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1.  Coping Strategies in Egyptian Ladies with Breast Cancer 
A diagnosis of breast cancer regardless of the stage can be stressful, impact multiple spheres of life, and disrupt physical status, emotional and spiritual well-being, and personal relationships for the patient and family. In order to adapt, the patient ought to employ certain coping mechanisms. Individuals with terminal illness who utilize coping strategies have better quality of life compared to those who do not.
This study aimed to determine the strategies used by females with breast cancer to cope with such stress by using Brief COPE scale and the hospital anxiety and depression scale. The study included 56 female patients diagnosed with operable breast cancer at Mansoura Oncology Center before surgery.
Large proportion of patients used acceptance, religion, and emotional support in coping with the stress of having breast cancer. Patients with depressive symptoms scored significantly higher venting while those with anxiety scored higher positive reframing, planning, and venting.
Efforts should be made to encourage women with breast cancer to use coping strategies that have been found to be helpful (eg, acceptance, emotional support, distraction, and active coping strategies).
PMCID: PMC4055407  PMID: 24940070
coping; depression; anxiety; breast cancer; Egypt
2.  Hyperactivated Signaling Pathways of Chemokine RANTES/CCL5 in Osteopathies of Jawbone in Breast Cancer Patients—Case Report and Research 
Hollow spaces in the jawbone have been defined as fatty degenerative osteonecrosis of jawbone (FDOJ) and have been linked with a dysregulated immune system. Little is known about the underlying relationship.
Samples of FDOJ were analyzed to assess expression of cytokines which can play a role in the pathogenesis of breast cancer (MaCa).
Samples of FDOJ extracted from 23 patients with MaCa and 19 healthy control jawbone samples were analyzed for 7 immune messengers.
RANTES was found to be highly overexpressed in disease samples. No change was observed in expression levels of the other immune mediators.
This data provides a compelling confirmation that FDOJ produces high levels of RANTES, a cytokine implicated in MaCa and metastasis. Levels detected in FDOJ are five-fold higher than that previously reported for MaCa tissue suggesting its role as a cytokine source in MaCa.
We thus hypothesize that FDOJ may serve as an expeditor of MaCa progression, through RANTES production.
PMCID: PMC4039184  PMID: 24899812
RANTES/CCL5; breast cancer; jawbone; osteonecrosis; metastasis; signaling pathways
3.  Pertuzumab in Combination with Trastuzumab and Chemotherapy in the Treatment of HER2-Positive Metastatic Breast Cancer: Safety, Efficacy, and Progression Free Survival 
Tyrosine kinase inhibitors have revolutionized the oncology community and were pioneered by the use in HER2-targeted therapies. Improved outcomes were seen with the advent of trastuzumab, leading investigators to develop newer agents to target the HER2 pathway such as the novel monoclonal antibody pertuzumab. In this paper, we describe the attributes of pertuzumab including: mechanism of action, pharmacokinetics and metabolism, safety/cardiotoxicity, drug interactions, efficacy, and role in HER2-positive breast cancer management. Newly reviewed here versus previously published reviews on pertuzumab oriented therapy are data of pertuzumab monotherapy as it is used in combination with other anti-HER2 agents derived from preclinical research and ongoing clinical trials.
A computer based literature search was carried out using PubMed data reported at international meetings (ASCO) up to September 2013 were included.
PMCID: PMC4022699  PMID: 24855372
pertuzumab; trastuzumab; HER2; breast cancer
4.  Breast Cancer Knowledge, Beliefs, and Screening Practices among Women Seeking Care at District Hospitals in Dar es Salaam, Tanzania 
Limited disease awareness among women may impact breast cancer stage-at-diagnosis in Tanzania, reducing survival. This study assessed breast cancer knowledge, screening practices, and educational preferences among outpatients at Tanzanian government-supported hospitals.
A convenience sample of women was surveyed regarding (1) knowledge/beliefs of breast cancer etiology, risk factors, symptoms, treatment, (2) early detection knowledge/practice, and (3) educational preferences.
