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2.
Virchows Arch ; 477(4): 545-555, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32383007

RESUMO

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement. Molecular subtype was determined visually by Ki67-LI in 484 pairs of CNB and SR specimens of invasive estrogen receptor (ER)-positive, human epidermal growth factor (HER2)-negative breast cancer. Luminal B disease was defined by Ki67-LI > 20% in SR. Correlation of molecular subtype agreement with age, menopausal status, CNB method, Breast Imaging Reporting and Data System imaging category, time between biopsies, type of surgery, and pathological tumor parameters was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. CNB had a sensitivity of 77.95% and a specificity of 80.97% for identifying luminal B tumors in CNB, compared with the final molecular subtype determination after surgery. The correlation of Ki67-LI between CNB and SR was moderate (ROC-AUC 0.8333). Specificity and sensitivity for CNB to correctly define molecular subtype of tumors according to SR were significantly associated with tumor grade, immunohistochemical progesterone receptor (PR) and p53 expression (p < 0.05). Agreement of molecular subtype did not significantly impact RFS and OS (p = 0.22 for both). The identified factors likely mirror intratumoral heterogeneity that might compromise obtaining a representative CNB. Our results challenge the robustness of a single CNB-driven measurement of Ki67-LI to identify luminal B breast cancer of low (G1) or intermediate (G2) grade.


Assuntos
Neoplasias da Mama/química , Antígeno Ki-67/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Proteína Supressora de Tumor p53/análise
3.
Am J Surg Pathol ; 44(8): 1092-1103, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32317606

RESUMO

To date, the apocrine variant of lobular carcinoma in situ (AP-LCIS) has been cursorily described as a subtype of lobular carcinoma in situ (LCIS). We retrospectively reviewed 34 cases of AP-LCIS (including 23 associated with invasive lobular carcinoma) to fully characterize it. AP-LCIS typically presented with screen-detected calcifications in older women (mean age: 65 y) and was characterized by distended terminal duct lobular units with relatively large "pleomorphic" cells, central necrosis, and calcifications. AP-LCIS cells exhibited abundant eosinophilic occasionally granular cytoplasm, hyperchromatic nuclei, and prominent nucleoli. Synchronous classic and/or florid LCIS was identified in 24/34 (70%) AP-LCIS, and in 9/11 (82%) pure AP-LCIS. Most (68%) cases of AP-LCIS were estrogen receptor-positive (50% strongly), 35% were progesterone receptor-positive, 26% were human epidermal growth factor 2-positive, 18% demonstrated high-proliferation rate (Ki67: >15%), and 90% were androgen receptor-positive. Aurora kinase A, immunoreactive in 38% of AP-LCIS cases, was not significantly associated with recurrence, development of invasion, or nodal positivity (P>0.05). Compared with conventional (nonapocrine) pleomorphic lobular carcinoma in situ (P-LCIS), aurora kinase A was expressed in a significantly greater proportion of P-LCIS (100%). AP-LCIS and P-LCIS did not otherwise differ in clinicopathologic features. Next-generation sequencing utilizing the Oncomine Comprehensive Panel v2, performed on 27 AP-LCIS cases, showed no specific molecular findings. In a mean follow-up of 57 months, 2 (of 11, 18%) pure AP-LCIS cases recurred (2 both in situ and invasive) and none metastasized or proved fatal. AP-LCIS should be regarded as another high-grade LCIS similar to P-LCIS in many respects, and pending additional studies should be managed similarly.


Assuntos
Glândulas Apócrinas , Carcinoma de Mama in situ/classificação , Neoplasias da Mama/classificação , Idoso , Glândulas Apócrinas/química , Glândulas Apócrinas/patologia , Aurora Quinase A/análise , Carcinoma de Mama in situ/química , Carcinoma de Mama in situ/genética , Carcinoma de Mama in situ/patologia , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Calcinose , Proliferação de Células , Bases de Dados Factuais , Fator de Crescimento Epidérmico/análise , Feminino , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Necrose , Recidiva Local de Neoplasia , Prognóstico , Receptores Androgênicos/análise , Receptores de Progesterona/análise , Estudos Retrospectivos
4.
Cancer Res ; 80(9): 1893-1901, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32245796

RESUMO

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Hispano-Americanos/genética , Receptor ErbB-2/análise , Adulto , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Neoplasias da Mama/genética , Colômbia/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Índios Norte-Americanos , Índios Sul-Americanos , América Latina/etnologia , Modelos Lineares , Modelos Logísticos , México/etnologia , Pessoa de Meia-Idade , Peru/etnologia , Receptor ErbB-2/genética , Receptores Estrogênicos/sangue , Receptores de Progesterona/sangue , Estados Unidos , Adulto Jovem
5.
Cancer Res ; 80(9): 1790-1798, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32075799

RESUMO

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.


