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Chronic inflammation associated with obesity is now recognized to be an important condition in promoting carcinogenesis and progression in breast cancer patients, mostly in postmenopausal women with tumors expressing estrogen and progesterone receptors. In obese patients, altered levels of several inflammatory mediators regulating aromatase and estrogen expression are one of the mechanisms responsible of increase breast cancer risk. Growing attention has also been paid to the local adipose inflammation and the role played by macrophages as determinants of breast cancer risk recurrence and prognosis. The inflammation-obesity axis offers different molecular signaling pathways for therapeutic interventions and potential pharmacological targets. The increasing rate of obesity worldwide associated with the recent findings linking inflammation and breast cancer urge further investigation.

Triple negative breast cancers, which are defined by lack of expression of estrogen, progesterone, or HER2 receptors, represent approximately 15% of all breast cancers, although they account for a much higher proportional of breast cancer mortality. This is due both to their innate aggressive biological characteristics, but also to lack of effective therapies. Conventional chemotherapy is currently the only treatment option, thus there is a critical need to find new and effective targeted therapies in this disease. While investigation of agents such as poly (ADP-ribose) polymerase (PARP) inhibitors and EGFR inhibitors continues, results from recent clinical trials indicate that these therapies are not as active in sporadic triple negative breast cancers as initially hoped. It is important therefore to consider other emerging therapeutic agents. Mutation in p53 is found in the vast majority of triple negative breast cancers, and as such is a target of particular interest. Within this review, several agents with potential activity against aberrant p53 signaling have been considered, as a novel approach to finding an effective targeted therapy for this aggressive breast cancer subtype.

Until now, no data are present in literature about the prototype Th1 chemokine (C–X–C motif) ligand 10 (CXCL10) in anaplastic thyroid cancer (ATC). This study aimed to test in “primary human ATC cells” (ANA) vs “normal thyroid follicular cells” (TFC): (a) CXCL10 secretion basally and after interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α stimulation; (b) peroxisome proliferator-activated receptor (PPAR)-γ activation by thiazolidinediones, rosiglitazone or pioglitazone, on CXCL10 secretion, on proliferation and apoptosis in ANA. We demonstrate that: (a) ANA, but not TFC, produced basally CXCL10, and did so in half of cases; (b) IFN-γ stimulated dose-dependently CXCL10, in ANA and TFC; (c) TNF-α did not induce CXCL10 secretion, in ANA and TFC; (d) IFN-γ + TNF-α induced a synergistic but variable release of CXCL10 in the different ANA preparations, while it was more reproducible in TFC; (e) rosiglitazone action on CXCL10 in ANA was inhibitory in 2/6, stimulatory in 1/6 and nil in 3/6, whereas it was inhibitory in TFC; (f) rosiglitazone inhibition of proliferation in ANA was not associated with the effect on CXCL10; (g) nuclear factor-κB and ERK1/2 were basally activated in ANA, increased by IFN-γ + TNF-α, and rosiglitazone inhibited that activation. On the whole, the present data first show that ANA cells are able to produce CXCL10, basally and under the influence of cytokines. However, the pattern of modulation by IFN-γ, TNF-α or thiazolidinediones is extremely variable, suggesting that the intracellular pathways involved in the chemokine modulation in ATC have different types of deregulation.

There are no clinical tools to functionally assess degree of DNA damage in breast cancer. The comet assay is an accepted research tool for assessing DNA damage, however, most cancer studies have assessed lymphocytes as surrogate cells. The aim of this pilot study was to use the comet assay in early breast cancer directly in tumor tissue to compare DNA damage between and within traditionally defined subgroups, and to explore intra-tumoral heterogeneity. Scrapings of tumor and healthy breast tissue were obtained at primary surgery from 104 women. Comet assay was applied to quantitatively assess DNA damage, revealing substantial inter- and intra-subgroup variation. Marked intra-tumoral heterogeneity was evident across all subgroups. The degree of DNA damage for an individual could not be predicted by breast cancer subgroup. Comet assay warrants further study as a potential clinical tool for identification of tumoral DNA damage and ultimately, individualised use of DNA damaging therapy.

The past decade has seen extensive research into potential markers of responsiveness to anthracycline therapy in breast cancer patients; however, such markers have remained elusive. The status of both human epidermal growth factor receptor-2 (HER2) and topoisomerase II alpha (TOP2A) genes has been investigated in this context, but neither can be considered a clinically reliable predictor of response to anthracyclines. Expression of the TOP2A protein is affected by a number of factors not always related to gene copy number, and these might provide future potential markers. Recent studies have suggested that stroma-related signatures could predict anthracycline resistance, and increased expression of tissue inhibitor of metalloproteinases 1 (TIMP1) has also been implicated in resistance. Deficiency of the BRCA1 and BRCA2 genes may render cells more sensitive to topoisomerase inhibitors such as anthracyclines by disrupting repair of damaged DNA. Chromosome 17 polysomy has also been associated with increased responsiveness to anthracyclines. Given the complexity of topoisomerases and DNA repair pathways, it may be that a multifactorial approach, rather than reliance on a single biomarker, is needed to identify anthracycline-sensitive patients.

Metabolomics, the study of metabolites and small intermediate molecules, may play a key role in further elucidation of breast cancer. This dynamic, simultaneous assessment of thousands of metabolites allows identification of the presence, concentration and fluxes of specific metabolites, and recognition of the critical metabolic pathways recruited in carcinogenesis. Studies of tumour cell and tissue allow focused analysis on the tumour, whilst studies of biofluids have the appeal of concurrent assessment of tumour and host. Elucidation of these metabolites and pathways may provide essential insights into both the intercellular environment and host/tumour interaction, allowing recognition of new biomarkers for diagnosis and prediction of outcome, new therapy targets and novel approaches for monitoring response and toxicity. Certainly, the field of metabolomics may evolve as a valuable, complementary clinical tool. In this review, current metabolomic data in breast cancer will be presented. The dominant metabolic pathways and metabolite disturbances associated with malignant transformation of breast cells will be outlined, leading to an overview of potential clinical implications for individuals with breast cancer.

Objective To provide an overview of a new approach for treatment of medullary thyroid carcinoma (MTC) and other endocrine tumors. Methods This review compiles recent information from the medical literature and scientific meetings focused on the use of tyrosine kinase inhibitors (TKIs) for the treatment of MTC and other endocrine tumors. Results The elucidation during the past 2 decades of multiple genetic abnormalities in endocrine tumors has provided specific targets for therapy. The identification of activating mutations of the RET tyrosine kinase receptor in both hereditary and sporadic MTC makes this malignant disease an excellent model for examination of the effect of a group of small organic molecule TKIs for treatment of metastatic MTC. Clinical trials with several TKIs targeting RET and other tyrosine kinase receptors have shown positive results with generally tolerable toxicity. Approximately one-third to one-half of patients with MTC have a reduction in tumor size of 0% to 50%, with the longest treatment duration of approximately 4 years. The most common treatment-related toxic effects are cutaneous effects, nausea, and diarrhea. Cardiovascular toxicity, such as hypertension, prolongation of the corrected QT interval, or heart failure, is uncommon but may be serious. Conclusion Despite promising initial results, these studies are in their early stages, and none of these therapies is currently approved by the US Food and Drug Administration for treatment in the United States. These studies highlight the potential for targeting endocrine cancer signaling pathways and provide a paradigm for treatment of endocrine cancer. (Endocr Pract. 2009;15:597-604)

Anaplastic thyroid carcinoma is a rare and universally fatal disease. Therefore, novel biomarkers are needed as surrogate end points in triaging patients for novel and selective biologic treatments. Up-regulation of several growth factor receptors has been shown to be associated with the biologic progression and response to targeted therapy of several malignancies. To determine the role of growth factor receptors in the biologic stratification of anaplastic thyroid carcinoma, we studied the expression of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor beta, and HER-2 receptor in a large cohort of anaplastic thyroid carcinomas by immunohistochemical techniques. The percentage of positive cells, staining intensity and localization of staining in the anaplastic component, and coexisting well-differentiated thyroid carcinoma and adjacent nonneoplastic thyroid were evaluated for these markers. EGFR, platelet-derived growth factor receptor beta, and HER-2 were overexpressed in 58%, 16%, and 16% of anaplastic carcinomas, respectively. In tumors with adjacent normal thyroid parenchyma and/or differentiated carcinoma components, overexpression of all 3 markers was noted exclusively in the anaplastic component. Mutational analysis of exons 18, 19, and 21 of the EGFR gene showed no mutations in all anaplastic carcinomas. We conclude that the expression of these markers (1) may play a role in a subset of thyroid tumorigenesis and anaplastic transformation and (2) can be validated for potential use in the stratification of patients for targeted therapy.

MicroRNAs (miRNAs) comprise a class of small endogenous non-coding RNA molecules that play critical roles in modulating numerous biological pathways by regulating gene expression. High throughput and expression profile studies have shown that miRNAs are commonly dysregulated in human cancer. The study of the mechanisms of action of miRNAs has uncovered an entirely new repertoire of potential biomarkers and generegulated pathways. MiRNAs may function as oncogenes or tumour suppressor genes and are characterised by unique properties such as stability, tissue specificity, ease of detection and manipulation. Additionally, miRNAs are differentially expressed in the blood of cancer patients versus healthy donors, providing a rationale for the detection of miRNAs as diagnostic and prognostic circulating biomarkers. Recent studies have shown that specific expression patterns of miRNAs could be used as potential predictors of response to treatments in clinical trials. Finally, manipulation of miRNA expression in cancer could be used for future molecular therapies.

C. Raschioni1, G. Bottai1, B. Szekely2, A. Losurdo3, L. Di Tommaso4, C. Tinterri5, L. Paladini1, J. Kulka2, M. Roncalli4, L. Santarpia1 Oncology Experimental Therapeutics Unit, Istituto Clinico Humanitas, Rozzano, Italy 2nd Department of Pathology, Semmelweis University, Budapest, Hungary Division of Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Italy Department of Pathology, Istituto Clinico Humanitas, Rozzano, Italy Breast Surgery Unit, Istituto Clinico Humanitas, Rozzano, Italy

Objectives We examined if gene expression patterns differ among HER2 positive breast cancers by estrogen receptor (ER) status. We also assessed the prognostic and chemotherapy response predictive values of over 3000 gene sets separately in the ER subsets. Methods Publically available, clinically annotated Affymetrix gene expression data of 537 HER+ (ER-/HER2+ n = 278, ER + /HER2+ n = 259) and 2985 HER2- (ER thinsp;+ /HER2- n = 1923, ER-/HER2- n = 1062) patients were studied including 121 node-negative, HER2+ cases with no systemic adjuvant therapy (ER+ n = 61, ER- n = 60) and 86 HER2+ patients treated with neoadjuvant taxane or anthracycicline chemotherapy (ER+ n = 27 and ER- n = 59). Results Genes that distinguished ER+ from ER- cases differed for HER2+ and HER2- cancers. HER2+ cancers showed less difference by ER status compared to HER2- cancers (differentially expressed genes by ER status: n = 194 and n = 6750, p Conclusions Among HER2+ tumors, ER- and ER+ cancers represent distinct molecular subtypes. Immune signatures predict for good prognosis and higher chemotherapy sensitivity in HER2+ cancers regardless of ER status. Disclosure All authors have declared no conflicts of interest.

Introduction Presence of circulating tumor cells (CTCs) in peripheral blood of patients with metastatic breast cancer (MBC) represents an independent prognostic factor. Discrepancies in HER2 status between primary breast tumors and CTCs have been reported. Indeed, 5-38% of patients with HER2 negative (HER2-) primary breast cancers show HER2 overexpression in corresponding CTCs at time of metastatic disease. However, the biological explanation of such discrepancies is still matter of debate. Sparse reports indicate that 5-30% of breast cancers show HER2 heterogeneity. We hypothesize that heterogeneity of HER2 expression within HER2- primary tumors might explain the presence of HER2 positive (HER2+) CTCs. Methods We analyzed 14 CTC positive (≥ 2 CTCs/7.5ml blood) MBC patients whose primary tumors were HER2- according to the adjuvant trastuzumab trials criteria. CTCs were evaluated for HER2 expression by immunofluorescence (CellSearch™ System, Veridex LLC) and defined positive if ≥ 50% cells stained for HER2. According to these criteria, seven of the patients had discordant HER2+ CTCs (cases), while seven had concordant HER2- CTCs (controls). For both cases and controls, we evaluated HER2 status by immunohistochemistry on additional tumor-bearing blocks, either from the primary tumor or from synchronous metastatic axillary lymphnodes (average of 3 blocks/patient). HER2 heterogeneity was defined as presence of incomplete or complete membrane staining in Results Five of the seven (71%) discordant cases showed HER2 heterogeneity. Heterogeneity was present either in the additional primary tumor blocks (40%) or in the metastatic axillary lymphnodes (40%) or in both (20%). Intriguingly, none of the concordant cases (controls) showed HER2 heterogeneity. Conclusion Here we show that areas of HER2 expression in HER2- tumors are associated with the presence of HER2+ CTCs at time of metastatic disease, suggesting that HER2+ clones might be selected during cancer progression. Trials investigating whether patients with HER2 heterogeneous tumors might benefit from HER2 targeted therapies are warranted. Disclosure A. Di Leo: Dr. Di Leo received research grants from GSK and honoraria as a speaker at satellite symposia or as a consultant from Roche and GSK. All other authors have declared no conflicts of interest.