Among 225 respondents, 98.2% knew of breast cancer; 22.2% knew someone affected by breast cancer. On average, 30% of risk factors and 51% of symptoms were identified. Most accepted one or more breast cancer myths. Among 126 aware of breast self-exam, 40% did not practice it; only 0.9% underwent regular clinical breast examinations despite 68% being aware of the procedure. Among treatments, 87% recognized surgery, 70% radiation, and fewer systemic therapy. Preferred educational sources were group sessions, television/radio, and meetings with breast cancer survivors.
This work reveals incomplete breast cancer awareness among Tanzanian women and promises to inform development of user-focused educational resources.
PMCID: PMC4022700  PMID: 24855371
breast cancer; awareness; urban; Tanzania; low income
5.  Diagnosis of a Nonpalpable Intraductal Papilloma without Radiological Abnormality by Nipple Discharge Smear Examination: A Case Report 
Nipple discharge is the third most common breast complaint after breast pain and breast mass, most commonly associated with endocrine alterations and/or medications, pregnancy, lactation, post lactation, fibrocystic disease, intraductal papilloma, duct ectasia, nipple adenoma, infection, chronic mastitis, subareolar abscess, and least frequently, breast carcinoma. Cytological examination of nipple discharge (ND) is a noninvasive method of diagnosing the underlying breast pathology. We report a 46 year old female, who presented with pain and blood-mixed ND from the right breast with an impalpable mass. Cytological examination of the discharge was done and diagnosis of papillary neoplasm with degeneration, metaplasia, and atypia was given, which was further confirmed on histology and positive IHC for HMWCK and p63. Final diagnosis was intraductal papilloma of the lactiferous duct with squamous metaplasia and infarction. Differentiating benign papilloma from a carcinoma is challenging to the cytopathologist and requires clinicopathological correlation and a good knowledge of cytology.
PMCID: PMC3981477  PMID: 24737934
nipple discharge; papillary neoplasms; infarction; HMWCK; p63
6.  Successful Remission of Hemolytic-Uremic Syndrome During the Third-line Weekly Gemcitabine for Metastatic Breast Cancer 
Sequential palliative chemotherapy for metastatic breast cancer incorporating weekly gemcitabine administered as three-weeks-on, one-week-off schedule is widely adopted throughout the East Asia region. Hemolytic-uremic syndrome (HUS) associated with weekly gemcitabine for a breast cancer patient is extremely rare. We report here a case of 43-year-old woman with metastatic breast cancer who received weekly gemcitabine as a third-line palliative chemotherapy for her disease. She developed HUS after a cumulative dose of 11,000 mg/m2 gemcitabine, evidenced by microangiopathic hemolytic anemia (MAHA) with schistocytes seen in peripheral blood smear, decreased haptoglobin level (<0.29 mmol/L), thrombocytopenia, negative direct Coombs test, and acute kidney injury. Owing to the ease of administration of weekly gemcitabine, gemcitabine-induced thrombocytopenia, multifactorial anemia in metastatic breast cancer, and possibility of cancer progression, HUS could have gone unnoticed. Breast cancer oncologist should be cognizant of this rare HUS even during weekly gemcitabine treatment.
PMCID: PMC3972075  PMID: 24701120
breast neoplasms; gemcitabine; hemolytic-uremic syndrome
7.  Protein Kinase C-ε Promotes EMT in Breast Cancer 
Protein kinase C (PKC), a family of serine/threonine kinases, plays critical roles in signal transduction and cell regulation. PKCε, a member of the novel PKC family, is known to be a transforming oncogene and a tumor biomarker for aggressive breast cancers. In this study, we examined the involvement of PKCε in epithelial to mesenchymal transition (EMT), the process that leads the way to metastasis. Overexpression of PKCε was sufficient to induce a mesenchymal phenotype in non-tumorigenic mammary epithelial MCF-10 A cells. This was accompanied by a decrease in the epithelial markers, such as E-cadherin, zonula occludens (ZO)-1, and claudin-1, and an increase in mesenchymal marker vimentin. Transforming growth factor β (TGFβ) induced Snail expression and mesenchymal morphology in MCF-10 A cells, and these effects were partially reversed by the PKCε knockdown. PKCε also mediated cell migration and anoikis resistance, which are hallmarks of EMT. Thus, our study demonstrates that PKCε is an important mediator of EMT in breast cancer.
