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Background: TNBC is a particularly aggressive subtype with high recurrence rates and poor long-term survival. Anthracycline-free regimens based on docetaxel plus carboplatin (TCb) achieve around 50-55% pathologic complete responses (pCR) which correlates with better survival outcomes. Identification of genomic predictors of response is key to individualize therapies for this heterogeneous breast cancer (BC) subgroup. FOXA1 is a pioneer factor for androgen (AR) and estrogen receptors (ER). Its under-expression has been linked to cancer stemness in TNBC and better prognosis in ER-positive BC. The differential expression of AR, FOXA1 and BRCA1 is associated with sensitivity to chemotherapy in TNBC patients. Data support the plasticity role of FOXA1 driving basal to luminal BC cells by inducing luminal genes but also by repressing the basal phenotype and thus, tumor aggressiveness, although its role as a biomarker in TNBC is still controversial. We have analyzed RNAseq data of FOXA1 and AR in a series of TNBC tumors homogenously treated with neoadjuvant TCb to study their correlation with survival and response. Methodology: 300 TNBC patients have been included in a multicenter, prospective, non-randomized trial aimed to identify predictors of response to TCb in the neoadjuvant setting (NCT01560663). 278/300 patients were evaluable. PAM50 subtypes (NanoString nCounter) and RNAseq (HiSeq2500) were analyzed for those patients with both available samples and evaluable pathological response (n=208). Correlations were studied by the Kendall method. Linear or logistic regressions were adjusted for univariant analysis depending on numerical or categorical response variables, respectively. Results: FOXA1 and AR were differentially expressed between basal and non-basal tumor subtypes (PAM50), being overexpressed in non-basal (p Citation Format: Sara López-Tarruella, María del Monte-Millán, Enrique Alvarez, Yolanda Jerez, José Ángel García Saenz, Isabel Echavarria, Fernando Moreno, Ivan Márquez-Rodas, Coralia Bueno-Muiño, Blanca Herrero, Maria Cebollero, Rocío Ramos-Medina, Nerea Lobato, Ricardo González del Val, Maria Isabel Palomero, Santiago Lizarraga, Uriel Bohn, Ana Isabel Ballesteros, Patricia Rincón, Tatiana Massarrah, Inmaculada Ocaña, Lucía Villarejo, Charles M Perou, Miguel Martin. Potential value of FOXA1 expression as genomic predictor of response to docetaxel and carboplatin neoadjuvant (NA) chemotherapy in patients with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-12.

Contains fulltext : 237689.pdf (Publisher’s version ) (Open Access) Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Made available in DSpace on 2019-10-06T16:34:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-01 Among the primary neoplasias that affect the liver, hepatocellular carcinoma (HCC) is the most frequent and the third leading cause of death related to cancer. Several risk factors predispose individuals to HCC such as nonalcoholic fatty liver disease (NAFLD), whose incidence has significantly increased worldwide. β-ionone (βI) isoprenoid is a known chemopreventive of hepatocarcinogenesis. However, the effects of this compound on NAFLD isolated or in association with hepatocarcinogenesis have not yet been evaluated. A high-fat emulsion administered for 6 weeks resulted in NAFLD in male rats, and oral treatment with βI during this period significantly attenuated its development. Moreover, the presence of NAFLD potentiated hepatocarcinogenesis induced by the resistant hepatocyte (RH) model in these animals by increasing the number and percentage of the liver section area occupied by placental glutathione S-transferase (GST-P)-positive persistent preneoplastic lesions (pPNLs), that are thought to evolve into HCC. This indicates that this NAFLD/RH protocol is suitable for studies of the influence of NAFLD on the HCC development. Therefore, here we also investigated the chemopreventive effect of βI under these two associated conditions. In this context, βI reduced the number and percentage of the liver section area occupied by pPNLs, as well as cell proliferation and the number of oval cells, which are considered potential targets for the development of HCC. Thus, βI presents not only a promising inhibitory effect on NAFLD isolated but also chemopreventive activity when it is associated with hepatocarcinogenesis. Laboratory of Diet Nutrition and Cancer Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Laboratory of Nutrigenomics and Programming of Cancer Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Laboratory of Development of Functional Foods Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Laboratory of Food Chemistry and Biochemistry Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Laboratory of Experimental and Chemical Carcinogenesis Department of Morphology Biosciences Institute of Botucatu São Paulo State University (UNESP) Laboratory of Experimental and Chemical Carcinogenesis Department of Morphology Biosciences Institute of Botucatu São Paulo State University (UNESP)

