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1.
Am J Surg Pathol ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31567278

RESUMO

Mammary adenoid cystic carcinoma (ACC) is a rare subtype of breast cancer with a favorable prognosis. Here we report on predictors of outcome based on a detailed morphologic review and analysis of 108 mammary ACC. Sixty-four tumors (59.2%) were pure conventional ACC, 23 (21.3%) were pure basaloid ACC. Follow-up was available for 87 patients (median: 51 mo). Eighteen patients (20.7%) developed recurrence: 7 (8%) had local recurrence and 14 (16%) had distant metastasis. Two patients died of disease, 1 died of an unrelated cause, 14 were alive with disease (including 8 in palliative care), and 70 (80.5%) were alive with no evidence of disease. Of 90 patients with known lymph node (LN) status 9 (10%) had nodal involvement (all with basaloid ACC). Distant metastases in patients with predominantly basaloid ACC compared with pure conventional ACC were more common (40% vs. 7.7%) and occurred earlier (22 vs. 84 mo). The following factors were found to be predictive of recurrence-free survival: positive margin, Nottingham grade, neovascularization, basaloid component, perineural invasion, lymphovascular invasion, >30% solid growth, necrosis and LN involvement; the first 3 remained statistically significant on multivariate analysis. Factors predictive of distant disease-free survival were neovascularization, Nottingham grade, lymphovascular invasion, solid component >50%, LN involvement, basaloid component >50%, tumor necrosis, perineural invasion, and final margin. Only neovascularization remained statistically significant on multivariate analysis. Basaloid ACC is an aggressive variant of mammary ACC with more frequent nodal involvement and higher incidence of distant spread. LN staging should be performed for all mammary basaloid ACC.

2.
Sci Rep ; 9(1): 6624, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036830

RESUMO

We report here that CYB5D2 is associated with tumor suppression function in breast cancer (BC). CYB5D2 expression was significantly reduced in tamoxifen resistant MCF7 cells and in MCF7 cell-derived xenografts treated with TAM. CYB5D2 overexpression induced apoptosis in MCF7 cells; CYB5D2 knockdown enhanced MCF7 cell proliferation. Using the TCGA and Curtis datasets within the Oncomine database, CYB5D2 mRNA expression was downregulated in primary BCs vs breast tissues and HER2-positive or triple negative BCs vs estrogen receptor (ER)-positive BCs. Using the TCGA and Metabric datasets (n = 817 and n = 2509) within cBioPortal, 660 and 4891 differentially expressed genes (DEGs) in relation to CYB5D2 were identified. These DEGs were enriched in pathways governing cell cycle progression, progesterone-derived oocyte maturation, oocyte-meiosis, estrogen-mediated S-phase entry, and DNA metabolism. CYB5D2 downregulation decreased overall survival (OS, p = 0.0408). A CYB5D2-derived 21-gene signature was constructed and robustly correlated with OS shortening (p = 5.72e-12), and independently predicted BC deaths (HR = 1.28; 95% CI 1.08-1.52; p = 0.004) once adjusting for known clinical factors. CYB5D2 reductions displayed relationship with mutations in PIK3CA, GATA3, MAP3K1, CDH1, TP53 and RB1. Impressively, 85% (560/659) of TP53 mutations occurred in the 21-gene signature-positive BC. Collectively, we provide the first evidence that CYB5D2 is a candidate tumor suppressor of BC.

3.
Histopathology ; 75(2): 225-235, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31017314

RESUMO

AIMS: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. METHODS AND RESULTS: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. CONCLUSIONS: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

4.
Sci Rep ; 8(1): 16562, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410118

RESUMO

Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone's cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone's anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.

5.
Mod Pathol ; 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143750

RESUMO

The nuclear proliferation biomarker Ki67 has potential prognostic, predictive, and monitoring roles in breast cancer. Unacceptable between-laboratory variability has limited its clinical value. The International Ki67 in Breast Cancer Working Group investigated whether Ki67 immunohistochemistry can be analytically validated and standardized across laboratories using automated machine-based scoring. Sets of pre-stained core-cut biopsy sections of 30 breast tumors were circulated to 14 laboratories for scanning and automated assessment of the average and maximum percentage of tumor cells positive for Ki67. Seven unique scanners and 10 software platforms were involved in this study. Pre-specified analyses included evaluation of reproducibility between all laboratories (primary) as well as among those using scanners from a single vendor (secondary). The primary reproducibility metric was intraclass correlation coefficient between laboratories, with success considered to be intraclass correlation coefficient >0.80. Intraclass correlation coefficient for automated average scores across 16 operators was 0.83 (95% credible interval: 0.73-0.91) and intraclass correlation coefficient for maximum scores across 10 operators was 0.63 (95% credible interval: 0.44-0.80). For the laboratories using scanners from a single vendor (8 score sets), intraclass correlation coefficient for average automated scores was 0.89 (95% credible interval: 0.81-0.96), which was similar to the intraclass correlation coefficient of 0.87 (95% credible interval: 0.81-0.93) achieved using these same slides in a prior visual-reading reproducibility study. Automated machine assessment of average Ki67 has the potential to achieve between-laboratory reproducibility similar to that for a rigorously standardized pathologist-based visual assessment of Ki67. The observed intraclass correlation coefficient was worse for maximum compared to average scoring methods, suggesting that maximum score methods may be suboptimal for consistent measurement of proliferation. Automated average scoring methods show promise for assessment of Ki67 scoring, but requires further standardization and subsequent clinical validation.

6.
Cancer Lett ; 426: 4-13, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29626519

RESUMO

We report that BMI1 promotes tamoxifen resistance in estrogen receptor (ER)-positive breast cancer (BC). BMI1 overexpression conferred MCF7 and TD47 cells resistance to tamoxifen; BMI1 knockdown sensitized the process. In MCF7-derived tamoxifen resistant cells, BMI1 expression was upregulated and BMI1 knockdown reduced the resistance. BMI1 is an oncogene; its oncogenic activity is attributed to BMI1-stimulated E3 ubiquitin ligase activity, a process that requires BMI1's ring finger (RF) domain. However, a BMI1 mutant without RF conferred tamoxifen resistance. Tamoxifen significantly reduced the growth of xenografts derived from MCF7 cells, but accelerated the growth of tumors produced by BMI1 overexpressing MCF7 cells. BMI1 enhances the pathways that promote resistance to endocrine therapy, including ER, androgen receptor, and MUC1. In patients with ER + BCs (n = 177), BMI1 expression was associated with BC recurrence. In the Curtis dataset consisting of ER + BCs (n = 1506) and ER- BCs (n = 474; cBioPortal), upregulations in BMI1 mRNA expression were correlated with ER + BCs; the upregulation was associated with a set of differentially expressed genes (DEGs). These DEGs were enriched with reductions in immunological processes, indicating a role of BMI1 in downregulation of the immune surveillance.

7.
Biochim Biophys Acta Mol Basis Dis ; 1864(3): 735-745, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29248549

RESUMO

SIPL1 inhibits PTEN function and stimulates NF-κB signaling; both processes contribute to resistance to hormone therapy in estrogen receptor positive breast cancer (ER+ BC). However, whether SIPL1 promotes tamoxifen resistance in BC remains unclear. We report here that SIPL1 enhances tamoxifen resistance in ER+ BC. Overexpression of SIPL1 in MCF7 and TD47 cells conferred tamoxifen resistance. In MCF7 cell-derived tamoxifen resistant (TAM-R) cells, SIPL1 expression was upregulated and knockdown of SIPL1 in TAM-R cells re-sensitized the cells to tamoxifen. Furthermore, xenograft tumors produced by MCF7 SIPL1 cells but not by MCF7 empty vector cells resisted tamoxifen treatment. Collectively, we demonstrated a role of SIPL1 in promoting tamoxifen resistance in BC. Increases in AKT activation and NF-κB signaling were detected in both MCF7 SIPL1 and TAM-R cells; using specific inhibitors and unique SIPL1 mutants to inhibit either pathway significantly reduced tamoxifen resistance. A SIPL1 mutant defective in activating both pathways was incapable of conferring resistance to tamoxifen, showing that both pathways contributed to SIPL1-derived resistance to tamoxifen in ER+ BCs. Using the Curtis dataset of breast cancer (n=1980) within the cBioPortal database, we examined a correlation of SIPL1 expression with ER+ BC and resistance to hormone therapy. SIPL1 upregulation strongly associates with reductions in overall survival in BC patients, particularly in patients with hormone naïve ER+ BCs. Taken together, we provide data suggesting that SIPL1 contributes to promote resistance to tamoxifen in BC cells through both AKT and NF-κB actions.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Ubiquitinas/fisiologia , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tamoxifeno/uso terapêutico , Ubiquitinas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Breast Cancer Res ; 19(1): 76, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28668076

RESUMO

BACKGROUND: Natural killer (NK) cells play a critical role in cancer immunosurveillance. Recent developments in NK cell ex-vivo expansion makes it possible to generate millions of activated NK cells from a small volume of peripheral blood. We tested the functionality of ex vivo expanded NK cells in vitro against breast cancer cell lines and in vivo using a xenograft mouse model. The study aim was to assess functionality and phenotype of expanded NK cells from breast cancer patients against breast cancer cell lines and autologous primary tumours. METHODS: We used a well-established NK cell co-culture system to expand NK cells ex vivo from healthy donors and breast cancer patients and examined their surface marker expression. Moreover, we tested the ability of expanded NK cells to lyse the triple negative breast cancer and HER2-positive breast cancer cell lines MDA-MB-231 and MDA-MB-453, respectively. We also tested their ability to prevent tumour growth in vivo using a xenograft mouse model. Finally, we tested the cytotoxicity of expanded NK cells against autologous and allogeneic primary breast cancer tumours in vitro. RESULTS: After 3 weeks of culture we observed over 1000-fold expansion of NK cells isolated from either breast cancer patients or healthy donors. We also showed that the phenotype of expanded NK cells is comparable between those from healthy donors and cancer patients. Moreover, our results confirm the ability of ex vivo expanded NK cells to lyse tumour cell lines in vitro. While the cell lines examined had differential sensitivity to NK cell killing we found this was correlated with level of major histocompatibility complex (MHC) class I expression. In our in vivo model, NK cells prevented tumour establishment and growth in immunocompromised mice. Finally, we showed that NK cells expanded from the peripheral blood of breast cancer patients show high cytotoxicity against allogeneic and autologous patient-derived tumour cells in vitro. CONCLUSION: NK cells from breast cancer patients can be expanded similarly to those from healthy donors, have a high cytotoxic ability against breast cancer cell lines and patient-derived tumour cells, and can be compatible with current cancer treatments to restore NK cell function in cancer patients.


Assuntos
Neoplasias da Mama/imunologia , Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Animais , Biomarcadores , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Imunofenotipagem , Imunoterapia Adotiva , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Knockout , Receptor ErbB-2/metabolismo
9.
Oncotarget ; 8(19): 32101-32116, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28404880

RESUMO

Breast tumors comprise an infrequent tumor cell population, termed breast tumor initiating cells (BTIC), which sustain tumor growth, seed metastases and resist cytotoxic therapies. Hence therapies are needed to target BTIC to provide more durable breast cancer remissions than are currently achieved. We previously reported that serotonergic system antagonists abrogated the activity of mouse BTIC resident in the mammary tumors of a HER2-overexpressing model of breast cancer. Here we report that antagonists of serotonin (5-hydroxytryptamine; 5-HT) biosynthesis and activity, including US Federal Food and Drug Administration (FDA)-approved antidepressants, targeted BTIC resident in numerous breast tumor cell lines regardless of their clinical or molecular subtype. Notably, inhibitors of tryptophan hydroxylase 1 (TPH1), required for 5-HT biosynthesis in select non-neuronal cells, the serotonin reuptake transporter (SERT) and several 5-HT receptors compromised BTIC activity as assessed by functional sphere-forming assays. Consistent with these findings, human breast tumor cells express TPH1, 5-HT and SERT independent of their molecular or clinical subtype. Exposure of breast tumor cells ex vivo to sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), reduced BTIC frequency as determined by transplanting drug-treated tumor cells into immune-compromised mice. Moreover, another SSRI (vilazodone; Viibryd) synergized with chemotherapy to shrink breast tumor xenografts in immune-compromised mice by inhibiting tumor cell proliferation and inducing their apoptosis. Collectively our data suggest that antidepressants in combination with cytotoxic anticancer therapies may be an appropriate treatment regimen for testing in clinical trials.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Expressão Gênica , Humanos , Camundongos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Lung Cancer ; 104: 65-69, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28213002

RESUMO

OBJECTIVES: Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM. METHODS: This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500mg/day for 5days on, 2days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design. RESULTS: 12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1. CONCLUSIONS: Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.


Assuntos
Benzimidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Quinolonas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Indutores da Angiogênese/sangue , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Imagem de Difusão por Ressonância Magnética/métodos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/patologia , Pessoa de Meia-Idade , Ontário , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Quinolonas/efeitos adversos , Quinolonas/farmacologia , Quinolonas/toxicidade , Receptores de Fatores de Crescimento de Fibroblastos/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
11.
PLoS One ; 12(1): e0168669, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28045912

RESUMO

Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.