PMCID: PMC3972078  PMID: 24701121
PKCε; EMT; breast cancer
8.  Host Cell Reactivation and Transcriptional Activation of Carboplatin-Modified BRCA1 
The breast cancer susceptibility gene 1 (BRCA1) has been shown to maintain genomic stability through multiple functions in the regulation of DNA damage repair and transcription. Its translated BRCT (BRCA1 C-terminal domain) acts as a strong transcriptional activator. BRCA1 damaged by carboplatin treatment may lead to a loss of such functions. To address the possibility of the BRCA1 gene as a therapeutic target for carboplatin, we investigated the functional consequences of the 3′-terminal region of human BRCA1 following in vitro platination with carboplatin. A reduction in cellular BRCA1 repair of carboplatin-treated plasmid DNA, using a host cell reactivation assay, was dependent on the platination levels on the reporter gene. The transcriptional transactivation activity of the drug-modified BRCA1, assessed using a one-hybrid GAL4 transcriptional assay, was inversely proportional to the carboplatin doses. The data emphasized the potential of the BRCA1 gene to be a target for carboplatin treatment.
PMCID: PMC3964185  PMID: 24678242
BRCA1; carboplatin; host cell reactivation; transcriptional activity; cancer chemotherapy
9.  Novel PI3K and mTOR Inhibitor NVP-BEZ235 Radiosensitizes Breast Cancer Cell Lines under Normoxic and Hypoxic Conditions 
In the present study, we assessed, if the novel dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 radiosensitizes triple negative (TN) MDA-MB-231 and estrogen receptor (ER) positive MCF-7 cells to ionizing radiation under various oxygen conditions, simulating different microenvironments as occurring in the majority of breast cancers (BCs). Irradiation (IR) of BC cells cultivated in hypoxic conditions revealed increased radioresistance compared to normoxic controls. Treatment with NVP-BEZ235 completely circumvented this hypoxia-induced effects and radiosensitized normoxic, reoxygenated, and hypoxic cells to similar extents. Furthermore, NVP-BEZ235 treatment suppressed HIF-1α expression and PI3K/mTOR signaling, induced autophagy, and caused protracted DNA damage repair in both cell lines in all tested oxygen conditions. Moreover, after incubation with NVP-BEZ235, MCF-7 cells revealed depletion of phospho-AKT and considerable signs of apoptosis, which were significantly enhanced by radiation. Our findings clearly demonstrate that NVP-BEZ235 has a clinical relevant potential as a radiosensitizer in BC treatment.
PMCID: PMC3964191  PMID: 24678241
radiosensibility; Akt; DNA repair protraction; apoptosis; hypoxia; autophagy
10.  A Proposal to Unify the Classification of Breast and Prostate Cancers Based on the Anatomic Site of Cancer Origin and on Long-term Patient Outcome 
The similarity between the structure and function of the breast and prostate has been known for a long time, but there are serious discrepancies in the terminology describing breast and prostate cancers. The use of the large, thick-section (3D) histology technique for both organs exposes the irrationality of the breast cancer terminology. Pathologists with expertise in diagnosing prostate cancer take the anatomic site of cancer origin into account when using the terms AAP (acinar adenocarcinoma of the prostate) and DAP (ductal adenocarcinoma of the prostate) to distinguish between the prostate cancers originating primarily from the fluid-producing acinar portion of the organ (AAP) and the tumors originating either purely from the larger ducts (DAP) or from both the acini and the main ducts combined (DAP and AAP). Long-term patient outcome is closely correlated with the terminology, because patients with DAP have a significantly poorer prognosis than patients with AAP.