Agents that inhibit angiogenic factors may prevent the development of hepatocellular carcinoma (HCC). Thus, the objective of this study was to kinetically evaluate the antiangiogenic activity of tributyrin (TB), a butyric acid prodrug, in the promotion stage of hepatocarcinogenesis. For this purpose, the resistant hepatocyte (RH) model was used for induction of preneoplastic lesions in Wistar rats. During the promotion phase, the animals received TB or maltodextrin (MD) as control daily. The rats were killed at three time-points (P1, P2 and P3). Increased expression of Vegfa and Vegfr2 was observed during promotion phase of hepatocarcinogenesis, which was not reversed by TB treatment. However, TB treatment reduced the expression of cluster of differentiation (CD) 34-positive vessels at P3 and α-smooth muscle actin (α-SMA)-positive vessels at P2 compared with MD. Enhanced levels of hypoxia inducible factor-1α (HIF-1α) and phosphorylated extracellular signal-regulated kinases (pERK) were detected at P3 when compared with P1 and P2 in the MD treatment. TB treatment reduced the levels of HIF-1α and pERK at P3 relative to the MD control. Experiments with human umbilical vein endothelial cells (HUVEC) showed that sodium butyrate (NaBu) inhibited cell migration and tube formation, confirming the antiangiogenic activity of its prodrug TB. In conclusion, antiangiogenic activity of TB is an early event that already occurs in preneoplastic livers, reinforcing its potential chemopreventive effects against HCC.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavilypretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/ HER2(-)) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2(-) mBC who had progressed on >= 4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus, This study was sponsored by Biomedical Research Foundation of the Hospital Clinico San Carlos (Madrid, Spain). The study was funded by an investigator sponsored research grant (WI236789) from Pfizer.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Made available in DSpace on 2020-12-12T02:06:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Capsaicin (CPS), an ingredient of Capsicum plants, has anti-inflammatory, antioxidant and antitumoral properties. The mechanisms of CPS on hepatocarcinogenesis preclinical bioassays are not described. Thus, the protective effects CPS were evaluated in the early stages of chemically-induced hepatocarcinogenesis. Male Wistar rats received diet containing 0.01% or 0.02% CPS for 3 weeks. Afterwards, animals received a dose of hepatocarcinogen diethylnitrosamine (DEN, 100 mg/kg body weight). From weeks 4–12, groups had their diet replaced by a 0.05% phenobarbital supplemented one to promote DEN-induced preneoplastic lesions. Animals were euthanized 24 h after DEN administration (n = 5/group) or at week 12 (n = 9/group). The estimated CPS intake in rats resembled human consumption. At the end of week 3, dietary 0.02% CPS attenuated DEN-induced oxidative damage and, consequently, hepatocyte necrosis by reducing serum alanine aminotransferase levels, liver CD68-positive macrophages, lipid peroxidation, while increasing antioxidant glutathione system. Additionally, 0.02% CPS upregulated vanilloid Trpv1 receptor and anti-inflammatory epoxygenase Cyp2j4 genes in the liver. Ultimately, previous 0.02% CPS intake decreased the number of GST-P-positive preneoplastic lesions at week 12. Thus, CPS attenuated preneoplastic lesion development, primarily by diminishing DEN-induced oxidative liver injury. Findings indicate that CPS is a promising chemopreventive agent when administered after and during the early stages of hepatocarcinogenesis. Department of Morphology Biosciences Institute São Paulo State University (UNESP) Department Pathology Medical School São Paulo State University (UNESP) Department of Chemistry and Biochemistry Biosciences Institute São Paulo State University (UNESP) Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Department of Morphology Biosciences Institute São Paulo State University (UNESP) Department Pathology Medical School São Paulo State University (UNESP) Department of Chemistry and Biochemistry Biosciences Institute São Paulo State University (UNESP)

OBJECTIVES Taxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome remain elusive. PATIENTS AND METHODS We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m(2) (n=84) or doxorubicin 75 mg/m(2) (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin. RESULTS We identified a significant association for rs162561, an intronic SNP located in the cytochrome P450 family 1 subfamily B member 1 (CYP1B1) gene, with tumor response in patients treated with single-agent docetaxel (dominant model: β=1.02, 95% confidence interval=0.49-1.55; P=1.77×10(-4)), and for rs717620, an SNP located in the promoter of the ATP-binding cassette subfamily C member 2 (ABCC2) gene, in patients treated with neoadjuvant doxorubicin (recessive model: β=1.67; 95% confidence interval=0.26-3.11; P=0.02). CONCLUSION We identified two polymorphisms in CYP1B1 and ABCC2 associated with tumor pathological response following docetaxel or doxorubicin neoadjuvant monotherapy, respectively. Although further validation is required, these variants could be potential predictive genetic markers for treatment outcome in breast cancer patients.

Purpose: Triple-negative breast cancer (TNBC) requires the iden- tification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of patients with TNBC treated with neoadjuvant carboplatin and docetaxel (TCb). Methods: Patients with TNBC were accrued in a nonrandomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 for six cycles. Response was evaluated in terms of pathologic complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans and colleagues. Lehmann's subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of seven DNA damage repair genes was conducted. Results: Ninety-four out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR, and 7.4% were classified as ER+. Response to NACT with TCb was significantly associated with Lehmann subtype (P = 0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%), and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2, and 30% were M. Conclusions: TNBCtype-4 is associated with significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT, respectively. Clin Cancer Res; 24(8); 1845–52. ©2018 AACR.

