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1.
BMJ Case Rep ; 14(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462019

RESUMO

Male breast cancer is rare and has been frequently associated with cancer predisposing variants, particularly in BRCA 1 and BRCA 2 genes. ATM pathogenic variants may also increase risk for breast and other cancers. However, less than 10 cases relating ATM mutations and male breast cancer have been previously reported. Therefore, risk estimates and surveillance recommendations are not well established. We report a case of a male patient with breast cancer found to be heterozygous for a pathogenic ATM variant after multigene testing. We also review the literature regarding increased cancer risk associated with ATM germline variants, with emphasis on potential recommendations for surveillance and follow-up.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/genética , Mutação em Linhagem Germinativa , Neoplasias da Mama Masculina/genética , Humanos , Masculino , Pessoa de Meia-Idade
2.
APMIS ; 128(9): 523-530, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579768

RESUMO

Male breast cancer (MBC) is a rare disease that is still to be fully understood. In female breast cancer, molecular subtyping by gene expression has proven its significance. In this study, we characterize a consecutive cohort of MBC patients surgically treated from 1997 to 2017, identified at our institution (N = 37), and report the association between molecular subtypes found by a surrogate panel of immunohistochemical (IHC) markers, and the PAM50 signature, as well as risk of recurrence score and overall survival for the different subtypes. PAM50 subtypes were determined using the nCounter FLEX system instrument and software. The distribution of molecular subtypes according to the PAM50 signature was as follows: 56% luminal B, 39% luminal A, and 5% basal-like. None of the tumors were HER2-enriched. Using IHC surrogate markers, we found 80% luminal B-like, 15% luminal A-like, and 5% basal-like. None were HER2-positive (non-luminal). We found a strong statistical association between subtypes found by PAM50 signature and the IHC surrogate markers (p < 0.001). Furthermore, we found luminal A tumors to be smaller in size compared to luminal B tumors (p = 0.04). Patients with luminal A subtype tumors had the lowest ROR scores with a mean of 39, whereas patients with luminal B subtype tumors had a mean ROR score of 69. Significant worse overall survival for luminal B tumors compared to luminal A tumors was seen (p = 0.02). Male breast cancer seems to be a mainly luminal disease, with luminal B being the most frequent subtype. Further studies are needed to ensure correct therapeutic strategies for this select group of patients.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama Masculina/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/metabolismo , Estudos de Coortes , Dinamarca , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Recidiva , Risco
3.
Am J Surg Pathol ; 44(9): 1266-1273, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32590455

RESUMO

Desmoid fibromatosis (DF) is a rare, locally aggressive, nonmetastasizing fibroblastic/myofibroblastic tumor with a tendency to recur and an unpredictable clinical course. A "wait-and-see" policy is the new standard of care. DF are characterized by activating alterations of the wnt/ß-catenin pathway: CTNNB1 or adenomatous polyposis coli gene (APC) mutations (these mutations being mutually exclusive). Desmoid-type fibromatosis of the breast (DFB) is rare with an incidence of 0.2% of breast tumors. The diagnosis of DFB is difficult, as it must be distinguished from metaplastic carcinoma and other spindle cell lesions. Sequencing of 128 DFB identified a lower rate of CTNNB1 mutations using Sanger (65.6%) or Sanger+next-generation sequencing (77.7%) and a higher rate of APC mutations (11.8%) than in all-site DF. By excluding patients with familial adenomatous polyposis (n=2), the rate of APC mutations in DFB was high (10.7%). The distribution of CTNNB1 mutations in DFB was different from all-site DF, with a higher rate of T41A (68.9%), a lower rate of S45F (5.7%), and a similar rate of S45T (12.6%). By combining the 2 molecular techniques in a 2-step manner (Sanger, then next-generation sequencing), we increased the detection rate of CTNNB1 mutations and lowered the rate of wild-type tumors from 34.4% to 9.8%, therefore improving the diagnosis of DFB. The identification of the exon 3 CTNNB1 mutation in breast spindle cell lesions is a highly specific tool for the diagnosis of DFB, in addition to extensive immunohistochemical analysis. Our study also underlines the importance of APC in DFB tumorigenesis. These findings have significant implications for patient care and management.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Fibromatose Agressiva/genética , Mutação , beta Catenina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/terapia , Feminino , Fibromatose Agressiva/patologia , Fibromatose Agressiva/terapia , França , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Fenótipo , Prognóstico , Adulto Jovem
4.
Expert Opin Pharmacother ; 21(12): 1493-1504, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32496137