The current breast cancer terminology could be improved by modeling it after the method of classifying prostate cancer to reflect the anatomic site of breast cancer origin and the patient outcome. The long-term survival curves of our consecutive breast cancer cases collected since 1977 clearly show that the non-palpable, screen-detected breast cancers originating from the milk-producing acini have excellent prognosis, irrespective of their histologic malignancy grade or biomarkers. Correspondingly, the breast cancer subtypes of truly ductal origin have a significantly poorer outcome, despite recent improvements in diagnosis and therapy. The mammographic appearance of breast cancers reflects the underlying tissue structure. Addition of these “mammographic tumor features” to the currently used histologic phenotypes makes it possible to distinguish the breast cancer cases of ductal origin with a poor outcome, termed DAB (ductal adenocarcinoma of the breast), from the more easily managed breast cancers of acinar origin, termed AAB (acinar adenocarcinoma of the breast), which have a significantly better outcome. This simple and easily communicable terminology could lead to better communication between the diagnostic and therapeutic team members and result in more rational treatment planning for the benefit of their patients.
PMCID: PMC3948717  PMID: 24653647
breast cancer terminology; prostate cancer terminology; ductal adenocarcinoma of the breast (DAB); acinar adenocarcinoma of the breast (AAB); subgross 3-D histology; neoductgenesis
11.  Challenges to the Control of Breast Cancer in A Small Developing Country 
The aim of this study is to determine the clinicopathological features of breast cancer in two dedicated cancer treatment centers in north Trinidad. The histological types and stage at presentation were also investigated.
A retrospective cohort design was used; data were collected from a review of medical records of patients meeting the entry criteria. Clinical and demographic data were extracted.
A total of 640 patients were selected for the study and were available for the analysis. The annual cumulative incidence rate of breast cancer for the calendar years 2010 and 2011 in north Trinidad was 32.4 per 100,000 and 24.6 per 100,000 of the population. The age group between 51–60 years had the highest proportion of cases of breast cancer. There was a significant ethnic disparity in the occurrence of breast cancer, as it was more common in people of African origin than among South East Asians. Surgery and chemotherapy were the major interventions employed.
Breast cancer prevalence continues to be high in Trinidad; we provide evidence of the extent of and the degree of sophistication required to care for patients with breast cancer in a health care system in a small developing country.
PMCID: PMC3921156  PMID: 24526837
breast cancer; epidemiology; developing countries
12.  Oncotype Dx Results in Multiple Primary Breast Cancers 
To determine whether multiple primary breast cancers have similar genetic profiles, specifically Oncotype Dx Recurrence Scores, and whether obtaining Oncotype Dx on each primary breast cancer affects chemotherapy recommendations.
A database of patients with hormone receptor-positive, lymph node-negative, breast cancer was created for those tumors that were sent for Oncotype Dx testing from the University of Michigan Health System from 1/24/2005 to 2/25/2013.
Retrospective chart review abstracted details of tumor location, histopathology, distance between tumors, Oncotype Dx results, and chemotherapy recommendations.
Six hundred and sixty-six patients for whom Oncotype Dx testing was sent were identified, with 22 patients having multiple breast tumor specimens sent. Of the 22 patients who had multiple samples sent for analysis, chemotherapy recommendations were changed in 6 of 22 patients (27%) based on significant differences in Oncotype Dx Recurrence Scores. Qualitatively, there seems to be a greater difference in genetic profile in tumors appearing simultaneously on different breasts when compared to multiple tumors on the same breast. There was no association between distance between tumors and difference in Oncotype Dx scores for tumors on the same breast.
Oncotype Dx testing on multiple primary breast cancers altered management in regards to chemotherapy recommendations and should be considered for multiple primary breast cancers.
PMCID: PMC3891573  PMID: 24453493
breast cancer; oncotype dx; recurrence score
13.  Hormone Receptors and Age Distribution in Breast Cancer Patients at a University Hospital in Northern Egypt 
Breast cancer is the most common cancer among Egyptian women. The disease is often advanced at diagnosis. Since molecular profiling is not feasible in routine practice, we sought to examine the association of age distribution with hormone receptor profile, disease stage and outcome among Egyptian women.