Resumen: Objetivo: Comprobar los resultados de un entrenamiento en habilidad para realizar ecocardioscopias para oncólogos por parte de cardiólogos y estudiar la variabilidad en las mediciones y la significación clínica de esa variabilidad. Métodos: Se incluyeron pacientes consecutivos que habían sido atendidos en las consultas de oncología previamente. Un oncólogo les realizó una ecocardioscopia con un equipo portátil. Por otro lado, un cardiólogo realizó un ecocardiograma reglado con un equipo de gama alta. Todos los oncólogos participantes recibieron un entrenamiento básico en ecocardioscopia por parte de cardiólogos especializados en imagen cardiovascular. Resultados: Se incluyeron 101 pacientes (31,7% varones; edad media 56,03 ± 16,88 años). Los resultados mostraron una clara curva de aprendizaje durante el periodo de reclutamiento, alcanzando a los dos meses una buena similitud entre oncólogo y cardiólogo para las medidas de los diámetros ventriculares, pero sin alcanzar la misma similitud hasta pasados 4 meses las medidas de la fracción de eyección del ventrículo izquierdo. De la misma manera, se produjo una importante reducción de las diferencias clínicamente significativas de la fracción de eyección del ventrículo izquierdo a partir del cuarto mes. Conclusiones: Un entrenamiento breve dirigido a Facultativos Especialistas en Oncología en ecocardioscopia dirigido por cardiólogos expertos en imagen cardiovascular permite al oncólogo obtener las habilidades necesarias para evaluar las dimensiones del ventrículo izquierdo y la fracción de eyección del ventrículo izquierdo de una forma precisa. El tiempo de entrenamiento se estima en una semana de formación teórico-práctica intensa, y adicionalmente cuatro meses de realización de ecocardioscopias supervisadas estrechamente por los cardiólogos. Abstract: Objective: To assess the results of a training to perform echocardioscopic studies to oncologists by cardiologists, and to study the variability in measurements, as well as the clinical significance of this variability. Methods: Participant oncologists received basic training in echocardioscopy by cardiologists specialised in cardiovascular imaging. Consecutive patients attending the oncology outpatient clinic were included in the study. Every patient underwent an echocardioscopic study performed by an oncologist with a portable device and an echocardiogram performed by a cardiologist using high-end equipment. Results: The study included 101 patients, with a mean age of 56.03 ± 16.88 years, and 31.7% were males. The results showed a clear learning curve over time, with a good similarity in ventricular diameters measurements between oncologists and cardiologist being reached in two months, but it took 4 months to reach the same similarity for left ventricular ejection fraction (LVEF) measurements. Likewise, there was a significant reduction in clinically significant differences in LVEF after the fourth month. Conclusions: A brief training in echocardioscopy for oncologists, led by cardiology experts in cardiovascular imaging, allows the oncologist to obtain the necessary skills to accurately assess left ventricular ejection fraction and diameters. The training time proposed is a week of intensive theoretical and practical training, followed by four months of completion of echocardioscopic examinations closely monitored by the cardiologist. Palabras clave: Ecocardiografía portátil, Oncología, Quimioterapia, Cardiotoxicidad, Entrenamiento, Keywords: Portable echocardiography, Oncology, Chemotherapy, Cardiotoxicity, Training

[Background]: Full RNA-Seq is a fundamental research tool for whole transcriptome analysis. However, it is too costly and time consuming to be used in routine clinical practice. We evaluated the transcript quantification agreement between RNA-Seq and a digital multiplexed gene expression platform, and the subtype call after running the PAM50 assay in a series of breast cancer patients classified as triple negative by IHC/FISH. The goal of this study is to analyze the concordance between both expression platforms overall, and for calling PAM50 triple negative breast cancer intrinsic subtypes in particular., [Results]: The analyses were performed in paraffin-embedded tissues from 96 patients recruited in a multicenter, prospective, non-randomized neoadjuvant triple negative breast cancer trial (NCT01560663). Pre-treatment core biopsies were obtained following clinical practice guidelines and conserved as FFPE for further RNA extraction. PAM50 was performed on both digital multiplexed gene expression and RNA-Seq platforms. Subtype assignment was based on the nearest centroid classification following this procedure for both platforms and it was concordant on 96% of the cases (N = 96). In four cases, digital multiplexed gene expression analysis and RNA-Seq were discordant. The Spearman correlation to each of the centroids and the risk of recurrence were above 0.89 in both platforms while the agreement on Proliferation Score reached up to 0.97. In addition, 82% of the individual PAM50 genes showed a correlation coefficient > 0.80., [Conclusions]: In our analysis, the subtype calling in most of the samples was concordant in both platforms and the potential discordances had reduced clinical implications in terms of prognosis. If speed and cost are the main driving forces then the preferred technique is the digital multiplexed platform, while if whole genome patterns and subtype are the driving forces, then RNA-Seq is the preferred method., M.M was supported by two research grants from Ministry of Economy and Competitiveness ISCIII-FIS grants (PI 12/02684): “Predictores genómicos de respuesta a la quimioterapia neoadyuvante con docetaxel-carboplatino en pacientes con cáncer de mama triple negativo”/“Genomic predictors of response to neoadjuvant chemotherapy with docetaxel-carboplatin in patients with triple negative breast cancer”; and (PI 15/00117): “Cáncer de mama triple negative: Predicción de respuesta a docetaxel-carboplatino neoadyuvante mediante caracterización de TILs y firmas inmunes basadas en secuenciación masiva de RNA”/” Triple negative breast cancer: Prediction of response to neoadjuvant docetaxel-carboplatin by characterization of TILs and immune signatures based on massive RNA sequencing”. C.M.P was supported by funds from the NCI Breast SPORE program (P50-CA58223).

