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1.
Cancer Radiother ; 25(4): 358-365, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33676830

RESUMO

PURPOSE: Breast protontherapy efficiently limits cardiac, lung and contralateral breast exposure, which may clinically translate into better late tolerance profile compared with classic photon techniques. While breast protontherapy is already implemented in the United States and in some European countries, clinical experience of breast cancer protontherapy is currently limited in France. The aim of this study is to evaluate the clinical practice of breast cancer protontherapy at the Institut Curie in order to implement this technique at a larger scale. MATERIALS AND METHODS: Data from all breast cancer patients that have been addressed to the protontherapy centre of Orsay (CPO, Institut Curie) for adjuvant breast protontherapy were retrieved. We analysed why these patients were ultimately treated with protontherapy or not. RESULTS: Between November 2019 and November 2020, eleven breast cancer patients have been evaluated for adjuvant protontherapy at the CPO. Two of them were ultimately treated with proton beams; adjuvant breast protontherapy therapy was well tolerated. The nine other patients were not treated with protontherapy due to lack of availability of protontherapy treatment rooms in acceptable time limits, at the time of patient evaluation. CONCLUSION: Despite dosimetric advantages and excellent clinical tolerance, lack of availability of protontherapy machines currently limits wider implementation of breast protontherapy.


Assuntos
Neoplasias da Mama/radioterapia , Terapia com Prótons , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Cardiotoxicidade/prevenção & controle , Feminino , França , Genes BRCA1 , Humanos , Mutação , Seleção de Pacientes , Terapia com Prótons/estatística & dados numéricos , Lesões por Radiação/prevenção & controle , Radioterapia Adjuvante/estatística & dados numéricos , Radioterapia de Intensidade Modulada , Reirradiação , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/cirurgia , Neoplasias Unilaterais da Mama/tratamento farmacológico , Neoplasias Unilaterais da Mama/genética , Neoplasias Unilaterais da Mama/radioterapia , Neoplasias Unilaterais da Mama/cirurgia , Adulto Jovem
2.
Int J Nanomedicine ; 16: 851-865, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574666

RESUMO

Background: Ionizing radiation (IR) is commonly used in triple-negative breast cancer (TNBC) treatment regimens. However, off-target toxicity affecting normal tissue and grueling treatment regimens remain major limitations. Hyperthermia is one of the greatest IR sensitizers, but only if heat is administered simultaneously or immediately prior to ionizing radiation. Difficulty in co-localizing ionizing radiation (IR) in rapid succession with hyperthermia, and confining treatment to the tumor have hindered widespread clinical adoption of combined thermoradiation treatment. Metal nanoparticle-based approaches to IR sensitization and photothermal heat generation may aid in overcoming these issues and improve treatment specificity. Methods: We assessed the potential to selectively treat MDA-MB-231 TNBC cells without affecting non-malignant MCF-10A breast cells using a multimodal approach based upon combined photothermal therapy, IR sensitization, and specific cytotoxicity using triangular silver nanoparticles (TAgNPs) with peak absorbance in the near-infrared light (NIR) spectrum. Results: We found that TAgNP-mediated photothermal therapy and radiosensitization offer a high degree of specificity for treatment of TNBC without affecting non-malignant mammary epithelial cells. Discussion: If given at a high enough dose, IR, heat, or TAgNPs alone could be sufficient for tumor treatment. However, when the dose of one or all of these modalities increases, off-target effects also increase. The challenge lies in identifying the minimal doses of each individual treatment such that when combined they provide maximum selectivity for treatment of TNBC cells with minimum off-target effects on non-malignant breast cells. Our results provide proof of concept that this combination is highly selective for TNBC cells while sparing non-malignant mammary epithelial cells. This treatment would be particularly important for patients undergoing breast conservation therapy and for treatment of invasive tumor margins near the periphery where each individual treatment might be at a sub-therapeutic level.


Assuntos
Nanopartículas Metálicas/uso terapêutico , Terapia Fototérmica , Radiação Ionizante , Prata/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinogênese/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Feminino , Humanos , Raios Infravermelhos , Nanopartículas Metálicas/ultraestrutura , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Prata/farmacologia , Neoplasias de Mama Triplo Negativas/patologia
3.
Nucleic Acids Res ; 48(18): 10342-10352, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32894284

RESUMO

Ribosomal DNA (rDNA) consists of highly repeated sequences that are prone to incurring damage. Delays or failure of rDNA double-strand break (DSB) repair are deleterious, and can lead to rDNA transcriptional arrest, chromosomal translocations, genomic losses, and cell death. Here, we show that the zinc-finger transcription factor GLI1, a terminal effector of the Hedgehog (Hh) pathway, is required for the repair of rDNA DSBs. We found that GLI1 is activated in triple-negative breast cancer cells in response to ionizing radiation (IR) and localizes to rDNA sequences in response to both global DSBs generated by IR and site-specific DSBs in rDNA. Inhibiting GLI1 interferes with rDNA DSB repair and impacts RNA polymerase I activity and cell viability. Our findings tie Hh signaling to rDNA repair and this heretofore unknown function may be critically important in proliferating cancer cells.


Assuntos
DNA Ribossômico/genética , Proteínas Hedgehog/genética , RNA Polimerase I/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Proteína GLI1 em Dedos de Zinco/genética , Proteínas de Ciclo Celular/genética , Nucléolo Celular/genética , Nucléolo Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , DNA Ribossômico/efeitos da radiação , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/efeitos da radiação , Humanos , RNA Polimerase I/efeitos da radiação , Radiação Ionizante , Ribossomos/genética , Ribossomos/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Transcrição Genética/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
4.
Mol Carcinog ; 59(5): 533-544, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32181526

RESUMO

Elevated expression of Copine 1 (CPNE1) has been observed in multiple cancers; however, the underlying mechanisms by which it affects cancer cells are unclear. We aimed to study the effect of CPNE1 on the tumorigenesis and radioresistance of triple-negative breast cancer (TNBC). Quantitative real-time polymerase chain reaction was used to detect the expression of CPNE1 in TNBC tissues and cell lines. Western blot, immunohistochemistry, and immunofluorescence were used to investigate the levels of CPNE1, p-AKT, AKT, cleaved caspase-3, cleaved PARP1, and γ-H2AX. Cell viability and apoptosis were measured by CCK-8 and flow cytometry, respectively. CPNE1 was overexpressed in TNBC tissues and cell lines and was associated with tumor size, distant metastases, and survival rates of patients with TNBC. Moreover, function study shows that CPNE1 promoted cell viability and inhibited cell apoptosis in vitro and inhibited the radiosensitivity of TNBC. Importantly, inactivation of AKT signaling inhibited the tumorigenesis and radioresistance mediated by CPNE1 in TNBC cells. In vivo xenograft study also shows that CPNE1 knockdown inhibited tumor growth and promoted cell apoptosis. Overall, our findings suggest that CPNE1 promotes tumorigenesis and radioresistance in TNBC by regulating AKT activation and targeted CPNE1 expression may be a strategy to sensitize TNBC cells toward radiation therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proliferação de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tolerância a Radiação , Neoplasias de Mama Triplo Negativas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/genética , Estudos de Coortes , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Br J Radiol ; 93(1106): 20190742, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778316

RESUMO

OBJECTIVE: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. METHODS: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. RESULTS: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. CONCLUSION: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas , Radiossensibilizantes/farmacologia , Antineoplásicos/farmacocinética , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Docetaxel/farmacocinética , Sinergismo Farmacológico , Feminino , Ouro/farmacocinética , Células HeLa , Humanos , Radiossensibilizantes/farmacocinética , Neoplasias de Mama Triplo Negativas/radioterapia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/radioterapia
6.
Radiother Oncol ; 142: 202-209, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31767471

RESUMO

INTRODUCTION: We analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells. MATERIALS AND METHODS: scRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand-receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells. RESULTS: Most RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand-receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand-receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells. CONCLUSIONS: RR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Linfócitos T/imunologia , Adulto , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Comunicação Celular/imunologia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , RNA/genética , Tolerância a Radiação/genética , Análise de Sequência de RNA , Linfócitos T/patologia , Transcriptoma , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia
7.
Asian Pac J Cancer Prev ; 20(12): 3679-3687, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31870109

RESUMO

BACKGROUND: Radioresistance remains a challenge for cancer radiotherapy. The present study aims to investigate the role of TMPRSS4 in triple negative breast cancer (TNBC) cell radiosensitivity. MATERIALS AND METHODS: After transfection of MDA-MD-468 triple negative breast cancer cells line by using the lentivirus vector, the effect of TMPRSS4 down-regulation on TNBC radiosensitivity was evaluated by using cloning assay and CCK-8 assay. The CCK-8 assay was also used for performing cell proliferation analysis. Western blot was carried out to detect the expression of certain proteins related to cell cycle pathways (cyclin D1), cell apoptosis pathways (Bax, Bcl2, and Caspase3), DNA damage and DNA damage repair (TRF2, Ku80 , Ë H2AX) . The cell cycle and cell apoptosis were also investigated using flow cytometer analysis. RESULTS: TMPRSS4 expression was down-regulated in MDA-MB-468 cells which enhanced MDA-MB-468 cells radiosensitivity. TMPRSS4 silencing also improved IR induced cell proliferation ability reduction and promoted cell arrested at G2/M phase mediated by 6 Gy IR associated with cyclin D1 expression inhibition. Moreover, TMPRSS4 inhibition enhanced TNBC apoptosis induced by 6 Gy IR following by over-expression of (Bax, Caspase3) and down-regulation of Bcl2 as the pro-apoptotic and anti-apoptotic proteins, respectively. Otherwise, TMPRSS4 down-regulation increases  DNA damage induced by 6 Gy IR and delays DNA damage repair respectively illustrated by downregulation of TRF2 and permanent increase of Ku80 and Ë H2AX expression at 1 h and 10 h post-IR. CONCLUSION: Down-regulation of TMPRSS4 increases triple negative breast cancer cell radiosensitivity and the use of TMPRSS4 inhibitor can be encouraged for improving radiotherapy effectiveness in TNBC radioresistant patients.


Assuntos
Apoptose/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Tolerância a Radiação/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação para Baixo/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Humanos
8.
Int J Mol Sci ; 20(19)2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591311

RESUMO

Proton therapy offers a distinct physical advantage over conventional X-ray therapy, but its biological advantages remain understudied. In this study, we aimed to identify genetic factors that contribute to proton sensitivity in breast cancer (BC). Therefore, we screened relative biological effectiveness (RBE) of 230 MeV protons, compared to 6 MV X-rays, in ten human BC cell lines, including five triple-negative breast cancer (TNBC) cell lines. Clonogenic survival assays revealed a wide range of proton RBE across the BC cell lines, with one out of ten BC cell lines having an RBE significantly different from the traditional generic RBE of 1.1. An abundance of cyclin D1 was associated with proton RBE. Downregulation of RB1 by siRNA or a CDK4/6 inhibitor increased proton sensitivity but not proton RBE. Instead, the depletion of cyclin D1 increased proton RBE in two TNBC cell lines, including MDA-MB-231 and Hs578T cells. Conversely, overexpression of cyclin D1 decreased the proton RBE in cyclin D1-deficient BT-549 cells. The depletion of cyclin D1 impaired proton-induced RAD51 foci formation in MDA-MB-231 cells. Taken together, this study provides important clues about the cyclin D1-CDK4-RB1 pathway as a potential target for proton beam therapy in TNBC.


Assuntos
Ciclina D1/genética , Tolerância a Radiação , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Células MCF-7 , Terapia com Prótons , Eficiência Biológica Relativa , Transdução de Sinais/efeitos da radiação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Raios X
9.
Breast Cancer Res ; 21(1): 116, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640747

RESUMO

BACKGROUND: Triple-negative breast cancer has extremely high risk of relapse due to the lack of targeted therapies, intra- and inter-tumoral heterogeneity, and the inherent and acquired resistance to therapies. In this study, we evaluate the potential of prostate-specific membrane antigen (PSMA) as target for radio-ligand therapy (RLT). METHODS: Tube formation was investigated after incubation of endothelial HUVEC cells in tumor-conditioned media and monitored after staining using microscopy. A binding study with 68Ga-labeled PSMA-addressing ligand was used to indicate targeting potential of PSMA on tumor-conditioned HUVEC cells. For mimicking of the therapeutic application, tube formation potential and vitality of tumor-conditioned HUVEC cells were assessed following an incubation with radiolabeled PSMA-addressing ligand [177Lu]-PSMA-617. For in vivo experiments, NUDE mice were xenografted with triple-negative breast cancer cells MDA-MB231 or estrogen receptor expressing breast cancer cells MCF-7. Biodistribution and binding behavior of [68Ga]-PSMA-11 was investigated in both tumor models at 30 min post injection using µPET. PSMA- and CD31-specific staining was conducted to visualize PSMA expression and neovascularization in tumor tissue ex vivo. RESULTS: The triple-negative breast cancer cells MDA-MB231 showed a high pro-angiogenetic potential on tube formation of endothelial HUVEC cells. The induced endothelial expression of PSMA was efficiently addressed by radiolabeled PSMA-specific ligands. 177Lu-labeled PSMA-617 strongly impaired the vitality and angiogenic potential of HUVEC cells. In vivo, as visualized by µPET, radiolabeled PSMA-ligand accumulated specifically in the triple-negative breast cancer xenograft MDA-MB231 (T/B ratio of 43.3 ± 0.9), while no [68Ga]-PSMA-11 was detected in the estrogen-sensitive MCF-7 xenograft (T/B ratio of 1.1 ± 0.1). An ex vivo immunofluorescence analysis confirmed the localization of PSMA on MDA-MB231 xenograft-associated endothelial cells and also on TNBC cells. CONCLUSIONS: Here we demonstrate PSMA as promising target for two-compartment endogenous radio-ligand therapy of triple-negative breast cancer.


Assuntos
Radioisótopos de Gálio/uso terapêutico , Glutamato Carboxipeptidase II/antagonistas & inibidores , Lutécio/uso terapêutico , Radioisótopos/uso terapêutico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Antígenos de Superfície/metabolismo , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/efeitos da radiação , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Dipeptídeos/metabolismo , Dipeptídeos/uso terapêutico , Ácido Edético/análogos & derivados , Ácido Edético/metabolismo , Ácido Edético/uso terapêutico , Glutamato Carboxipeptidase II/metabolismo , Compostos Heterocíclicos com 1 Anel/metabolismo , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Ligantes , Células MCF-7 , Camundongos Nus , Oligopeptídeos/metabolismo , Oligopeptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
J Cancer Res Ther ; 15(5): 1031-1034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603106

RESUMO

Background: Triple-negative breast cancers (TNBCs) form a heterogeneous group of cancers typically exhibiting an aggressive behavior resulting in increased risk of locoregional relapse (LRR) and distant metastases. The effect of radiotherapy on LRR risk and overall survival (OS) in women treated with mastectomy alone for early-stage TNBC remains unclear. Aim: The aim of this study is to compare the locoregional recurrence rate, disease-free survival (DFS), and OS following breast conservation therapy (BCT) or modified radical mastectomy (MRM) alone in women with stage I and IIA TNBC and to assess the impact of tumor and treatment-related factors. Materials and Methods: Patients with early-stage (pT1-2, N0) TNBC-treated between January 1, 2010, and December 31, 2011, were identified from the hospital-based registry records. The mean age was 48 years. Forty-nine patients underwent BCT, and 121 underwent MRM. The majority of the patients in both groups had T2 and grade 3 disease. None of the patients had margin positive status after surgery. Five patients had lymphovascular invasion (LVI). Results: At a median follow-up of 50 months (range: 4-83 months), there was no locoregional recurrence (LRR) in either arm. Eight patients relapsed, six developed distant metastases, and one patient each had a new primary in the contralateral breast and ovary. Two patients died of disseminated cancer, one each in the BCT and MRM groups. The five-year DFS was 95.8% and 91.1% for the BCT group and MRM group, respectively, (P = 0.83). The corresponding 5-year OS was 98% and 97.5% (P = 0.527). There was no statistically significant difference in outcome based on age, grade, LVI, or margin status between both groups. Conclusion: This retrospective analysis identified no statistically significant difference in outcome regarding LRR, DFS, or OS in patients treated without adjuvant radiation for women with pT1-T2N0 TNBC who underwent MRM in comparison to BCT.


Assuntos
Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática/patologia , Mastectomia/métodos , Mastectomia Radical Modificada/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias/métodos , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologia
11.
Int J Radiat Oncol Biol Phys ; 105(3): 471-472, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31540590
12.
Mol Pharm ; 16(12): 4807-4816, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31518138

RESUMO

Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin, where it confers enhanced proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study, cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple-negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R, which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates were effectively internalized in SUM149PT and were cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than that of unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of the SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post injection and was 9.9 ± 0.5% injected activity per gram (%IA/cc). In radiotherapy studies, we evaluated the effect of the specific activity of 225Ac-cixutumumab on efficacy following a tail vein injection of two doses (days 0 and 10) of the investigation agent or controls. Cixutumumab (2.5 mg/kg) prolonged the survival of the SUM149PT tumor-bearing mice with a median survival of 87 days compared to the PBS control group (median survival of 62 days). Median survival of high specific activity 225Ac-cixutumumab (8 kBq/µg, 225 nCi, 0.05 mg/kg) was 103.5 days compared to 122 days for low specific activity 225Ac-cixutumumab (0.15 kBq/µg, 225 nCi, 2.5 mg/kg). Additionally, low specific activity radioimmunoconjugate led to complete tumor remission in 2/6 mice. The data suggest that the efficacy of cixutumumab can be enhanced by radiolabeling with 225Ac at a low specific activity.


Assuntos
Actínio/química , Anticorpos Monoclonais Humanizados/química , Índio/química , Radiossensibilizantes/química , Receptor IGF Tipo 1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Biopolímeros/química , Feminino , Citometria de Fluxo , Humanos , Células MCF-7 , Camundongos , Radioimunoterapia/métodos
13.
Breast Cancer Res Treat ; 178(1): 75-86, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31372790

RESUMO

PURPOSE: Radiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells. METHODS: Glucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity. RESULTS: Exposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population. CONCLUSIONS: Radiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC.


Assuntos
Proteínas de Transporte/metabolismo , Glucose/metabolismo , Ácido Láctico/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/metabolismo , Radiação Ionizante , Neoplasias de Mama Triplo Negativas/radioterapia , Regulação para Cima
14.
EBioMedicine ; 47: 163-169, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416721

RESUMO

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.


Assuntos
Doses de Radiação , Tolerância a Radiação/genética , Radioterapia Adjuvante , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Idoso , Biomarcadores Tumorais , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante/métodos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade
15.
J Med Imaging Radiat Oncol ; 63(5): 698-706, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368670

RESUMO

INTRODUCTION: We aimed to investigate the impact of radiation treatment in early-stage triple negative breast cancer (TNBC). METHODS: Patients with early stage (T1-3, N0-2, M0) TNBC were identified using the New Zealand breast cancer register. The outcomes of local recurrence (LRFR), local recurrence free survival (LRFS), loco-regional recurrence free rate (LRRFR), loco-regional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), metastasis free (MFS) and overall survival (OS) were determined. Predefined univariate and multivariate cox regression analyses were used to explore associations between known prognostic and treatment factors. RESULTS: 1209 patients were identified with a median follow-up of 3.88 years. The majority were post- menopausal. The mean tumour size was 26mm, the majority had grade III disease and a third were node positive. 625 patients had mastectomy and 584 had breast conservation surgery (BCS). 92% of BCS and 38% of mastectomy patients received radiation. 67% received adjuvant chemotherapy. The 5 year OS was 77.6% (95% CI 74.6-80.2), 5 year BSS was 82.1% (95%CI 79.1-84.7), 5 year LRRFS was 73.9% (95% CI 73.87-73.93), 5 year LRFS was 75.4 (75.37-75.43) and the 5 year LRFR was 92.4% (95% CI 90.6-94.2). The significant prognostic/predictive factors for OS were adjuvant radiation treatment, chemotherapy, T stage, lymph node involvement and lympho-vascular space invasion. Results were similar for BSS, DMFS, LRFS and LRRFS except that LVSI was not significantly associated with BCSS, LRFS or LRRFS. When analysed by surgical type, in the WLE group, radiation was found to be significantly associated with improvement in all outcomes. In mastectomy group, radiation was not found to be significant for BCSS, LRFS, LRRFS or OS. CONCLUSION: Radiation treatment is significantly associated with improved outcomes in early stage TNBC. This argues against the hypothesis that TNBC has inherent radiation resistance.


Assuntos
Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Nova Zelândia , Prognóstico , Sistema de Registros , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/patologia
16.
Int J Radiat Biol ; 95(11): 1507-1516, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31348739

RESUMO

Purpose: Based on clinical and molecular data, breast cancer is a heterogeneous disease. Breast cancers that have no expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are defined as triple negative breast cancers (TNBCs); luminal cancers have different expressions of ER, PR and/or HER2. TNBCs are frequently linked with advanced disease, poor prognosis and occurrence in young African women, and about 15% of the cases are associated with germline BRCA1/2 mutations. Since radiotherapy is utilized as a principle treatment in the management of TNBC, we aimed to investigate the chromosomal instability and radiosensitivity of lymphocytes in TNBC patients compared to luminal breast cancer patients and healthy controls using the micronucleus (MN) assay. The effect of mutations in breast cancer susceptibility genes on chromosomal radiosensitivity was also evaluated.Methods: Chromosomal radiosensitivity was evaluated in the G0 (83 patients and 90 controls) and S/G2 (34 patients and 17 controls) phase of the cell cycle by exposing blood samples from all patients and controls to 2 and 4 Gy ionizing radiation (IR).Results: In the G0 MN assay, the combined cohort of all breast cancer, TNBC and luminal patients' exhibit significantly elevated spontaneous MN values compared to controls indicating chromosomal instability. Chromosomal radiosensitivity is also significantly elevated in the combined cohort of all breast cancer patients compared to controls. The TNBC patients, however, do not exhibit enhanced chromosomal radiosensitivity. Similarly, in the S/G2 phase, 76% of TNBC patients do not show enhanced chromosomal radiosensitivity compared to the controls. In both the G0 and S/G2 phase, luminal breast cancer patients demonstrate a shift toward chromosomal radiosensitivity compared to TNBC patients and controls.Conclusions: The observations of the MN assay suggest increased chromosomal instability and chromosomal radiosensitivity in South African breast cancer patients. However, in TNBC patients, the irradiated MN values are not elevated. Our results suggest that the healthy lymphocytes in TNBC patients could handle higher doses of IR.


Assuntos
Instabilidade Cromossômica , Cromossomos/efeitos da radiação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Proteína BRCA1/genética , Estudos de Casos e Controles , Ciclo Celular , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Testes para Micronúcleos , Pessoa de Meia-Idade , Mutação , Tolerância a Radiação , Radiação Ionizante
17.
Breast J ; 25(6): 1126-1133, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31273872

RESUMO

BACKGROUND: Although randomized data support omitting adjuvant radiotherapy (RT) following breast conservation for T1-2N0 estrogen receptor positive breast cancer in ≥70-year-old women, there remains a knowledge gap regarding its omission for triple-negative BC (TNBC). METHODS AND MATERIALS: The National Cancer Database (NCDB) was queried for ≥70-year-old females with newly diagnosed T1-2N0M0 TNBC treated with breast conservation. Multivariable logistic regression ascertained factors associated with adjuvant RT administration. Overall survival (OS) between patients treated with or without adjuvant RT was estimated using the Kaplan-Meier method. Cox proportional hazards modeling determined variables associated with OS. RESULTS: Of 8526 patients, 6283 (74%) patients received adjuvant RT, and 2243 (26%) did not. RT was more frequently withheld in older patients, those with higher comorbidities, lower income, pT2 disease, following margin-positive resection, receipt of chemotherapy, and at academic centers (P < 0.05 for all). Median follow-up was 38.0 months. Five-year OS was greater in the adjuvant RT group (77.2% vs 55.3%, P < 0.001); these differences persisted when stratifying for age, T stage, and chemotherapy utilization (P < 0.001 for all). Omission of RT was also independently associated with poorer OS on multivariate analysis (P < 0.001). CONCLUSIONS: This investigation, the largest known such study to date, observed that omission of adjuvant RT for elderly women with T1-2N0 TNBC was associated with poorer OS; this was observed across a range of age groups, as well as following stratification by T stage and chemotherapy usage. Although these results do not imply causation, caution must be exercised when considering omission of adjuvant RT in node-negative TNBC patients.


Assuntos
Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/radioterapia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Factuais , Status Econômico/estatística & dados numéricos , Feminino , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar , Modelos de Riscos Proporcionais , Radioterapia Adjuvante/mortalidade , Estudos Retrospectivos
18.
Int J Radiat Oncol Biol Phys ; 105(2): 267-274, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175905

RESUMO

PURPOSE: To report 5-year outcomes of a phase 2 trial of hypofractionated whole breast irradiation (HF-WBI) completed in 3 weeks, inclusive of a sequential boost. METHODS AND MATERIALS: Women with stage 0-IIIA breast cancer (ductal carcinoma in situ through T2N2a) were enrolled on a prospective, phase 2 trial of accelerated HF-WBI. We delivered a whole breast dose of 36.63 Gy in 11 fractions of 3.33 Gy, with an equivalent dose to the regional nodes when indicated, followed by a tumor bed boost of 13.32 Gy in 4 fractions of 3.33 Gy over a total of 15 treatment days. The primary endpoint was locoregional control; secondary endpoints included acute/late toxicity and physician-assessed and patient-reported breast cosmesis. RESULTS: Between 2009 and 2017, we enrolled 150 patients, of whom 146 received the protocol treatment. Median age was 54 years (range, 33-82) and median follow-up was 62 months. Patients with higher-risk disease comprised 59% of the cohort, including features such as young age (33% ≤50 years), positive nodes (13%), triple-negative disease (11%), and treatment with regional nodal irradiation (11%) and/or neoadjuvant/adjuvant chemotherapy (36%). Five-year estimated locoregional and distant control were 97.7% (95% confidence interval [CI], 93.0%-99.3%) and 97.9% (95% CI, 93.6%-99.3%), respectively. Five-year breast cancer-specific and overall survival were 99.2% (95% CI, 94.6%-99.9%) and 97.3% (95% CI, 91.9%-99.1%), respectively. Acute/late grade 2 and 3 toxicities were observed in 30%/10% and 1%/3% of patients, respectively. There were no grade 4 or 5 toxicities. Physicians assessed breast cosmesis as good or excellent in 95% of patients; 85% of patients self-reported slight to no difference between the treated and untreated breast. CONCLUSIONS: Our phase 2 trial offers one of the shortest courses of HF-WBI; at 5 years of follow-up there continues to be excellent locoregional control and low toxicity with favorable cosmetic outcomes in a heterogeneous cohort of patients.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Intraductal não Infiltrante/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/patologia , Quimioterapia Adjuvante , Intervalos de Confiança , Feminino , Humanos , Modelos Lineares , Irradiação Linfática , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Hipofracionamento da Dose de Radiação , Radiodermatite/etiologia , Planejamento da Radioterapia Assistida por Computador , Radioterapia Conformacional/efeitos adversos , Reirradiação , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia
19.
Br J Radiol ; 92(1100): 20190283, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31219711

RESUMO

OBJECTIVE: The incorporation of high atomic number materials such as gold nanoparticles (GNPs) into tumor cells is being tested to enhance the local radiotherapy (RT) dose. It is also known that the radiosensitivity of tumor cells depends on the phase of their cell cycle. Triple combination of GNPs, phase of tumor cell population, and RT for improved outcomes in cancer treatment. METHODS: We used a double-thymidine block method for synchronization of the tumor cell population. GNPs of diameters 17 and 46 nm were used to capture the size dependent effects. A radiation dose of 2 Gy with 6 MV linear accelerator was used to assess the efficacy of this proposed combined treatment. A triple negative breast cancer cell line, MDA-MB-231 was chosen as the model cell line. Monte Carlo (MC) calculations were done to predict the GNP-mediated cell death using the experimental GNP uptake data. RESULTS: There was a 1.5- and 2- fold increase in uptake of 17 and 46 nm GNPs in the synchronized cell population, respectively. A radiation dose of 2 Gy with clinically relevant 6 MV photons resulted in a 62 and 38 % enhancement in cell death in the synchronized cell population with the incorporation of 17 and 46 nm GNPs, respectively. MC data supported the experimental data, but to a lesser extent. CONCLUSION: A triple combination of GNPs, cell cycle synchronization, and RT could pave the way to enhance the local radiation dose while minimizing side effects to the surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show that the combined use of GNPs, phase of tumor cell population, and RT could enhance tumor cell death.


Assuntos
Ouro/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias de Mama Triplo Negativas/radioterapia , Feminino , Humanos , Nanopartículas Metálicas , Dosagem Radioterapêutica , Células Tumorais Cultivadas
20.
Cancer Genomics Proteomics ; 16(4): 257-266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31243106

RESUMO

BACKGROUND/AIM: Radiation therapy (RT) represents a therapeutic option in breast cancer (BC). Even if a great number of BC patients receive RT, not all of them report benefits, due to radioresistance that gets activated through several factors, such as the hormone receptor status. Herein, we analyzed the gene expression profiles (GEP) induced by RT in triple-negative BC (TNBC) MDA-MB-231, to study signalling networks involved in radioresistance. MATERIALS AND METHODS: GEP of MDA-MB-231 BC cells treated with a high dose of radiation, went through cDNA microarray analysis. In addition, to examine the cellular effects induced by RT, analyses of morphology and clonogenic evaluation were also conducted. RESULTS: A descriptive report of GEP and pathways induced by IR is reported from our microarray data. Moreover, the MDA-MB-231 Radioresistent Cell Fraction (RCF) selected, included specific molecules able to drive radioresistance. CONCLUSION: In summary, our data highlight, the RT response of TNBC MDA-MB-231 cell line at a transcriptional level, in terms of activating radioresistance in these cells, as a model of late-stage BC.


Assuntos
Radiação Ionizante , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/patologia
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