Patients and methods:
We conducted a retrospective review of breast cancer patients treated at Mansoura University Cancer Center in the Nile Delta from 2006 through 2011. Age groups were examined in relation to hormone receptors status and tumor clinicopathological criteria. Additionally, the effect of receptor status on disease relapse and disease-free survival was examined with logistic regression and Kaplan–Meier analysis.
A total of 263 patients were included in the current analysis. About 66.9% (n = 176) of patients were hormone receptor positive, 14.1% (n = 37) were Her2/neu positive, and 19.0% (n = 50) were triple negative. Median age of the patients was 52 years and was equal across all receptor status types. Triple negative status correlated with increased risk of disease relapse (odds ratio = 1.8, P = 0.03) and with shortened disease-free survival (hazards ratio = 2.6, P < 0.01).
The age distribution and receptor status pattern in the Nile Delta region does not explain the aggressive behavior of the disease. The age of the patients at diagnosis is older than patients in earlier studies from Egypt emphasizing the importance of implementing mammographic screening programs.
PMCID: PMC3694824  PMID: 23825439
breast cancer; hormone receptors; Egypt; prognosis
14.  Dose Distribution in the Heart and Cardiac Chambers Following 4-field Radiation Therapy of Breast Cancer: a Retrospective Study 
To evaluate cardiac doses in breast cancer patients with stage II/III treated with 4-field radiotherapy based on computed tomography (CT) dose planning.
Methods and Materials:
Based on archived CT images, whole heart and cardiac chamber radiation doses were analyzed in 216 (111 left-sided and 105 right-sided) mastectomized or lumpectomized breast cancer patients treated at a single institution, the Norwegian Radium Hospital, between 2000–2002. Individual dose volume histograms for the whole heart and for the four cardiac chambers were obtained, and mean, median and maximum doses to these structures were calculated. The dose (Gy) delivered to the 5% of the volume of each cardiac structure (D5%), and the volume percentage of each structure receiving ≥ 25 Gy (V25Gy) were reported. Normal tissue complication probability (NTCP) calculations were used to estimate the risk for ischemic heart disease (IHD).
Cohort-based medians of the whole heart mean dose (Dmean) for left- and right-sided tumors were 3.2 Gy and 1.3 Gy, respectively, with similar ventricular but lower atrial values. The atrial doses did not differ according to laterality of the breast tumor. In 13 patients with left-sided cancer, 5% of the heart volume was exposed to >25 Gy. The NTCP estimates were generelly low, with a maximum of 2.8%.
During adjuvant CT-based locoregional radiotherapy of women with breast cancer, the cardiac radiation doses are, at the group level, below recommended threshold values (D5% < 25 Gy), though individual patients with left-sided disease may exceed these limits.
PMCID: PMC3615991  PMID: 23589693
heart; cardiac chambers; breast cancer and radiation therapy
15.  Axillary Ultrasound for Breast Cancer Staging: an Attempt to Identify Clinical/Histopathological Factors Impacting Diagnostic Performance 
To assess the diagnostic value of pre-surgery axillary ultrasound for nodal staging in patients with primary breast cancer and to identify clinical/histopathological factors impacting diagnostic performance.
Study design:
Single-center, retrospective chart analysis. We assessed sensitivity, specificity, and positive and negative predictive value of clinical examination as well as axillary ultrasound vs. clinical examination alone. The histopathological results were the standard of truth. In addition, we analyzed clinical and histopathological factors regarding their potential to impact sensitivity and specificity.
We enrolled a total of 172 women in the study. Sensitivity of clinical examination plus ultrasound was significantly higher than for clinical examination alone (58% vs. 31.6%). Specificity and positive predictive value were similar while the negative predictive value increased from 63.4% to 73% when additionally applying ultrasound. Sensitivity and specificity of axillary ultrasound were impacted by tumor size (P = 0.2/0.04), suspicious axillary palpation (P < 0.01/<0.01), number of affected lymph nodes (P < 0.01/−) and distant metastases (P = 0.04/<0.01). All other factors had no impact.