Recent meta-analyses indicate that coffee consumption reduces the risk for digestive tract (oral, esophageal, gastric and colorectal) and, especially, liver cancer. Coffee bean-derived beverages, as the widely-consumed espresso and "common" filtered brews, present remarkable historical, cultural and economic importance globally. These drinks have rich and variable chemical composition, depending on factors that vary from "seeding to serving". The alkaloids caffeine and trigonelline, as well as the polyphenol chlorogenic acid, are some of the most important bioactive organic compounds of these beverages, displaying high levels in both espresso and common brews and/or increased bioavailability after consumption. Thus, we performed a comprehensive literature overview of current knowledge on the effects of coffee beverages and their highly bioavailable compounds, describing: 1) recent epidemiological and experimental findings highlighting the beneficial effects against gastrointestinal/liver carcinogenesis, and 2) the main molecular mechanisms in these in vitro and in vivo bioassays. Findings predominantly address the protective effects of coffee beverages and their most common/bioavailable compounds individually on gastrointestinal and liver cancer development. Caffeine, trigonelline and chlorogenic acid modulate common molecular targets directly implicated in key cancer hallmarks, what could stimulate novel translational or population-based mechanistic investigations.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

During the development of hepatocellular carcinoma (HCC), there is deregulation of cell systems involved in DNA repair, cell cycle control, apoptosis, HMG-CoA reductase regulation, and membrane fluidity, among others. It is thought that epigenetic alterations may be linked to hepatocarcinogenesis. Because these modifications, including epimutations, are potentially reversible, they are important targets for HCC chemoprevention. Bioactive food compounds (BFCs) and several drugs have the potential to reverse epigenetic events associated with the development of HCC, such as DNA methylation, histone modifications, and microRNA expression. According to their pleiotropic properties and possible selectivity to preneoplastic and neoplastic cells, BFCs can also act on autophagy and in signaling pathways from stem cells. Thus, since chemopreventive agents can have multiple roles in hepatocarcinogenesis, strategies for HCC chemoprevention can be designed, including the use of these agents either intermittently or continuously as adjuvant therapies to obtain a synergistic effect with or without synthetic lethality against cancer.

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers. The rising incidence of HCC worldwide and its resistance to pharmacotherapy indicate that the prevention of HCC development may be the most impactful strategy to improve HCC-related morbidity and mortality. Among the broad range of chemopreventive agents, the use of dietary and nutritional agents is an attractive and promising approach; however, a better understanding of the mechanisms of their potential cancer suppressive action is needed to justify their use. In the present study, we investigated the underlying molecular pathways associated with the previously observed suppressive effect of butyrate-containing structured lipids (STLs) against liver carcinogenesis using a rat “resistant hepatocyte” model of hepatocarcinogenesis that resembles the development of HCC in humans. Using whole transcriptome analysis, we demonstrate that the HCC suppressive effect of butyrate-containing STLs is associated with the inhibition of the cell migration, cytoskeleton organization, and epithelial-to-mesenchymal transition (EMT), mediated by the reduced levels of RACGAP1 and RAC1 proteins. Mechanistically, the inhibition of the Racgap1 and Rac1 oncogenes is associated with cytosine DNA and histone H3K27 promoter methylation. Inhibition of the RACGAP1/RAC1 oncogenic signaling pathways and EMT may be a valuable approach for liver cancer prevention.

Objective To determine whether metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are able to predict recurrence risk in locally advanced breast cancer (LABC) patients. Material and methods Retrospective study of LABC patients who undertook neoadjuvant, local and adjuvant treatment and follow up. A 18F-FDG PET/CT study for initial staging was performed analysing in this study different metabolic parameters (MTV, TLG, SUVmax and SUVmed) both in the primary tumor (T) as well as in axillary nodes (N) and whole-body (WB). Results Forty females were included between January 2010 and 2011; follow up until January 2015 was completed. The average follow-up was 46 months. Twenty percent presented recurrence: local disease (n = 2) and distant metastasis (n = 6); 3 patients died (38% of the patients which recurred and 7.5% from the total). SUVmax, MTV and TLG, in T, N and WB, were higher in those patients with recurrence. The MTV and TLG parameters in the tumor (T) were related to the recurrence rate (p = .020 and p = .028, respectively); whereas SUVmax in the lymph nodes (N) was significantly related (p = .008) to the recurrence rate. The best cut-off points to predict recurrence where: MTV T ≥ 19.3 cm3, TLG T ≥ 74.4 g and SUVmax N ≥ 13.8, being 10–12 times more likely to recidivate when these thresholds where exceeded. Tumor grade was the only clinical-pathological variable which was related to recurrence probability (p = .035). Conclusions In this study of LABC patients the metabolic parameters which have a better relationship with recurrence rate are: MTV and TLG in the primary tumor, SUVmax in the regional lymph node disease and whole-body PET data.

Resumen Objetivo Conocer si el volumen metabolico tumoral (VMT) y la glucolisis tumoral total (GTT) pueden predecir el riesgo de recurrencia en cancer localmente avanzado de mama (CLAM). Material y metodos Estudio retrospectivo de pacientes con CLAM tratados con tratamiento neoadyuvante, local y adyuvante; en seguimiento. Se realizo una 18F-FDG PET/TC para estadificar la enfermedad, midiendose diferentes parametros metabolicos (VMT, GTT, SUVmax y SUVmed), tanto en el tumor primario (T) como en los ganglios metastasicos (N) y en el cuerpo entero (CE). Resultados Se incluyeron 40 mujeres entre enero de 2010-2011; seguimiento hasta enero de 2015. Con una mediana de seguimiento de 46 meses el 20% tuvieron recidiva, local (n = 2) o a distancia (n = 6); fallecieron 3 (38% de aquellas con recidiva y 7,5% del total). EL SUVmax, VMT y GTT, tanto en T, como N y CE, fue mayor en aquellas que presentaron recidiva. En el T tanto el VMT como la GTT se relacionaron con la recidiva de la enfermedad (p = 0,020 y p = 0,028, respectivamente), mientras que en la N fue el SUVmax (p = 0,008). Los puntos de corte optimos para predecir recurrencia fueron: VMT T ≥ 19,3 cm3, GTT T ≥ 74,4 g y SUVmax N ≥ 13,8, existiendo 10-12 veces mas probabilidad de experimentar progresion tumoral cuando superaban estos umbrales. El grado tumoral fue la unica variable clinico-patologica asociada con la recidiva (p = 0,035). Conclusiones En este estudio de CLAM los parametros metabolicos que mas se asocian con la tasa de recidiva son el VMT y la GTT en el tumor primario, el SUVmax en la enfermedad ganglionar regional y los 3 indices PET en el cuerpo entero. Estos parametros podrian utilizarse en la practica asistencial para identificar a las pacientes con mayor riesgo.

MicroRNAs (miRNAs) are post-transcriptional gene expression regulators which expression is frequently altered in hepatocellular carcinoma (HCC). β-ionone (βI) is noted for its ability to inhibit persistent preneoplastic lesions (pPNLs) in liver rats. We evaluated the expression of miRNAs involved in carcinogenesis and possible targets modulated by βI, in pPNLs and surrounding of microdissected tissues. Rats subjected to resistant hepatocyte model were treated during promotion stage with βI (16 mg/100 g body weight) or corn oil (CO; 0.25 mL/100 g body weight; controls). Five animals receive no treatment (NT). In CO group, 38 and 29 miRNAs showed reduced expression relative to NT (P 0.05) in the expression of miRNAs in surrounding. In pPNLs βI increased expression of miR-122 and miR-34a (P ≤ 0.05) and reduced of Igf2 (P ≤ 0.05), target of the latter, compared to CO. Additionally, βI decreased the expression of miR-181c and its target Gdf2 (P ≤ 0.05). βI reduced the expression of miR-181b and miR-708 (P ≤ 0.05) and increased the expression of their respective target mRNAs Timp3 and Mtss1 (P ≤ 0.05), relative to CO group. Modulation of miRNAs target genes by βI was confirmed in vitro. βI is a promising chemopreventive agent in the initial stages of hepatocarcinogenesis, as it modulates the expression of the miRNAs and target genes that can alter the metastatic phenotype of HCC. © 2016 Wiley Periodicals, Inc.

The primary cause of tumor-related death in breast cancer is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. Circulating tumor cells (CTCs) play a major role in the metastatic spread of breast cancer. Different analytical systems for CTCs isolation and detection have been developed and novel areas of research are directed towards developing assays for CTCs molecular characterization. This review describes the current state of art on CTCs detection techniques and the present and future clinical implications of CTCs enumeration and characterization.

PIK3CA gene is frequently mutated in patients with breast cancer and it has been the focus of intense research. Inhibitors of PI3K pathway are being evaluated in ongoing clinical trials but the impact of PIKC3A mutation status on tumor response is yet uncertain. In the metastatic setting, several studies are evaluating the predictive value of PIK3CA mutations. However, results could be biased by biopsy localization. Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood and can potentially overcome such situation. As a proof of the concept, we present the case of a metastatic patient with a PIK3CA wild-type primary tumor in which the PIK3CA E545K mutation was identified in both the circulating-free DNA obtained from a peripheral blood sample and in the formalin-fixed, paraffin-embedded liver metastasis.

Made available in DSpace on 2020-12-12T02:22:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile. Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP) Department of Pathology School of Veterinary Medicine and Animal Science University of São Paulo (USP) Molecular Oncology Research Center Barretos Cancer Hospital Department of In Vitro Toxicology and Dermato-Cosmetology Faculty of Medicine and Pharmacy Vrije Universiteit Brussel Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Life and Health Sciences Research Institute (ICVS) School of Medicine University of Minho 3B's - PT Government Associate Laboratory Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP) FAPESP: #2016/12015–0 FAPESP: #2016/14420–0 FAPESP: #2017/16596–0

Made available in DSpace on 2018-12-11T17:22:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-09-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Hepatocellular carcinoma causes ~10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 μL/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (α-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models. Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Morphology Biosciences Institute São Paulo State University (UNESP) Department of Pathology School of Veterinary Medicine and Animal Science University of São Paulo (USP) Department of Chemistry and Biochemistry Biosciences Institute São Paulo State University (UNESP) Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP) Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Morphology Biosciences Institute São Paulo State University (UNESP) Department of Chemistry and Biochemistry Biosciences Institute São Paulo State University (UNESP) CNPq: #140251/2016-2 FAPESP: #2016/ 12015-0 FAPESP: #2016/14420-0

Purpose:Prognostic value of pathologic complete response (pCR) and extent of pathologic response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC.Patients and Methods:One-hundred and ninety patients with stage I–III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m2) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan–Meier method.Results:Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14–0.62; P = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10–0.63; P = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS.Conclusions:Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.

Background In Spain luminal metastatic Breast Cancer accounts for more than 3000 deaths yearly. Ribociclib+letrozole has shown efficacy on prolonging progression free survival (PFS) vs placebo+letrozol in two phase 3 trials. However, data on efficacy and tolerability is lacking for a broader population. We present interim data from CompLEEment-1, an ongoing, open-label, phase 3b trial evaluating ribociclib+letrozole as first-line endocrine therapy in an expanded population of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). Methods Patients treated with ≤1 line of prior chemotherapy and no prior endocrine therapy for advanced disease received ribociclib 600 mg/day (3-weeks-on/1week-off) + letrozole (2.5 mg/day; plus monthly goserelin or leuprolide in men and premenopausal women). The primary objective was safety and tolerability. Here we report a sub-analysis of CompLEEment-1 for the Spanish population. Results 526 patients were evaluated over a median follow-up of 10.3 months. Baseline characteristics indicated a diverse population with median age of 55.6 years (range 24-85); 0.8% of patients were male, 34.6% female pre-menopausal and 64.6% female post-menopausal. 71% had visceral metastasis, in 8 cases at the CNS. 55.9% had measurable disease at baseline. The rate of all-grade and grade ≥ 3 treatment-related adverse events (AEs) was 98.5% and 70.0%, respectively. Treatment-related serious AEs occurred in 12.2% of patients. All-grade and grade ≥ 3 AEs leading to ribociclib discontinuation occurred in 13.7% and 8.2% of patients, respectively. Rates of ≥ 3 AEs of special interest (AESI) were 59.5% for neutropenia, 6.8% for increased alanine aminotransferase, 4.8% for increased aspartate aminotransferase, and 0.6% for QTcF prolongation. Patient health-related quality of life was maintained versus baseline. Conclusions Initial results from the Spanish cohort in CompLEEment-1 are consistent with previous data showing efficacy and a manageable safety profile of ribociclib plus letrozole as a first-line treatment option in a diverse group of patients with HR+, HER2– ABC. Acknowledgement: Dr. J. Gavila-Gregori, Dr. M.J. Martinez-Serrano and Dr. M. Perello contributed equally to this study. Clinical trial identification NCT02941926. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure E.M. Ciruelos: Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker and ad.board honoraria: Pfizer. R. Villanueva Vazquez: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche. F. Moreno: Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. I. Alvarez: Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. S. Gonzalez-Santiago: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. A. Barnadas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Genomic Health; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. B. Cantos: Research grant / Funding (institution), Study enrollment: Fundacion para la Investigacion del Hospital Puerta de Hierro de Majadahonda; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: AstraZeneca. M. Bellet Ezquerra: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly. M. Martin: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Taiho Oncology; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Puma. N. Martinez: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Objective: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. Methods: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. Results: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. Conclusions: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

// Aline de Conti 1, * , Juliana Festa Ortega 1, 2, * , Volodymyr Tryndyak 1 , Kostiantyn Dreval 1 , Fernando Salvador Moreno 2 , Ivan Rusyn 3 , Frederick A. Beland 1 and Igor P. Pogribny 1 1 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas, USA 2 Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil 3 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA * These authors have contributed equally to this work Correspondence to: Igor P. Pogribny, email: igor.pogribny@fda.hhs.gov Keywords: hepatocarcinogenesis, non-alcoholic steatohepatitis, epigenetics, microRNAs, miR-93-5p Received: June 20, 2017 Accepted: July 06, 2017 Published: August 01, 2017 ABSTRACT Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b~25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.

Background Accurate measurement of tumor burden in breast cancer disease is essential to improve the clinical management of patients. In this study, we evaluate whether the fluctuations in the fraction of PIK3CA mutant allele correlates with tumor response according to RECIST criteria and tumor markers quantification. Methods Eighty six plasma samples were analyzed by digital PCR using Rare Mutation Assays for E542K, E545K and H1047R. Mutant cfDNA and tumor markers CA15-3 and CEA were compared with radiographic imaging. Results The agreement between PIK3CA mutation status in FFPE samples and circulating tumor DNA (ctDNA) was moderate (K = 0.591; 95% IC = 0.371–0.811). Restricting the analysis to the metastatic patients, we found a good agreement between PIK3CA mutation status assessed in liquid and solid biopsy (K = 0.798 95%; IC = 0.586–1). ctDNA showed serial changes with fluctuations correlating with tumor markers 15.3 and CEA in 7 out of 8 cases with Pearson correlation coefficients ranging from 0.99 to 0.46 and from 0.99 to 0.38 respectively. Similarly, fluctuations in the fraction of PIK3CA mutant allele always correlated with changes in lesion size seen on images, although in two cases it did not correlate with treatment responses as defined by RECIST criteria. Conclusion oncogenic mutation quantification in plasma samples can be useful to monitor treatment outcome. However, it might be limited by tumor heterogeneity in advanced disease and it should be evaluated together with radiographic imaging. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3185-9) contains supplementary material, which is available to authorized users.

The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.

Chile is a disproportionately long and narrow country defined by the southern Andes and Pacific coastline where a level of genetic sub-structure resulting from distances of several thousand kilometers might be expected across the most distantly separated regions. Although STR databases created for the Chilean Legal Medical Service indicate an absence of sub-structure, such a characteristic requires further exploration when introducing additional forensic markers. Notably, Single Nucleotide Polymorphisms (SNPs) have a much lower mutation rate than STRs and can show more stable distributions of genetic variation if population movement is restricted. In this study we evaluated 451 Chilean urban samples from the North, North-Central, Central, South-Central and South regions of Chile for the 52 SNPs of the SNPforID forensic identification panel to explore the underlying genetic structure of Chilean populations. Results reveal similar genetic distances between groups suggesting a single SNP database for the whole of Chile is appropriate. To further understand the genetic composition of Chilean populations that comprise the bulk of individuals with both European and Native American ancestries, ancestral membership proportions were evaluated and pairwise comparisons to other American populations were made.

The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic “resistant hepatocyte” model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione-S-transferase placental form (GSTP)-positive foci. Microarray analysis showed significant changes in gene expression. A total of 501, 655, and 940 of differentially expressed genes, involved in cell cycle, p53-signaling, angiogenesis, and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor-suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone.

In an era where neoadjuvant dual blockade is emerging as the standard of care for early and locally advanced HER2-positive breast cancer, we aimed to identify predictors of response to single-blockade chemotherapy. This retrospective analysis reviewed all the incident stage I–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in three institutions. pCR was defined as the absence of invasive tumor in breast and axillary nodes (ypT0/isypN0). From 2008 to 2015, 84 patients receiving neoadjuvant TCH were identified within our institutions. The mean age at diagnosis was 51.8 years. 59.5% of the patients were hormone receptor (HR) positive, lymph node involvement occurred in 67.9%, and clinical distribution was 2.4, 65.5, and 32.1% for stage I, II, and III, respectively. pCR rate was 47.6%; there was a significantly lower response in HR-positive patients compared to HR-negative ones (34 vs 67.6%, p = 0.005). pCR rate was associated with tumor size, whereas differences did not reach significance either for stage or for nodal status. Multivariate analysis found that only HR status was associated with response (p = 0.003). At a median follow-up of 31.7 months, disease-free survival, distant disease-free survival, and overall survival were 78.6, 85.7, and 94%, respectively. Breast-conserving surgery was performed in 44% of the patients. Overall, TCH was well tolerated, with low rates of grade 3–4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported. Neoadjuvant TCH, an anthracycline-free single-blockade regimen, achieved a pCR of 47.6%. Further molecular analyses are required in order to identify stronger predictive markers of pCR and thus for an accurate selection of patients who do not benefit from dual blockade.

Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease often diagnosed at intermediate or advanced stages, which substantially limits therapeutic approaches to its successful treatment. This indicates that the prevention of HCC may be the most promising strategy in reducing its incidence and mortality. Emerging evidence indicates that numerous nutrients and nonnutrient dietary bioactive components can reduce the occurrence and/or delay the development of HCC through modifications of deregulated epigenetic mechanisms. This review examines the existing knowledge on the epigenetic mechanism-based studies in in vitro and in vivo models of HCC on the chemopreventive potential of epigenetic food components, including dietary methyl-group donors, epigallocatechin-3-gallate, sodium butyrate, resveratrol, curcumin, and sulforaphane, on liver carcinogenesis. Future direction and potential challenges in the effective use of bioactive food constituents in the prevention of HCC are highlighted and discussed.

We describe the status and frequency of germline DNA genetic findings in an unselected prospective cohort of triple negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. Study population includes 124 consecutive patients with stage II-III TNBC from a trial exploring the antitumor activity of neoadjuvant carboplatin/docetaxel chemotherapy enrolled between 2012 and March 2015, to determine the frequency of germline DNA genetic mutations. 17.1 % of the patients with germline DNA tested had deleterious mutations in any of the analyzed genes (12.38 % in BRCA1, 1.9 % in BRCA2 and BARD1 and 0.95 % in RAD51D). Attending the intrinsic subtype, all the BRCA1/2 carriers tested had basal-like subtype. Among wild-type (WT) patients, 70.11 % had basal subtype, 16.09 % HER2 enriched, 1.15 % Luminal B, and 4.60 % Normal-like. Mean age at diagnosis was significantly lower in mutation-carriers compared with no carriers (43.72 vs 53.10, p = 0.004). 3 BRCA1/2 carriers were detected between 51 and 60 years, and only one deleterious mutation (BARD1) over 60 years. A positive familiar history of breast and ovarian cancer was more frequent in patients with deleterious mutations (39.39 vs 17.94 %, p = 0.043). Our study confirms the prevalence of BRCA1/2 mutations in TNBC patients. TNBC should therefore be considered by itself as a criterion for BRCA1/2 genetic testing. Determination of other breast cancer predisposition genes implicated in homologous recombination should also be discussed in this population. However, no definitive conclusions can be reached due to the low prevalence and the uncertain clinical impact of most of the genes included.