Assuntos
Neoplasias da Mama/prevenção & controle , Mama/fisiologia , Lactação/fisiologia , Idade Materna , Metástase Neoplásica , Período Pós-Parto/fisiologia , Adulto , Animais , Antígenos CD/metabolismo , Aleitamento Materno , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Ligadas por GPI/metabolismo , Saúde Global/estatística & dados numéricos , Humanos , Incidência , Fígado/fisiologia , Camundongos , Proteínas de Neoplasias/metabolismo , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/patologia , Proteína Plasmática A Associada à Gravidez/metabolismo , Semaforinas/metabolismo , Fatores de Tempo , Adulto Jovem
6.
Cancer Res ; 80(8): 1762-1772, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32094303

RESUMO

Breast microcalcifications are a common mammographic finding. Microcalcifications are considered suspicious signs of breast cancer and a breast biopsy is required, however, cancer is diagnosed in only a few patients. Reducing unnecessary biopsies and rapid characterization of breast microcalcifications are unmet clinical needs. In this study, 473 microcalcifications detected on breast biopsy specimens from 56 patients were characterized entirely by Raman mapping and confirmed by X-ray scattering. Microcalcifications from malignant samples were generally more homogeneous, more crystalline, and characterized by a less substituted crystal lattice compared with benign samples. There were significant differences in Raman features corresponding to the phosphate and carbonate bands between the benign and malignant groups. In addition to the heterogeneous composition, the presence of whitlockite specifically emerged as marker of benignity in benign microcalcifications. The whole Raman signature of each microcalcification was then used to build a classification model that distinguishes microcalcifications according to their overall biochemical composition. After validation, microcalcifications found in benign and malignant samples were correctly recognized with 93.5% sensitivity and 80.6% specificity. Finally, microcalcifications identified in malignant biopsies, but located outside the lesion, reported malignant features in 65% of in situ and 98% of invasive cancer cases, respectively, suggesting that the local microenvironment influences microcalcification features. This study confirms that the composition and structural features of microcalcifications correlate with breast pathology and indicates new diagnostic potentialities based on microcalcifications assessment. SIGNIFICANCE: Raman spectroscopy could be a quick and accurate diagnostic tool to precisely characterize and distinguish benign from malignant breast microcalcifications detected on mammography.


Assuntos
Doenças Mamárias/metabolismo , Doenças Mamárias/patologia , Mama/patologia , Calcinose/metabolismo , Calcinose/patologia , Análise Espectral Raman/métodos , Biomarcadores/análise , Biópsia , Mama/química , Carcinoma de Mama in situ/química , Carcinoma de Mama in situ/diagnóstico , Carcinoma de Mama in situ/patologia , Doenças Mamárias/diagnóstico , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Calcinose/diagnóstico , Fosfatos de Cálcio/análise , Carbonatos/análise , Feminino , Humanos , Fosfatos/análise , Sensibilidade e Especificidade
7.
Hum Pathol ; 98: 10-21, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027910

RESUMO

The aim of the study was to evaluate the impact of the updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline on human epidermal growth factor receptor 2 (HER2) interpretation in breast cancer compared with that of the previous guidelines and also the significance of in situ hybridization (ISH) groups proposed by the updated guideline. HER2 ISH reports and immunohistochemistry (IHC) data from 1,348 invasive breast cancers diagnosed at a single institution were included in this study. HER2 IHC was reassessed using the 2018 guideline, and HER2 ISH status was determined by the 2007, 2013, and 2018 guidelines. When applying the updated guideline, most of the HER2 ISH-equivocal cases as per the previous guidelines were reclassified as ISH negative, and 0.8% of HER2 ISH-positive tumors as per the 2007 guideline and 2.5% of those as per the 2013 guideline were changed to ISH negative. Accordingly, the negative HER2 ISH results significantly increased in the 2018 guideline compared with the 2013 guideline. HER2 ISH-positive tumors in ISH group 3 (HER2/chromosome enumeration probe 17 [CEP17] ratio <2.0 and average HER2 copy number ≥6.0 per cell) were characterized by equivocal HER2 protein expression, CEP17 copy number gain, and low HER2 copy numbers compared with classic HER2 ISH-positive tumors in ISH group 1 (HER2/CEP17 ratio ≥2.0 and average HER2 copy number ≥4.0 per cell). HER2 ISH-negative tumors in ISH group 4 (HER2/CEP17 ratio <2.0 with average HER2 copy number ≥4.0 and < 6.0 per cell) revealed more aggressive clinicopathologic features and poorer clinical outcomes than those in ISH group 5 (HER2/CEP17 ratio <2.0 and average HER2 copy number <4.0 per cell), especially in the hormone receptor-positive subgroup. In conclusion, implementation of the updated 2018 ASCO/CAP guideline leads to a significant increase in HER2 ISH-negative results compared with the 2013 guideline, mainly via reclassification of the ISH-equivocal cases to ISH-negative ones. ISH groups proposed by the updated guideline provide additional information on the clinicopathologic characteristics of the tumors.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Hibridização In Situ/normas , Guias de Prática Clínica como Assunto/normas , Receptor ErbB-2/genética , Sociedades Médicas/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Consenso , Feminino , Humanos , Imuno-Histoquímica/normas , Hibridização in Situ Fluorescente/normas , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Receptor ErbB-2/análise , Reprodutibilidade dos Testes , Adulto Jovem
8.
Nat Commun ; 11(1): 375, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953382

RESUMO

Lipids play a pivotal role in biological processes and lipid analysis by mass spectrometry (MS) has significantly advanced lipidomic studies. While the structure specificity of lipid analysis proves to be critical for studying the biological functions of lipids, current mainstream methods for large-scale lipid analysis can only identify the lipid classes and fatty acyl chains, leaving the C=C location and sn-position unidentified. In this study, combining photochemistry and tandem MS we develop a simple but effective workflow to enable large-scale and near-complete lipid structure characterization with a powerful capability of identifying C=C location(s) and sn-position(s) simultaneously. Quantitation of lipid structure isomers at multiple levels of specificity is achieved and different subtypes of human breast cancer cells are successfully discriminated. Remarkably, human lung cancer tissues can only be distinguished from adjacent normal tissues using quantitative results of both lipid C=C location and sn-position isomers.


Assuntos
Lipidômica/métodos , Lipídeos/química , Animais , Neoplasias da Mama/química , Bovinos , Linhagem Celular Tumoral/química , Diabetes Mellitus Tipo 2/sangue , Escherichia coli/química , Glicerofosfolipídeos/análise , Glicerofosfolipídeos/química , Humanos , Isomerismo , Lipídeos/análise , Neoplasias Pulmonares/química , Fotoquímica , Plasma/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
9.
Int J Radiat Oncol Biol Phys ; 106(3): 503-510, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31654782

RESUMO

PURPOSE: Postmastectomy radiation therapy (PMRT) improves recurrence rates and overall survival in breast cancer patients. However, it remains unclear whether these findings can be applied to human epidermal growth factor receptor 2 (HER-2) positive patients treated with trastuzumab. METHODS AND MATERIALS: The Herceptin Adjuvant (HERA) trial is a phase III randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The present study is a retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models, and LRR curves were generated by the Kaplan-Meier method. RESULTS: Our analysis included 940 patients (57.6%) who received PMRT and 693 patients (42.4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At a median follow-up of 11 years, no significant difference in LRR was noted after PMRT in node negative (N0) patients (P = .96). Patients with 1 to 3 positive lymph nodes had a LRR-free survival of 97% in the PMRT group compared with 90% in the no PMRT group (hazard ratio = 0.28, P = .004) and a nonsignificant improved overall survival after PMRT (hazard ratio = 0.63, P = .06). CONCLUSIONS: PMRT delivery in HER-2 positive breast cancer patients with 1 to 3 positive lymph nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historic studies, the present findings are in favor of PMRT for HER-2 positive breast cancer patients with 1 to 3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer patients benefit the most from PMRT.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/radioterapia , Recidiva Local de Neoplasia , Receptor ErbB-2 , Adulto , Idoso , Análise de Variância , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Período Pós-Operatório , Modelos de Riscos Proporcionais , Receptores Estrogênicos , Receptores de Progesterona , Estudos Retrospectivos , Trastuzumab/uso terapêutico , Resultado do Tratamento
10.
Cancer ; 126(6): 1175-1182, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31851385