Assuntos
Neoplasias da Mama/metabolismo , Claudina-1/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Claudina-1/genética , Análise por Conglomerados , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Invasividade Neoplásica , Recidiva Local de Neoplasia , Fenobarbital/metabolismo , Fenótipo , Prognóstico , Resultado do Tratamento
12.
Breast Cancer Res Treat ; 161(1): 117-134, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27796716

RESUMO

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.


Assuntos
Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Biomarcadores Tumorais , Cromossomos Humanos Par 11 , Feminino , Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Humanos , Locos de Características Quantitativas , Risco
13.
BMC Cancer ; 16: 555, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27469239

RESUMO

BACKGROUND: Lymph node (LN) status is the most important prognostic variable used to guide ER positive (+) breast cancer treatment. While a positive nodal status is traditionally associated with a poor prognosis, a subset of these patients respond well to treatment and achieve long-term survival. Several gene signatures have been established as a means of predicting outcome of breast cancer patients, but the development and indication for use of these assays varies. Here we compare the capacity of two approved gene signatures and a third novel signature to predict outcome in distinct LN negative (-) and LN+ populations. We also examine biological differences between tumours associated with LN- and LN+ disease. METHODS: Gene expression data from publically available data sets was used to compare the ability of Oncotype DX and Prosigna to predict Distant Metastasis Free Survival (DMFS) using an in silico platform. A novel gene signature (Ellen) was developed by including patients with both LN- and LN+ disease and using Prediction Analysis of Microarrays (PAM) software. Gene Set Enrichment Analysis (GSEA) was used to determine biological pathways associated with patient outcome in both LN- and LN+ tumors. RESULTS: The Oncotype DX gene signature, which only used LN- patients during development, significantly predicted outcome in LN- patients, but not LN+ patients. The Prosigna gene signature, which included both LN- and LN+ patients during development, predicted outcome in both LN- and LN+ patient groups. Ellen was also able to predict outcome in both LN- and LN+ patient groups. GSEA suggested that epigenetic modification may be related to poor outcome in LN- disease, whereas immune response may be related to good outcome in LN+ disease. CONCLUSIONS: We demonstrate the importance of incorporating lymph node status during the development of prognostic gene signatures. Ellen may be a useful tool to predict outcome of patients regardless of lymph node status, or for those with unknown lymph node status. Finally we present candidate biological processes, unique to LN- and LN+ disease, that may indicate risk of relapse.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metástase Linfática/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Receptor ErbB-2/biossíntese , Receptores Estrogênicos/biossíntese , Tamoxifeno/uso terapêutico
14.
Mod Pathol ; 29(10): 1155-64, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27363491

RESUMO

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.


Assuntos
Neoplasias da Mama/imunologia , Interpretação de Imagem Assistida por Computador/normas , Linfócitos do Interstício Tumoral/imunologia , Patologia Clínica/normas , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Linfócitos do Interstício Tumoral/patologia , Patologia Clínica/métodos
15.
NPJ Breast Cancer ; 2: 16014, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28721378

RESUMO

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81-0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999-0.93) and hot-spot methods (0.84; 95% CI: 0.77-0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.

16.
Rare Tumors ; 7(2): 5698, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-26266008

RESUMO

Plasmacytoid melanoma is an unusual variant of malignant melanoma. The plasmacytoid morphology can be found in a variety of other malignancies including carcinomas, plasma cell neoplasms, lymphoproliferative disorders, and sarcomas. The authors report a rare case of plasmacytoid amelanotic malignant melanoma in a 78-year-old man presenting with an enlarging palpable, erythematous mass on his left posterior shoulder. A fine needle aspirate showed atypical findings with single amelanotic cells with high nuclear to cytoplasmic ratio, mono- and multi-nucleation with prominent nucleoli and intranuclear inclusions. Review of the excision and immunohistochemical analysis revealed the malignant plasmacytoid cells stained with vimentin, S-100, HMB-45, and other staining patterns consistent with melanoma. Initial evaluation was negative for other sites of disease. However, 4 months later, the patient was noted to have metastatic disease to his lungs and liver. Given that the tumor was noted to be BRAF V600R mutated, the patient was started on single agent dabrafenib. The plasmacytoid morphology can be found in a variety of malignancies. Melanoma should be considered in the differential diagnosis of any malignancy presenting with plasmacytoid features.

17.
Oncotarget ; 6(19): 17713-24, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25991675

RESUMO

PURPOSE: Basal-like breast cancer (BLBC) is a molecular subtype of breast cancer associated with poor clinical outcome, although some patients with BLBC experience long-term survival. Apart from nodal status, current clinical/histopathological variables show little capacity to identify BLBC patients at either high- or low-risk of disease recurrence. Accordingly, we sought to develop a network based genomic predictor for predicting the outcome of patients with BLBC. EXPERIMENTAL DESIGN: We performed network analysis on global gene expression profiling data of BLBCs, and identified BLBC network modules associated with AP-1 transcription, G-protein coupled receptors, and T-, B-, and NK-cells that are significant predictors of BLBC patient survival. RESULTS: In gene expression and tissue microarray (TMA) validation cohorts of 210 and 102 BLBC patients, respectively, the identified network modules were robustly associated with patient outcome. In the gene expression validation cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 90%, whereas in the high-risk group it was a 56%. In the TMA cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 98%, whereas in the high-risk group it was 71%. CONCLUSIONS: The capacity to distinguish between patients with BLBC at high- or low-risk of recurrence at the time of diagnosis could permit timely intervention with more aggressive therapeutic regimens in those patients predicted to be high-risk, and to avoid such therapy in low-risk patients.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Perfilação da Expressão Gênica/métodos , Feminino , Humanos , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de Tecidos
18.
Curr Med Chem ; 22(19): 2360-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25882671

RESUMO

Estrogen receptor-alpha positive (ER(+)) breast cancer constitutes 70-75% of the disease incidence. Tamoxifen has been the basis of endocrine therapy for patients with ER(+) breast cancer for more than three decades. The treatment reduces the annual mortality rate of breast cancer by 31%, and remains the most effective targeted cancer therapy. However, approximately one-third of patients treated with adjuvant tamoxifen suffer from aggressive recurrent disease. Resistance to tamoxifen, thus, remains a major challenge in providing effective treatments for these patients. In an effort to overcome the resistance, intensive research has been conducted to understand the underlying mechanisms; this has resulted in the identification of complex factors/pathways contributing to tamoxifen resistance, including modulations of the ERsignaling, upregulation of a set of growth factor receptor networks (HER2, EGFR, FGFR, and IGF1R), alterations of the PI3K-PTEN/AKT/mTOR pathway, and an elevation of the NF-κB signaling. Despite these advances, our understanding of the acquired resistance remains fragmented and there is a lack of a platform to integrate these diversified molecular factors/ pathways into a cohesive mechanistic model. Nonetheless, at the cellular level, it is becoming increasingly recongnized that cancer stem cells (CSCs) are key in driving cancer metastasis and therapy resistance. Likewise, evidence is emerging for the critical contributions of breast cancer stem cells (BCSCs) to tamoxifen resistance. In this review, we will discuss these recent developments of BCSC-mediated resistance to tamoxifen and the contributions of those demonstrated molecular factors/pathways to BCSC expansion during the emergency of tamoxifen resistance.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tamoxifeno/química
19.
Mod Pathol ; 28(6): 778-86, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25698062

RESUMO

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Imuno-Histoquímica/normas , Antígeno Ki-67/análise , Análise Serial de Tecidos/normas , Feminino , Humanos
20.
Breast Cancer Res Treat ; 149(1): 293-301, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25542270

RESUMO

We determined the expression of two transcriptional variants of thyroid hormone receptor alpha (THRα1 and THRα2) in samples from a cohort of breast cancer patients and correlated expression levels with survival. 130 women who were diagnosed with invasive breast carcinoma between 2007 and 2008 were included. Representative sections of their tumours were analyzed in triplicate on a tissue microarray for expression of THRα1 and THRα2 by immunohistochemistry. The prognostic significance of THRα1 and THRα2 expression was assessed using Kaplan-Meier survival analyses, adjusted for known prognostic factors. Seventy-four percent of tumours had high expression of THRα1 (Allred score ≥6) and 40 % had high expression of THRα2. Expression of THRα2 correlated positively with ER expression (p < 0.001) and with PR expression (p < 0.001), but negatively with HER2 expression (p = 0.018). Patients with low THRα2 expression had inferior 5-year overall survival (75.3 %) compared to those with high expression (91.7 %; p = 0.06). In a multivariate model, high THRα2 expression was a significant and independent prognosticator of improved overall survival (HR = 0.84; 95 % CI 0.71-0.98). Many breast tumours express THRα2 at high levels and these patients experience improved survival. Thyroid hormone signalling may be important in a proportion of breast cancers and THRα2 expression may be a regulator of signalling in this pathway.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/sangue , Receptor ErbB-2/biossíntese , Receptores alfa dos Hormônios Tireóideos/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Transdução de Sinais , Receptores alfa dos Hormônios Tireóideos/sangue
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