Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. Patients and Methods Patients were randomly assigned to first-or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand-foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). Conclusion Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer

BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.)

PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients

OBJECTIVES: The phosphatidylinositol 3-kinase/AKT axis is an important cell-signaling pathway that mediates cell proliferation and survival, two biological processes that regulate malignant cell growth. The phosphatidylinositol 3-kinase CA gene encodes the p110 alpha subunit of the phosphatidylinositol 3-kinase protein. There are phosphatidylinositol 3-kinase CA mutations in several types of human tumors, and they are frequently observed in breast cancer. However, these mutations have not been investigated in Brazilian breast cancer patients. METHODS: PCR-SSCP and direct DNA sequencing were performed to identify phosphatidylinositol 3-kinaseCA exon 9 and exon 20 mutations in 86 patients with sporadic breast cancer. The relationships between PIK3CA mutations and patient clinicopathological characteristics and survival were analyzed. The presence of the TP53 mutation was also examined. RESULTS: Twenty-three (27%) of the 86 primary breast tumors contained PIK3CA mutations. In exons 9 and 20, we identified the hotspot mutations E542K, E545K, and H1047R, and we identified two new missense mutations (I1022V and L1028S) and one nonsense (R992X) mutation. Phosphatidylinositol 3-kinase CA exon 20 mutations were associated with poor overall survival and TP53 gene mutations. CONCLUSIONS: Phosphatidylinositol 3-kinase CA mutations are common in tumors in Brazilian breast cancer patients, and phosphatidylinositol 3-kinase CA and TP53 mutations are not mutually exclusive. Phosphatidylinositol 3-kinase CA exon 20 mutations are associated with poor survival, and they may be useful biomarkers for identifying breast cancer patients with aggressive tumors and for predicting the response to treatment with PI3K pathway inhibitors.

Safety and efficacy of gemcitabine plus cisplatin combination in pretreated metastatic breast cancer patients

Metastatic breast cancers (MBC) previously treated with anthracyclines (A) and taxanes (T) have a complicated management. Gemcitabine (G)-cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and are considered as another option for patients with important symptoms and aggressive visceral disease. We analyzed the safety and efficacy of GC in AT-pretreated MBC, as well as overall survival (OS) and time to progression (TTP). Forty-nine subjects received IV G 750 mg/m(2) and C 30 mg/m(2), both d1 and d8 every 3 weeks. Response evaluation was performed every second cycle and in the end of treatment. GC protocol was the first-line palliative chemotherapy in half of the cases, and median number of cycles/patient were 4(2-12). Lung (75.5%) was the most frequent site of metastasis. Most of the patients related clinical improvement with chemotherapy with minimal/mild tolerable collateral effects in 85.7% of cases. Following 34 months, mean OS/TTP was 13.12/6.6 months. Objective-responded patients (40.3%) were statistically associated with the improvement in symptoms after CT (P < 0.01), and OS was directly correlated with chemotherapy response (P < 0.01). HER-2 overexpression was a prognostic factor with reduced OS (P = 0.01). GC protocol was effective and tolerable in objective-responded patients.

Coordinated expression of oestrogen and androgen receptors in HER2-positive breast carcinomas: impact on proliferative activity

Aims Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are aggressive neoplasms associated with a variable response to systemic therapies. Therefore, the identification of biomarkers to better characterise this heterogeneity would improve treatment efficacy. The aim of this study was to evaluate the influence of androgen receptor (AR) and oestrogen receptor (ER) on clinicopathological features in a series of HER2-positive breast carcinomas. Methods A total of 104 carcinomas were selected and reviewed. Immunohistochemical studies for ER, progesterone receptor and Ki-67 were analysed on tumour whole histological sections. AR expression was analysed on samples represented on tissue microarrays. According to steroid receptor expression, cases were classified into three groups: AR positive/ER positive (48 cases), AR positive/ER negative (41 cases) and AR negative/ER negative (13 cases). Results AR-positive tumours corresponded to 89 (85.6%) of 104 carcinomas. AR-positive carcinomas were associated with a higher frequency of ER and progesterone receptor co-expression and lower proliferative activity determined by the expression of Ki-67. AR-negative carcinomas were more often high grade. The group of AR-positive/ER-negative carcinomas was associated with the highest frequency of apocrine morphological features. The group of AR-negative/ER-negative carcinomas was associated with the highest proliferative activity and the highest frequency of high histological and nuclear grade. The lowest frequency of high-grade tumours and the lowest proliferative activity were seen among tumours with expression of both receptors. Conclusions These results suggest that co-expression of AR and ER can provide a protective effect based on phenotypical presentation of HER2-positive carcinomas. Furthermore, lack of both steroid hormone receptors characterises the most aggressive phenotype.