RESUMO

INTRODUCTION: Despite its rarity, male breast cancer shows a steadily rising incidence. Given the absence of ad hoc prospective randomized clinical trials, treatment strategies are based on extrapolation from female breast cancer recommendations or solely on population-based data. AREAS COVERED: This review discusses the current treatment landscape for male breast cancer in the adjuvant and in the metastatic setting. The authors also discuss the biology and genomic landscape of male breast cancer. Original research and review articles, relative to the period 2010-2019, were included in the review of the literature. EXPERT OPINION: There is a major medical need to include male patients with breast cancer in prospective clinical trials. The call to equality in breast cancer care can be pursued via two divergent paths: (i) a gender-neutral delivery of breast cancer information and (ii) the creation of separate sections, for the more common female breast cancer and for the rare male ones. We propose to differentiate male breast cancer care, acknowledging unique onco-sexual and social needs that can be only partially shared.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Tamoxifeno/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama Masculina/patologia , Ensaios Clínicos como Assunto , Dano ao DNA , Reparo do DNA , Humanos , Masculino , Receptor ErbB-2/antagonistas & inibidores , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
7.
Clin Cancer Res ; 26(1): 101-109, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748278

RESUMO

PURPOSE: Prognostic value of Oncotype DX Breast Recurrence Score (RS) in male patients with breast cancer is understudied. We evaluated associations of RS with overall mortality in male patients with breast cancer and compared it with female counterparts. EXPERIMENTAL DESIGN: With a cohort of 848 male and 110,898 female patients with breast cancer identified from the National Cancer Database (2010-2014), we estimated HRs and 95% confidence intervals (CI) for overall mortality associated with RS using Cox regression models. RS was evaluated continuously, as well as by categorization following respective traditional (≤17, 18-30, and ≥31) and TAILORx (≤10, 11-25, and ≥26) cutoffs. RESULTS: RS was positively associated with mortality in male patients (HR = 1.13; 95% CI, 1.02-1.26 per unit RS increment) up to RS > 21, after which the risk plateaued. Among female patients, mortality began to increase with RS only when RS > 23 (HR = 1.02; 95% CI, 1.01-1.02 per unit of RS increment). The intermediate- (HR = 5.37; 95% CI, 1.79-16.11) and high-risk diseases (HR = 4.28; 95% CI, 1.22-14.97) defined by TAILORx, but not traditional cutoffs established for female patients, were associated with elevated mortality risk in men even after adjustment for demographic, clinical characteristics, and treatments, except chemotherapy. CONCLUSIONS: RS is associated with mortality in male patients with breast cancer at a much lower threshold than that for female patients. Studies are needed to establish specific guidelines for RS thresholds for male patients with breast cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama/mortalidade , Recidiva Local de Neoplasia/mortalidade , Receptores Estrogênicos/metabolismo , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Receptores de Progesterona/metabolismo , Fatores Sexuais , Taxa de Sobrevida , Adulto Jovem
8.
Cancer Genet ; 240: 23-32, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706072

RESUMO

The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with breast carcinoma. In this study, a total of 603 breast cancer subjects from Turkey were screened for BRCA1/BRCA2 mutations using HDA and Sanger sequencing. In the present study, 21 BRCA1 and BRCA2 pathogenic variants were detected in 30 patients and BRCA1/2 mutations were significantly associated with a family history of breast/ovarian cancer. Analysis of overall survival for BRCA1/BRCA2 mutation carriers showed a trend for poor overall survival only in BRCA1 carriers, although this was not statistically significant in BRCA1 and BRCA2 mutation carriers. The c.5266dupC mutation is one of the most frequently reported mutations in BRCA1 and was identified in five breast cancer patients in our study. The most common BRCA2 gene mutations in the present study were c.8940delA and c.9097dupA, which were found in seven patients. We found mostly BRCA1 and BRCA2 mutation carriers in those patients who showed hormone-positive features. In conclusion, our data showed differences in the distribution of the mutation spectrum of BRCA1 and BRCA2 in Turkey.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Adulto , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama Masculina/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Turquia/epidemiologia
9.
Cancer ; 126(1): 26-36, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588557