RESUMO

BACKGROUND: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)-positive disease. METHODS: This was a protocol-predefined secondary analysis of the randomized phase 3 Pan-European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node-positive or high-risk, node-negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse-free survival. In addition, HER2-positive patients and an equal number of HER2-negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow-up. RESULTS: There were 342 HER2-positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse-free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37-1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow-up did not differ significantly between HER2-positive and HER2-negative patients or between the 2 treatment groups. CONCLUSIONS: The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2 , Trastuzumab/administração & dosagem , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/métodos , Intervalos de Confiança , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Coração/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Trastuzumab/efeitos adversos , Adulto Jovem
11.
Cancer ; 126(6): 1193-1201, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31860136

RESUMO

BACKGROUND: Despite data demonstrating the safety of omitting axillary surgery in older women with early-stage breast cancer, the incidence of axillary surgery remains high. It was hypothesized that the prevalence of nodal positivity would decrease with advancing age. METHODS: The National Cancer Data Base was used to construct a cohort of adult women with early-stage, clinically node-negative, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative breast cancer treated between 2013 and 2015. Multivariable logistic regression was used to assess the relationship between age and nodal positivity, and this was stratified by the axillary surgery category. Modified Poisson regression was used to estimate the proportion of women receiving adjuvant therapy according to age and nodal status. RESULTS: The incidence of axillary surgery among women aged 70 and older (n = 51,917) remained high nationwide (86%). There was a significant decrease in nodal positivity with advancing age in women with early-stage, ER+, clinically node-negative breast cancer from the youngest cohort up to patients aged 70 to 89 years, and this was independent of histologic subtype (ductal vs lobular), race, comorbidities, and socioeconomic factors. Overall, less than 10% of women aged 70 or older who underwent surgery had node-positive disease, regardless of axillary surgery type, and almost 95% of node-positive patients aged 70 or older were at pathological stage N1mi or N1. CONCLUSIONS: Axillary surgery may be safely omitted for many older women with ER+, clinically node-negative, early-stage breast cancer. Nodal positivity declines with advancing age, and this suggests varied biology in older patients versus younger patients.


Assuntos
Fatores Etários , Neoplasias da Mama/cirurgia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/química , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Carcinoma Lobular/terapia , Quimioterapia Adjuvante , Estudos de Coortes , Comorbidade , Feminino , Humanos , Linfonodos/patologia , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Distribuição de Poisson , Radioterapia Adjuvante , Receptor ErbB-2 , Receptores Estrogênicos , Análise de Regressão , Fatores Socioeconômicos , Adulto Jovem
12.
Lancet Oncol ; 21(2): 250-260, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31859246

RESUMO

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. METHODS: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. FINDINGS: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64). INTERPRETATION: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration
13.
Nucleic Acids Res ; 48(3): e17, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31853536

RESUMO

Multiplexed RNA in situ hybridization for the analysis of gene expression patterns plays an important role in investigating development and disease. Here, we present a method for multiplexed RNA-ISH to detect spatial tumor heterogeneity in tissue sections. We made use of a microfluidic chip to deliver ISH-probes locally to regions of a few hundred micrometers over time periods of tens of minutes. This spatial multiplexing method can be combined with ISH-approaches based on signal amplification, with bright field detection and with the commonly used format of formalin-fixed paraffin-embedded tissue sections. By using this method, we analyzed the expression of HER2 with internal positive and negative controls (ActB, dapB) as well as predictive biomarker panels (ER, PgR, HER2) in a spatially multiplexed manner on single mammary carcinoma sections. We further demonstrated the applicability of the technique for subtype differentiation in breast cancer. Local analysis of HER2 revealed medium to high spatial heterogeneity of gene expression (Cohen effect size r = 0.4) in equivocally tested tumor tissues. Thereby, we exemplify the importance of using such a complementary approach for the analysis of spatial heterogeneity, in particular for equivocally tested tumor samples. As the method is compatible with a range of ISH approaches and tissue samples, it has the potential to find broad applicability in the context of molecular analysis of human diseases.


Assuntos
Hibridização In Situ/métodos , Técnicas Analíticas Microfluídicas/métodos , RNA Neoplásico/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias da Mama/química , Neoplasias da Mama/classificação , Linhagem Celular , Feminino , Humanos , Dispositivos Lab-On-A-Chip , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
14.
J BUON ; 24(5): 1889-1897, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786852

RESUMO

PURPOSE: The onset characteristics of the anaplastic large cell lymphoma (BI-ALCL) are non-specific and the diagnosis is often difficult and based on clinical suspicion and cytological sampling. The presence of non-pathognomonic radiological signs may delay the diagnosis of BI-ALCL, influencing patient prognosis. This could have an important social impact, considering that the incidence of BI-ALCL correlates with the number of prosthetic implants, which is in constant increase worldwide. The aim of this study was to verify if fibrin can represent a potential early radiological sign of the disease. METHODS: In this study, we present two cases of our series and review the previous studies already described in literature, searching for any early radiological sign of the disease and reporting a diagnostic work-up process for an early diagnosis. RESULTS: Signs clearly recognizable only of magnetic resonance were the following: thickening and hyperemia of the fibrous capsule with seroma and amorphous material (fibrin) present in 8 out of 10 cases (80%) detected on magnetic resonance images (certain or doubtful). CONCLUSION: The presence of fibrin in the periprosthetic effusion, well detectable by magnetic resonance imaging, could represent an early pathognomonic sign of the disease.


Assuntos
Biomarcadores Tumorais/análise , Implante Mamário/efeitos adversos , Implante Mamário/instrumentação , Implantes de Mama/efeitos adversos , Neoplasias da Mama/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Fibrina/análise , Linfoma Anaplásico de Células Grandes/diagnóstico por imagem , Imagem por Ressonância Magnética , Adulto , Neoplasias da Mama/química , Neoplasias da Mama/cirurgia , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/química , Linfoma Anaplásico de Células Grandes/cirurgia , Pessoa de Meia-Idade , Valor Preditivo dos Testes
15.
Molecules ; 24(23)2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771216

RESUMO

In this work, we successfully developed a novel and sensitive gas sensor for the determination of trace acetophenone based on its cataluminescence (CTL) emission on the surface of nano-praseodymium oxide (nano-Pr6O11). The effects of working conditions such as temperature, flow rate, and detecting wavelength on the CTL sensing were investigated in detail. Under the optimized conditions, the sensor exhibited linear response to the acetophenone in the range of 15-280 mg/m3 (2.8-52 ppm), with a correlation coefficient (R2) of 0.9968 and a limit of detection (S/N = 3) of 4 mg/m3 (0.7 ppm). The selectivity of the sensor was also investigated, no or weak response to other compounds, such as alcohols (methanol, ethanol, n-propanol, iso-propanol, n-butanol), aldehyde (formaldehyde and acetaldehyde), benzenes (toluene, o-xylene, m-xylene, p-xylene), n-pentane, ethyl acetate, ammonia, carbon monoxide, carbon dioxide. Finally, the present sensor was applied to the determination of acetophenone in human exhaled breath samples. The results showed that the sensor has promising application in clinical breath analysis.


Assuntos
Acetofenonas/análise , Neoplasias da Mama/diagnóstico , Óxidos/síntese química , Praseodímio/química , Técnicas Biossensoriais , Neoplasias da Mama/química , Testes Respiratórios , Catálise , Feminino , Humanos , Luminescência , Nanopartículas/química , Óxidos/química , Propriedades de Superfície
16.
Radiol Med ; 124(12): 1229-1237, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31773458

RESUMO

The aim of our study was to assess the performance of contrast-enhanced digital mammography (CEDM) in the preoperative loco-regional staging of invasive lobular carcinoma (ILC) patients, about the valuation of the extension of disease and in measurement of lesions. Then, we selected retrospectively, among the 1500 patients underwent to CEDM at the Breast Diagnostics Department of the Careggi University Hospital of Florence and the National Cancer Institute of Milan from September 2016 to November 2018, 31 women (mean age 57.1 aa; range 41-78 aa) with a definitive histological diagnosis of ILC. CEDM has proved to be a promising imaging technique, being characterized by a sensitivity of 100% in the detection of the index lesion, and of 84.2% in identifying any adjunctive lesions: It was the presence of a non-mass enhancement (NME) to lower the sensitivity of the technique (25% vs. 100% for mass-like enhancements or a mass closely associated with a NME). Specificity in the characterization of additional lesions was 66.7%, and the diagnosis of the extension of disease was correct in 77.4% of cases: NME also led to a decrease in diagnostic accuracy in the evaluation of disease extension up to 40% versus 85% for masses and 80% for masses associated with NME (M/NME). Moreover, in 12/31 (38.7%), CEDM allowed to correctly identify lesions not shown by mammography + ultrasonography + tomosynthesis: In the half of these (6/12), there was a multicentricity, thus allowing an adequate surgical planning change. CEDM was also very accurate in analyzing the maximum diameter of the masses, while it was much less reliable in the case of the M/NME and pure NME. In conclusion, CEDM is a new promising imaging technique in the loco-regional preoperative staging and in the evaluation of disease extension for ILC, especially in case of mass enhancement lesions.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Lobular/diagnóstico por imagem , Meios de Contraste , Iohexol/análogos & derivados , Mamografia/métodos , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Carcinoma Lobular/química , Carcinoma Lobular/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Cuidados Pré-Operatórios , Intensificação de Imagem Radiográfica/métodos , Padrões de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Carga Tumoral , Ultrassonografia Mamária
17.
BMC Complement Altern Med ; 19(1): 324, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752829

RESUMO

BACKGROUND: The present study was designed to investigate the effects of Berberis vulgaris (BV) juice consumption on plasma levels of insulin-like growth factor (IGF-1), IGF-binding proteins (IGFBPs), and the expression of PPAR-γ, VEGF and HIF in women with benign breast disease. METHODS: This parallel design randomized, double-blind controlled clinical trial was conducted on 85 eligible patients diagnosed with benign breast disease. They were assigned randomly into either BV juice group (n = 44, BV juice: 480 ml/day) or placebo group (n = 41, BV placebo juice: 480 ml/day) for 8 weeks intervention. Participants, caregivers and those who assessed laboratory analyses were blinded to the assignments. Plasma levels of biomarkers were measured at baseline and after 8 weeks by ELISA. Quantitative real-time PCR was used to measure the fold change in the expression of each interested gene. RESULTS: The compliance of participants was 95.2% and 40 available subjects analyzed in each group at last. Relative treatment (RT) effects for BV juice caused 16% fall in IGF-1 concentration and 37% reduction in the ratio of IGF-1/1GFBP1. Absolute treatment effect expressed 111 ng/ml increased mean differences of IGFBP-3 between BV group and placebo. Plasma level of PPAR-γ increased in both groups but it was not significant. Fold changes in the expressions of PPAR-γ, VEGF and HIF showed down-regulation in the intervention group compared to placebos (P < 0.05). CONCLUSIONS: The BV juice intervention over 8 weeks was accompanied by acceptable efficacy and decreased plasma IGF-1, and IGF-1/IGFBP-1 ratio partly could be assigned to enhanced IGFBP-1 level in women with BBD. The intervention caused reductions in the expression levels of PPAR, VEGF, and HIF which are remarkable genomic changes to potentially prevent breast tumorigenesis. TRIAL REGISTRATION: IRCT2012110511335N2. Registered 10 July 2013 (retrospectively registered).


Assuntos
Berberis , Neoplasias da Mama , Sucos de Frutas e Vegetais , Adulto , Mama/química , Mama/patologia , Neoplasias da Mama/química , Neoplasias da Mama/dietoterapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Fator 1 Induzível por Hipóxia/análise , Fator 1 Induzível por Hipóxia/metabolismo , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Pessoa de Meia-Idade , PPAR gama/análise , PPAR gama/metabolismo , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
18.
Med Oncol ; 37(1): 6, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31734829

RESUMO

BACKGROUND: We previously showed that cobalt chloride (CoCl2) induction of polyploid giant cancer cells (PGCCs) was characterized by abnormal cell cycle-related protein expression and G2/M arrest. The role of the p38MAPK-ERK-JNK signaling pathway in cell cycle regulation has been reported, but the mechanism by which p38MAPK-ERK-JNK regulates PGCCs formation remains unclear. This study examined p38MAPK-ERK-JNK-CDC25C expression in PGCCs and their daughter and control cells and assessed the clinicopathological significance of p38MAPK, ERK, JNK, and CDC25C expression in human ovarian and breast cancers. METHODS: CoCl2 was used to induce the formation of PGCCs in HEY and BT-549 cells. Western blotting and immunocytochemical staining were used to compare the expression and subcellular localization of p38MAPK, ERK, JNK, and CDC25C in the control group and CDC25C knockdown before and after CoCl2 treatment. The specific combination of p38MAPK and ERK with pCDC25C-Ser216 was detected by immunoprecipitation. In addition, p38MAPK, ERK, JNK, and CDC25C immunohistochemical staining were performed to compare the clinicopathologic significances in 81 cases of ovarian cancer tissue, including 20 cases of primary breast cancer with lymph node metastasis (group I), and their corresponding metastatic lymph nodes (group II), 31 cases of primary breast cancer without metastasis (group III), and 10 cases of benign breast tumors (group IV). Breast tumor tissue from 229 was divided into two groups: 167 cases of primary invasive breast cancer (group 1) and 62 cases of lymph node metastatic breast cancer (group 2). RESULTS: Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl2-treated cells. Moreover, ERK displayed a trend of increased expression in HEY PGCCs and decreased expression in BT-549 PGCCs. p38MAPK and ERK regulated CDC25C by phosphorylating the CDC25C-Ser216 site and participated in the G2/M phase transition. Immunohistochemical (IHC) analysis of the ovarian tumor tissues showed significant positive staining rates of p38MAPK (P = 0.001), ERK (P = 0.002), JNK (P = 0.000), and CDC25C (P = 0.000) among the four groups. In breast tumor tissues, the overall expression in p38MAPK (P = 0.029), ERK (P = 0.002), JNK (P = 0.013), and CDC25C (P = 0.001) also differed significantly between the two groups. CONCLUSION: The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.


Assuntos
Tumores de Células Gigantes , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatases cdc25/metabolismo , Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Tumores de Células Gigantes/química , Tumores de Células Gigantes/metabolismo , Tumores de Células Gigantes/patologia , Humanos , Imuno-Histoquímica , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Poliploidia , Fosfatases cdc25/genética
19.
Gac Med Mex ; 155(Suppl 1): S39-S43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31638609

RESUMO

Background: Breast cancer subtype classification according to hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) using immunohistochemistry is the standard practice for therapeutic decision making. Objective: To design future studies information on characteristics and survival of each subtype is essential. Method: We conducted a retrospective study to analyze clinical and pathologic features as well as survival data according to breast cancer immunohistochemistry subtype. Results: There were 211 women with a RH(+)/HER2(-) breast cancer subtype, 53 HR(+)/HER2(+), 16 HER2(+) and 23 HR(-)/HER2(-), with a median overall survival in months of 39 (20.5-62.7), 42 (25.5-65), 42 (13.7-67.7) and 26 (11-78), respectively, for a 3.7 hazard ratio of death (95% Confidence Interval [CI]: 1.3-10.3) for the triple negative group as compared to the HR(+)/HER2(-) group (p = 0.01). Conclusions: HR positive subtypes by immunohistochemistry where most frequent and showed a greater overall survival compared to the triple negative subtype.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Receptores ErbB/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Adulto , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Radiol Oncol ; 53(3): 285-292, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31553709

RESUMO

Background The standard treatment of hormone receptor positive, HER2 negative early breast cancer (BC) is surgery followed by adjuvant systemic therapy either with endocrine therapy alone or with the addition of chemotherapy followed by endocrine therapy. Adjuvant systemic therapy reduces the risk of recurrence and death from BC. Whether an individual patient will benefit from adjuvant chemotherapy is an important clinical decision. Decisions that rely solely on clinical-pathological factors can often lead to overtreatment. Multigene signatures represent an important progress in optimal selection of high risk patients that might benefit from the addition of chemotherapy to adjuvant endocrine therapy. Conclusions Several signatures are already commercially available and also accepted by international guidelines. Oncotype DX and MammaPrint have been most extensively validated and supported by level IA evidence.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Testes Genéticos/métodos , Família Multigênica , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Feminino , Genes erbB-2 , Humanos , Linfonodos/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Testes Farmacogenômicos/métodos , Transcriptoma
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