Study of electron densities of normal and neoplastic human breast tissues by Compton scattering using synchrotron radiation

Electron densities of 33 samples of normal (adipose and fibroglangular) and neoplastic (benign and malignant) human breast tissues were determined through Compton scattering data using a mono-chromatic synchrotron radiation source and an energy dispersive detector. The area of Compton peaks was used to determine the electron densities of the samples. Adipose tissue exhibits the lowest values of electron density whereas malignant tissue the highest. The relationship with their histology was discussed. Comparison with previous results showed differences smaller than 4%. (C) 2012 Elsevier Ltd. All rights reserved.

Immunohistochemical features of claudin-low intrinsic subtype in metaplastic breast carcinomas

Purpose: The claudin-low molecular subtype of breast cancer includes triple negative invasive carcinomas, with a high frequency of metaplastic and medullary features. The aim of this study was to evaluate the immunohistochemistry expression of claudins in a series of metaplastic breast carcinomas. We also assessed other claudin-low features, such as the cancer stem cell-like and epithelial-to-mesenchymal transition phenotypes. Results: The majority of the cases showed weak or negative staining for membrane claudins expression. We found 76.9% (10/13) low expressing cases for claudin-1, 84.6% (11/13) for claudin-3 and claudin-4, and 92.3% (12/13) for claudin-7. Regarding the cancer stem cell marker ALDH1, 30.8% (4/13) showed positive staining. We also showed that the majority of the cases presented a CD44(+)CD24(-/low) phenotype, positivity for vimentin and lack of E-cadherin expression. Interestingly, these claudin-low molecular features were specific of the mesenchymal component of metaplastic breast carcinomas, since its frequency was very low in other breast cancer molecular subtypes, as luminal, HER2-overexpressing and non-metaplastic triple negative tumors. Conclusions: The negative/low expression of claudins and E-cadherin, high levels of vimentin, and the breast cancer stem cell phenotype suggests that metaplastic breast carcinomas have similar features to the ones included in the claudin-low molecular subtype, specially their mesenchymal components. (C) 2012 Elsevier Ltd. All rights reserved.

Germline DNA copy number variation in familial and early-onset breast cancer

Introduction: Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease." Methods: Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations. Results: The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer. Conclusions: This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.

Do the physical discomforts from breast cancer treatments affect the sexuality of women who underwent mastectomy?

The objective of this integrative review is to analyze the scientific production addressing the sexuality of women with breast cancer following mastectomy, focused on the effects that the physical discomfort due to cancer treatments have on their sex life. The search included articles published in the period between 2000 and 2009 on the MEDLINE, LILACS and PsycINFO databases, using the following descriptors: mastectomy, breast neoplasms, sexuality, sexual behavior, amputation, psychosexual development, and marital relations. Nine articles were selected, which addressed the effects of the physical discomfort from cancer treatments on the patients' sexuality. The findings revealed that, even when the patient's sex life is intense and fulfilling before the disease, factors such as stress, pain, fatigue, insult to body image, and low self-esteem due to the treatments may alter the sexual functioning of the affected woman. Healthcare professionals must be sensitized in order to welcome and include the topic in policies as well as in preventive, diagnostic, and therapeutic strategies.

Breast Milk and Glucose for Pain Relief in Preterm Infants: A Noninferiority Randomized Controlled Trial

OBJECTIVE: The study goal was to compare the efficacy of expressed breast milk (EBM) versus 25% glucose on pain responses of late preterm infants during heel lancing. METHODS: In a noninferiority randomized controlled trial, a total of 113 newborns were randomized to receive EBM (experimental group [EG]) or 25% glucose (control group [CG]) before undergoing heel lancing. The primary outcome was pain intensity (Premature Infant Pain Profile [PIPP]) and a 10% noninferiority margin was established. Secondary outcomes were incidence of cry and percentage of time spent crying and adverse events. Intention-to-treat (ITT) analysis was used. RESULTS: Groups were similar regarding demographics and clinical characteristics, except for birth weight and weight at data collection day. There were lower pain scores in the CG over 3 minutes after lancing (P<.001). A higher number of infants in the CG had PIPP scores indicative of minimal pain or absence of pain (P = .002 and P = .003 on ITT analysis) at 30 seconds after lancing, and the mean difference in PIPP scores was 3 (95% confidence interval: 1.507-4.483). Lower incidence of cry (P = .001) and shorter duration of crying (P = .014) were observed for CG. Adverse events were benign and self-limited, and there was no significant difference between groups (P = .736 and P = .637 on ITT analysis). CONCLUSIONS: Results based on PIPP scores and crying time indicate poorer effects of EBM compared with 25% glucose during heel lancing. Additional studies exploring the vol and administration of EBM and its combination with other strategies such as skin-to-skin contact and sucking are necessary. Pediatrics 2012;129:664-670

Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines

The recently emerged concept of cancer stem cell (CSC) has led to a new hypothesis on the basis for tumor progression. Basically, the CSC theory hypothesizes the presence of a hierarchically organized and relatively rare cell population, which is responsible for tumor initiation, self-renewal, and maintenance, in addition to accumulation of mutation and resistance to chemotherapy. CSCs have recently been described in breast cancer. Different genetic markers have been used to isolate breast CSCs, none of which have been correlated with the tumorigenicity or metastatic potential of the cells, limiting their precise characterization and clinical application in the development of therapeutic protocols. Here, we sought for subpopulations of CSCs by analyzing 10 judiciously chosen stem cell markers in a normal breast cell line (MCF10-A) and in four human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435, and Hs578-T) displaying different degrees of metastatic and invasiveness potential. We were able to identify two markers, which are differentially expressed in nontumorigenic versus tumor cells. The CD90 marker was highly expressed in the malignant cell lines. Interestingly, the CD14 molecule displayed higher expression levels in the nontumorigenic cell line. Therefore, we demonstrated that these two markers, which are more commonly used to isolate and characterize stem cells, are differentially expressed in breast tumor cells, when compared with nontumorigenic breast cells. (C) 2012 International Society for Advancement of Cytometry

Compton scattering spectrum as a source of information of normal and neoplastic breast tissues' composition

In this work we measured X-ray scatter spectra from normal and neoplastic breast tissues using photon energy of 17.44 key and a scattering angle of 90 degrees, in order to study the shape (FWHM) of the Compton peaks. The obtained results for FWHM were discussed in terms of composition and histological characteristics of each tissue type. The statistical analysis shows that the distribution of FWHM of normal adipose breast tissue clearly differs from all other investigated tissues. Comparison between experimental values of FWHM and effective atomic number revealed a strong correlation between them, showing that the FWHM values can be used to provide information about elemental composition of the tissues. (C) 2012 Elsevier Ltd. All rights reserved.

Angiotensin II Facilitates Breast Cancer Cell Migration and Metastasis

Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN) were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pretreatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

Minimally invasive mastectomy: minimal incisions for better aesthetic quality of breast reconstruction

Background: Women with a family history of breast cancer who develop this disease are confronted with important situations regarding the increased risk for development of a second cancer in the contralateral breast. Prophylactic contralateral mastectomy (PCM) reduces by approximately 95% the risk for contralateral breast cancer. In spite of an increase in indications for PCM, the technical difficulties are many regarding the accomplishment of these procedures. The aim of this study is to describe the technique of mastectomy with preservation of the nipple-areola complex and a small incision, reducing surgical difficulties and complications attributed to this technique, thus allowing better aesthetic results in breast reconstruction. Methods: Forty-six patients with indications for PCM (28 bilateral) were submitted to minimally invasive mastectomy from March 2005 to November 2007. A small incision in the superior pole of the areola, sufficient to pass a liposuction 4 mm cannula is made. With the help of this cannula, detachment of the skin from the gland tissue is performed. Then a 3.5 to 4.5-cm long incision in the inframammary fold is made. Glandular detachment is completed using cautery in the sub,glandular portion and scissors in the upper breast portion cutting the restraints left by the cannula. The mammary gland tissue is removed through this incision. Results: Seventy-four breasts were operated on. The resected breast mass ranged from 285 g to 475 g. All 43 patients were reconstructed with prostheses. There was no necrosis of the nipple-areola complex or of the skin. Conclusions: This technique is an option for cases of patients with indications for PCM.

Down-regulation of ANAPC13 and CLTCL1: Early Events in the Progression of Preinvasive Ductal Carcinoma of the Breast

Alterations in the gene expression profile in epithelial cells during breast ductal carcinoma (DC) progression have been shown to occur mainly between pure ductal carcinoma in situ (DCIS) to the in situ component of a lesion with coexisting invasive ductal carcinoma (DCIS-IDC) implying that the molecular program for invasion is already established in the preinvasive lesion. For assessing early molecular alterations in epithelial cells that trigger tumorigenesis and testing them as prognostic markers for breast ductal carcinoma progression, we analyzed, by reverse transcription-quantitative polymerase chain reaction, eight genes previously identified as differentially expressed between epithelial tumor cells populations captured from preinvasive lesions with distinct malignant potential, pure DCIS and the in situ component of DCIS-IDC. ANAPC13 and CLTCL1 down-regulation revealed to be early events of DC progression that anticipated the invasiveness manifestation. Further down-regulation of ANAPC13 also occurred after invasion appearance and the presence of the protein in invasive tumor samples was associated with higher rates of overall and disease-free survival in breast cancer patients. Furthermore, tumors with low levels of ANAPC13 displayed increased copy number alterations, with significant gains at 1q (1q23.1-1q32.1), 8q, and 17q (17q24.2), regions that display common imbalances in breast tumors, suggesting that down-regulation of ANAPC13 contributes to genomic instability in this disease.