RESUMO

BACKGROUND: Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. METHODS: Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan-Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. RESULTS: A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast-conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor-positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node-negative, estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy (P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor-positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. CONCLUSIONS: Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.


Assuntos
Neoplasias da Mama Masculina/epidemiologia , Mama/cirurgia , Prognóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Idoso , Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/cirurgia , Neoplasias da Mama Masculina/terapia , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/cirurgia , Neoplasias de Mama Triplo Negativas/terapia , Estados Unidos/epidemiologia
10.
Cancer Biomark ; 26(4): 513-522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31771045

RESUMO

BACKGROUND: Male breast cancer (MBC) is a rare and aggressive disease. Thus, identification of new therapeutic targets is crucial. OBJECTIVE: Our objective was to evaluate the protein expression of MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) in MBC and to investigate its prognostic value. MATERIALS AND METHODS: MARCKS protein expression in tumor and stromal cells was analyzed by immunohistochemistry (IHC) in a retrospective series of 96 pre-chemotherapy MBC samples and 80 normal breast samples, from Tunisian patients treated at Salah Azaiez Institute. Correlations were searched between MARCKS expression and clinicopathological features including overall survival (OS). RESULTS: MARCKS was overexpressed in epithelial tumor cells in 66% of the MBC samples versus 26% of normal samples (p= 1.40 × 10-7). Such positive MARCKS expression in epithelial tumor cells was associated with positive HER2 status (p= 4.0 × 10-3). It was associated with shorter OS in uni-and multivariate analysis. By contrast, stromal IHC MARCKS expression was correlated only with tumor grade. CONCLUSION: MARCKS tumor cell overexpression might in part explain the aggressiveness and the poor prognosis of MBC. MARCKS can represent a potential therapeutic target for MBC.


Assuntos
Neoplasias da Mama Masculina/metabolismo , Substrato Quinase C Rico em Alanina Miristoilada/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Substrato Quinase C Rico em Alanina Miristoilada/genética , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
11.
Br J Cancer ; 121(12): 991-1000, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719684

RESUMO

BACKGROUND: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. METHODS: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method). RESULTS: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001). CONCLUSIONS: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. CLINICAL TRIAL REGISTRATION: NCT03275311.


Assuntos
Neoplasias da Mama Masculina/epidemiologia , Neoplasias do Sistema Nervoso/epidemiologia , Neoplasias de Mama Triplo Negativas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/classificação , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Cinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias do Sistema Nervoso/genética , Neoplasias do Sistema Nervoso/patologia , Neoplasias do Sistema Nervoso/secundário , Prognóstico , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
12.
Presse Med ; 48(10): 1092-1100, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31706893

RESUMO

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação , Fatores Etários , Antígenos CD/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/genética , Caderinas/genética , Saúde da Família , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , França , Genes BRCA1 , Genes BRCA2 , Genes p53 , Testes Genéticos , Síndrome do Hamartoma Múltiplo/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Gravidez , Mastectomia Profilática , Fatores de Risco , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/genética
13.
Breast Cancer Res Treat ; 178(3): 557-564, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31512090