Purpose: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC. Experimental Design: The study population includes 190 patients with stage I–III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m2) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated. Results: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event. Conclusions: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline–taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649–57. ©2016 AACR.

Hepatocellular carcinoma (HCC), an aggressive and the fastest growing life-threatening cancer worldwide, is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of hepatocarcinogenesis is probably the most promising approach to reduce both the HCC incidence and cancer-related mortality. In previous studies, we demonstrated a potent chemopreventive effect of tributyrin, a butyric acid prodrug, on experimental hepatocarcinogenesis. The cancer-inhibitory effect of tributyrin was linked to the suppression of sustained cell proliferation and induction of apoptotic cell death driven by an activation of the p53 apoptotic signaling pathway. The goal of the present study was to investigate the underlying molecular mechanisms linked to tributyrin-mediated p53 activation. Using in vivo and in vitro models of liver cancer, we demonstrate that an increase in the level of p53 protein in nuclei, a decrease in the level of cytoplasmic p53, and, consequently, an increase in the ratio of nuclear/cytoplasmic p53 in rat preneoplastic livers and in rat and human HCC cell lines caused by tributyrin or sodium butyrate treatments was associated with a marked increase in the level of nuclear chromosome region maintenance 1 (CRM1) protein. Mechanistically, the increase in the level of nuclear p53 protein was associated with a substantially reduced binding interaction between CRM1 and p53. The results demonstrate that the cancer-inhibitory activity of sodium butyrate and its derivatives on liver carcinogenesis may be attributed to retention of p53 and CRM1 proteins in the nucleus, an event that may trigger activation of p53-mediated apoptotic cell death in neoplastic cells.

Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.

The combined treatment with histone deacetylase inhibitors (HDACi) and retinoids has been suggested as a potential epigenetic strategy for the control of cancer. In the present study, we investigated the effects of treatment with butyrate, a dietary HDACi, combined with vitamin A on MCF-7 human breast cancer cells. Cell proliferation was evaluated by the crystal violet staining method. MCF-7 cells were plated at 5 x 10(4) cells/mL and treated with butyrate (1 mM) alone or combined with vitamin A (10 µM) for 24 to 120 h. Cell proliferation inhibition was 34, 10 and 46% following treatment with butyrate, vitamin A and their combination, respectively, suggesting that vitamin A potentiated the inhibitory activities of butyrate. Furthermore, exposure to this short-chain fatty acid increased the level of histone H3K9 acetylation by 9.5-fold (Western blot), but not of H4K16, and increased the expression levels of p21WAF1 by 2.7-fold (Western blot) and of RARβ by 2.0-fold (quantitative real-time PCR). Our data show that RARβ may represent a molecular target for butyrate in breast cancer cells. Due to its effectiveness as a dietary HDACi, butyrate should be considered for use in combinatorial strategies with more active retinoids, especially in breast cancers in which RARβ is epigenetically altered.

The chemopreventive potential of water extracts of the Brassica vegetables cabbage and kale was evaluated by administering their aqueous extracts in drinking water ad libitum to Wistar rats submitted to Ito's hepatocarcinogenesis model (CB group and K group, respectively - 14 rats per group). Animals submitted to this same model and treated with water were used as controls (W group - 15 rats). Treatment with the vegetable extracts did not inhibit (P > 0.05) placental glutathione S-transferase-positive preneoplastic lesions (PNL). The number of apoptotic bodies did not differ (P > 0.05) among the experimental groups. Ex vivo hydrogen peroxide treatment of rat livers resulted in lower (P < 0.05) DNA strand breakage in cabbage- (107.6 +/- 7.8 microm) and kale- (110.8 +/- 10.0 microm) treated animals compared with control (120.9 +/- 12.7 microm), as evaluated by the single cell gel (comet) assay. Treatment with cabbage (2 +/- 0.3 microg/g) or kale (4 +/- 0.2 microg/g) resulted in increased (P < 0.05) hepatic lutein concentration compared with control (0.5 +/- 0.07 microg/g). Despite the absence of inhibitory effects of cabbage and kale aqueous extracts on PNL, these Brassica vegetables presented protection against DNA damage, an effect possibly related to increased hepatic lutein concentrations. However, it must be pointed out that the cause-effect relationship between lutein levels and protection is hypothetical and remains to be demonstrated.

Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticarcinogenic agent. However, its short half-life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of "resistant hepatocyte" model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (p < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB-induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways.