RESUMO
The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.
Assuntos
Bancos de Espécimes Biológicos , Neoplasias da Mama , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Biomarcadores Farmacológicos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Testes Farmacogenômicos , Células Tumorais CultivadasRESUMO
Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.
Assuntos
Imunoterapia , Linfócitos T , Neoplasias de Mama Triplo Negativas , Humanos , Linfócitos B/imunologia , Biópsia , Linfócitos T CD8-Positivos/imunologia , Granzimas/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos CD15/metabolismo , Terapia Neoadjuvante , Medicina de Precisão , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/genética , Receptores de Estrogênio/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Modelos Biológicos , Metástase Neoplásica/genética , Recidiva Local de Neoplasia/patologia , Especificidade de Órgãos , Prognóstico , Receptor ErbB-2/deficiência , Receptor ErbB-2/genética , Receptores de Estrogênio/análise , Receptores de Estrogênio/deficiência , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Luminal breast cancers with high proliferation (MKShi) and low ER-related signalling (ERSlo) have a poor prognosis. We investigated treatment responses and molecular features of MKShi/ERSlo tumours to inform potential therapies. METHODS: Gene expression data from patients who received neoadjuvant chemotherapy (NAC) without (MDACC, N = 199) or with pembrolizumab (I-SPY2, N = 40), or endocrine therapy (NET) without (POETIC, N = 172) or with palbociclib (NeoPalAna, N = 32) were analyzed to assess treatment response by MKS/ERS-subgroups. TCGA was used to assess the mutational landscape and biomarkers associated with palbociclib-resistance (Cyclin-E, RBsig, IRPR) and immunotherapy-response (TMB, TILs, T-cell inflamed) by MKS/ERS-subgroups. RESULTS: Compared to MKShi/ERShi tumours, MKShi/ERSlo tumours had higher pathological response rates to NAC (22% vs 8%, p = 0.06) but a higher recurrence risk (4-year metastasis-free survival 70% vs 94%, p = 0.01). MKShi/ERSlo tumours frequently harboured TP53 (34%) and PIK3CA (33%) mutations, and showed high expression of Cyclin-E, RBsig and IRPR, high TMB and elevated TIL and T-cell inflamed metagene expression. MKShi/ERSlo tumours retained high proliferation after NET with or without palbociclib but had higher pathological complete response rates when pembrolizumab was added to NAC (42% vs 21%, p = 0.07). CONCLUSIONS: MKShi/ERSlo tumours have dismal outcomes and are enriched in chemotherapy-sensitive but ET- and palbociclib-resistant tumours. Biomarker analysis and clinical data suggest a potential role for immunotherapy in this group.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Biomarcadores , Intervalo Livre de Doença , Proliferação de Células , Ciclinas/uso terapêutico , Terapia Neoadjuvante , PrognósticoRESUMO
Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively. Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug. The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.
Assuntos
Lipossarcoma Mixoide , Adulto , Animais , Modelos Animais de Doenças , Humanos , Lipossarcoma Mixoide/tratamento farmacológico , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Camundongos , Trabectedina/uso terapêuticoRESUMO
Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.
Assuntos
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Estruturas Linfoides Terciárias , Humanos , Mesotelioma/genética , Neoplasias Pleurais/genética , Sobreviventes , Estruturas Linfoides Terciárias/patologia , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Patient-Derived Tumour Xenografts (PDTXs) have emerged as the pre-clinical models that best represent clinical tumour diversity and intra-tumour heterogeneity. The molecular characterization of PDTXs using High-Throughput Sequencing (HTS) is essential; however, the presence of mouse stroma is challenging for HTS data analysis. Indeed, the high homology between the two genomes results in a proportion of mouse reads being mapped as human. RESULTS: In this study we generated Whole Exome Sequencing (WES), Reduced Representation Bisulfite Sequencing (RRBS) and RNA sequencing (RNA-seq) data from samples with known mixtures of mouse and human DNA or RNA and from a cohort of human breast cancers and their derived PDTXs. We show that using an In silico Combined human-mouse Reference Genome (ICRG) for alignment discriminates between human and mouse reads with up to 99.9% accuracy and decreases the number of false positive somatic mutations caused by misalignment by >99.9%. We also derived a model to estimate the human DNA content in independent PDTX samples. For RNA-seq and RRBS data analysis, the use of the ICRG allows dissecting computationally the transcriptome and methylome of human tumour cells and mouse stroma. In a direct comparison with previously reported approaches, our method showed similar or higher accuracy while requiring significantly less computing time. CONCLUSIONS: The computational pipeline we describe here is a valuable tool for the molecular analysis of PDTXs as well as any other mixture of DNA or RNA species.
Assuntos
Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Perfilação da Expressão Gênica , Humanos , Camundongos , Mutação , Alinhamento de Sequência , Análise de Sequência de DNA , Análise de Sequência de RNARESUMO
BACKGROUND: Interactions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value. METHODS: Gene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples. RESULTS: Plasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n = 57 each) and SPARC (n = 90 each). Higher plasma levels of COL10A1 were detected in patients (p ≤ 0.001), a difference that was driven specifically by females (p < 0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p < 0.001) with good performance in discriminating the two groups (AUC = 0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival. CONCLUSION: Soluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Colágeno Tipo XI/sangue , Colágeno Tipo X/sangue , Osteonectina/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , Intervalo Livre de Doença , Matriz Extracelular , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Caracteres Sexuais , FumantesRESUMO
Metachronous (MBC) and synchronous bilateral breast tumors (SBC) are mostly distinct primaries, whereas paired primaries and their local recurrences (LRC) share a common origin. Intra-pair gene expression variability in MBC, SBC, and LRC derives from time/tumor microenvironment-related and tumor genetic background-related factors and pairs represents an ideal model for trying to dissect tumor-related from microenvironment-related variability. Pairs of tumors derived from women with SBC (n = 18), MBC (n = 11), and LRC (n = 10) undergoing local-regional treatment were profiled for gene expression; similarity between pairs was measured using an intraclass correlation coefficient (ICC) computed for each gene and compared using analysis of variance (ANOVA). When considering biologically unselected genes, the highest correlations were found for primaries and paired LRC, and the lowest for MBC pairs. By instead limiting the analysis to the breast cancer intrinsic genes, correlations between primaries and paired LRC were enhanced, while lower similarities were observed for SBC and MBC. Focusing on stromal-related genes, the ICC values decreased for MBC and were significantly different from SBC. These findings indicate that it is possible to dissect intra-pair gene expression variability into components that are associated with genetic origin or with time and microenvironment by using specific gene subsets.
Assuntos
Neoplasias da Mama/patologia , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Fatores de Risco , Microambiente TumoralRESUMO
Cancer is a complex disease, driven by the accumulation of several somatic aberrations but fostered by a two-way interaction between tumour cells and the surrounding microenvironment. Cancer associated fibroblasts (CAFs) represent one of the major players in tumour-stroma crosstalk. Recent in vitro and in vivo studies, often conducted by employing high throughput approaches, have started unravelling the key pathways involved in their functional effects. This review focus on open challenges in the study of CAF properties and function, highlighting at the same time the existence of common mechanisms as well as peculiarities in different cancer types (breast, prostate and lung cancer). Although still limited by current experimental models, which are unable to deal with the full level of complexity of the tumour microenvironment, a better understanding of these mechanisms may enable the identification of new biomarkers and therapeutic targets, to improve current strategies for cancer diagnosis and treatment.
Assuntos
Comunicação Celular , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/patologia , Células Estromais/metabolismo , Microambiente Tumoral , Animais , Biomarcadores , Comunicação Celular/genética , Matriz Extracelular , Fibroblastos/patologia , Humanos , Metanálise como Assunto , Neoplasias/metabolismo , Transdução de Sinais , Células Estromais/patologia , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is available, i.e., that of hemolysis-related miRNAs deregulation, so as to compare our results with existing evidence. RESULTS: We developed a structured strategy with innovative applications of existing bioinformatics methods for supervised analyses including: 1) the combination of two statistical (t- and Anderson-Darling) test results to detect miRNAs with significant fold change or general distributional differences in class comparison, which could reveal hidden differential biological processes worth to be considered for building predictive tools; 2) a bootstrap selection procedure together with machine learning techniques in class prediction to guarantee the transferability of results and explore the interconnections among the selected miRNAs, which is important for highlighting their inherent biological dependences. The strategy was applied to develop a classifier for discriminating between hemolyzed and not hemolyzed plasma samples, defined according to a recently published hemolysis score. We identified five miRNAs with increased expression in hemolyzed plasma samples (miR-486-5p, miR-92a, miR-451, miR-16, miR-22). CONCLUSIONS: We identified four miRNAs previously reported in the literature as hemolysis related together with a new one (miR-22).which needs further investigations. Our findings confirm the validity of the proposed strategy and, in parallel, the hemolysis score capability to be used as pre-analytic hemolysis detector. R codes for implementing the approaches are provided.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/genética , Hemólise/genética , MicroRNAs/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genéticaRESUMO
BACKGROUND: Determining the transcriptional profile of circulating tumor cells (CTCs) may allow the acquisition of clinically relevant information while overcoming tumor heterogeneity-related biases associated with use of tissue samples for biomarker assessment. However, such molecular characterization is challenging because CTCs are rare and outnumbered by blood cells. METHODS: Here, we describe a technical protocol to measure the expression of >29 000 genes in CTCs captured from whole blood with magnetic beads linked with antibodies against epithelial cell adhesion molecule (EpCAM) and the carcinoma-associated mucin, MUC1, designed to be used for CTC characterization in clinical samples. Low numbers of cells (5-200) from the MCF7 and MDA-MB-468 breast cancer cell lines were spiked in healthy donor blood samples and isolated with the AdnaTest EMT-1/Stem CellSelect kit. Gene expression profiles (GEPs) were obtained with the WG-DASL HT assay and compared with GEPs obtained from RNA isolated from cultured cell lines and unspiked samples. RESULTS: GEPs from samples containing 25 or more spiked cells correlated (r = 0.95) with cognate 100-ng RNA input samples, clustered separately from blood control samples, and allowed MCF7 and MDA-MB-468 cells to be distinguished. GEPs with comparable technical quality were also obtained in a preliminary series of clinical samples. CONCLUSIONS: Our approach allows technically reliable GEPs to be obtained from isolated CTCs for the acquisition of biologically useful information. It is reproducible and suitable for application in prospective studies to assess the clinical utility of CTC GEPs, provided that >25 CTCs can be isolated.
Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Células Neoplásicas Circulantes/metabolismo , Transcriptoma/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Técnicas de Cultura de Células , Feminino , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Células MCF-7 , Células Neoplásicas Circulantes/patologiaRESUMO
Over recent years, analyses of secretomes (complete sets of secreted proteins) have been reported in various organisms, cell types, and pathologies and such studies are quickly gaining popularity. Fungi secrete enzymes can break down potential food sources; plant secreted proteins are primarily parts of the cell wall proteome; and human secreted proteins are involved in cellular immunity and communication, and provide useful information for the discovery of novel biomarkers, such as for cancer diagnosis. Continuous development of methodologies supports the wide identification and quantification of secreted proteins in a given cellular state. The role of secreted factors is also investigated in the context of the regulation of major signaling events, and connectivity maps are built to describe the differential expression and dynamic changes of secretomes. Bioinformatics has become the bridge between secretome data and computational tasks for managing, mining, and retrieving information. Predictions can be made based on this information, contributing to the elucidation of a given organism's physiological state and the determination of the specific malfunction in disease states. Here we provide an overview of the available bioinformatics databases and software that are used to analyze the biological meaning of secretome data, including descriptions of the main functions and limitations of these tools. The important challenges of data analysis are mainly related to the integration of biological information from dissimilar sources. Improvements in databases and developments in software will likely substantially contribute to the usefulness and reliability of secretome studies. This article is part of a Special Issue entitled: An Updated Secretome.
Assuntos
Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Biologia de Sistemas/métodos , Animais , Bases de Dados de Proteínas , Humanos , SoftwareRESUMO
BACKGROUND: Cellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis. The epithelial to mesenchymal transition (EMT) is a transcriptional programme associated with increased cell motility and stemness. Besides EMT, the mesenchymal to amoeboid transition (MAT) has been described during tumour progression but to date, little is known about its transcriptional control and involvement in stemness. The aim of this manuscript is to investigate (i) the transcriptional profile associated with the MAT programme and (ii) to study whether MAT acquisition in melanoma cancer cells correlates with clonogenic potential to promote tumour growth. RESULTS: By using a multidisciplinary approach, we identified four different treatments able to induce MAT in melanoma cells: EphA2 overexpression, Rac1 functional inhibition using its RacN17 dominant negative mutant, stimulation with Ilomastat or treatment with the RhoA activator Calpeptin. First, gene expression profiling identified the transcriptional pathways associated with MAT, independently of the stimulus that induces the MAT programme. Notably, gene sets associated with the repression of mesenchymal traits, decrease in the secretion of extracellular matrix components as well as increase of cellular stemness positively correlate with MAT. Second, the link between MAT and stemness has been investigated in vitro by analysing stemness markers and clonogenic potential of melanoma cells undergoing MAT. Finally, the link between MAT inducing treatments and tumour initiating capability has been validated in vivo. CONCLUSION: Taken together, our results demonstrate that MAT programme in melanoma is characterised by increased stemness and clonogenic features of cancer cells, thus sustaining tumour progression. Furthermore, these data suggest that stemness is not an exclusive feature of cells undergoing EMT, but more generally is associated with an increase in cellular plasticity of cancer cells.
Assuntos
Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Melanoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Dipeptídeos/farmacologia , Humanos , Melanoma/patologia , Células-Tronco Neoplásicas/fisiologia , Receptor EphA2/genética , Receptor EphA2/metabolismo , Transcrição Gênica , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/agonistas , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Importance: Clinical trials are the path to test and introduce new therapies in the clinic. Trials that are unable to produce results represent inefficiency in the system and may also undermine patient confidence in the new drug development process. Objectives: To survey the immunotherapy clinical trial landscape of breast cancer between January 2004 and April 2023 and examine what fraction of trials with primary completion date up to November 30, 2022, failed to report outcome, assessing the proportion of trials that yielded positive results and describing trial features associated with these 2 outcomes. Design, Setting, and Participants: This cross-sectional study included breast cancer immunotherapy trials identified in ClinicalTrials.gov. Trial details and results were retrieved in December 2023. Google Scholar, PubMed, and LARVOL CLIN websites were also searched for reports. Main Outcomes and Measures: Trial outcome reported as abstract or manuscript. Reported trials were categorized as positive (ie, met its end point) or negative. Association between reporting and trial features were tested using Fisher exact test. Results: A total of 331 immuno-oncology trials were initiated in breast cancer by April 2023; 242 trials were phase II, 47 were phase I, and 42 phase III. By setting, 212 studies (64.0%) were conducted in metastatic, 94 (28.4%) in neoadjuvant, and 25 (7.6%) in adjuvant settings. Among phase II and III trials, 168 (59.2%) were nonrandomized. One hundred twenty trials had primary completion dates up to November 30, 2022, of which 30 (25.0%; enrolling a combined 2428 patients) failed to report their outcomes; 7 phase I trials (31.8%), 21 phase II trials (23.6%), and 2 phase III trials (22.2%) were unreported. Single-center studies were significantly more likely to be unreported than multicenter studies (19 of 54 [35.2%] vs 9 of 60 [15.0%]; P = .02). Of the 90 reported trials, 47 (52.2%) and 43 (47.8%) were positive and negative, respectively. Seventeen of 19 (89.5%) of the reported randomized trials (accruing a total of 4189 patients) were negative. Conclusions and Relevance: In this cross-sectional study of immunotherapy breast cancer trials, the large number of trials yielded modest clinical impact. Single-center trials commonly failed to report their outcomes and many phase II studies have not translated into corresponding successful phase III trials.
Assuntos
Neoplasias da Mama , Ensaios Clínicos como Assunto , Imunoterapia , Humanos , Neoplasias da Mama/terapia , Neoplasias da Mama/tratamento farmacológico , Feminino , Imunoterapia/métodos , Imunoterapia/estatística & dados numéricos , Estudos TransversaisRESUMO
The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.
Assuntos
Neoplasias , Medicina de Precisão , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/diagnóstico , Medicina de Precisão/métodos , Terapia de Alvo Molecular/métodos , Procedimentos ClínicosRESUMO
The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Genômica/métodos , Microambiente TumoralRESUMO
MicroRNAs have been found to be deregulated in several diseases and, due to their high stability in body fluids, represent promising noninvasively detectable biomarkers. However, numerous technical variables can affect accurate measurement of circulating miRNAs. Using a microarray-based method we assessed the: (i) adequate intra- and inter-array reproducibility of miRNA profiling; (ii) feasibility of using archival plasma samples stored for an extended period of time and available in limited amounts; (iii) good correlation between different batches; and (iv) time-dependent increase of background signals close to the chip expiration date.
Assuntos
MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Reprodutibilidade dos Testes , Preservação de Tecido , TranscriptomaRESUMO
Tau (MAPT) is a microtubule-associated protein causing common neurodegenerative diseases or rare inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA repair and P53 regulation suggests its involvement in cancer. To bring new evidence for a relevant role of Tau in cancer, we carried out an in-silico pan-cancer analysis of MAPT transcriptomic profile in over 10000 clinical samples from 32 cancer types and over 1300 pre-clinical samples from 28 cancer types provided by the TCGA and the DEPMAP datasets respectively. MAPT expression associated with key cancer hallmarks including inflammation, proliferation, and epithelial to mesenchymal transition, showing cancer-specific patterns. In some cancer types, MAPT functional networks were affected by P53 mutational status. We identified new associations of MAPT with clinical outcomes and drug response in a context-specific manner. Overall, our findings indicate that the MAPT gene is a potential major player in multiple types of cancer. Importantly, the impact of Tau on cancer seems to be heavily influenced by the specific cellular environment.