RESUMO

PURPOSE: In order to better define the breast cancer (BC) genetic risk factors in men, a germline investigation was carried out on 81 Male BC cases by screening the 24 genes involved in BC predisposition, genome stability maintenance and DNA repair mechanisms by next-generation sequencing. METHODS: Germline DNAs were tested in a custom multi-gene panel focused on all coding exons and exon-intron boundaries of 24 selected genes using two amplicon-based assays on PGM-Ion Torrent (ThermoFisher Scientific) and MiSeq (Illumina) platforms. All variants were recorded and classified by using a custom pipeline. RESULTS: Clinical pathological data and the family history of 81 Male BC cases were gathered and analysed, revealing the average age of onset to be 61.3 years old and that in 35 cases there was a family history of BC. Our genetic screening allowed us to identify a germline mutation in 22 patients (23%) in 4 genes: BRCA2, BRIP1, MUTYH and PMS2. Moreover, 12 variants of unknown clinical significance (VUS) in 9 genes (BARD1, BRCA1, BRIP1, CHEK2, ERCC1, NBN, PALB2, PMS1, RAD50) were predicted as potentially pathogenic by in silico analysis bringing the mutation detection rate up to 40%. CONCLUSION: As expected, a positive family history is a strong predictor of germline BRCA2 mutations in male BC. Understanding the potential pathogenicity of VUS represents an extremely urgent need for the management of BC risk in Male BC cases and their own families.


Assuntos
Neoplasias da Mama Masculina/genética , Reparo do DNA/genética , Predisposição Genética para Doença/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/patologia , Testes Genéticos , Genoma Humano/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
14.
Am J Surg Pathol ; 43(12): 1693-1700, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31498178

RESUMO

Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in <5% of tumor cells and 1 (0.5%) showed focal membranous staining. All histologic mimics were negative. In conclusion, diffuse and/or at least focally strong nuclear pan-TRK staining is a sensitive and specific marker for secretory carcinoma of the breast.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama Masculina/enzimologia , Neoplasias da Mama/enzimologia , Carcinoma/enzimologia , Fusão Gênica , Imuno-Histoquímica , Receptores de Fator de Crescimento Neural/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Carcinoma/genética , Carcinoma/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Paris , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-ets/genética , Receptores de Fator de Crescimento Neural/genética , Proteínas Repressoras/genética , Estados Unidos , Adulto Jovem
15.
Endocr Relat Cancer ; 26(10): 779-794, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31340200

RESUMO

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.


Assuntos
Neoplasias da Mama Masculina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/patologia , Variações do Número de Cópias de DNA , Feminino , Amplificação de Genes , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Oncogenes/genética , Prognóstico
16.
Pan Afr Med J ; 33: 22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312338

RESUMO

Breast cancer is a complex disease characterized by the accumulation of multiple molecular alterations giving each tumor phenotype and an own evolutionary potential. This study aimed to describe the distribution of the profile and molecular subtypes of breast cancers followed at Surgical Oncology Unit of Donka National Hospital. This was retrospective and descriptive study on cases of breast cancer in which the hormone receptor status and expression of the Her2 oncogene have been performed from 2007 to 2016. We recorded 58 cases including 56 (96.6%) women and 2 (3.4%) men. The average age was 48.2 ± 10.9. Invasive ductal carcinoma accounted for 50 (86.2%) cases. The SBR grade was II in 31(53.4%) cases, III in 21 (36.2%) cases and I in 6 (10.3%) cases. The tumor was classified as T4 in 36 (62.1%) cases; it was metastatic in 11(19.0%) cases. Estrogen receptors were positive in 29 (50.0%) cases, progesterone receptors positive in 25 (43.1%) cases, the Her2 oncogene was positive in 22 (39.3%) cases. The distribution of molecular sub-types was: 20 (34.5%) luminal A, 15 (25.9%) triple negative, 13 (22.4%) Her2 overexpressed, 8 (13.8%) luminal B and 2 (3.2%) undetermined. This preliminary study showed the poor accessibility of immunohistochemistry for the molecular diagnosis of breast cancer in our country. Luminal A subtypes and triple negatives were more common. The determination of molecular subtypes is a rational basis for hormone therapy and targeted therapy, thus personalizing the treatment of breast cancer.


