Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 170
Filtrar
1.
Sci Rep ; 11(1): 4233, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608588

RESUMO

Correctly estimating the hormone receptor status for estrogen (ER) and progesterone (PGR) is crucial for precision therapy of breast cancer. It is known that conventional diagnostics (immunohistochemistry, IHC) yields a significant rate of wrongly diagnosed receptor status. Here we demonstrate how Dempster Shafer decision Theory (DST) enhances diagnostic precision by adding information from gene expression. We downloaded data of 3753 breast cancer patients from Gene Expression Omnibus. Information from IHC and gene expression was fused according to DST, and the clinical criterion for receptor positivity was re-modelled along DST. Receptor status predicted according to DST was compared with conventional assessment via IHC and gene-expression, and deviations were flagged as questionable. The survival of questionable cases turned out significantly worse (Kaplan Meier p < 1%) than for patients with receptor status confirmed by DST, indicating a substantial enhancement of diagnostic precision via DST. This study is not only relevant for precision medicine but also paves the way for introducing decision theory into OMICS data science.

2.
Radiology ; : 201600, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591888

RESUMO

Background Tissue sodium concentration (TSC) is elevated in breast cancer and can determine chemotherapy response. Purpose To test the feasibility of using a sodium 23 (23Na) MRI protocol at 7.0 T for TSC quantification to predict early treatment outcomes of neoadjuvant chemotherapy in breast cancer and to determine whether those quantitative values provide additional information about efficacy. Materials and Methods Women with primary breast cancer were included in this prospective study. From July 2017 to June 2018, participants underwent 7.0-T 23Na MRI. Multichannel data sets were acquired with a density-adapted, three-dimensional radial projection reconstruction pulse sequence. Two-dimensional tumor size and TSC were evaluated before and after the first and second chemotherapy cycle, and statistical tests were performed based on the presence or absence of a pathologic complete response (pCR). Results Fifteen women with breast cancer and six healthy women were enrolled. The mean baseline tumor size in women with a pCR was 7.0 cm2 ± 5.0 (standard deviation), and the mean baseline tumor size in women without a pCR was 19.0 cm2 ± 12.0. After the first chemotherapy cycle, women with a pCR showed a reduced tumor size of 32.9% (2.3 cm2/7.0 cm2), compared with 15.3% (2.9 cm2/19.0 cm2) in those without a pCR. The areas under the receiver operating characteristic curve for tumor size reduction after the first and second chemotherapy cycle were 0.73 (95% CI: 0.09, 0.50; P = .12) and 0.93 (95% CI: 0.04, 0.60; P < .001), respectively. Women with a pCR had a mean baseline TSC of 69.4 mmol/L ± 6.1, with a reduction of 12.0% (8.3 mmol/L), whereas those without a pCR had a mean baseline TSC of 71.7 mmol/L ± 5.7, with a reduction of 4.7% (3.4 mmol/L) after the first cycle. The areas under the receiver operating characteristic curve for TSC after the first and second cycles were 0.96 (95% CI: 0.86, 1.00; P < .001) and 1.000 (95% CI: 1.00, P < .001), respectively. Conclusion Using 7.0-T MRI for tissue sodium concentration quantification to predict early treatment outcomes of neoadjuvant chemotherapy in breast cancer is feasible, with reduced tissue sodium concentration indicative of cancer response. © RSNA, 2021 Online supplemental material is available for this article.

3.
Am J Obstet Gynecol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

4.
Neoplasma ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33147051

RESUMO

The increasing number of diagnosed breast lesions lead to the critical need for new markers that would elucidate the process of tumorigenesis. The objective of the study was to examine COX-2, p16, and Ki67 expression in a broad spectrum of breast lesions in order to define the proteins' phenotype throughout the tumorigenesis. Expression was studied by immunohistochemistry in 308 human breast samples divided into 7 subgroups - flat epithelial atypia (FEA), atypical hyperplasia (ADH), intraductal carcinoma (DCIS), invasive cancer (IC), benign lesions (BLs), normal tissue adjacent to breast cancer (CANT), and fatty tissue (FT). Analysis among 4 subgroups - premalignant lesions (DIN), IC, BLs, and normal tissue was also performed. High prevalence of COX-2 overexpression was found in all breast lesions including BLs (70% FEA, 89% ADH, 86% DCIS, 81% IC, 44% CANT, 92% BLs, 29% FT). Significant dominance of p16 overexpression was found in premalignant lesions and BLs (50% FEA, 67% ADH, 50% DCIS, 37% IC, 8% CANT, 58% BLs, 21% FT). The location of staining within p16+ cells differed - BLs showed nuclear positivity, whereas in IC it was exclusively cytoplasmic. Premalignant lesions showed all types of p16 positivity. Significantly higher prevalence of COX-2+p16+Ki67+ phenotype was in premalignant tumors with the highest prevalence in ADH (40% of FEA, 67% ADH, 35% DCIS, 20% IC, 3% CANT, 20% BLs, 14% FT). Our observations showed a high prevalence of COX-2+p16+Ki67+ phenotype in premalignant lesions. Further studies are needed in order to elucidate if this phenotype reflects any specific pathway of future progression of premalignant breast lesions.

5.
Gynecol Oncol ; 159(3): 820-826, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33010967

RESUMO

OBJECTIVE: BRCA mutation carriers face a high lifetime risk of developing ovarian cancer. The strong inverse association between breastfeeding and the risk of ovarian cancer is established in the general population but is less well studied among women with a germline BRCA1 or BRCA2 mutation. METHOD: Thus, we conducted a matched case-control analysis to evaluate the association between breastfeeding history and the risk of developing ovarian cancer. After matching for year of birth, country of residence, BRCA gene and personal history of breast cancer, a total of 1650 cases and 2702 controls were included in the analysis. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with various breastfeeding exposures. RESULTS: A history of ever-breastfeeding was associated with a 23% reduction in risk (OR = 0.77; 95%CI 0.66-0.90; P = 0.001). The protective effect increased with breastfeeding from one month to seven months after which the association was relatively stable. Compared to women who never breastfed, breastfeeding for seven or more months was associated with a 32% reduction in risk (OR = 0.68; 95%CI 0.57-0.81; P < 0.0001) and did not vary by BRCA gene or age at diagnosis. The combination of breastfeeding and oral contraceptive use was strongly protective (0.47; 95%CI 0.37-0.58; P < 0.0001). CONCLUSIONS: These findings support a protective effect of breastfeeding for at least seven months among women with a BRCA1 or BRCA2 mutation, that is independent of oral contraceptive use.

6.
NPJ Breast Cancer ; 6: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964118

RESUMO

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

7.
Horm Mol Biol Clin Investig ; 41(3)2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32989958

RESUMO

Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

8.
Biomed Res Int ; 2020: 1363827, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832541

RESUMO

Precision medicine for breast cancer relies on biomarkers to select therapies. However, the reliability of biomarkers drawn from gene expression arrays has been questioned and calls for reassessment, in particular for large datasets. We revisit widely used data-normalization procedures and evaluate differences in outcome in order to pinpoint the most reliable reprocessing methods biomarkers can be based upon. We generated a database of 3753 breast cancer patients out of 38 studies by downloading and curating patient samples from NCBI-GEO. As gene-expression biomarkers, we select the assessment of receptor status and breast cancer subtype classification. Each normalization procedure is applied separately, and biomarkers are then evaluated for each patient. Differences between normalization pipelines are quantified as percentages of patients having outcomes different for each pipeline. Some normalization procedures lead to quite consistent biomarkers, differing only in 1-2% of patients. Other normalization procedures-some of them have been used in many clinical studies-end up with distrusting discrepancies (10% and more). A good deal of doubt regarding the reliability of microarrays may root in the haphazard application of inadequate preprocessing pipelines. Several modes of batch corrections are evaluated regarding a possible improvement of receptor prediction from gene expression versus the golden standard of immunohistochemistry. Finally, we nominate those normalization methods yielding consistent and trustable results. Adequate bioinformatics data preprocessing is key and crucial for any subsequent statistics to arrive at trustable results. We conclude with a suggestion for future bioinformatics development to further increase the reliability of cancer biomarkers.

9.
Eur J Cancer ; 134: 99-106, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32502940

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial. PATIENTS AND METHODS: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB). RESULTS: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85]). CONCLUSIONS: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
10.
Clin Cancer Res ; 26(21): 5682-5688, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32546648

RESUMO

PURPOSE: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. EXPERIMENTAL DESIGN: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. RESULTS: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). CONCLUSIONS: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.