Since pre-surgery axillary nodal staging is currently used to determine disease management, axillary ultrasound is a useful add-on tool in the diagnostic armamentarium for breast cancer patients. Tumor size, suspicious axillary palpation, number of affected lymph nodes and distant metastases increase diagnostic performance of this diagnostic modality.
PMCID: PMC3595984  PMID: 23515655
breast cancer; axillary ultrasound; staging
16.  Combining mTOR Inhibitors with Chemotherapy and Other Targeted Therapies in Advanced Breast Cancer: Rationale, Clinical Experience, and Future Directions 
Improvements in survival of patients with breast cancer have been attributed to the development of agents that target key components of dysregulated pathways involved in oncogenesis and progression of breast cancer. Aberrant mammalian target of rapamycin (mTOR) activation has been implicated in oncogenesis, angiogenesis, and the development of estrogen independence and resistance to chemotherapy in breast tumors. Several mTOR inhibitors (sirolimus, everolimus, temsirolimus, and ridaforolimus) have demonstrated antitumor activity in breast cancer cells. Combining mTOR inhibitors with endocrine therapies has demonstrated clinical antitumor activity in patients with metastatic breast cancer. In addition, mTOR inhibitor combinations with various targeted biologic agents or cytotoxic chemotherapeutic agents are being examined in more than 40 clinical trials with some early promising results. Combination therapies targeting multiple components of these central signaling pathways may be an optimal treatment strategy for patients with advanced breast cancer.
PMCID: PMC3579426  PMID: 23492649
mTOR; hormone receptor; HER2; advanced breast cancer
17.  ER, PR, HER2, Ki-67 and CK5 in Early and Late Relapsing Breast Cancer—Reduced CK5 Expression in Metastases 
Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2–), luminal B (ER or PR+HER2+), HER2 overexpressing (ER–PR–HER2+), triple-negative (ER–PR–HER2–), basal-like (ER–PR–HER2–CK5+), non-classified (ER–PR–HER2–CK5–) and luminobasal (ER or PR+CK5+). In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2– luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.
PMCID: PMC3579427  PMID: 23514931
early and late relapsing breast cancers; CK5; immunohistochemistry
18.  Adjuvant Chemotherapy for Breast Cancer in a Patient with Primary Autoimmune Neutropenia 
We report an extremely rare and complex case of a 44-year-old woman diagnosed with an early stage triple negative breast cancer in the setting of primary autoimmune neutropenia with a pre-existing severe neutropenia. This case-report demonstrates that adjuvant chemotherapy for breast cancer can be administered in a patient with severe neutropenia. The management is however complicated and requires careful monitoring of side-effects related to both chemotherapy and treatment of autoimmune neutropenia. The role of chemotherapy in the treatment of triple negative breast cancer, the approach to autoimmune neutropenia and potential interactions are reviewed. To our knowledge, this is the first case reporting on the use of chemotherapy in a patient with severe pre-existing primary autoimmune neutropenia.
PMCID: PMC3572877  PMID: 23440399
breast cancer; autoimmune neutropenia; chemotherapy
19.  Why, After Chemotherapy, is it Necessary to Assess Memory Using Translational Testing? 
As the number of cancer survivors rises, so does the importance of understanding what happens post-chemotherapy. The evidence is clear that chemotherapy affects not only cancer cells, but also healthy cells including neurons, leading to long-term cognitive dysfunction in a large portion of survivors. In order to understand the mechanism of action and in the hope of reducing the potential neurocognitive side effects of chemotherapy, pre-clinical testing should be used more effectively. However, the field is lacking translation from clinical studies to animal models. Spatial learning and memory paradigms based on the water maze, the most commonly used rodent model, are available for translational testing in humans and could overcome this weakness. There is an overwhelming need in the field to understand whether the water maze is an adequate model for post-chemotherapy impairments or whether other paradigms should be used. This is of great importance for the understanding of the mechanisms, side effects of new drugs, appropriate pharmacotherapy, and confounding factors related to chemotherapy treatment regiments. This review is very important to both basic scientists and clinicians determining how translational paradigms are critical to future cancer research, as well as what type of paradigms are appropriate in our technically advancing society.
PMCID: PMC3512448  PMID: 23226022
water maze; cancer; memory; spatial; translation
20.  Is the Improved Efficacy of Trastuzumab and Lapatinib Combination Worth the Added Toxicity? A Discussion of Current Evidence, Recommendations, and Ethical Issues Regarding Dual HER2-Targeted Therapy 
Following FDA approval of trastuzumab in 1998 and lapatinib in 2007, several clinical studies have addressed the question of whether trastuzumab and lapatinib combination therapy is better than trastuzumab alone in the metastatic breast cancer and neoadjuvant setting. In this review, updated to September 2012, we focus on the relevant clinical trials that address this question and, based on the available data, reach conclusions regarding a rational and reasonably individualized approach to the management of HER2+ breast cancer. With the FDA approval of pertuzumab in June 2012 and the likely approval of T-DM1 approaching, several ethical issues overshadow the excitement oncologists have for these new treatment options. We discuss the potential evolution of highly active anti-HER2 therapy (HAAHT) as an optimal treatment paradigm for HER2+ breast cancer. Additionally, we review lessons learned from the evolution of HAART for HIV treatment.
PMCID: PMC3512454  PMID: 23226023
HER2; breast cancer; lapatinib; trastuzumab; dual; T-DM1; pertuzumab
21.  Five-Year Follow-Up of Patients with Early Stage Breast Cancer After a Randomized Study Comparing Additional Treatment with Viscum Album (L.) Extract to Chemotherapy Alone 
Additional therapy with extracts of Viscum album [L.] (VaL) increases the quality of life of patients suffering from early stage breast cancer during chemotherapy. In the current study patients received chemotherapy, consisting of six cycles of cyclophosphamide, anthracycline, and 5-Fluoro-Uracil (CAF). Two groups also received one of two VaL extracts differing in their preparation as subcutaneous injection three times per week. A control group received CAF with no additional therapy. Six of 28 patients in one of the VaL groups and eight of 29 patients in the control group developed relapse or metastasis within 5 years. Subgroup analysis for hormone- and radiotherapy also showed no difference between groups. Additional VaL therapy during chemotherapy of early stage breast cancer patients appears not to influence the frequency of relapse or metastasis within 5 years.
PMCID: PMC3493140  PMID: 23150723
mistletoe therapy; chemotherapy; breast cancer; randomized clinical trial; disease-free survival rate; 5-year follow-up
22.  Taxanes for the Treatment of Metastatic Breast Cancer 
Taxanes have remained a cornerstone of breast cancer treatment over the past three decades, improving the lives of patients with both early- and late-stage disease. The purpose of this review is to summarize the current role of taxanes, including an albumin-bound formulation that enhances delivery of paclitaxel to tumors, in the management of metastatic breast cancer (MBC). Since the introduction of Cremophor EL-paclitaxel to the clinic in the mid-1990s, a substantial amount of investigation has gone into subjects such as formulation, dose, schedule, and taxane resistance, allowing physicians greater flexibility in treating patients with MBC. This review will also examine how the shrinking pool of taxane-naive patients, a result of the expansion of taxanes into the neoadjuvant and adjuvant settings, will respond to taxane retreatment for metastatic disease. Taxane treatment seems likely to continue to play an important role in the treatment of MBC.
PMCID: PMC3486789  PMID: 23133315
taxanes; metastatic breast cancer; paclitaxel; docetaxel; nab-paclitaxel
23.  NGlycolylGM3/VSSP Vaccine in Metastatic Breast Cancer Patients: Results of Phase I/IIa Clinical Trial 
Patients treated with vaccines based on NGlycolil gangliosides have showed benefit in progression free survival and overall survival. These molecules, which have been observed in breast cancer cells, are minimally or not expressed in normal human tissue and have been considered as antigen tumor-specific. For this reason they are very attractive to immunotherapy. A phase I/II clinical trial was carried out in metastatic breast cancer patients with the NGlycolylGM3/VSSP vaccine administered by subcutaneous route. Selecting the optimal biological doses of the vaccine in these patients was the principal objective based on the immunogenicity, efficacy and safety results. Six levels of doses of vaccine were studied. Treatment schedule consisted of five doses every two weeks and then monthly until reaching a fifteenth doses. Doses levels studied were 150, 300, 600, 900, 1200 and 1500 μg. Five patients in each level were included except at the 900 μg dose, in which ten patients were included. Immunogenicity was determined by levels of antibodies generated in patients after vaccination. The response criteria of evaluation in solid tumors (RECIST) was used to evaluate antitumoral effect. Safety was evaluated by Common Toxicity Criteria of Adverse Event (CTCAE). The vaccine administration was safe and immunogenic in all does levels. Most frequent adverse events related to vaccination were mild or moderate and were related to injection site reactions and “flu-like” symptoms. Vaccination induced specific anti-NeuGcGM3 IgM and IgG antibodies responses in all patients. Disease control (objective response or stable disease) was obtained in 72.7% of evaluated patients. Median overall survival was 15.9 months. Two patients of two different dose levels achieved overall survival values of about six years. The dose of 900 μg was selected as biological optimal dose in which overall survival was 28.5 months.
PMCID: PMC3465086  PMID: 23055739
metastatic breast cancer; clinical trial; therapeutic vaccine; ganglioside; NGcGM3
24.  Oscillation of Clock and Clock Controlled Genes Induced by Serum Shock in Human Breast Epithelial and Breast Cancer Cells: Regulation by Melatonin 
This study investigates differences in expression of clock and clock-controlled genes (CCGs) between human breast epithelial and breast cancer cells and breast tumor xenografts in circadian intact rats and examines if the pineal hormone melatonin influences clock gene and CCG expression. Oscillation of clock gene expression was not observed under standard growth conditions in vitro, however, serum shock (50% horse serum for 2 h) induced oscillation of clock gene and CCG expression in MCF-10A cells, which was repressed or disrupted in MCF-7 cells. Melatonin administration following serum shock differentially suppressed or induced clock gene (Bmal1 and Per2) and CCG expression in MCF10A and MCF-7 cells. These studies demonstrate the lack of rhythmic expression of clock genes and CCGs of cells in vitro and that transplantation of breast cancer cells as xenografts into circadian competent hosts re-establishes a circadian rhythm in the peripheral clock genes of tumor cells.
PMCID: PMC3448497  PMID: 23012497
melatonin; clock genes; circadian; serum shock; breast cancer
25.  Early Contralateral Shoulder-Arm Morbidity in Breast Cancer Patients Enrolled in a Randomized Trial of Post-Surgery Radiation Therapy 
Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity.
Patients were 118 women enrolled in a RT trial. Arm volume and shoulder mobility were assessed before and 1–3 months after RT. Correlations and linear regression were used to analyze changes affecting ipsilateral and contralateral arms, and changes affecting relative interlimb differences (RID).
Changes affecting one limb correlated with changes affecting the other limb. Arm volume between the two limbs correlated (R = 0.57). Risk factors were weight increase and axillary dissection. Contralateral and ipsilateral loss of abduction strongly correlated (R = 0.78). Changes of combined RID exceeding 10% affected the ipsilateral limb in 25% of patients, and the contralateral limb in 18%. Aromatase inhibitor therapy was significantly associated with contralateral loss of abduction.
High incidence of early contralateral arm morbidity warrants further investigations.
PMCID: PMC3418149  PMID: 22904635
early breast cancer; short-course radiation therapy; image-guided radiation therapy; shoulder/arm morbidity; breast cancer-related lymphedema

Results 1-25 (54)