regression analysis, Kaplan-Meier curves, and the log-rank test. Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor were upregulated in 60.46% (185/306) and 53.92% (165/306) of tumor tissues, respectively, as assessed by immunohistochemistry. The statistical correlation analysis indicated that Eps15 homology domain 1 overexpression was positively correlated with the increases in phosphorylation of epithelial growth factor receptor ( r = 0.242, p < 0.001) and RAB11FIP3 ( r = 0.165, p = 0.005) expression. The multivariate Cox proportional hazard model analysis demonstrated that the expression of Eps15 homology domain 1 alone is a significant prognostic marker of breast cancer for the overall survival in the total, chemotherapy, and human epidermal growth factor receptor 2 (-) groups. However, the use of combined expression of Eps15 homology domain 1 and phosphorylation of epithelial growth factor receptor markers is more effective for the disease-free survival in the overall population, chemotherapy, and human epidermal growth factor receptor 2 (-) groups. Moreover, the combined markers are also significant prognostic markers of breast cancer in the human epidermal growth factor receptor 2 (+), estrogen receptor (+), and estrogen receptor (-) groups. Eps15 homology domain 1 has a tumor suppressor function, and the combined marker of Eps15 homology domain 1/phosphorylation of epithelial growth factor receptor expression was identified as a better prognostic marker in breast cancer diagnosis. Furthermore, RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor.

Sato R, Nakano T, Hosonaga M, et al.
RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.
Biomed Res Int. 2017; 2017:8032910 [PubMed] Free Access to Full Article Related Publications
Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

Cheng S, Castillo V, Welty M, et al.
BreastDefend enhances effect of tamoxifen in estrogen receptor-positive human breast cancer in vitro and in vivo.
BMC Complement Altern Med. 2017; 17(1):115 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tamoxifen (TAM) has been widely used for the treatment of estrogen receptor (ER)-positive breast cancer and its combination with other therapies is being actively investigated as a way to increase efficacy and decrease side effects. Here, we evaluate the therapeutic potential of co-treatment with TAM and BreastDefend (BD), a dietary supplement formula, in ER-positive human breast cancer.
METHODS: Cell proliferation and apoptosis were determined in ER-positive human breast cancer cells MCF-7 by MTT assay, quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP, respectively. The molecular mechanism was identified using RNA microarray analysis and western blotting. Tumor tissues from xenograft mouse model were analyzed by immunohistochemistry.
RESULTS: Our data clearly demonstrate that a combination of 4-hydroxytamoxifen (4-OHT) with BD lead to profound inhibition of cell proliferation and induction of apoptosis in MCF-7 cells. This effect is consistent with the regulation of apoptotic and TAM resistant genes at the transcription and translation levels. Importantly, TAM and BD co-treatment significantly enhanced apoptosis, suppressed tumor growth and reduced tumor weight in a xenograft model of human ER-positive breast cancer.
CONCLUSION: BD sensitized ER-positive human breast cancer cells to 4-OHT/TAM treatment in vitro and in vivo. BreastDefend can be used in an adjuvant therapy to increase the therapeutic effect of tamoxifen in patients with ER-positive breast cancer.

Bonert M, Tate AJ
Mitotic counts in breast cancer should be standardized with a uniform sample area.
Biomed Eng Online. 2017; 16(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitotic rate is routinely assessed in breast cancer cases and based on the assessment of 10 high power fields (HPF), a non-standard sample area, as per the College of American Pathologists cancer checklist. The effect of sample area variation has not been assessed.
METHODS: A computer model making use of the binomial distribution was developed to calculate the misclassification rate in 1,000,000 simulated breast specimens using the extremes of field diameter (FD) and mitotic density cutoffs (3 and 8 mitoses/mm(2)), and for a sample area of 5 mm(2). Mitotic counts were assumed to be a random sampling problem using a mitotic rate distribution derived from an experimental study (range 0-16.4 mitoses/mm(2)). The cellular density was 2500 cell/mm(2).
RESULTS: For the smallest microscopes (FD = 0.40 mm, area 1.26 mm(2)) 16% of cases were misclassified, compared to 9% of the largest (FD 0.69 mm, area 3.74 mm(2)), versus 8% for 5 mm(2). An excess of 27% of score 2 cases were misclassified as 1 or 3 for the lower FD.
CONCLUSION: Mitotic scores based on ten HPFs of a small field area microscope are less reliable measures of the mitotic density than in a bigger field area microscope; therefore, the sample area should be standardized. When mitotic counts are close to the cut-offs the score is less reproducible. These cases could benefit from using larger sample areas. A measure of mitotic density variation due to sampling may assist in the interpretation of the mitotic score.