11.
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
12.
Eur J Cancer ; 132: 43-52, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325419

RESUMO

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
14.
Breast Cancer Res ; 22(1): 8, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948486

RESUMO

BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Mutação , Salpingo-Ooforectomia/métodos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Humanos , Incidência , Agências Internacionais , Menopausa , Pessoa de Meia-Idade , Estudos Prospectivos , Comportamento de Redução do Risco
15.
Cancer Epidemiol Biomarkers Prev ; 29(2): 368-378, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792088

RESUMO

BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

16.
BMC Cancer ; 19(1): 695, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307407

RESUMO

BACKGROUND: It is important to identify biomarkers associated with BRCA mutation in women with early breast cancer (BC) to improve early identification of mutation carriers. Thus, in this study, we examined the protein expression of claudin (CLDN) 3, CLDN4, CLDN7, and E-cadherin. Moreover, we analyzed additional histopathological variables and their associations in familial BC. METHODS: Immunohistochemical analysis for CLDNs and E-cadherin was performed on 237 BC cases of three different subsets of BC tumors: 62 from BRCA1 mutation carriers, 59 from BRCA2 mutation carriers, and 116 tumors from patients with BRCA wild type (WT) as controls. Histopathological data were also analyzed in the different subgroups. Logistic regression and receiver operation characteristic (ROC) curve were conducted to investigate factors associated with BRCA tumors. RESULTS: Expression of CLDN3 positively correlated with BRCA-mutated BC. CLDN3 was expressed in 58% of BRCA1-mutated tumors compared to only 7% in BRCA2-mutated tumors (p < 0.001) and 1% in WT tumors (p < 0.001). CK5 and CK14 expression were also more likely to arise in BRCA1 tumors (44 and 16%, respectively) than in the control group (8 and 4%) (p < 0.001, p = 0.012, respectively). We also found a significantly higher proportion of CK5+ among BRCA1 tumors (44%) in comparison with BRCA2-related BC (8%) (p < 0.001). In addition, there was a significant difference between both groups regarding CK14: positive expression in 16 and 5%, respectively (p = 0.030). CK5 and CK14 did not differ between the BRCA2 group and the WT tumors significantly. In a multivariate regression model, expression of CK5 (Odds ratio (OR): 6.46; 95% confidence interval (CI): 1.52-27.43; p = 0.011), and CLDN3 (OR: 200.48; 95% CI: 21.52-1867.61; p < 0.001) were associated with BRCA1 mutation status. CONCLUSIONS: Our data suggests that CLDN3, CK5, and CK14 in combination with ER, PR and HER2 are associated with BRCA1 mutation status.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Claudina-3/metabolismo , Mutação em Linhagem Germinativa , Queratina-14/metabolismo , Queratina-5/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Caderinas/metabolismo , Carcinoma Ductal de Mama/genética , Claudina-3/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Queratina-5/genética , Modelos Logísticos , Pessoa de Meia-Idade , Curva ROC , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
17.
Cancer Lett ; 459: 1-12, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31150822

RESUMO

High grade serous ovarian cancer (HGSOC) is the most frequent type of ovarian cancer. Most patients have primary response to platinum-based chemotherapy but frequently relapse, which leads to patient death. A lack of well documented and characterized patient-derived HGSOC cell lines is so far a major barrier to define tumor specific therapeutic targets and to study the molecular mechanisms underlying disease progression. We established 34 patient-derived HGSOC cell lines and characterized them at cellular and molecular level. Particularly, we demonstrated that a cancer-testis antigen PRAME and Estrogen Receptor could serve as therapeutic targets. Notably, data from the cell lines did not demonstrate acquired resistance due to tumor recurrence that matched with clinical observations. Finally, we presented that all HGSOC had no or very low CDKN1A (p21) expression due to loss of wild-type TP53, suggesting that loss of cell cycle control is the determinant for tumorigenesis and progression. In conclusion, patient-derived cell lines reveal that PRAME is a potential tumor specific therapeutic target in HGSOC and counteracting the down-regulation of p21 caused by loss of wild-type TP53 might be the key to impede disease progression.


Assuntos
Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Carboplatina/farmacologia , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Cistadenocarcinoma Seroso/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Neoplasias Ovarianas/genética , Receptores Estrogênicos/biossíntese , Receptores Estrogênicos/genética , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
18.
Clin Cancer Res ; 25(13): 3865-3872, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31064782