Assuntos
Neoplasias da Mama Masculina/patologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/epidemiologia , Feminino , Guiné/epidemiologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Receptor ErbB-2/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia
17.
Med Oncol ; 36(8): 70, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31203460

RESUMO

Alterations in BRCA2, PALB2, CHEK2, and p53 genes have been identified for their association with male breast cancer in various studies. The incidence of male breast cancer in India is consistent with its global rate. The present study was carried out with an aim to evaluate the genetic alterations in male breast cancer patients from Malwa region of Punjab, India. Four male breast cancer patients belonging to different families were recruited from Guru Gobind Singh Medical College and Hospital, Faridkot, India. A total of 51 genes reported with implications in the pathogenesis of breast cancer were screened using next generation sequencing. Germline variations were found in BRCA1, BRCA2, PMS2, p53, and PALB2 genes, previously reported to be associated with MBC as well as FBC. In addition to these, 13 novel missense alterations were detected in eight genes including STK11, FZR1, PALB2, BRCA2, NF2, BAP1, BARD1, and CHEK2. Impact of these missense alterations on structure and function of protein was also analyzed through molecular dynamics simulation. Structural analysis of these single nucleotide polymorphisms (SNPs) revealed significant impact on the encoded protein functioning.


Assuntos
Neoplasias da Mama Masculina/genética , Idoso , Proteína BRCA2/genética , Neoplasias da Mama Masculina/epidemiologia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
18.
PLoS One ; 14(6): e0217521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242196

RESUMO

BACKGROUND: PPM1D (Protein phosphatase magnesium-dependent 1δ) is known as a damage response regulator, a part of the p53 negative feedback loop. Truncating mutations of PPM1D, resulting in overexpression, are frequently found in the blood of patients with breast or ovarian cancer. To identify whether the PPM1D mutation predisposes patients to such cancers or if it results from the cancer and therapy, somatic PPM1D mutations in association with previous cancer and chemotherapy need to be explored. METHODS: We performed next-generation sequencing (NGS) analysis of blood samples from patients suspected to have hereditary cancer. We grouped the patients according to their diagnoses and history of chemotherapy. For the patients with PPM1D mutations in blood, tumor tissue specimens were examined for the PPM1D mutation using conventional sequencing. RESULTS: A total of 1,195 patients, including 719 patients with breast cancer and 240 with ovarian cancer, were tested, and four (~0.3%) had the truncating mutation in PPM1D. All truncating mutations were in exon 6, in mosaic form, with a mean allele fraction of 11.15%. While 395 out of the 1,195 patients had undergone chemotherapy, the four with the truncating mutation had a history of cisplatin-based chemotherapy. No corresponding mutations were identified in the tumor tissues. CONCLUSIONS: We investigated the frequency of the somatic mosaic PPM1D mutation, in patients with breast or ovarian cancer, which is suggested to be low and related to a history of cisplatin-based chemotherapy. It may be a marker of previous exposure to selective pressure for cells with an impaired DNA damage response.


Assuntos
Neoplasias da Mama Masculina , Cisplatino/administração & dosagem , Mosaicismo , Proteínas de Neoplasias , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Proteína Fosfatase 2C , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Síndromes Neoplásicas Hereditárias/sangue , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteína Fosfatase 2C/sangue , Proteína Fosfatase 2C/genética
19.
Am J Mens Health ; 13(3): 1557988319847856, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068065

RESUMO

Male breast cancer (MBC) is uncommon in clinical practice. Using the 21-gene assay to facilitate decision-making on comprehensive treatment of MBC is rarely reported. This study reports the case of a 53-year-old man with left breast cancer. Modified radical mastectomy was performed. Endocrine treatment was chosen for the patient according to the result of the 21-gene assay, a recommended genomic test of breast cancer. The patient remained in good health without evidence of recurrence at 18-month follow-up. This case provides a reference mode for the comprehensive management of early-stage, estrogen receptor-expressing and lymph node-negative MBC patients.


Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/terapia , Tomada de Decisão Clínica , Perfilação da Expressão Gênica , Carcinoma/genética , Carcinoma/terapia , Humanos , Masculino , Mastectomia Radical Modificada , Pessoa de Meia-Idade , Medicina de Precisão , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico
20.
Int J Cancer ; 145(7): 1782-1797, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050813

RESUMO

Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10-14 ). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90-17.47; p = 1.1 × 10-14 ) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10-4 ), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24-13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77-22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.


Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Linhagem Celular , República Tcheca , Feminino , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Deleção de Sequência , Adulto Jovem
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