Jeong YJ, Jung JW, Cho YY, et al.
Correlation of hypoxia inducible transcription factor in breast cancer and SUVmax of F-18 FDG PET/CT.
Nucl Med Rev Cent East Eur. 2017; 20(1):32-38 [PubMed] Related Publications
BACKGROUND: Tumor hypoxia induces the expression of several genes via the hypoxia-inducible transcription factor-1 alpha (HIF-1a). It is associated with the prognosis of several cancers. We studied the immunohistochemical expression of HIF-1a in patients with invasive ductal cancer (IDC) of the breast and the possible correlation with the maximum standardized uptake value of the primary tumor (pSUVmax) as well as other biological parameters. Prognostic significance of pSUVmax and expression of HIF-1a for the prediction of progression-free survival (PFS) was also assessed.
MATERIAL AND METHODS: Two-hundred seven female patients with IDC who underwent pretreatment fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) were enrolled. The pSUVmax was compared with clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), axillary lymph node (LN) metastasis, stage and HIF-1a expression. The prognostic value of pSUVmax for PFS was assessed using the Kaplan-Meier method.
RESULTS: pSUVmax was significantly higher in patients with HIF-1a expression ≥ 2 compared to patients with HIF-1a expression < 2 (5.2 ± 4.5 vs. 3.7 ± 3.1, p = 0.008). pSUVmax was also significantly higher in higher stage (p < 0.000001), ER-negative tumors (p < 0.0001), PR-negative tumors (p = 0.0011) and positive LN metastasis (p = 0.0013). pSUVmax was significantly higher in patients with progression compared to patients who were disease-free (6.8 ± 4.4 vs. 4.1 ± 3.7, p = 0.0005). A receiver-operating characteristic curve demonstrated a pSUVmax of 6.51 to be the optimal cutoff for predicting PFS (sensitivity: 53.6%, specificity: 86.0%). Patients with high pSUVmax (> 6.5) had significantly shorter PFS compared to patients with low pSUVmax (p < 0.0001).
CONCLUSIONS: pSUVmax on pretreatment F-18 FDG PET/ CT reflect expression of HIF-1a and can be used as a good surrogate marker for the prediction of progression in patients with IDC. The amount of FDG uptake is determined by the presence of glucose metabolism and hypoxia in breast cancer cell.

Okada T, Kurabayashi A, Akimitsu N, Furihata M
Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model.
Biomed Res Int. 2017; 2017:8494286 [PubMed] Free Access to Full Article Related Publications
We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells' anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow.

Cheng F, Pan Y, Lu YM, et al.
RNA-Binding Protein Dnd1 Promotes Breast Cancer Apoptosis by Stabilizing the Bim mRNA in a miR-221 Binding Site.
Biomed Res Int. 2017; 2017:9596152 [PubMed] Free Access to Full Article Related Publications
RNA-binding proteins (RBPs) and miRNAs are capable of controlling processes in normal development and cancer. Both of them could determine RNA transcripts fate from synthesis to decay. One such RBP, Dead end (Dnd1), is essential for regulating germ-cell viability and suppresses the germ-cell tumors development, yet how it exerts its functions in breast cancer has remained unresolved. The level of Dnd1 was detected in 21 cancerous tissues paired with neighboring normal tissues by qRT-PCR. We further annotated TCGA (The Cancer Genome Atlas) mRNA expression profiles and found that the expression of Dnd1 and Bim is positively correlated (p = 0.04). Patients with higher Dnd1 expression level had longer overall survival (p = 0.0014) by KM Plotter tool. Dnd1 knockdown in MCF-7 cells decreased Bim expression levels and inhibited apoptosis. While knockdown of Dnd1 promoted the decay of Bim mRNA 3'UTR, the stability of Bim-5'UTR was not affected. In addition, mutation of miR-221-binding site in Bim-3'UTR canceled the effect of Dnd1 on Bim mRNA. Knockdown of Dnd1 in MCF-7 cells confirmed that Dnd1 antagonized miR-221-inhibitory effects on Bim expression. Overall, our findings indicate that Dnd1 facilitates apoptosis by increasing the expression of Bim via its competitive combining with miR-221 in Bim-3'UTR. The new function of Dnd1 may contribute to a vital role in breast cancer development.

Wu HC, Southey MC, Hibshoosh H, et al.
DNA Methylation in Breast Tumor from High-risk Women in the Breast Cancer Family Registry.
Anticancer Res. 2017; 37(2):659-664 [PubMed] Related Publications
To examine DNA methylation profiles in breast tumors of women with a strong breast cancer family history, we measured methylation by bisulfite sequencing in 40 genes in 40 breast tumor tissues from women in the Breast Cancer Family Registry. We selected candidate genes from analysis of the Cancer Genome Atlas project (TCGA) breast data. Compared to TCGA breast cancer, BCFR cases are younger and more likely to be ER-negative. Overall, we found that many of the methylation differences between BCFR tumor and normal adjacent tissues were smaller than that in TCGA samples. We found only 32% of tested genes were hypermethylated in BCFR; the largest difference was 36.1% for SEPW1, and the smallest difference was 10% for RYR2. These data suggest the importance of examining breast cancer cases including familial cases enriched with early-onset cancers to identify methylation markers that can be examined in blood as biomarkers for early detection.

Onishi H, Suyama K, Yamasaki A, et al.
CD24 Modulates Chemosensitivity of MCF-7 Breast Cancer Cells.
Anticancer Res. 2017; 37(2):561-565 [PubMed] Related Publications
The role of cluster of differentiation (CD) 24 in breast cancer remains unclear; previously, we showed that CD24 suppresses malignant phenotypes by inactivating Hedgehog signaling through signal transducer and activator of transcription (STAT) 1 inhibition. In this study, we examined how CD24 affects chemosensitivity in breast cancer cells. The CD44(+)CD24(+) breast cancer cell line MCF-7 was transfected with CD24 with/without STAT1 siRNA, and chemosensitivity to 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) was measured. CD24 inhibition reduced chemosensitivity to 5-FU, while STAT1 inhibition did not affect chemosensitivity to 5-FU in CD24 siRNA-transfected cells. Conversely, CD24 inhibition did not affect chemosensitivity to CDDP, while STAT1 inhibition reduced chemosensitivity to CDDP in CD24 siRNA-transfected cells. STAT1 inhibition, but not CD24 inhibition, reduced expression of the ATP-binding cassette (ABC) transporter genes, ABCB1 and ABCG2. In conclusion, CD24 inhibition may modulate chemosensitivity according to drug type, but ABC transporter expression appears not to contribute to this mechanism. This study contributes to determining the role of CD24 in breast cancer.

Agosto-Arroyo E, Isayeva T, Wei S, et al.
Differential Gene Expression in Ductal Carcinoma In Situ of the Breast Based on ERBB2 Status.
Cancer Control. 2017; 24(1):102-110 [PubMed] Related Publications
BACKGROUND: The molecular signature of ductal carcinoma in situ (DCIS) in the breast is not well understood. Erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly known as HER2/neu]) positivity in DCIS is predictive of coexistent early invasive breast carcinoma. The aim of this study is to identify the gene-expression signature profiles of estrogen receptor (ER)/progesterone receptor (PR)-positive, ERBB2, and triple-negative subtypes of DCIS.
METHODS: Based on ER, PR, and ERBB2 status, a total of 18 high nuclear grade DCIS cases with no evidence of invasive breast carcinoma were selected along with 6 non-neoplastic controls. The 3 study groups were defined as ER/PR-positive, ERBB2, and triple-negative subtypes.
RESULTS: A total of 49 genes were differentially expressed in the ERBB2 subtype compared with the ER/PR-positive and triple-negative groups. PROM1 was overexpressed in the ERBB2 subtype compared with ER/PR-positive and triple-negative subtypes. Other genes differentially expressed included TAOK1, AREG, AGR3, PEG10, and MMP9.
CONCLUSIONS: Our study identified unique gene signatures in ERBB2-positive DCIS, which may be associated with the development of invasive breast carcinoma. The results may enhance our understanding of the progression of breast cancer and become the basis for developing new predictive biomarkers and therapeutic targets for DCIS.

Nanjappa S, Pla-Fernandez CA, Apuri S, et al.
Liver-Directed Embolization for the Long-Term Control of Hypercalcemia of Malignancy in Metastatic Breast Cancer.
Cancer Control. 2017; 24(1):57-59 [PubMed] Related Publications
Hypercalcemia of malignancy is a common complication of certain types of cancers. No standard therapies exist for the treatment of hypercalcemia secondary to paraneoplastic syndromes that result in the long-term control of serum calcium levels. We report a case of metastatic breast cancer with parathyroid hormone-related protein associated with hypercalcemia of malignancy that was treated with transarterial embolization of the hepatic metastatic lesions.

Le Rhun E, Taillibert S, Chamberlain MC
Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases.
Cancer Control. 2017; 24(1):22-32 [PubMed] Related Publications
BACKGROUND: Neoplastic meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates.
METHODS: A review of the literature of articles published in English was conducted with regard to neoplastic meningitis.
RESULTS: The incidence of neoplastic meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop neoplastic meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated neoplastic meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of neoplastic meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with neoplastic meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival.
CONCLUSIONS: The prognosis of neoplastic meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on neoplastic meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.

Mitchell KB, Lin H, Shen Y, et al.
DCIS and axillary nodal evaluation: compliance with national guidelines.
BMC Surg. 2017; 17(1):12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) provide guidelines regarding axillary nodal evaluation in ductal carcinoma in situ (DCIS), but data regarding national compliance with these guidelines remains incomplete.
METHODS: We conducted a retrospective review of the National Cancer Data Base (NCDB) analyzing all surgical approaches to axillary evaluation in patients with DCIS. Logistic regression analysis was used to assess the multivariate relationship between patient demographics, clinical characteristics, and probability of axillary evaluation.
RESULTS: We identified 88,083 patients diagnosed with DCIS between 1998 and 2011; 31,912 (37%) underwent total mastectomy (TM) and 55,349 (63%) had breast conserving therapy (BCT). Axillary evaluation increased from 44.4% in 1998 to 63.3% in 2011. In TM patients, axillary evaluation increased from 74.3% in 1998 to 93.4% in 2011. This correlated with an increase in sentinel lymph node biopsy (SLNB) from 24.3 to 77.1%, while ALND decreased from 50.0 to 16.3% (p <0.01). In BCT patients, evaluation increased from 20.1 to 43.9%; SLNB increased from 7.2 to 39.4% and ALND decreased from 12.9 to 4.5%. Factors associated with axillary nodal evaluation in BCT patients included practice type and facility location. Among TM patients, use of axillary lymph node dissection (ALND) for axillary staging was associated with earlier year of diagnosis, black race, and older age, as well as community practice setting and practice location in the Southern US.
CONCLUSIONS: Compliance with national guidelines regarding axillary evaluation in DCIS remains varied. Practice type and location-based differences suggest opportunities for education regarding the appropriate use of axillary nodal evaluation in patients with DCIS.

Eldehna WM, Almahli H, Al-Ansary GH, et al.
Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.
J Enzyme Inhib Med Chem. 2017; 32(1):600-613 [PubMed] Related Publications
Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

Shui Y, Yu X, Duan R, et al.
miR-130b-3p inhibits cell invasion and migration by targeting the Notch ligand Delta-like 1 in breast carcinoma.
Gene. 2017; 609:80-87 [PubMed] Related Publications
Breast carcinoma is the most common malignancy in women, and the incidence rate has increased dramatically in recent years. Metastasis is responsible for most advanced breast cancer mortality, but the underlying mechanisms remain poorly understood despite extensive research. Recently, short non-coding RNA molecules, including miRNAs, which mediate changes in signalling pathways, have emerged as metastatic regulators of the breast carcinoma. Previous reports have suggested that miR-130b-3p has both oncogenic and tumour suppressor functions in a cancer type-dependent manner. However, the roles and underlying molecular mechanisms of miR-130b-3p in the development of metastasis in breast carcinoma remain unclear. Here, we reported for the first time that miR-130b-3p was differentially expressed in early-stage non-invasive MCF-7 human breast carcinoma cells and aggressive late-stage MDA-MB-231 cells. In gain-of-function and loss-of-function studies, we demonstrated that miR-130b-3p could inhibit breast carcinoma cell invasion and migration by directly targeting the Notch ligand Delta-like 1 (DLL1). Our data also indicated that MMP-9, MMP-13, and VEGF were regulated by miR-130b-3p and may be involved in the inhibition of cell invasion and migration in breast carcinoma. Collectively, our findings reveal a new regulatory mechanism of miR-130b-3p and suggest that miR-130b-3p may be a potential target against human breast cancer metastasis.

Dekel Y, Machluf Y, Gefen T, et al.
Formation of multimeric antibodies for self-delivery of active monomers.
Drug Deliv. 2017; 24(1):199-208 [PubMed] Related Publications
Proteins and peptides have been used as drugs for almost a century. Technological advances in the past 30 years have enabled the production of pure, stable proteins in vast amounts. In contrast, administration of proteins based on their native active conformation (and thus necessitating the use of subcutaneous injections) has remained solely unchanged. The therapeutic anti-HER2 humanized monoclonal immunoglobulin (IgG) Trastuzumab (Herceptin) is a first line of the treatment for breast cancer. Chicken IgY is a commercially important polyclonal antibody (Ab). These Abs were examined for their ability to self-assemble and form ordered aggregates, by several biophysical methods. Atomic force microscopy analyses revealed the formation of multimeric nanostructures. The biological activity of multimeric IgG or IgY particles was retained and restored, in a dilution/time-dependent manner. IgG activity was confirmed by a binding assay using HER2 + human breast cancer cell line, SKBR3, while IgY activity was confirmed by ELISA assay using the VP2 antigen. Competition assay with native Herceptin antibodies demonstrated that the binding availability of the multimer formulation remained unaffected. Under long incubation periods, IgG multimers retained five times more activity than native IgG. In conclusion, the multimeric antibody formulations can serve as a storage depositories and sustained-release particles. These two important characteristics make this formulation promising for future novel administration protocols and altogether bring to light a different conceptual approach for the future use of therapeutic proteins as self-delivery entities rather than conjugated/encapsulated to other bio-compounds.

Aitelhaj M, Lkhoyaali S, Rais G, et al.
First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study.
Pan Afr Med J. 2016; 24:324 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lung was the first metastatic site in 60% of the cases, followed by bone, liver, nodes, skin and brain. All patients received chemotherapy with Trastuzumab: 9 of them with Docetaxel, 8 with vinorelbine, and 3 with capecitabine. The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab based chemotherapy was generally well tolerated; 5 patients (25%) presented cardiotoxicity. The results of this study join the literature and show the benefit of Trastuzumab to chemotherapy in first line metastatic breast cancer HER-2 positive.

Salako O, Robert AA, Okunade KS, et al.
Utilization of Cancer Information System for Breast Cancer Control in Lagos, Nigeria.
Pan Afr Med J. 2016; 24:323 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: There is a substantial increase in the incidence of breast cancer in Nigeria usually with the late stage presentations and subsequent poor rates of survival attributed mainly to a low level of cancer awareness and ignorance amongst patients. Cancer information system (CIS) is now assuming an emerging role in this respect.
METHODS: This was a descriptive study carried out over a one year period using a health communications program comprising of 3 breast help lines. An initial period of public awareness was carried out over a 3 months period after which members of the public were encouraged to call the help lines. Breast cancer information was provided and the socio-demographic characteristics and other relevant data of the callers were recorded by the information specialists.
RESULTS: A total of 294 people were reached during the study period. Majority of the callers (82%) sought information for themselves while the remaining 18% called on behalf of a loved one or friend. Majority [248 (84.3%)] of callers had no breast abnormality, 38 (13%) called to report breast abnormalities and required information on what to do and 8 (2.7%) were breast cancer patients who required information on how to live and cope as breast cancer survivors.
CONCLUSION: The rapid growth of mobile phone use in the Nigeria has presented a unique opportunity and promise to improve cancer care. There is evidence to suggest that mHealth can be used to deliver increased health care services to the increasing population of cancer patients in Nigeria.

Irawan C, Atmakusumah D, Siregar NC, et al.
Expression of Biomarkers CXCR4, IL11-RA, TFF1, MLF1P in Advanced Breast Cancer Patients with Bone Metastatic: a Diagnostic Study.
Acta Med Indones. 2016; 48(4):261-268 [PubMed] Related Publications
AIM: to analyze expression of biomarkers CXCR4, IL11-RA, TFF1 and MLF1P, and clinicopathology in advanced breast cancer patients with bone metastatic.
METHODS: this is a cross-sectional study. Analysis was done against a total of 92 breast cancer patients, including 46 bone metastatic patients and 46 non-bone metastatic patients. Immunohistochemistry and microarray analysis was performed in 81 formalin fixed paraffin embedded (FFPE) samples from 81 patients were used. Data were collected through medical records, immunohistochemistry (IHC), and microarray with nanoString nCounterTM.
RESULTS: this article is part one of a two stage reporting research results. In part one we got the results of the IHC analysis, IL11-RA with cut-off ≥103.5 showed OR 3.803 (95 % confidence interval [CI], 1.375-10.581), p=0.010, MLF1P with cut-off ≥83.0 OR 2.784 (95% CI, 1.009-7.681), p=0.048, and ER+ OR 7.640 (95 % CI, 2.599-22.459), p<0.000, were associated with bone metastastic incidences in advanced breast cancer, and were statistically significantly different. A combination of IL-11RA, MLF1P and ER+, showed an accuracy of approaching 80% to discriminate between bone metastatic and non bone metastatic in advanced breast cancer patients.
CONCLUSION: IL11-RA, MLF1P, and ER+ were the determinants that were associated with increasing bone metastasis incidence.

Chen G, Ouyang Z, Wang F, et al.
Evaluation of Tc-99m-3PRGD2 Integrin Receptor Imaging in the Differential Diagnosis of Breast Lesions and Comparison With Mammography.
Cancer Invest. 2017; 35(2):108-115 [PubMed] Related Publications
PURPOSE: The aims of this study were to evaluate and compare efficacies of Tc-99m-3PRGD2 integrin receptor imaging under variety of conditions for the diagnosis of breast lesions, in addition to comparison with mammography.
MATERIALS AND METHODS: Seventy-two female patients with established breast lesions were recruited. All patients were examined by Tc-99m-3PRGD2 integrin receptor imaging and mammography. Whole-body scan and SPECT/CT were acquired at dual time points of 2 and 4 h after injection using standard protocol. The processed images were evaluated by visual and semi-quantitative analysis. Mammography was performed using up and down and internal and external oblique views. The gold standard of diagnosis was based on histopathological findings.
RESULTS: Sensitivity greater than 85.0% and accuracy greater than 80.0% were observed under any technical method. For dense mammary gland, the sensitivity, specificity, and accuracy of Tc-99m-3PRGD2 SPECT/CT 4-h imaging and mammography were 95.2, 75.0, and 90.7%, and 71.4, 58.3, and 68.5% respectively. Combined two methods' sensitivity, specificity, and accuracy for detection of breast cancer can reach 98.3, 86.7, and 96.0%.
CONCLUSIONS: Tc-99m-3PRGD2-based molecular imaging is a sensitive method for the differential diagnosis of breast lesions. Particularly, Tc-99m-3PRGD2-SPECT/CT has better diagnostic value in dense mammary gland as compared with mammography. Combining two methods can significantly improve the diagnostic efficiency.

Yang CH, Moi SH, Chuang LY, et al.
Interaction of MRE11 and Clinicopathologic Characteristics in Recurrence of Breast Cancer: Individual and Cumulated Receiver Operating Characteristic Analyses.
Biomed Res Int. 2017; 2017:2563910 [PubMed] Free Access to Full Article Related Publications
The interaction between the meiotic recombination 11 homolog A (MRE11) oncoprotein and breast cancer recurrence status remains unclear. The aim of this study was to assess the interaction between MRE11 and clinicopathologic variables in breast cancer. A dataset for 254 subjects with breast cancer (220 nonrecurrent and 34 recurrent) was used in individual and cumulated receiver operating characteristic (ROC) analyses of MRE11 and 12 clinicopathologic variables for predicting breast cancer recurrence. In individual ROC analysis, the area under curve (AUC) for each predictor of breast cancer recurrence was smaller than 0.7. In cumulated ROC analysis, however, the AUC value for each predictor improved. Ten relevant variables in breast cancer recurrence were used to find the optimal prognostic indicators. The presence of any six of the following ten variables had a high (79%) sensitivity and a high (70%) specificity for predicting breast cancer recurrence: tumor size ≥ 2.4 cm, tumor stage II/III, therapy other than hormone therapy, age ≥ 52 years, MRE11 positive cells > 50%, body mass index ≥ 24, lymph node metastasis, positivity for progesterone receptor, positivity for epidermal growth factor receptor, and negativity for estrogen receptor. In conclusion, this study revealed that these 10 clinicopathologic variables are the minimum discriminators needed for optimal discriminant effectiveness in predicting breast cancer recurrence.

Wang H, Zhang C, Kong L, et al.
Better survival in PMRT of female breast cancer patients with >5 negative lymph nodes: A population-based study.
Medicine (Baltimore). 2017; 96(4):e5998 [PubMed] Free Access to Full Article Related Publications
Many studies have confirmed the role of postmastectomy radiotherapy (PMRT) for breast cancer patients with at least 4 lymph nodes invasion in the postoperative therapy. Recently, the number of negative lymph nodes (NLNs) has been increasingly paid attention to and recognized as a prognostic indicator in different kinds of caners. Therefore, it is very necessary to study the association between the number of NLNs and the prognosis of PMRT in breast cancer patients. In our study, we used Surveillance, Epidemiology, and End Results (SEER) population-based data and identified 16,686 breast cancer patients to explore their correlation. The ROC curve and the log-rank χ test were applied to determine the appropriate cutoff point of the number of NLNs and 5 was selected as the cutoff point. Furthermore, the cutoff point 5 was validated as an independent prognostic factor affecting cancer-specific survival (CSS) and overall survival (OS) in breast cancer patients, as confirmed by both univariate and multivariate analysis (P < 0.001). In addition, subgroup analysis showed that the number of NLNs >5 can be a prognostic indicator in patients with PMRT according to different clinical variables (all, P < 0.001). Importantly, our results showed that PMRT obviously improved CSS and OS in patients regardless of the number of NLNs (P < 0.001). In conclusion, our study showed the number of NLNs is an independent prognostic factor for breast cancer patients with PMRT, and those who have higher number of NLNs have an increased CSS and OS.

Du Z, Wan H, Chen Y, et al.
Bioimpedance spectroscopy can precisely discriminate human breast carcinoma from benign tumors.
Medicine (Baltimore). 2017; 96(4):e5970 [PubMed] Free Access to Full Article Related Publications
Intraoperative frozen pathology is critical when a breast tumor is not diagnosed before surgery. However, frozen tumor tissues always present various microscopic morphologies, leading to a high misdiagnose rate from frozen section examination. Thus, we aimed to identify breast tumors using bioimpedance spectroscopy (BIS), a technology that measures the tissues' impedance. We collected and measured 976 specimens from breast patients during surgery, including 581 breast cancers, 190 benign tumors, and 205 normal mammary gland tissues. After measurement, Cole-Cole curves were generated by a bioimpedance analyzer and parameters R0/R∞, fc, and α were calculated from the curve. The Cole-Cole curves showed a trend to differentiate mammary gland, benign tumors, and cancer. However, there were some curves overlapped with other groups, showing that it is not an ideal model. Subsequent univariate analysis of R0/R∞, fc, and α showed significant differences between benign tumor and cancer. However, receiver operating characteristic (ROC) analysis indicated the diagnostic value of fc and R0/R∞ were not superior to frozen sections (area under curve [AUC] = 0.836 and 0.849, respectively), and α was useless in diagnosis (AUC = 0.596). After further research, we found a scatter diagram that showed a synergistic effect of the R0/R∞ and fc, in discriminating cancer from benign tumors. Thus, we used multivariate analysis, which revealed that these two parameters were independent predictors, to combine them. A simplified equation, RF = 0.2fc + 3.6R0/R∞, based on multivariate analysis was developed. The ROC curve for RF' showed an AUC = 0.939, and the sensitivity and specificity were 82.62% and 95.79%, respectively. To match a clinical setting, the diagnostic criteria were set at 6.91 and 12.9 for negative and positive diagnosis, respectively. In conclusion, RF' derived from BIS can discriminate benign tumor and cancers, and integrated criteria were developed for diagnosis.

Weissenborn C, Ignatov T, Nass N, et al.
GPER Promoter Methylation Controls GPER Expression in Breast Cancer Patients.
Cancer Invest. 2017; 35(2):100-107 [PubMed] Related Publications
Recently, we found that G-protein-coupled estrogen receptor (GPER) protein expression decreased during breast carcinogenesis, and that GPER promoter is methylated. Here we analyzed GPER promoter methylation in 260 primary breast cancer specimens by methylation-specific polymerized chain reaction. The results demonstrated that GPER protein down-regulation significantly correlated with GPER promoter hypermethylation (p < .001). Comparison of 108 tumors and matched normal breast tissues indicated a significant GPER down-regulation in cancer tissues correlating with GPER promoter hypermethylation (p < .001). The latter was an unfavorable factor for overall survival of patients with triple-negative breast cancer (p = .025). Thus GPER promoter hypermethylation might be used as a prognostic factor.

Robertson JF, Herrod PJ, Matthew J, et al.
Treatment of the axilla in patients with primary breast cancer and low burden axillary disease: Limitations of the evidence from randomised controlled trials.
Crit Rev Oncol Hematol. 2017; 110:74-80 [PubMed] Related Publications
Invasive breast cancer is the second most common cancer worldwide. It is known to metastasise to the regional axillary lymph nodes but there has been debate over what is the best way to stage and treat the axilla in patients presenting with primary breast cancer. Multiple trials over the last two decades have led to a change in practice from routine axillary lymph node dissection to sentinel lymph node biopsy in patients who are clinically lymph node negative preoperatively. This has resulted in new questions regarding subsequent treatment of some patients. This review will critically appraise the evidence on axillary treatment in patients with low burden axillary disease and highlight limitations of relevant randomised controlled trials.

Porto-Mascarenhas EC, Assad DX, Chardin H, et al.
Salivary biomarkers in the diagnosis of breast cancer: A review.
Crit Rev Oncol Hematol. 2017; 110:62-73 [PubMed] Related Publications
Salivary biomarkers could be helpful to characterize breast cancer. Therefore, this review was performed to evaluate the capability of salivary biological markers in the diagnosis and monitoring of breast cancer. Studies were eligible for inclusion if they assessed the potential diagnostic value or other discriminatory properties of biological markers in saliva of patients with breast cancer. The search was performed in six electronic databases (Cochrane, LILACS, PubMed, Science Direct, Scopus, Web of Science). In addition the biomarkers were classified according to their potential clinical application. We identified 567 pertinent studies, of which 13 met the inclusion criteria. Combined biomarker approaches demonstrated better ability to predict breast cancer patients than individual biomarkers. As single biomarker, namely proline, reported great capacity in both early and late stage breast cancer diagnosis. Taurine showed interesting capability to identify early breast cancer individuals. Furthermore, valine also demonstrated excellent diagnostic test accuracy for advanced stages of breast cancer. Only seven studies reported sensitivity and specificity (Zhang et al., 2010; Streckfus et al., 2000a; Brooks et al., 2008; Cheng et al., 2015; Bigler et al., 2002; Zhong et al., 2016; Streckfus, 2009), which varied considerably from 50% to 100%, and from 51% to 97%, respectively. In general, salivary biomarkers identified advanced stages of breast cancer better than early stages. There is currently limited evidence to confirm the putative implementation of salivary biomarkers as diagnostic tools for breast cancer. However, current review provides new research directions.

Tsoutsou PG, Vozenin MC, Durham AD, Bourhis J
How could breast cancer molecular features contribute to locoregional treatment decision making?
Crit Rev Oncol Hematol. 2017; 110:43-48 [PubMed] Related Publications
Systemic treatments are tailored to breast cancer (BC) heterogeneity, which is not yet taken into account for radiotherapy (RT) personalization. The primary objective of this review is to summarize existing data suggesting BC subtypes and genetic assays are prognostic and predictive biomarkers useful for RT decision-making and to provide implications for their incorporation into future translational and clinical research. The evidence suggesting that BC subtypes also exhibit distinct "locoregional recurrence (LRR)" patterns is retrospective but consistent and validated in over fifteen studies. The HER-2 positive and triple negative subtypes are the most susceptible to locoregional failure. The high risk of the HER-2 positive subtype can be reversed with trastuzumab administration. Very little is known on the subtypes' intrinsic radiosensitivity properties. Genetic assays have assessed retrospectively signatures' prognostic and predictive value in patients' cohorts (several coming from prospective studies) for LRR risk and radiotherapy (RT) benefit. Further confirmation is needed before their introduction into clinical routine. Evidence on the use of molecular biomarkers for adjuvant RT tailoring is emerging but needs validation and introduction into prospective studies. The plethora of modern RT options (partial breast irradiation, hypofractionation), as well as recent evidence pointing towards more extensive radiotherapy, demand introduction of biological features into clinical trials to improve therapeutic decisions. Open questions, such as tailoring of irradiation after neo-adjuvant chemotherapy in complete responders and the understanding of the interplay between local control, systemic recurrence and survival given modern systemic treatments, need to be addressed under the prism of biology within this heterogeneous disease. Intrinsic radiobiological properties within this heterogeneity need to be highlighted in order to further improve outcomes.

Rabasco P, Caivano R, Simeon V, et al.
Can Diffusion-Weighted Imaging and Related Apparent Diffusion Coefficient be a Prognostic Value in Women With Breast Cancer?
Cancer Invest. 2017; 35(2):92-99 [PubMed] Related Publications
PURPOSE: To analyze diffusion-weighted imaging (DWI) and the related apparent diffusion coefficient (ADC) in women with breast cancer, correlating these values with the presence at 3 years of distant metastases, and to demonstrate that DWI-Magnetic Resonance Imaging (MRI) and related ADC values may represent a prognostic value in the study of women with breast cancer.
MATERIALS AND METHODS: Sixty women (aged 45-73 years) affected with breast cancer with a follow-up in 3 years were enrolled. On DWI, we obtained the ADC values, and these were correlated with the clinical condition of patients at 3 years. Moreover, tumour size, lymph node status, and molecular markers, including estrogens receptor, progesterone receptor, Ki-67 index, and human growth factor receptor 2 protein, were correlated with ADC values. This study was approved by the Scientific Committee of our institution.
RESULTS: We considered patients with metastasis at 3 years (12 patients - 20%) and without metastasis (48 patients - 80%). The mean ADC value in patients with no metastases at 3 years was 1.06 ± 0.38, while for patients with metastases it was 0.74 ± 0.34 (p = .011). The receiver-operator curve analysis identified a value of 0.75 (<0.75 with risk to develop metastasis) as the best predictive cutoff for ADC values, with the highest sensitivity (81.25%) and higher specificity (66.67%). After regression analysis, ADC value, positivity to estrogen-progestin receptors, and presence of lymph nodes were the only prognostic factors found to be statistically significant.
CONCLUSIONS: DWI-MRI and related ADC values may represent a prognostic value in women with breast cancer.

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