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1.  Circulating tumor cells in newly diagnosed inflammatory breast cancer 
Introduction
Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC.
Methods
This retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy.
Results
The proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P = 0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P = 0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR) = 0.60; P = 0.02) and overall survival (HR = 0.59; P = 0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR = 0.66; 95% confidence interval (CI), 0.31 to 1.39; P = 0.29) and OS (HR = 0.54; 95% CI, 0.24 to 1.26; P = 0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage.
Conclusions
CTCs can be detected in a large proportion of patients with newly diagnosed IBC and are a strong predictor of worse prognosis in patients with newly diagnosed IBC.
doi:10.1186/s13058-014-0507-6
PMCID: PMC4318180  PMID: 25572591
2.  Simvastatin Radiosensitizes Differentiated and Stem-Like Breast Cancer Cell Lines and Is Associated With Improved Local Control in Inflammatory Breast Cancer Patients Treated With Postmastectomy Radiation 
The authors studied the radiosensitization of breast cancer stem-like cells in vitro after treatment with the most commonly used statin, simvastatin, and examined the influence on local control after postmastectomy radiation among inflammatory breast cancer patients taking statins. This work provides new insight on combination regimens for breast cancer treatment and radiosensitization of this clinically radioresistant disease.
Reported rates of local failure after adjuvant radiation for women with inflammatory breast cancer (IBC) and triple-negative non-IBC are higher than those of women with receptor-expressing non-IBC. These high rates of locoregional recurrence are potentially influenced by the contribution of radioresistant cancer stem cells to these cancers. Statins have been shown to target stem cells and improve disease-free survival among IBC patients. We examined simvastatin radiosensitization of multiple subtypes of breast cancer cell lines in vitro in monolayer and mammosphere-based clonogenic assays and examined the therapeutic benefit of statin use on local control after postmastectomy radiation (PMRT) among IBC patients. We found that simvastatin radiosensitizes mammosphere-initiating cells (MICs) of IBC cell lines (MDA-IBC3, SUM149, SUM190) and of the metaplastic, non-IBC triple-negative receptor cell line (SUM159). However, simvastatin radioprotects MICs of non-IBC cell lines MCF-7 and SKBR3. In a retrospective clinical study of 519 IBC patients treated with PMRT, 53 patients used a statin. On univariate analysis, actuarial 3-year local recurrence-free survival (LRFS) was higher among statin users, and on multivariate analysis, triple negative breast cancer, absence of lymphatic invasion, neoadjuvant pathological tumor response to preoperative chemotherapy, and statin use were independently associated with higher LRFS. In conclusion, patients with IBC and triple-negative non-IBC breast cancer have the highest rates of local failure, and there are no available known radiosensitizers. We report significant improvement in local control after PMRT among statin users with IBC and significant radiosensitization across triple-negative and IBC cell lines of multiple subtypes using simvastatin. These data suggest that simvastatin should be justified as a radiosensitizing agent by a prospective clinical trial.
doi:10.5966/sctm.2013-0204
PMCID: PMC4073823  PMID: 24833589
Statins; Inflammatory breast cancer; Local recurrence; Radiation
3.  Primary Tumor Resection as a Component of Multimodality Treatment May Improve Local Control and Survival in Stage IV Inflammatory Breast Cancer 
Cancer  2014;120(9):1319-1328.
Background
The benefit of primary tumor resection for metastatic inflammatory breast cancer (IBC) patients is unknown.
Methods
We reviewed 172 cases of metastatic IBC. All received chemotherapy with or without radiotherapy and/or surgery. Patients were classified as responders or non-responders to chemotherapy. Five-year overall (OS) and distant progression-free survival (DPFS) and local control at last follow-up were evaluated.
Results
Seventy-nine (46%) patients underwent surgery. OS and DPFS were better with surgery vs no surgery (47% vs 10%, respectively, p<0.001 and 30% vs 3%, p<0.001). Surgery plus radiotherapy was associated with better survival compared to treatment with surgery or radiotherapy alone (OS: 50% vs 25% vs 14%, respectively, DPFS: 32% vs 18% vs 15%, p<0.0001 for both). Surgery was associated with better survival for both responders (surgery vs no surgery OS: 49% vs 23%, p<0.0001, DPFS: 31% vs 8%, p<0.0001) and non-responders (surgery vs no surgery OS: 40% vs 6%, p<0.0001, DPFS: 30% vs 0, p<0.0001). On multivariate analysis, treatment with surgery plus radiotherapy and response to chemotherapy were significant predictors of better OS and DPFS. Local control at last follow-up was 4-fold more likely in patients who underwent surgery with or without radiotherapy compared to patients who received chemotherapy alone (81% vs 18%, p<.0001). Surgery and response to chemotherapy independently predicted local control on multivariate analysis.
Conclusion
This study demonstrates that for select patients with metastatic IBC, multimodality treatment including primary tumor resection may result in better local control and survival. A randomized trial is needed to validate these findings.
doi:10.1002/cncr.28550
PMCID: PMC4278570  PMID: 24510381
breast cancer; inflammatory breast cancer; survival; local control; multimodality treatment; combined modality therapy; metastatic breast cancer
4.  Breast Cancer Biomarkers: Utility in Clinical Practice 
Current breast cancer reports  2013;5(4):10.1007/s12609-013-0125-9.