RESUMO

PURPOSE: Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up. EXPERIMENTAL DESIGN: EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.6 years; N = 1,702). Distant recurrence-free rate (DRFR; 95% confidence interval) was assessed 10 and 15 years after diagnosis. RESULTS: Overall, 62.6% of patients had low-risk EPclin scores with significantly improved DRFR relative to high-risk patients (HR, 4.77; 95% CI, 3.37-6.67; P < 0.0001). Ten-year DRFR (0-10 years) was improved among patients with low-risk versus high-risk EPclin scores in the full cohort [95.5% (94.1%-97.0%) vs. 80.3% (76.9%-83.9%)] as well as for patients with node-negative disease [95.5% (94.0%-97.1%) vs. 87.0% (82.6%-91.7%)] or with 1 to 3 positive nodes [95.6% (92.2%-99.1%) vs. 80.9% (75.9%-86.1%)]. The molecular and EPclin scores were significant predictors of DRFR after adjusting for clinical variables, regardless of nodal status. Similar results were observed for late recurrence (5-15 years; HR, 4.52; 95% CI, 2.65-7.72; P < 0.0001). The EPclin score significantly added prognostic information to a late metastasis nomogram (CTS5 score; P < 0.001). CONCLUSIONS: This study demonstrates that EPclin can identify patients at low risk for early or late recurrence who may safely forgo adjuvant chemotherapy or extended endocrine therapy, respectively, regardless of nodal status.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Resultado do Tratamento
19.
Cancer Med ; 8(4): 1875-1881, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30821131

RESUMO

We investigated the prevalence of germline BRCA mutations in a population-based cohort of Austrian women diagnosed with ovarian cancer and its association with family history of cancer. We prospectively collected family pedigrees of 443 Austrian ovarian cancer patients who had been tested for the presence of a germline BRCA or 2 mutations and correlated the familial breast and ovarian cancer burden with the prevalence of BRCA mutations and disease onset. The probability of carrying a gBRCA mutation in patients without family history of cancer is 14% (95% CI 9%-22%), as opposed to 45% (95% CI 31%-59%) of patients with at least one family member with ovarian cancer, and 47% (95% CI 40%-54%) if other relatives have developed breast cancer. If both breast and ovarian cancer are diagnosed in the family, the probability of carrying a germline BRCA1 or 2 mutations is 60% (95% CI 50%-68%). germline BRCA1 or mutations in families with ovarian cancer only are commonly located in the Ovarian Cancer Cluster Regions when compared to families with both breast and ovarian cancer (P = 0.001, and P = 0.020, respectively). While gBRCA mutation carriers with ovarian cancer do not have a significantly different age at onset than patients with a family history of cancer, gBRCA1 carriers in general have an earlier onset than gBRCA2 carriers (P = 0.002) and patients without a mutation (P = 0.006). The rate of germline BRCA1 or 2 mutations in ovarian cancer patients without a family history or breast or ovarian cancer is low. However, in women with additional family members affected, the prevalence is considerably higher than previously reported.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Adulto Jovem
20.
Magn Reson Imaging ; 59: 77-87, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30880110

RESUMO

OBJECTIVES: To investigate the feasibility of chemical exchange saturation transfer (CEST) MRI in patients with breast carcinomas and possible correlations between magnetization transfer asymmetry (MTRasym) values and histological features, such as tumor grade and the Ki-67 proliferation index. MATERIALS AND METHODS: Nine healthy subjects and 18 female patients were enrolled for this study. The imaging protocol for the patients consisted of diffusion-weighted imaging (DWI), CEST imaging, and T1-weighted, contrast-enhanced (CE)-MRI. CEST was performed using a 3D gradient echo (GRE) sequence, employing eight pre-saturation pulses of a duration of 50 ms and a duty cycle (DC) of 80%, with a mean amplitude of the saturation pulse train of 1 µT. The Z-spectrum was plotted and MTRasym values calculated for the frequency of the maximum of MTRasym curve, were correlated with the Ki-67 proliferation index and apparent diffusion coefficient (ADC). Patient data were statistically assessed using the Games-Howell post-hoc and Pearson's correlation test. RESULTS: Different tumor types had asymmetry peaks at different positions of Z-spectrum. MTRasym (mean ±â€¯SD) (%) calculated for G1 (3.0 ±â€¯0.3; range: 2.70-3.50) was not significantly lower than for G2 (4.50 ±â€¯1.30; range: 3.20-6.50; p = 0.066). In contrast, the increase in MTRasym between G1 and G3 (6.40 ±â€¯1.70; range: 4.80-9.80) lesions was significant (p = 0.007). No significant difference was observed between G2 and G3 with regard to MTRasym (p = 0.089). There was a strong positive correlation between the MTRasym, and Ki-67 proliferation index (r = 0.890; p = 0.001), while there was a moderate negative correlation between MTRasym and ADC values (r = -0.506; p = 0.027). CONCLUSIONS: Calculated MTRasym demonstrates a strong positive correlation with tumor proliferation and has the potential to become a valuable biomarker for breast tumor characterization.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Imagem por Ressonância Magnética , Gradação de Tumores , Adulto , Biomarcadores , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA