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1.
Breast Cancer Res ; 22(1): 68, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576280

RESUMO

BACKGROUND: Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. METHODS: Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. RESULTS: Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR-/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER- and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. CONCLUSIONS: These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Linhagem Celular Tumoral , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Técnicas de Cultura de Células , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
2.
Cancer Res ; 80(7): 1486-1497, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32060147

RESUMO

Invasive lobular carcinoma (ILC) accounts for 8%-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin-deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2-induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2-induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. SIGNIFICANCE: Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/genética , Carcinoma Lobular/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas Supressoras de Tumor/genética , Actomiosina/metabolismo , Animais , Caderinas/genética , Carcinogênese/patologia , Carcinoma Lobular/induzido quimicamente , Carcinoma Lobular/genética , Adesão Celular/genética , Células Cultivadas , Elementos de DNA Transponíveis/genética , Progressão da Doença , Células Epiteliais , Feminino , Imidazóis/toxicidade , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Transgênicos , Mutação , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Oxidiazóis/toxicidade , Cultura Primária de Células , Proteínas Supressoras de Tumor/metabolismo
3.
Eur J Cancer ; 127: 240-250, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31956037

RESUMO

BACKGROUND: The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. PATIENTS AND METHODS: Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these human epidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. RESULTS: TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68-0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. CONCLUSION: In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Tiotepa/administração & dosagem , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia
4.
Asian Pac J Cancer Prev ; 21(1): 255-258, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31983193

RESUMO

BACKGROUND: Paraoxonase 1 (PON1), a multifactorial antioxidant enzyme, has a defensive role against oxidative stress, which is believed to contribute to cancer development. This study aimed to investigate the association of PON1-L55M functional polymorphism with breast cancer risk. MATERIAL AND METHODS: In the experimental study, blood samples were collected from 150 healthy women controls and 150 breast cancer subjects. The L55M genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Our analysis showed that the genotypes distribution is in Hardy-Weinberg equilibrium for both case and control groups. Our data revealed that there are significant associations between PON1-L55M polymorphism and breast cancer risk in homozygote (OR= 2.13, 95%CI= 1.14-4.00, p= 0.018), dominant (OR= 1.72, 95%CI= 1.07-2.76, p= 0.024), and allelic (OR= 1.55, 95%CI= 1.12-2.15, p= 0.008) models. CONCLUSIONS: Our results suggest that the PON1-L55M genetic variation could be a genetic risk factor for breast cancer risk and it could be considered as a molecular biomarker for screening of susceptible women.
.


Assuntos
Arildialquilfosfatase/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Predisposição Genética para Doença , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Polimorfismo Genético , Prognóstico , Fatores de Risco
5.
J Clin Pathol ; 73(9): 597-601, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31980561

RESUMO

Metaplastic breast carcinoma is a rare subtype of breast cancer. This subtype is mostly found in association with poorly differentiated ductal breast carcinomas and rarely with other breast carcinoma types. We report the case of a 69-year-old woman with an exceptional invasive lobular breast carcinoma associated with metaplastic squamous cell bone metastasis occurring 2 years after the initial breast cancer diagnosis. Whole-exome sequencing and subsequent immunohistochemistry of the lesions were used to link the squamous cell bone metastasis of unknown origin to the primary breast carcinoma initially diagnosed. Searching for primary carcinoma when metastatic lesions of unknown origin occur can be complex. Current molecular biology techniques may help pathologists in associating metastasis with the primary carcinoma by identifying shared specific gene mutations, even when different morphological and immunohistochemical profiles are observed between the tumours.


Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Sequenciamento Completo do Exoma , Idoso , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Exoma/genética , Feminino , Humanos , Imuno-Histoquímica , Metaplasia/patologia , Mutação , Metástase Neoplásica
6.
Breast ; 49: 233-241, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918322

RESUMO

PURPOSE: To investigate the effect of 21-gene recurrence score (RS) on chemotherapy-decision making and prognosis in breast cancer patients aged <40 years. METHODS: Using the Surveillance, Epidemiology, and End Results program, we included patients aged <40 years with tumor size ≤5 cm, node negative, and estrogen receptor-positive breast cancer between 2004 and 2015. Correlations among the 21-gene RS, chemotherapy decision-making and prognosis were analyzed. RESULTS: We included 2721 patients in this study. According to TAILORx cutoffs, 352 (12.9%), 1814 (66.7%), and 555 (20.4%) patients were classified as low-, intermediate-, and high-risk cohorts, respectively. The 21-gene RS categories were associated with the probability of receiving chemotherapy, with 7.1%, 33.4%, and 77.1% of patients in low-, intermediate-, and high-risk cohorts treated with chemotherapy, respectively (P < 0.001). Those in the intermediate-risk cohort were significantly less likely to receive chemotherapy over time (P = 0.008), and the trends of chemotherapy receipt were stable in the low-risk and high-risk cohorts over time. Multivariate analysis showed that the 21-gene RS was an independent prognostic indicator for breast cancer specific survival. In the stratified analysis, the receipt of chemotherapy was associated with better breast cancer specific survival in the high-risk cohort (P = 0.028), but not in the intermediate-risk cohort (P = 0.223). CONCLUSIONS: 21-gene RS has clinical implications for young breast cancer patients with respect to optimizing chemotherapy-decisions. Despite increasing rates of chemotherapy receipt in young patients, more studies are needed to determine the definitive effect of chemotherapy in young patients with three RS categories.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Regras de Decisão Clínica , Tomada de Decisão Clínica/métodos , Testes Genéticos/métodos , Recidiva Local de Neoplasia/genética , Adulto , Fatores Etários , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/mortalidade , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Estudos Retrospectivos , Medição de Risco , Programa de SEER , Análise de Sobrevida
7.
Mayo Clin Proc ; 95(2): 306-318, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31685261

RESUMO

OBJECTIVE: To select optimal therapies based on the detection of actionable genomic alterations in tumor samples is a major challenge in precision medicine. METHODS: We describe an effective process (opened December 1, 2017) that combines comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensiona ex vivo models for drug screening to assess response to therapeutic agents targeting specific genomic alterations. The process was applied to a patient with widely metastatic, weakly hormone receptor positive, HER2 nonamplified, infiltrating lobular breast cancer refractory to standard therapy. RESULTS: Clinical testing of liver metastasis identified BRIP1, NF1, CDH1, RB1, and TP53 mutations pointing to potential therapies including PARP, MEK/RAF, and CDK inhibitors. The comprehensive genomic analysis identified 395 mutations and several structural rearrangements that resulted in loss of function of 36 genes. Meta-analysis revealed biallelic inactivation of TP53, CDH1, FOXA1, and NIN, whereas only one allele of NF1 and BRIP1 was mutated. A novel ERBB2 somatic mutation of undetermined significance (P702L), high expression of both mutated and wild-type ERBB2 transcripts, high expression of ERBB3, and a LITAF-BCAR4 fusion resulting in BCAR4 overexpression pointed toward ERBB-related therapies. Ex vivo analysis validated the ERBB-related therapies and invalidated therapies targeting mutations in BRIP1 and NF1. Systemic patient therapy with afatinib, a HER1/HER2/HER4 small molecule inhibitor, resulted in a near complete radiographic response by 3 months. CONCLUSION: Unlike clinical testing, the combination of tumor profiling, data integration, and functional validation accurately assessed driver alterations and predicted effective treatment.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Carcinoma Lobular/genética , Carcinoma Lobular/terapia , Genômica/métodos , Medicina de Precisão/métodos , Algoritmos , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Análise Mutacional de DNA , Feminino , Genes Neoplásicos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica
8.
Sci Rep ; 9(1): 16726, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723206

RESUMO

The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) recently issued updated guidelines on human epidermal growth factor receptor 2 (HER2) testing by fluorescence in situ hybridization (FISH) in invasive breast cancers. In this study, we aimed to investigate the impact of the new recommendations on HER2 FISH interpretation in invasive breast cancers with immunohistochemically (IHC) equivocal results. 1810 breast cancer cases with IHC equivocal results were enrolled in this study between January 2012 and May 2019. Concomitant IHC was performed on the same tissue blocks detected by FISH testing. According to the 2018 guidelines, all the cases in ISH group 2 were categorized as HER2 negative; three of four cases in ISH group 3 were considered as HER2 positive, while the one scored IHC 1+ was reclassified as HER2 negative; Fifty-three previously ISH equivocal cases were redistributed into ten HER2-positive cases and forty-three HER2-negative cases. In conclusion, the utility of 2018 ASCO/CAP guidelines resulted in a slight decrease in HER2 positive rate, due to the reclassification of cases in ISH group 2 and group 4. The implementation of the new guidelines can reduce reflex FISH test and make the diagnosis of HER2 gene status more definitive.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Imuno-Histoquímica/normas , Hibridização in Situ Fluorescente/normas , Guias de Prática Clínica como Assunto/normas , Receptor ErbB-2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor ErbB-2/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Sociedades Médicas
9.
Anticancer Res ; 39(11): 6183-6192, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704846

RESUMO

AIM: To investigate the feasibility of hookwire-guided sentinel lymph node biopsy (SLNB) using contrast-enhanced ultrasonography (CEUS) followed by a one-step nucleic acid amplification (OSNA) assay. PATIENTS AND METHODS: Clinical T1-2N0M0 breast cancer patients scheduled to undergo SLNB participated in this study. Both Sonazoid® and dye were used as tracers, and the most upstream sentinel lymph node (SLN) at each lymphatic flow detected by CEUS (First-SLN) was sampled under hookwire guidance, a procedure called "Sona-Hook". RESULTS: In each of the 50 cases, at least one First-SLN was extracted by "Sona-Hook". All contrast-enhanced SLNs (CE-SLNs) were dye-positive, and the mean number of CE-SLNs sampled per patient was lower than that of dye-positive SLNs (1.48 vs. 1.88, p<0.01). Through OSNA, qualitative assessment of tumor metastasis between First-SLNs and all SLNs completely matched together. CONCLUSION: "Sona-Hook" for First-SLN followed by an OSNA assay may be a feasible minimally invasive SLNB strategy.


Assuntos
Neoplasias da Mama/patologia , Meios de Contraste , Biópsia Guiada por Imagem/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Linfonodo Sentinela/patologia , Ultrassonografia Mamária/métodos , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/secundário , Adenocarcinoma Mucinoso/cirurgia , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/genética , Carcinoma Lobular/secundário , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Prognóstico , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/cirurgia
10.
Sci Rep ; 9(1): 13123, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511599

RESUMO

The 21-gene recurrence score (RS) assay is prognostic and predictive for hormone receptor (HR)+/HER2-/node- breast cancer (BC) patients. However, its clinical value in node + patients hasn't been elucidated. HR+/HER2-/pN1 patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital from January 2014 to December 2018, with available RS results were retrospectively included. Clinico-pathological characteristics were compared. Adjuvant chemotherapy recommendations pre-/post- RS assay and actual usage were analyzed. A total of 303 patients were included, with 59, 178, 66 RS < 18, 18-30 and ≥ 31. Age (P < 0.001), comorbidity (P = 0.013), and RS category (P < 0.001) were independently associated with chemotherapy recommendation. Compared with low RS patients, those with intermediate (OR 6.58, 95% CI 2.37-18.31, P < 0.001) or high (OR 54.14, 95% CI 3.77-776.54, P = 0.003) RS were more likely to be recommended with chemotherapy. RS independently influence chemotherapy decision in postmenopausal population as well. Chemotherapy recommendation changed for 9.57% patients after RS assay. Patient adherence rate to chemotherapy recommendation was 94.72% (287/303). The 21-gene RS independently influenced chemotherapy recommendation in pN1 BC patients, which could provide additional information to guide chemotherapy decision with relatively good treatment adherence rate.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Quimioterapia Adjuvante/métodos , Técnicas de Apoio para a Decisão , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos
11.
Int J Oncol ; 55(5): 1003-1018, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545416

RESUMO

Human epidermal growth factor receptor (HER)­2­positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER­2­positive breast cancer. CD44+/CD24­/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24­/low cells was almost zero in SK­BR­3 cells; however, it was >90% in MDA­MB­231 cells, as determined by flow cytometry. Since SK­BR­3 and MDA­MB­231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK­BR­3 cells. Therefore, transcriptome sequencing was performed for SK­BR­3 and MDA­MB­231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK­BR­3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK­BR­3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription­polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER­2­positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of ß­catenin in the Wnt signaling pathway was lower in SK­BR­3 cells compared with in MDA­MB­231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER­2­positive breast cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Proliferação de Células , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Prognóstico , Transcriptoma , Células Tumorais Cultivadas , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Asian Pac J Cancer Prev ; 20(9): 2749-2755, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31554373

RESUMO

Background: Breast cancer (BC) is the second most common cancer worldwide. MicroRNAs are a group of non-coding, single stranded RNAs of ~ 22 nucleotides, which regulate gene expression at the post-transcriptional level. Circulating miRNAs have been found as potential blood based predictive biomarkers. Purpose: we aim to evaluate miR-34a and miR-125b to predict outcome from neoadjuvant chemotherapy in Egyptian BC patients. Methodology: Quantitative assessment of plasma miR-34a and miR-125b expression was performed by qRT-PCR. Thirty nine newly diagnosed locally advanced BC female patients with 10 age and sex matched healthy volunteers were included in the study. Results: We performed ROC curve analysis to evaluate the diagnostic value for the miR-34a with AUCs = 0.995, cutoff point of 2.57 sensitivity 97.4%, specificity 100%, PPV 100%, NPV 83.3% and accuracy 97.7%. miR-125b had AUC = 0.68 and a cutoff point of 8.69 with sensitivity 66.7%, specificity 70.0%, PPV 90.6%, NPV 41.2% and accuracy 73.5%. miR-34a expression were significantly higher in BC patients compared to controls with p value <0.001*. Also, miR-34a expression level was significantly higher in patients with progressive disease with P value =0.03*. However, miR-125b expression levels were insignificantly higher in responsive patients with p value = 0.2. Conclusion: miRNAs are crucial candidates for novel molecular targeted therapies due to their capability to regulate numerous genes in molecular pathways. Our data suggest that circulating miR-34a and miR-125b expression levels could be promising highly accurate non-invasive biomarkers in diagnosing BCs. miR-34a can predict chemotherapeutic resistance associated with higher expression levels in non-responsive patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , MicroRNA Circulante/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/sangue , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , MicroRNA Circulante/sangue , Egito , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico
13.
Asian Pac J Cancer Prev ; 20(9): 2841-2846, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31554385

RESUMO

Background: The phosphatidylinositol-3 kinase (PI3K) intracellular signaling pathway plays an important role in breast cancer. The current study aimed to evaluate the expressions of two main regulators of PI3K pathway; phosphatidylinositol-3- kinase catalytic subunit alpha as activator (PIK3CA), and phosphatase and tensin-homolog as inhibitor (PTEN), in breast carcinoma tissue, and compare with their expressions in adjacent normal breast tissue. Methods: A total of fifty female patients with breast carcinoma from surgical oncology unit of Alexandria-Main University Hospital were included in this study. The Quantitative Real Time PCR was used to quantify expressions of PIK3CA and PTEN. Results: PIK3CA mRNA expression was significantly increased in breast cancer tissues compared to normal breast tissues (P<0.001, Z=5.700), also PTEN mRNA expression was significantly higher in breast carcinoma tissue compared to normal breast tissue (P<0.001, Z=5.362). Conclusion: Increased the expressions of PIK3CA and PTEN mRNA in breast cancer tissue compared to normal breast tissue.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Estudos de Casos e Controles , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Prognóstico , Adulto Jovem
14.
Sci Rep ; 9(1): 11679, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406196

RESUMO

Breast cancer treatment depends on human epidermal growth factor receptor-2 (HER2) status, which is often determined using dual probe fluorescence in situ hybridisation (FISH). Hereby, also loss and gain of the centromere of chromosome 17 (CEP17) can be observed (HER2 is located on chromosome 17). CEP17 gain can lead to difficulty in interpretation of HER2 status, since this might represent true polysomy. With this study we investigated whether isolated polysomy is present and how this effects HER2 status in six breast cancer cell lines and 97 breast cancer cases, using HER2 FISH and immunohistochemistry, DNA ploidy assessment and multiplex ligation dependent probe amplification. We observed no isolated polysomy of chromosome 17 in any cell line. However, FISH analysis did show CEP17 gain in five of six cell lines, which reflected gains of the whole chromosome in metaphase spreads and aneuploidy with gain of multiple chromosomes in all these cases. In patients' samples, gain of CEP17 indeed correlated with aneuploidy of the tumour (91.1%; p < 0.001). Our results indicate that CEP17 gain is not due to isolated polysomy, but rather due to widespread aneuploidy with gain of multiple chromosomes. As aneuploidy is associated with poor clinical outcome, irrespective of tumour grade, this could improve future therapeutic decision making.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Centrômero/química , Cromossomos Humanos Par 17/química , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/patologia , Linhagem Celular Tumoral , Feminino , Duplicação Gênica , Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Ploidias , Prognóstico
15.
Cancer Prev Res (Phila) ; 12(11): 763-770, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451522

RESUMO

Because the contribution of genetic factors to the burden of breast cancer is not well investigated in Iran, we aimed to examine the prevalence of mutations in breast cancer susceptibility genes, BRCA1/2 and PALB2, and to investigate the predictive potential of hereditary breast cancer risk criteria for genetic testing in Iranian population. Next-generation sequencing was conducted on a population consisting of 299 and 125 patients with breast cancer, with and without hereditary cancer risk criteria for genetic testing, respectively. The pathogenic mutation frequency rate was 10.7% in patients with hereditary cancer criteria versus 1.6% in no criteria group (P = 0.0017). None of the 107 tested patients with only young age at onset (<40) criterion had a pathogenic mutation. Patients who had only a single heritable risk criterion [OR, 6.15; 95% confidence interval (CI), 1.26-58.59; P = 0.009] and patients with multiple heritable risk criteria (OR, 22.5; 95% CI, 5.19-201.31; P < 0.0001) had higher probabilities of carrying a mutation compared with no criteria group. Our results showed that young age at onset alone is not an indicator of hereditary breast cancer at least in the Iranian population. This is while women with multiple hereditary breast cancer risk criteria were enriched for BRCA1/2 mutations. Given such high risk of identification of a disease-causing mutation, multiple hereditary criteria should be regarded as a strong predictor for a hereditary breast cancer syndrome. These findings are important concerning the optimization of genetic counseling and furthermore establishing criteria for BRCA1/2 testing of the Iranian population.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/diagnóstico , Adulto , Idade de Início , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Irã (Geográfico)/epidemiologia , Pessoa de Meia-Idade , Taxa de Mutação , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Prognóstico , Adulto Jovem
16.
Nat Commun ; 10(1): 3800, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444332

RESUMO

E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina. Remarkably, E-cadherin-deficient MMECs can breach the basal lamina but do not disseminate into the surrounding fat pad. Basal lamina components laminin and collagen IV supported adhesion and survival of E-cadherin-deficient MMECs while collagen I, the principle component of the mammary stromal micro-environment did not. We uncovered that relaxation of actomyosin contractility mediates adhesion and survival of E-cadherin-deficient MMECs on collagen I, thereby allowing ILC development. Together, these findings unmask the direct consequences of E-cadherin inactivation in the mammary gland and identify aberrant actomyosin contractility as a critical barrier to ILC formation.


Assuntos
Actomiosina/metabolismo , Neoplasias da Mama/patologia , Caderinas/metabolismo , Carcinoma Lobular/patologia , Neoplasias Mamárias Experimentais/patologia , Animais , Neoplasias da Mama/genética , Caderinas/genética , Carcinoma Lobular/genética , Adesão Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Células Epiteliais , Feminino , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Transgênicos , Cultura Primária de Células
17.
Clin Breast Cancer ; 19(5): e563-e577, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31362911

RESUMO

INTRODUCTION: Single nucleotide polymorphisms account for most genetic predispositions to breast cancer in the general population. Because of the lack of studies concerning the 2 common polymorphisms in caspase 8 (CASP8), namely rs104548 and rs10931936 in Iranian population, we evaluated the association of these 2 polymorphisms and their haplotypes with breast cancer and molecular profile. MATERIALS AND METHOD: Blood samples were collected from 287 breast cancer patients and 490 controls. Genotyping of rs1045485 and rs10931936 was conducted using an amplification refractory mutation system and polymerase chain reaction restriction fragment length polymorphism, respectively. PHASE version 2 (Matthew Stephens) was used to estimate the frequencies of haplotypes. Statistical analysis was performed using SPSS 16.0 (SPSS Inc). RESULTS: Although hormone receptors and the molecular profile did not indicate any significant association with different genotypes (P > .05), patients with CC genotype of rs1045485 were more likely to have HER2-positive breast cancer than those with GG genotype (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.0 4-8.26). In addition, CC genotype of D302H was associated with a decreased risk of breast cancer to 48% (OR, 0.52; 95% CI, 0.30-0.90) whereas no significant association was found between rs10931936 and breast cancer. Haplotype analysis indicated C-C haplotype is associated with the decreased risk of breast cancer (OR, 0.69; 95% CI, 0.52-0.91). CONCLUSION: Our data showed a protective effect for CC genotype of rs1045485 variant and C-C haplotype of rs10931936-rs104548 in CASP8 in association with the decrease risk of breast cancer whereas rs10931936 showed no significant association. CASP8 rs1045485 polymorphism might be a candidate genetic marker to evaluate risk of breast cancer. However, further larger studies can confirm such findings.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Caspase 8/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Fatores de Risco
18.
Hum Pathol ; 92: 32-38, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351155

RESUMO

HER2 mutations have been reported in approximately 2% of breast cancers. Regardless of HER2 overexpression or amplification status, breast cancer with HER2 mutations may respond to HER2-targeted therapy. As HER2 mutation is rare, the clinical and pathological features of HER2-mutated breast cancers, such as hormonal status, histological grade, and metastasis, remain poorly defined. Therefore, the identification of HER2-mutated breast cancer has clinical significance. We retrospectively screened patients with metastatic breast cancer in whom molecular profiling had been performed using next-generation sequencing from 2012 to 2015; we identified 18 patients with HER2 mutation. Mutations were found on next-generation sequencing-based panels, including Ion AmpliSeq Cancer Hotspot, Oncomine, FoundationOne, and Guardant360. HER2 mutations were identified in both the tyrosine kinase (n = 14) and extracellular (n = 4) domains. Of the 14 cases with tyrosine kinase domain mutations, 13 were estrogen receptor positive; the 4 cases with extracellular domain mutations were exclusively estrogen receptor negative. In addition, 11 of 14 patients with tyrosine kinase domain mutations had bone metastasis, whereas no patients with HER2 extracellular domain mutations had bone metastasis. Histologically, 13 patients had invasive ductal carcinoma, 1 had metaplastic carcinoma, and 4 had invasive lobular carcinoma (ILC). All 4 ILCs were high grade and pleomorphic, and not only had an HER2 mutation in the kinase domain but also had an HER2 mutation involving the L755 site. Specific mutation sites may be involved in the pathogenesis of nonclassic ILC.


Assuntos
Neoplasias da Mama/genética , Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Receptor ErbB-2/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
19.
Ann Surg Oncol ; 26(10): 3232-3239, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342379

RESUMO

BACKGROUND: The utilization of OncotypeDx in the setting of neoadjuvant chemotherapy (NCT) is not well defined. The objective of this study was to determine what proportion of hormone receptor (HR)-positive patients undergoing NCT would not benefit from chemotherapy based on OncotypeDx recurrence scores (RS) and predictors of a high RS as defined by the TAILORx trial. METHODS: The National Cancer Data Base was used to identify patients with unilateral clinical stage I-III HR+/Her2- breast cancer who had an OncotypeDx score and who had undergone NCT. Patients undergoing adjuvant chemotherapy were used as a comparison group. RESULTS: Of 307,666 patients, 41.8% had testing with OncotypeDx. Of these, 76.6% had no chemotherapy, 22.3% adjuvant chemotherapy, and 1.1% NCT. OncotypeDx testing in NCT patients increased from 4.9% in 2010 to 8.2% in 2015. Of NCT patients with OncotypeDx testing, 11.6% had RS < 11, 44.4% RS 11-25, and 43.9% RS > 25. In patients age ≤ 50 years, 14.5% had RS < 11, 12.4% RS 11-15, 31.4% RS 16-25, and 41.7% RS > 25. Predictors of RS > 25 on multivariable analysis included grade 3 tumors (odds ratio [OR] 3.83) and PR-negative tumors (OR 5.26) but not clinical T or N stage (p > 0.05). CONCLUSIONS: More than half of patients with OncotypeDx testing are being overtreated with NCT, and a third of younger patients are being overtreated. Predictors of a high RS are reliably available at core biopsy, suggesting an application of OncotypeDx in determining the need for NCT for some HR-positive breast cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Sobremedicalização/estatística & dados numéricos , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Quimioterapia Adjuvante , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
20.
Ann Surg Oncol ; 26(10): 3185-3193, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342395

RESUMO

BACKGROUND: Pathological response to neoadjuvant chemotherapy (NAC) is critical in prognosis and selection of systemic treatments for patients with triple-negative breast cancer (TNBC). The aim of this study is to identify gene expression-based markers to predict response to NAC. PATIENTS AND METHODS: A survey of 43 publicly available gene expression datasets was performed. We identified a cohort of TNBC patients treated with NAC (n = 708). Gene expression data from different studies were renormalized, and the differences between pretreatment (pre-NAC), on-treatment (post-C1), and surgical (Sx) specimens were evaluated. Euclidean statistical distances were calculated to estimate changes in gene expression patterns induced by NAC. Hierarchical clustering and pathway enrichment analyses were used to characterize relationships between differentially expressed genes and affected gene pathways. Machine learning was employed to refine a gene expression signature with the potential to predict response to NAC. RESULTS: Forty nine genes consistently affected by NAC were involved in enhanced regulation of wound response, chemokine release, cell division, and decreased programmed cell death in residual invasive disease. The statistical distances between pre-NAC and post-C1 significantly predicted pathological complete response [area under the curve (AUC) = 0.75; p = 0.003; 95% confidence interval (CI) 0.58-0.92]. Finally, the expression of CCND1, a cyclin that forms complexes with CDK4/6 to promote the cell cycle, was the most informative feature in pre-NAC biopsies to predict response to NAC. CONCLUSIONS: The results of this study reveal significant transcriptomic changes induced by NAC and suggest that chemotherapy-induced gene expression changes observed early in therapy may be good predictors of response to NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Transcriptoma , Neoplasias de Mama Triplo Negativas/patologia , Área Sob a Curva , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
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