Breast cancer is a heterogeneous disease. For the past decades, new technical tools have been developed for biomarkers at the DNA, RNA and protein levels to better understand the biology of breast cancer. This progress is essential to classify the disease into clinically relevant subtypes, which may lead to new therapeutic opportunities. Novel biomarker development is paramount to deliver personalized cancer therapies. Further, tumor evolution, being natural or under treatment pressure, should be monitored and “liquid biopsies” by detecting circulating tumor cells or circulating free tumor DNA in blood samples will become an important option. This paper reviews the new generation of biomarkers and the current evidence to demonstrate their analytical validity, clinical validity and clinical utility.
doi:10.1007/s12609-013-0125-9
PMCID: PMC3882751  PMID: 24416469
Biomarkers; Breast cancer; Prognosis; Prediction; Clinical utility
5.  FLUDARABINE-MELPHALAN AS PREPARATIVE REGIMEN FOR REDUCED-INTENSITY ALLOGENEIC STEM CELL TRANSPLANTATION IN RELAPSED AND REFRACTORY HODGKIN’S LYMPHOMA: THE UPDATED M.D. ANDERSON CANCER CENTER EXPERIENCE 
Haematologica  2008;93(2):257-264.
Background and Objective
The role of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) in relapsed/refractory (R/R) Hodgkin’s lymphoma (HL) remains poorly defined. We hereby present an update of our single-center experience with fludarabine-melphalan (FM) as preparative regimen.
Design and Methods
Fifty-eight patients with R/R HL underwent RIC and allo-SCT from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). Forty-eight (83%) had received a prior autologous SCT. Disease status at transplant was refractory relapse (n=28) or sensitive relapse (n=30).
Results
Cumulative day 100 and 2-year transplant-related mortality (TRM) were 7% and 15%, respectively (day 100 TRM MRD vs. MUD 8% vs. 6%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) GVHD (first 100 days) was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic GVHD at any time was 73% (MRD vs. MUD 57% vs. 85%, p=0.006). Projected 2-year overall (OS) and progression-free (PFS) survival are 64% (49–76) and 32% (20–45), with 2-year disease progression/relapse (PD) at 55% (43–70). There was no statistically significant difference between MRD and MUD transplants in OS, PFS and PD. There was a trend for the response status pretransplant to favorably impact PFS (p=0.07) and PD (p=0.049), but not OS (p=0.4).
Interpretation and Conclusions
FM as preparative regimen for RIC allo-SCT in R/R HL is associated with a significant reduction in TRM, with comparable results in MRD and MUD allografts. Optimizing pretransplant response status may improve patient outcome.
doi:10.3324/haematol.11828
PMCID: PMC4238917  PMID: 18223284
Hodgkin’s lymphoma; Hodgkin’s disease; allogeneic stem cell transplantation; bone marrow transplantation; peripheral blood stem cell transplantation
6.  Outcomes after Multidisciplinary Treatment of Inflammatory Breast Cancer in the Era of Neoadjuvant HER2-Directed Therapy 
American journal of clinical oncology  2013;10.1097/COC.0b013e3182937921.
Objectives
We previously reported survival trends among patients with inflammatory breast cancer (IBC) over a 30-year-period before 2005. Here we evaluated survival outcomes for women with IBC diagnosed before or after October 2006, in the era of HER2-directed therapy and after opening a dedicated multidisciplinary IBC clinic.
Methods
We retrospectively identified and reviewed 260 patients with newly diagnosed IBC without distant metastasis, 168 treated before October 2006 and 92 treated afterward. Most patients received anthracycline and taxane-based neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Survival outcomes were compared between the two groups.
Results
Median follow-up time was 29 months for the entire cohort (39 mo and 24 mo for patients treated before and after October 2006). Patients treated more recently were more likely to have received neoadjuvant HER2-directed therapy for HER2-positive tumors (100% vs. 54%, P<0.001). No differences were found in receipt of hormone therapy. Three-year overall survival (OS) rates were 63% for those treated before and 82% for those treated after October 2006 (log-rank P=0.02). Univariate Cox analysis demonstrated better OS among patients treated after October 2006 than among those treated beforehand (hazard ratio [HR] 0.5, 95% confidence Interval [CI] 0.34-0.94); a trend toward improved survival was noted in the multivariate analysis (HR=0.47, 95% CI 0.19-1.16, P=0.10). Significant factors in the multivariate model included HER2-directed therapy (HR=0.38, 95% CI 0.17-0.84, P=0.02) and estrogen receptor positivity (HR=0.32, 95% CI 0.14-0.74, P=0.01).
Conclusions
Survival improved in the context of the IBC clinic and prompt initiation of neoadjuvant Her-2 directed therapeutics.
doi:10.1097/COC.0b013e3182937921
PMCID: PMC3880388  PMID: 23648437
Inflammatory breast cancer; survival; multidisciplinary clinic; targeted therapy
7.  A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells 
Cancer hallmarks  2013;1(2-3):59-66.
A hallmark of metastatic cancer cells is their invasion through the basal membrane and endothelial layer, which requires a highly elastic cytoskeleton and nucleus. Therefore, cellular deformability can serve as a universal biophysical marker for detecting a tumor’s propensity for invasion, migration, and metastasis. In this review, we define the importance of the biophysical features of cancer cells in tumor metastasis and summarize the state-of-the-art technology for the study of cell biomechanics. This review will serve as a brief introduction to the interdisciplinary character of cancer cell biophysics for cancer biologists, physicists, and engineers.
doi:10.1166/ch.2013.1010
PMCID: PMC4189832  PMID: 25309822
Cancer metastasis; Biophysics; Cell biomechanics; Microfluidics; Mechanobiology
8.  Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes 
Purpose
The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and Bauer et al is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathological complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.
Experimental Design
We revalidated the Lehmann and Bauer et al. experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 TNBC patients with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathological response data. We classified the TNBC samples by subtype, then correlated subtype and pCR status using Fisher’s exact test and a logistic regression model. We also assessed survival and compared the subtypes to PAM50 intrinsic subtypes and residual cancer burden (RCB) index.
Results
TNBC subtype and pCR status were significantly associated (P=0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor (LAR) had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P=0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs non basal-like).
Conclusions
Classifying TNBC by 7 subtypes predicts high vs. low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for TNBC patients.
doi:10.1158/1078-0432.CCR-13-0799
PMCID: PMC3813597  PMID: 23948975
Triple negative breast cancer; Molecular subtypes; Predictive factor; Pathological complete response; mRNA array analysis
9.  Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination 
Introduction
Traditional factors currently used for prognostic stratification do not always adequately predict treatment response and disease evolution in advanced breast cancer patients. Therefore, the use of blood-based markers, such as circulating tumor cells (CTCs), represents a promising complementary strategy for disease monitoring. In this retrospective study, we explored the role of CTC counts as predictors of disease evolution in breast cancer patients with limited metastatic dissemination.
Methods
A total of 492 advanced breast cancer patients who had a CTC count assessed by CellSearch prior to starting a new line of systemic therapy were eligible for this analysis. Using the threshold of 5 CTCs/7.5 ml of blood, pretreatment CTC counts were correlated in the overall population with metastatic site distribution, evaluated at baseline and at the time of treatment failure, using Fisher’s exact test. Time to visceral progression and time to the development of new metastatic lesions and sites were estimated in patients with nonvisceral metastases and with single-site metastatic disease, respectively, by the Kaplan-Meier method. Survival times were compared between groups according to pretreatment CTC count by logrank test.
Results
In the overall population, a pretreatment level ≥5 CTCs/7.5 ml was associated with an increased baseline number of metastatic sites compared with <5 CTCs/7.5 ml (P = 0.0077). At the time of treatment failure, patients with ≥5 CTCs/7.5 ml more frequently developed new metastatic lesions and sites compared with those with <5 CTCs/7.5 ml (development of new lesions: P = 0.0002; development of new sites: P = 0.0031). Among patients with disease originally confined to nonvisceral sites, ≥5 CTCs/7.5 ml was associated with remarkably shorter time to visceral metastases (P = 0.0021) and overall survival (P = 0.0006) compared with <5 CTCs/7.5 ml. In patients with single-site metastatic disease, ≥5 CTCs/7.5 ml was associated with a significant reduction of the time to development of new metastatic sites (P = 0.0051) and new lesions (P = 0.0002) and with worse overall survival (P = 0.0101).
Conclusion
Our results suggest that baseline CTC counts can be used as an early predictor of metastatic potential in breast cancer patients with limited metastatic dissemination.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0440-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0440-8
PMCID: PMC4303121  PMID: 25223629
10.  Different Biological Processes are Associated with the Different Molecular Subtypes of Inflammatory Breast Cancer 
Purpose
The goal of this study was to determine whether gene expression differences exist between inflammatory breast cancers (IBC) and stage-matched non-IBC patiens stratified by hormone receptor and HER2 status.
Experimental Design
We used Affymetrix GeneChips to analyze 82 tumor samples (25 T4d, 25 patients and 57, T4a-c patients) of newly diagnosed breast cancers. Genes that were differentially expressed between the IBC and non-IBC specimens were identified using the t-test, and differential expression of gene sets was assessed using gene set analysis. Three distinct clinical subtypes of IBC and non-IBC were compared: ER-positive/HER2-normal, HER2-amplified, and ER-negative/HER2-normal.
Results
When we compared expression data from all IBC with all non-IBC, we found no significant differences after adjusting for multiple testing. When IBC and non-IBC tumors were compared by clinical subtype, however, significant differences emerged. Complement and immune system-related pathways were overexpressed in ER-positive/HER2-normal IBC. Protein translation and mTOR signaling were overexpressed in HER2-amplified IBC. Apoptosis-, neural-, and lipid metabolism-related pathways were overexpressed in ER-negative/HER2-normal IBC compared with non-IBC of the same receptor phenotype. In this stage-matched case-control study, the survival curves of patients with IBC and non-IBC were similar for all three clinical subtypes.
Conclusions
IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC.
doi:10.1007/s10549-010-1280-6
PMCID: PMC4109066  PMID: 21153052
Inflammatory breast cancer; receptor subtypes; cDNA microarray; Gene set analysis
11.  Ink4a/Arf−/− and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f− quiescent cells 
Oncogene  2013;33(4):440-448.
Intratumoral heterogeneity within individual breast tumors is a well-known phenomenon that may contribute to drug resistance. This heterogeneity is dependent on several factors, such as types of oncogenic drivers and tumor precursor cells. The purpose of our study was to engineer a mouse mammary tumor model with intratumoral heterogeneity by using defined genetic perturbations. To achieve this, we used mice with knockout (−/−) of Ink4a/Arf, a tumor suppressor locus; these mice are known to be susceptible to non-mammary tumors such as fibrosarcoma. To induce mammary tumors, we retrovirally introduced an oncogene, HRAS(G12V), into Ink4a/Arf−/− mammary cells in vitro, and those cells were inoculated into syngeneic mice mammary fat pads. We observed 100% tumorigenesis. The tumors formed were negative for estrogen receptor, progesterone receptor, and HER2. Further, they had pathological features similar to those of human triple-negative breast cancer (e.g. pushing borders, central necrosis). The tumors were found to be heterogeneous and included two subpopulations: CD49f− quiescent cells and CD49f+ cells. Contrary to our expectation, CD49f− quiescent cells had high tumor-initiating potential and CD49f+ cells had relatively low tumor-initiating potential. Gene expression analysis revealed that CD49f− quiescent cells overexpressed epithelial-to-mesenchymal transition-driving genes, reminiscent of tumor-initiating cells and claudin-low breast cancer. Our animal model with intratumoral heterogeneity, derived from defined genetic perturbations, allows us to test novel molecular targeted drugs in a setting that mimics the intratumoral heterogeneity of human triple-negative breast cancer.
doi:10.1038/onc.2012.609
PMCID: PMC3957346  PMID: 23376849
Ink4a/Arf; HRAS(G12V); Triple negative breast cancer; Intratumoral heterogeneity; Tumor-initiating cell
12.  Bisphosphorylated PEA-15 Sensitizes Ovarian Cancer Cells to Paclitaxel by Impairing the Microtubule-Destabilizing Effect of SCLIP 
Molecular cancer therapeutics  2013;12(6):1099-1111.
Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. PEA-15's functions are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis that PEA-15 phosphorylated at both Ser104 and Ser116 (pPEA-15) sensitizes ovarian cancer cells to paclitaxel. We first found that knockdown of PEA-15 in PEA-15-high-expressing HEY and OVTOKO ovarian cancer cells resulted in paclitaxel resistance, whereas re-expression of PEA-15 in these cells led to paclitaxel sensitization. We next found that SKOV3.ip1-DD cells (expressing phosphomimetic PEA-15) were more sensitive to paclitaxel than SKOV3.ip1-AA cells (expressing nonphosphorylatable PEA-15). Compared to SKOV3.ip1-vector and SKOV3.ip1-AA cells, SKOV3.ip1-DD cells displayed reduced cell viability, inhibited anchorage-independent growth, and augmented apoptosis when treated with paclitaxel. Furthermore, HEY and OVTOKO cells displayed enhanced paclitaxel sensitivity when transiently overexpressing phosphomimetic PEA-15 and reduced paclitaxel sensitivity when transiently overexpressing nonphosphorylatable PEA-15. These results indicate that pPEA-15 sensitizes ovarian cancer cells to paclitaxel. cDNA microarray analysis suggested that SCLIP (SCG10-like protein), a microtubule (MT)-destabilizing protein, is involved in pPEA-15-mediated chemosensitization. We found that reduced expression and possibly posttranslational modification of SCLIP following paclitaxel treatment impaired SCLIP's MT-destabilizing effect, thereby promoting induction of mitotic arrest and apoptosis by paclitaxel. Our findings highlight the importance of pPEA-15 as a promising target for improving the efficacy of paclitaxel-based therapy in ovarian cancer.
doi:10.1158/1535-7163.MCT-12-0737
PMCID: PMC3681833  PMID: 23543364
PEA-15; SCLIP; paclitaxel; chemosensitivity; ovarian cancer
13.  Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates 
BMC Biology  2014;12:40.
Background
Various senses and sensory nerve architectures of animals have evolved during adaptation to exploit diverse environments. In craniates, the trunk sensory system has evolved from simple mechanosensory neurons inside the spinal cord (intramedullary), called Rohon-Beard (RB) cells, to multimodal sensory neurons of dorsal root ganglia (DRG) outside the spinal cord (extramedullary). The fish and amphibian trunk sensory systems switch from RB cells to DRG during development, while amniotes rely exclusively on the DRG system. The mechanisms underlying the ontogenic switching and its link to phylogenetic transition remain unknown.
Results
In Xenopus, Six1 overexpression promoted precocious apoptosis of RB cells and emergence of extramedullary sensory neurons, whereas Six1 knockdown delayed the reduction in RB cell number. Genetic ablation of Six1 and Six4 in mice led to the appearance of intramedullary sensory neuron-like cells as a result of medial migration of neural crest cells into the spinal cord and production of immature DRG neurons and fused DRG. Restoration of SIX1 expression in the neural crest-linage partially rescued the phenotype, indicating the cell autonomous requirements of SIX1 for normal extramedullary sensory neurogenesis. Mouse Six1 enhancer that mediates the expression in DRG neurons activated transcription in Xenopus RB cells earlier than endogenous six1 expression, suggesting earlier onset of mouse SIX1 expression than Xenopus during sensory development.
Conclusions
The results indicated the critical role of Six1 in transition of RB cells to DRG neurons during Xenopus development and establishment of exclusive DRG system of mice. The study provided evidence that early appearance of SIX1 expression, which correlated with mouse Six1 enhancer, is essential for the formation of DRG-dominant system in mice, suggesting that heterochronic changes in Six1 enhancer sequence play an important role in alteration of trunk sensory architecture and contribute to the evolution of the trunk sensory system.
doi:10.1186/1741-7007-12-40
PMCID: PMC4084797  PMID: 24885223
Dorsal root ganglia; Enhancer; Evolution; Neural crest cell; Rohon-Beard cell; Sensory neuron; Six genes
14.  Genomic and Expression Analysis of Microdissected Inflammatory Breast Cancer 
Purpose
Inflammatory breast cancer (IBC) is a unique clinical entity characterized by rapid onset of erythema and swelling of the breast often without an obvious breast mass. Many studies have examined and compared gene expression between IBC and non-IBC (nIBC), repeatedly finding clusters associated with receptor subtype, but no consistent gene signature associated with IBC has been validated. Here we compared microdissected IBC tumor cells to microdissected nIBC tumor cells matched based on estrogen and HER-2/neu receptor status.
Methods
Gene expression analysis and comparative genomic hybridization were performed. An IBC gene set and genomic set were identified using a training set and validated on the remaining data. The IBC gene set was further tested using data from IBC consortium samples and publically available data.
Results
Receptor driven clusters were identified in IBC; however no IBC-specific gene signature was identified. Fifteen genes were correlated between increased genomic copy number and gene overexpression data. An expression-guided gene set upregulated in the IBC training set clustered the validation set into two clusters independent of receptor subtype but segregated only 75% of samples in each group into IBC or nIBC. In a larger consortium cohort and in published data the gene set failed to optimally enrich for IBC samples. However, this gene set had a high negative predictive value for excluding the diagnosis of IBC in publically available data (100%). An IBC enriched genomic data set accurately identified 10/16 cases in the validation data set.
Conclusions
Even with microdissection, no IBC-specific gene signature distinguishes IBC from nIBC. Using microdissected data, a validated gene set was identified that is associated with IBC tumor cells. IBC comparative genomic hybridization data are presented, but a validated genomic data set that identifies IBC is not demonstrated.
doi:10.1007/s10549-013-2501-6
PMCID: PMC3677826  PMID: 23568481
Inflammatory breast cancer; CGH; array; gene signature
15.  Predictors of durable no evidence of disease status in de novo metastatic inflammatory breast cancer patients treated with neoadjuvant chemotherapy and post-mastectomy radiation 
SpringerPlus  2014;3:166.
Introduction
Definitive locoregional therapy including surgery and post-mastectomy radiation therapy (PMRT) has been offered to select IBC patients with de novo metastatic disease. Herein we examined predictive factors for progression-free survival after comprehensive PMRT radiation +/- locoregional treatment of metastatic sites.
Methods
Charts of T4d, any N, M1 (de novo) patients who completed PMRT to ≥ 50 Gy from 2006–2011 were reviewed. Patients who received doses <50Gy to the primary site, received radiation at another facility or were treated pre-operatively were excluded. The remaining 36 patients formed the study cohort. Progression-free survival post-PMRT (PFSx) was assessed from the last day of radiation. Median dose to primary fields was 51 Gy. Boost doses ranged from 6–16 Gy.
Results
Median age at diagnosis was 54 (range 33–70). Median follow up from primary irradiation completion was 31 months. Sixteen patients were Stage IV NED at last follow-up (IR 37–60 mo). Fifteen patients died of disease. Five patients experienced an in-field recurrence, three of which resulted from local recurrence at the medial edge of the field. Actuarial 5 year locoregional control (LRC) was 86%. Median PFSx was 20 months. All sites of gross disease were treated with radiation in 21/36 patients. Location of metastatic disease had no correlation with PFSx. Estrogen receptor (ER)- patients had shorter 5-yr actuarial PFSx (28% vs. 66%, P = 0.03) and 5 year actuarial OSx (37% vs 71%, P = 0.02). Nine patients (25%) developed a pathological complete response (pCR) after chemotherapy and with a median follow-up of 59 months, 7 remained without evidence of disease.
Conclusions
Despite the poor prognosis associated with metastatic IBC, our data suggest that select patients may be appropriate candidates for locoregional therapy. Patients who achieve a pCR or those with ER + disease have a favorable PFSx. It remains unclear whether all gross disease needs to be addressed with locoregional therapy to provide benefit.
doi:10.1186/2193-1801-3-166
PMCID: PMC3977020  PMID: 24711988
Post-mastectomy; Radiation therapy; Inflammatory breast cancer; Metastatic disease; Pathologic complete response
16.  Clinical Outcomes of Patients with Desmoplastic Small Round Cell Tumor of the Peritoneum Undergoing Autologous HCT: a CIBMTR Retrospective Analysis 
Bone marrow transplantation  2012;47(11):1455-1458.
Desmoplastic small round cell tumor of the peritoneum (DSRCTP) is a rare, frequently fatal tumor. This retrospective study, based on CIBMTR registry data, describes the largest reported cohort of DSRCTP patients who have undergone autologous stem cell transplant (ASCT). The probabilities of disease-free survival (DFS) at one year for patients in complete remission (CR) and not in CR were 75% (95% confidence interval: 48–94%) and 35% (15–59%), respectively. The probability of overall survival (OS) at three years was 57% (29–83%) and 28% (9–51%) for patients in CR and not in CR respectively. Median survival for the entire cohort was 31 months (36 months and 21 months for those in CR and not in CR respectively). Engraftment at 42 days was 97% (88–100%). Treatment-related mortality was low, with only one death in the first 100 days. ASCT is a tolerable approach in patients with DSRCTP, with the greatest benefit seen in those patients who obtain CR. For those not in CR, the median OS in this series is greater than previously reported (21 months versus 17 months), suggesting ASCT is useful in prolonging DFS and OS, even in patients with residual or persistent disease pre transplant.
doi:10.1038/bmt.2012.57
PMCID: PMC3951901  PMID: 22465977
Autologous; Transplant; Outcomes; Desmoplastic; Tumor
17.  ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR NEUROBLASTOMA: THE CIBMTR EXPERIENCE 
Bone marrow transplantation  2013;48(8):1056-1064.
While the role of auto-HCT is well established in neuroblastoma, the role of allo-HCT is controversial. The CIBMTR conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto HCT (n=46 and 97, respectively). One-year and five-year overall survival (OS) were 59% and 29% for Group 1 and 50% and 7% for Group 2. Amongst donor types, disease free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not 5 years post-HCT. Patients in complete response (CR) or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared to those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared to those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.
doi:10.1038/bmt.2012.284
PMCID: PMC3661721  PMID: 23419433
neuroblastoma; allogeneic HCT; autologous HCT; CIBMTR
18.  A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer 
Clinical breast cancer  2012;13(1):10.1016/j.clbc.2012.09.004.
In this pilot study, we prospectively compared the response of bone metastasis assessed by our MD Anderson (MDA) bone tumor response criteria (computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) with the response assessed by the World Health Organization (WHO) criteria (XR and SS). Both MDA and WHO criteria predicted progression-free survival (PFS) of patients at 6 months but not at an earlier time point.
Background
In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases.
Methods
We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions.
Results
The median follow-up period was 26.7 months (range, 6.1–53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases.
Conclusion
MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose (18F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria.
doi:10.1016/j.clbc.2012.09.004
PMCID: PMC3863546  PMID: 23098575
one metastasis; Bone tumor response criteria; Breast cancer; Computed tomography; Plain radiography; Skeletal scintigraphy
19.  Retrospective analysis of anti tumor effects of zoledronic acid in breast cancer patients with bone-only metastases 
Cancer  2011;118(8):2039-2047.
Background
Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases.
Patients and methods
We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997, to December 31, 2008, at MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS.
Results
Patients who had more than one bone metastasis and ECOG performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR]=0.72, p=0.058 in univariate analysis and HR=0.80, p=0.235 in multivariate analysis) nor with longer OS (HR=1.04, p=0.863 in univariate analysis and HR=1.34, p=0.192 in multivariate analysis).
Conclusion
Our study demonstrates that for patients with bone-only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone-only metastasis, we could not demonstrate antitumor effects of zoledronic acid.
doi:10.1002/cncr.26512
PMCID: PMC3893069  PMID: 22139648
Zoledronic acid; breast cancer; bone-only metastases; bisphosphonate
20.  High Serum miR-19a Levels Are Associated with Inflammatory Breast Cancer and Are Predictive of Favorable Clinical Outcome in Patients with Metastatic HER2+ Inflammatory Breast Cancer 
PLoS ONE  2014;9(1):e83113.
Introduction
Altered serum microRNA (miRNA) levels may be correlated with a dysregulated expression pattern in parental tumor tissue and reflect the clinical evolution of disease. The overexpression of miR-21, miR-10b, and miR-19a is associated with the acquisition of malignant characteristics (increased tumor cell proliferation, migration, invasion, dissemination, and metastasis); thus, we determined their utility as serum biomarkers for aggressive breast cancer (HER2-overexpressed or -amplified [HER2+] and inflammatory breast cancer [IBC]).
Experimental Design
In this prospective study, we measured miR-21, miR-10b, and miR-19a levels using quantitative reverse transcriptase-polymerase chain reaction in the serum of 113 breast cancer patients and determined their association with clinicopathologic factors and clinical outcome. Thirty healthy donors with no history of cancer were enrolled as controls.
Results
Patients with non-metastatic HER2+ breast cancer had higher serum miR-21 median levels than patients with non-metastatic HER2− disease (p = 0.044); whereas patients with metastatic HER2+ breast cancer had higher serum miR-10b median levels than patients with metastatic HER2− disease (p = 0.0004). There were no significant differences in serum miR-19a median levels between HER2+ and HER2− groups, regardless of the presence of metastases. High serum miR-19a levels were associated with IBC (p = 0.039). Patients with metastatic IBC had significantly higher serum miR-19a median levels than patients with metastatic non-IBC (p = 0.019). Finally, high serum miR-19a levels were associated with longer progression-free survival time (10.3 vs. 3.2 months; p = 0.022) and longer overall survival time (median not reached vs. 11.2 months; p = 0.003) in patients with metastatic HER2+ IBC.
Conclusion
High levels of miR-21 and miR-10b were present in the serum of patients with non-metastatic and metastatic HER2+ breast cancer, respectively. High levels of serum miR-19a may represent a biomarker for IBC that is predictive for favorable clinical outcome in patients with metastatic HER2+ IBC.
doi:10.1371/journal.pone.0083113
PMCID: PMC3885405  PMID: 24416156
21.  Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer 
Breast cancer research and treatment  2012;137(2):10.1007/s10549-012-2336-6.
Adjuvant hormonal therapy for hormone receptor (HR)-positive primary breast cancer patients and a human epidermal growth factor receptor 2 (HER2)-targeted agent for HER2-positive primary breast cancer patients are standard treatment. However, it is not well known whether adding hormonal therapy to the combination of preoperative or postoperative chemotherapy and HER2-targeted agent contributes any additional clinical benefit in patients with HR-positive/HER2-positive primary breast cancer regardless of cross-talk between HR and HER2. We retrospectively reviewed records from 897 patients with HR-positive/ HER2-positive primary breast cancer with clinical stage I–III disease who underwent surgery between 1988 and 2009. We determined the overall survival (OS) and disease-free survival (DFS) rates according to whether they received hormonal therapy or not and according to the type of hormonal therapy, tamoxifen and aromatase inhibitor, they received. The median followup time was 52.8 months (range 1–294.6 months). Patients who received hormonal therapy with chemotherapy and trastuzumab (n = 128) had significantly higher OS and DFS rates than did those who received only chemotherapy and trastuzumab (n = 46) in log-rank analysis (OS 96.1 vs. 87.0 %, p = 0.023, DFS 86.7 vs. 78.3 %, p = 0.029). There was no statistical difference in OS or DFS between those given an aromatase inhibitor and those given tamoxifen. In multivariate analysis, receiving hormonal therapy in addition to the combination of chemotherapy and trastuzumab was the sole independent prognostic factor for DFS (hazard ratio 0.446; 95 % CI 0.200–0.992; p = 0.048), and there was a similar trend in OS. Our study supported that hormonal therapy, whether in the form of an aromatase inhibitor or tamoxifen, confers a survival benefit when added to chemotherapy and trastuzumab in patients with HR-positive/HER2-positive primary breast cancer. Adjuvant treatment without hormonal therapy is inferior for this patient population.
doi:10.1007/s10549-012-2336-6
PMCID: PMC3860360  PMID: 23184079
Hormonal therapy; Hormone receptor; Human epidermal growth factor receptor 2; Breast neoplasm; Chemotherapy
22.  cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer 
Journal of Cancer  2014;5(9):745-753.
Background: EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines.
Methods: TNBC lines (MDA-MB-468, HCC-1395, and MDA-MB-231), and a hormone receptor-positive breast cancer line (T47D) were stimulated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Lines were then treated with different concentrations of EGFR inhibitors (gefitinib or cetuximab), with or without a MET tyrosine kinase inhibitor (EMD 1214063). Proliferation was measured by MTS assay, in soft agar and with a matrigel assay. Synergy was measured with Calcusyn. Protein expression and signaling were examined with immunoblotting.
Results: There was activation of ligand-receptor-downstream signaling pathways in MDA-MB-468 and HCC-1395 upon stimulation with EGF and HGF. In these cell lines, we observed synergism when combining EGFR and MET inhibitors. These results were observed across assays. In western blotting, combination therapy resulted in abrogation of pAKT and pMAPK while monotherapy did not.
Conclusion: Our data demonstrate that dual EGFR/MET inhibition is synergistic in TNBC. Targeting both EGFR and MET receptors may provide an effective therapeutic strategy in TNBC.
doi:10.7150/jca.9696
PMCID: PMC4216798  PMID: 25368674
cMET; EGFR; Therapy resistance; Triple-negative breast cancer
23.  Prognostic value of HER2-positive circulating tumor cells in patients with metastatic breast cancer 
International journal of clinical oncology  2011;17(2):10.1007/s10147-011-0260-0.
Backgrounds
The presence of ≥5 circulating tumor cells (CTCs) in 7.5 ml blood is a poor prognostic marker in metastatic breast cancer (MBC). However, the role of human epidermal growth factor receptor 2 (HER2) status in CTCs is not known.
Methods
We prospectively assessed the prognostic value of this parameter for patients with MBC who started a new line of systemic therapy. The CTC count (≥5 or <5) and the HER2 status in CTCs at the initiation of the therapy and 3–4 weeks later (first follow-up) were determined.
Results
The median follow-up time of the 52 enrolled patients was 655.0 days (18–1,275 days). HER2-positive CTCs were present in 14 of the 52 patients (26.9%) during the study period. Eight of 33 patients (24.2%) with HER2-negative primary tumors had HER2-positive CTCs during the study period. At first follow-up, patients with HER2-positive CTCs had significantly shorter progression-free (n = 6; P = 0.001) and overall (P = 0.013) survival than did patients without HER2-positive CTCs (n = 43) in log-rank analysis. In multivariate analysis, HER2-positive CTCs at first follow-up (P = 0.029) and the number of therapies patients received before this study (P = 0.006) were independent prognostic factors in terms of progression-free survival. The number of therapies (P = 0.001) and a count of ≥5 CTCs (P = 0.043) at baseline were independent prognostic factors in terms of overall survival.
Conclusions
We showed that HER2 status in CTCs may be a prognostic factor for MBC. Well-powered prospective studies are necessary to determine the potential role of HER2-targeted therapies for patients with HER2-positive CTCs and HER2-negative primary tumors.
doi:10.1007/s10147-011-0260-0
PMCID: PMC3860324  PMID: 21671160
Circulating tumor cell; Breast neoplasm; HER2; Metastasis
24.  Serum HER2 levels determined by two methods in patients with metastatic breast cancer 
International journal of clinical oncology  2011;17(1):10.1007/s10147-011-0253-z.
Background
The role and the optimal measurement method of serum HER2 levels are not defined in patients with metastatic breast cancer (MBC). We prospectively assessed the prognostic value of serum HER2 levels in MBC using two methods, enzyme immunoassay (EIA) and chemiluminescence immunoassay (CLIA).
Methods
We collected blood samples from patients with MBC at baseline and at subsequent 3- to 4-week intervals up to 12 weeks. Samples were divided, and serum HER2 levels were determined using EIA and CLIA. We also determined whether serum HER2 levels had decreased by ≥20% at first follow-up. These results were evaluated against overall survival, progression-free survival, and tumor response.
Results
We obtained 196 samples from 52 patients. In 59 samples from patients who received trastuzumab, serum HER2 positivity rates were significantly lower for EIA (n = 22) than for CLIA (n = 33, P = 0.042); in 137 samples from patients who did not receive trastuzumab, there was no significant difference in rates of serum HER2 positivity for CLIA (n = 83) and EIA (n = 80). Serum HER2 level at baseline, the level at first follow-up, and a decrease of ≥20% between baseline and first follow-up were not associated with overall survival, progression-free survival, and tumor response.
Conclusions
Chemiluminescence immunoassay was a more sensitive method than EIA for measuring serum HER2 levels in patients who received trastuzumab. However, because serum HER2 levels did not correlate with patient outcome, we do not currently recommend measuring serum HER2 levels by either method for prognostic evaluation in patients with MBC.
doi:10.1007/s10147-011-0253-z
PMCID: PMC3860357  PMID: 21607830
Breast neoplasm; HER2; Metastasis; Serum HER2; Trastuzumab
25.  Improvement of survival and prospect of cure in patients with metastatic breast cancer 
Breast cancer (Tokyo, Japan)  2011;19(3):10.1007/s12282-011-0276-3.
Patients with metastatic breast cancer have traditionally been considered incurable with conventional treatment. However, 5–10% of those patients survive more than 5 years, and 2–5% survive more than 10 years. Recent studies suggest that the survival of patients with metastatic breast cancer has been slowly improving. In this review, we examine the possible curative approach for a certain group of patients with metastatic breast cancer. We identify that patients most likely to benefit from such an aggressive approach are young and have good performance status, adequate body functional reserve, long disease-free interval before recurrence, oligometastatic disease, and low systemic tumor load. An aggressive multidisciplinary approach including both local treatment of macroscopic disease and systemic treatment of microscopic disease can result in prolonged disease control in certain patients with metastatic breast cancer. Whether patients with prolonged disease control are “cured” remains controversial.
doi:10.1007/s12282-011-0276-3
PMCID: PMC3860359  PMID: 21567170
Metastatic breast cancer; Chemotherapy; Targeted therapy; Radiation therapy; Surgery

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