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Introduction: Psychiatric disorders have become a global problem that leads millions of people to use psychotropic medications, especially benzodiazepines. The effects of these substances are widely known regarding tolerance and chemical dependence, however, from epigenetics perspective, there are still little known. Objective: To evaluate the association between psychotropic drug use, NR3C1 gene methylation and its relation with symptoms suggestive of depression in adult individuals assisted in the public health system. Methods: 385 adult volunteers (20-59 years) users of the Brazilian Unified Health System were recruited to evaluate socioeconomic, health, lifestyle conditions in a cross sectional study. BDI-II evaluated symptoms suggestive of depression and pyrosequencing evaluated NR3C1 DNA methylation. Bivariate and multivariate Poisson regression model with robust variance (p < 0.05) evaluated the association between psychotropic drug use and NR3C1 gene methylation. Results: Specific depressive symptoms such as irritability, insomnia and fatigability were associated with psychotropic drug use. Symptoms of past failure, indecision and loss of appetite were associated with hypermethylation patterns in CpGs 40 to 47 of NR3C1 gene. Moreover, psychotropic drug use is associated with 50% reduction in NR3C1 gene methylation, through model adjusted with socioeconomic, health and lifestyle confounding variables. Conclusions: Psychotropic drug use and depressive symptoms was associated with changes in NR3C1 DNA methylation. In this context, epigenetic modification resulting from psychotropic drug use and depressive symptoms could be considered, mainly in population studies with epigenetic evaluation, where these factors may be influencing the findings of future studies.

Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population.The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations.The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Fourteen questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations.For all questions including risk-reduction bilateral salpingo-oophorectomy, hysterectomy, and mastectomy, major agreement was achieved by the participants, always using accessible alternatives.This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO, and it should serve as an important reference for the management of families with cancer predisposition.

Malignant primary brain tumors remain among the most difficult cancers to treat, in particular, Glioblastoma Multiforme (GBM) is the deadliest brain tumor. The standard therapies currently used are not efficient enough in improving patients’ survival and quality of life. Cisplatin (CDDP), a platinum-based drug, has shown efficacy against different solid neoplasms, but it is also associated to different forms of off-target toxicity. To overcome the limitation in the use of CDDP in the treatment of GBM patients, fourth generation platinum compounds are been synthesized, one of them is the Pt(IV)Ac-POA, a prodrug with a medium-chain fatty acid as axial ligand, which acts as a histone 3 deacetylase inhibitor. Moreover, recently, the antioxidant effects of medicinal mushrooms have been shown to induce a lowering of the toxicity of chemotherapy drugs, inducing greater therapeutic efficiency, thus the combined therapy of chemotherapy and micotherapy could be helpful in the treatment of GBM reducing the adverse effects of the former thanks to phytotherapy’s antioxidant, anti-inflammatory, immunomodulatory and antitumoral activities. Here, through immunoblotting, ultrastructural and immunofluorescence analysis, we evaluated the contribution in the activation of different cell death pathway of Micotherapy U-Care, a medicinal blend supplement, used together with platinum-based compounds on human glioblastoma U251 cells.

Tamoxifen is widely used in adjuvant therapy for breast cancer patients, but up to one-third of patients recur within 15 years after surgery even with its regular use. Low plasma levels of (Z)-endoxifen, the most active tamoxifen metabolite, have been studied as a possible predictor of treatment failure. Here, we evaluated plasma (Z)-endoxifen as a predictor of response to adjuvant treatment in breast cancer patients. Methods: One hundred forty nine patients were selected from a prospective cohort of consecutive newly diagnosed breast cancer patients recruited at a national referral center for treatment of cancer in Curitiba, Southern Brazil. Inclusion criteria were breast cancer women on stage I - III, positive hormone receptor tumors, operable, undergoing or not (neo)adjuvant chemotherapy, and signed for adjuvant tamoxifen for at least five years. At diagnosis, peripheral blood samples were collected for CYP2D6 genotyping for *1 *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29 and *41 and subsequent metabolic activity scores according to phenotypes assigned for each allele (poor metabolizer PM; intermediate, IM; extensive, EM and ultrarapid metabolizer, UM). After the tamoxifen initiation, patients were evaluated at months 3, 6, and 12 for adherence and drug interactions, and plasma (Z)-endoxifen quantification. They were followed from April 2014 to April 2019. The study's primary objective was to evaluate whether (Z)-endoxifen plasma levels predict early recurrence in patients on adjuvant tamoxifen. The secondary aim was to evaluate an association between (Z)-endoxifen levels and clinical and phenotypic CYP2D6 metabolism variables. A Cox model estimated hazard ratios (HR) comparing recurrence free survival (RFS) according to (Z)-endoxifen plasma levels. The survival was compared using the Kaplan-Meier method and the log-rank test. Results: The median follow-up period was 52.3 months and at that point, there were 20 recurrences of 149 patients. At 3 months there were no cases of low adherence to tamoxifen. The (Z)-endoxifen levels were established by quartiles, with the first lower quartile being used as a cutoff (14.72nM). High (Z)-endoxifen levels at 3 months (>14.72nM) were detected in 75.8% (n = 113) of cases and low levels (≤14.72nM) in 24.2% (n = 36). There was no statistically significant difference between the groups with low or high (Z)-endoxifen levels regarding clinical and pathological variables, but there was a higher CYP2D6 PM/IM frequency in the low (Z)-endoxifen levels group (p Citation Format: Thais Almeida, Werner Schroth, Jeanine Marie Nardin, Thomas Mürdter, Solane Picolotto, Reiner Hoppe, Jenifer Primon Kogin, Elisa Daniele Gaio, Angela Dasenbrock, Raquel Cristina Skrsypcsak, Lucia Noronha, Hiltrud Brauch, José Claudio Casali-da-Rocha. Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-08.

Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC); however, it is still underrecognized and underdiagnosed. While international guidelines gravitate towards universal screening, the underuse of screening methods has been reported in real-world scenarios. This study aims to evaluate screening for LS among patients diagnosed with CRC in a public cancer center in Brazil and evaluate access to genetic counseling and testing for abnormal screens. For that purpose, all patients with CRC registered in our institution from July 2012 to December 2018 had their charts reviewed. Demographic and clinical characteristics were noted, as well as immunohistochemistry and microsatellite instability analysis results, when available. After applying exclusion criteria, a total of 1234 charts were reviewed. Among these, 257 patients were screened for LS, making up a 20.8% screening rate; when considering Jerusalem criteria, screening rate was 24.5%; for Bethesda criteria, it was 35.1%. Almost 80% of patients fulfilling Amsterdam criteria I/II were screened. There were 64 abnormal screens, from which 40 (62.5%) underwent genetic counseling and 12 (18.7%) underwent genetic testing. We concluded that overall screening rates for LS among CRC patients in a public cancer center in Brazil are low, and still very guided by stringent clinical criteria. Referral to genetic counseling and access to testing is limited, calling the whole process into question. Public policies aiming to raise awareness on hereditary cancer and include genetic testing in the public health system could help improve this scenario.

Terbium citrate staining represents the method of choice for RNA visualization at transmission electron microscopy. Because of its affinity for guanosines in RNA rather than in DNA, terbium citrate gives precise results being a selective staining. However, difficulties often arise when performing this technique, especially in crucial and delicate steps such as rinses, when it is not uncommon to excessively reduce the already feeble contrast. For these reasons, we developed a straightforward and secure approach to overcome such complications. Here we report a new method for RNA single molecule localization by means of terbium citrate vapors, viable for every type of fixation and embedding.

Potassium permanganate solution has been used both as a fixative and as a staining for ultrathin sections at transmission electron microscopy, due to its ability to provide good contrast of different tissue components. Subsequently, it has been forgotten due to disadvantages such as conspicuous formation of precipitates and fragility of the tissue sections treated with this dye when placed under the electron beam. Here we demonstrate that the observed granularity of the sections is not related to the formation of non-specific precipitates, but rather to basic proteins such as chromatin proteins closely associated with DNA and ribosomal particles which are intensely stained. This results in a marked contrast of the nuclei, in particular of the heterochromatin areas, the granular component of the nucleoli, and the rough endoplasmic reticulum, that are rich in these protein complexes. We also show how the embedding in LR white acrylic resin can preserve a good morphology and be less sensitive to the treatment with potassium permanganate than the epoxy resin sections, also allowing to perform immunocytochemistry. The fragility of the epoxy resin sections can be partially improved by using formvar-coated grids.

Introduction: Phyllodes tumor (PT) of the breast, particularly malignant phyllodes tumor (mPT), is a rare fibroepithelial neoplasm. A complex diagnosis is based on pathologic, radiologic, and clinical findings, with controversies about what is the best therapeutic strategy. Objective: Our objective was to provide an overview of the clinical, pathologic, and therapeutic aspects of this rare tumor. Conclusions: mPT is a rare presentation of breast cancer and a challenge in clinical practice. A multidisciplinary approach should take into account some aspects like pathogenic mutations and hereditary syndromes. Oncologic surgery is the fundamental approach, and the use of adjuvant therapies is still controversial due to the lack of clinical trials. Treatment recommendations should be individualized according to patient risk and preferences. Prospective studies are fundamental to clarifying the best treatment for these tumors.

In the last decades, it has become increasingly clear how the modulation of spatial organization of chromatin over time and through the cell cycle is closely connected to gene function regulation. Different physicochemical stimuli contribute to the realization of specific transcriptional programs and finally to a specific cellular phenotype. In this review, we aim to describe the current knowledge about the dynamics regulating the movements and the interactions of molecules within the nucleus and their impact on gene functions. In particular, taking into account that these forces exert their effect in a nuclear environment characterized by a high concentration of molecules, we will discuss the role of proteins and structures that regulate these movements and transduce physicochemical signals acting on the cell to the nucleus.

Adherence to treatment and use of co-medication, but also molecular factors such as CYP2D6 genotype, affect tamoxifen metabolism, with consequences for early breast cancer prognosis. In a prospective study of 149 tamoxifen-treated early-stage breast cancer patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinico-pathological factors. Twenty-five patients (16.8%) had recurred or died at a median follow-up of 52.3 months. When we applied a putative 15 nM threshold used in previous independent studies, (Z)-endoxifen levels below the threshold showed an association with shorter EFS in univariate analysis (p = 0.045) and after adjustment for stage (HR 2.52; 95% CI 1.13–5.65; p = 0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: p = 0.158; adjusted for stage: p = 0.117). Hence, in our small exploratory study, the link between impaired tamoxifen metabolism and early breast cancer recurrence could not be unanimously demonstrated. This inconsistency justifies larger modeling studies backed up by mechanistic pharmacodynamic analyses to shed new light on this suspected association and the stipulation of an appropriate predictive (Z)-endoxifen threshold.

Objective: Adherence to treatment and use of co-medication, molecular factors such as CYP2D6 genotype affect tamoxifen metabolism with consequences for early breast cancer (BC) prognosis. CYP2D6 polymorphisms have been promoted as potential biomarkers, yet they only partially explain the variability of plasma (Z)-endoxifen concentrations. The objective of this study was to evaluate whether plasma (Z)-endoxifen levels predicted early BC events (recurrence or death) within 5 years in patients receiving adjuvant tamoxifen treatment. The secondary aim was to evaluate whether (Z)-endoxifen levels were associated with clinical, pathological, and phenotypic CYP2D6 metabolism variables. Methods: In a prospective study on 149 tamoxifen-treated early-stage BC patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinicopathological factors. We apply this approach to patients from a Brazilian prospective cohort (Tamoxifen Adjuvant Interferers Study) Results: In all, 25 (16.8%) patients had recurred or died at a median follow-up of 52.3 months. When we applied a putative 15 nM threshold used in previous independent studies, (Z)-endoxifen levels below the threshold showed an association with shorter EFS in an univariate analysis (p=0.045) and after adjustment for stage (HR 2.52; 95%CI 1.13–5.65; p=0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: p=0.158; adjusted for stage: p=0.117). Hence, in this small exploratory study, the link between impaired tamoxifen metabolism and early BC recurrence could not be unanimously demonstrated. This inconsistency justifies larger modeling studies backed up by mechanistic pharmacodynamic analyses to shed new light on this suspected association and the stipulation of an appropriate predictive (Z)-endoxifen threshold. Conclusion: As expected, significant associations with CYP2D6 metabolism phenotypes were detected. In individual and grouped (PM+IM vs. NM+UM) comparisons, PM and IM phenotypes had lower median (Z)-endoxifen levels (7.7 and 16.3 nM, respectively) than patients with NM or UM phenotypes (27.6 and 38.0 nM, respectively; p

Objective: Getting back to regular physical activity soon after completing the treatment for breast cancer may be a challenge for most women. To assess the impact of physical exercise on physical fitness and body composition in women who have completed breast cancer treatment, we designed a personalized program of physical exercises, considering their individual basal physical activity levels. Methods: The prospective study included 107 women aged 18–60 years shortly after curative treatment for localized breast cancer. All participants were evaluated for cardiovascular morbidities, body composition, and exercise performance. After careful physical evaluation by a personal physical trainer, each woman was individually oriented on how to perform each exercise correctly and follow the program of nonsupervised exercises on their own at home, either indoor or outdoor. Women were motivated to adhere to personalized aerobic exercises, localized muscular strength/resistance, and flexibility exercises, considering individual capabilities and limitations. Evaluations including body composition, VO2max, and localized muscle resistance were performed preintervention (basal) and after 6 and 9 months of intervention. Results: Among all, 25.23% and 44.85% were fat or overweight, respectively, at the study entrance, and 21.49% reported doing physical exercise regularly; 78 women adhered to the training program (72.8%), and 29 chose not to adhere (27.2%). After 9 months of regular and individualized intervention, adherent women showed significantly better results in all variables of body composition and physical fitness: body mass (-4.38±3.67 kg; p0.05), as well as it was not influenced by breast cancer characteristics (e.g., histology, stage, and molecular subtypes) or treatment (e.g., mastectomy, axillary surgery, chemotherapy, or radiotherapy) (p>0.05). Conclusion: Our study reinforces that women in follow-up after breast cancer, regardless of body fatness or fitness, can adopt lifestyle measures to prevent a recurrence, and medical societies should include recommendations to promote physical activity early during surveillance.

One-third of early breast cancer patients with estrogen receptor (ER) positive tumors treated with the selective estrogen receptor modulator tamoxifen either relapse or die from the disease in the following decade. Improvement of tamoxifen efficacy requires a better knowledge of factors determining outcome of which the medication-taking behavior, i.e. adherence, is a strong suspect. Discontinuation and non-adherence to tamoxifen are frequent and result in increased mortality. Commonly used methods to assess drug adherence such as prescription-refill patterns infer that the medication is taken exactly as prescribed yet, partial adherence or actual use of the medication cannot be controlled. An objective surrogate of tamoxifen adherence is the monitoring of drug concentrations in the patients’ plasma including the parent drug and its active metabolite (Z)-endoxifen (endoxifen), however individual concentrations depend on pharmacogene polymorphisms particularly those of the liver enzyme cytochrome P450 2D6 (CYP2D6). Patients without CYP2D6 variants have normal enzyme function (extensive metabolizer, EM) and achieve high endoxifen concentrations compared to patients with variants conferring absent activity (poor metabolizer, PM) or reduced activity (intermediate metabolizer, IM) who have significantly lower plasma concentrations of the active metabolite. A putative threshold of 5.9 ng/mL endoxifen has been proposed suggesting that patients with endoxifen concentration above or below threshold have lower or higher risk for recurrence, assuming that low endoxifen exposure in the tumor likely results in incomplete inhibition of ER-dependent growth signaling. During tamoxifen treatment it is therefore important that patients achieve clinically relevant endoxifen levels while at the same time avoid confounders of which adherence is a prime candidate. To this end, we investigated patients’ ability to achieve relevant plasma concentrations during tamoxifen treatment in relation to their CYP2D6 metabolizer status and their tamoxifen adherence behavior. Our prospective study included 192 Brazilian breast cancer patients treated with 20 mg tamoxifen daily. Two-thirds of the patients were premenopausal. Plasma levels of tamoxifen and its metabolites were measured by LC-MS/MS at 3, 6 and 12 months of treatment. Adherence to tamoxifen was evaluated by the questionnaire-based Morisky medication adherence scale. CYP2D6 polymorphisms were determined by MALDI-TOF mass spectrometry and real-time PCR. Adherence to tamoxifen decreased from 74% at month 3 to 64% at month 12, and explained 47% of the variability of tamoxifen plasma concentrations (P Citation Format: Jose Claudio Casali da Rocha, Jeanine M Nardin, Werner Schroth, Thais A Almeida, Thomas Mürdter, Solange Picolotto, Evelyn CL Vendramini, Reiner Hoppe, Jenifer P Kogin, Diandra Miqueleto, Silvia DR Moraes, Matthias Schwab, Roberto F Pecoits-Filho, Hiltrud Brauch. The influences of adherence to tamoxifen and CYP2D6 pharmacogenetics on plasma concentrations of the active metabolite (Z)-endoxifen in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-12.

Aims: The breast cancer is one of the most common types and it treatment brings complications such as skin, dermis and subcutaneous toxicity. Studies about genetic variations of patients are those that enable the identification of prognostic factors for treatment, generally based on greater risk of injury to healthy tissue. Study design: This study examined the association between single nucleotide polymorphisms (SNPs) of ATM gene in patients with breast cancer with adverse reactions presented in normal tissues as result of radiotherapy. Place and Duration of Study: The study was conduct at Pontifícia Universidade Católica de Goiás, and the patients were recruited at Hospital Araújo Jorge, Associação de Combate ao Câncer em Goiás, Radiotherapy Service. Methodology: We evaluated 76 patients, through a retrospective study, based on data contained in records and teletherapy records of patients with this cancer who underwent radiotherapy for at least 5 years. Polymorphisms of the ATM gene were analyzed by microarray technique. Results: The mean age of patients was 50 years and the total dose of radiation was an average of 50,21 Gy ranging from 45Gy to 50.4Gy. Regarding the late toxicities, patients analyzed showed a higher frequency of low-grade morbidities when compared to high grade. Nineteen patients interrupted the radiation therapy for any reason. Patients who have studied polymorphisms have no increased risk of developing acute toxicity changes of the skin. (P>.05). Patients presenting polymorphisms AX-8315255 (TTT insertion) (RR=11.0, 1.08 - 111.97, p=0.045) and rs56128736 (RR=11.0, 1.08 - 111.97, p=0.045) had an increased risk for developing late skin toxicity, but not at subcutaneous tract. Conclusion: ATM is a large gene with many variants documented. Association studies of these SNPs will be needed in larger sample groups to establish whether the single base variants or haplotypes of this gene may indeed contribute to the toxicity of normal tissue. Thus, the personalized treatment with ionizing radiation can be prescribed for patients decreasing complications and improving the effectiveness of treatment and quality of life of patients.

Simple Summary Male breast cancer is a rare disease, representing around 0.5% of the malignances in men. Although they receive the same treatment as women with breast cancer, there is increasing knowledge showing that both have a distinct genetic background. Pathogenic variants in cancer predisposing genes are a likely etiology for male breast cancer in 4% to 40% of the cases, and it is currently recommended that all men diagnosed with breast cancer be offered genetic counseling followed by genetic testing. Even though, men are still less likely to undergo the test than women for many reasons, which include an unfamiliarity with the issue by health professionals. The purpose of this article is to review the current knowledge of the germline genetic background of male breast cancer and its impact in the management of the patients and their families. Abstract Male breast cancer (MBC) is now considered molecularly different from female breast cancer (FBC). Evidence from studies indicates that common genetic and epigenetic features of FBC are not shared with those diagnosed in men. Genetic predisposition is likely to play a significant role in the tumorigenesis of this rare disease. Inherited germline variants in BRCA1 and BRCA2 account for around 2% and 10% of MBC cases, respectively, and the lifetime risk of breast cancer for men harboring BRCA1 and BRCA2 mutations is 1.2% and 6.8%. As for FBC, pathogenic mutations in other breast cancer genes have also been recently associated with an increased risk of MBC, such as PALB2 and CHEK2 mutations. However, while multigene germline panels have been extensively performed for BC female patients, the rarity of MBC has resulted in limited data to allow the understanding of the magnitude of risk and the contribution of recently identified moderate penetrance genes of FBC for MBC predisposition. This review gathers available data about the germline genetic landscape of men affected by breast cancer, estimated risk associated with these genetic variants, and current guidelines for clinical management.

The NR3C1 glucocorticoid receptor (GR) gene is a component of the stress response system, which can be regulated by epigenetic mechanisms. NR3C1 methylation has been associated with trauma and mental issues, including depression, post-traumatic stress, anxiety, and personality disorders. Previous studies have reported that stressful events are involved in NR3C1 gene methylation, suggesting that its regulation under environmental effects is complex. The present study aimed to analyze associations involving stressors such as socioeconomic status, health conditions, and lifestyle in relation to NR3C1 methylation in adults. This study included 386 individual users of the Brazilian Public Unified Health System (SUS), and evaluated socioeconomic and health conditions, body mass index, cortisol levels, and lifestyle. Data were correlated with NR3C1 methylation, determined using DNA pyrosequencing. The results showed that alcohol consumption, overweight, and high cortisol levels were related to NR3C1 demethylation, while depression was related to its methylation. Habits, lifestyle, and health status may influence NR3C1 gene regulation via methylation, revealing the complexity of environmental impacts on NR3C1 methylation.

Introdução: A Polipose Associada ao gene MUTYH (MAP) é uma síndrome recessiva causada por mutações bialélicas em MUTYH, as quais inativam o gene e levam a uma alta ocorrência de transversões G:C à T:A, gerando a mutação KRAS c.34G>T; G12C. A mutação ocorre em menos de 5% dos casos de câncer colorretal (CCR) esporádicos, mas é altamente frequente em CCR de pacientes MAP. Objetivo: O objetivo do estudo é avaliar a taxa de detecção de variantes germinativas patogênicas/provavelmente patogênicas em MUTYH em pacientes com CCR e mutação somática KRAS G12C. Metodologia: Avaliaremos 3 variantes patogênicas de MUTYH (p.Tyr179Cys, p.Gly396Asp e deleção dos éxons 4 a 16) por PCR multiplex, eletroforese e sequenciamento de nova geração (NGS). Pacientes com 1 variante em heterozigose serão submetidos ao sequenciamento completo do MUTYH. As características clínicas e anatomopatológicas dos pacientes serão correlacionadas com resultados que serão descritos estatisticamente. Resultados preliminares: Até o momento foram identificados 121 pacientes com CCR mutação KRAS c.34G>T; G12C com média de idade de 59 anos, dos quais 51 apresentavam história familiar positiva (42,14%) e 46 apresentavam ao menos 1 pólipo (38,01%). Para 39 pacientes identificamos disponibilidade de material no Biobanco da instituição. Em análises prévias, avaliamos 9 pacientes com CCR antes dos 50 anos e identificamos 3 (33%) com alteração em MUTYH, sendo 2 com variantes patogênicas em ambos os alelos e 1 com uma variante patogênica e uma de significado incerto (VUS). Conclusão: Esperamos verificar se pacientes com CCR mutação somática KRAS G12C apresentam maior risco de detecção de variantes germinativas patogênicas no gene MUTYH, podendo-se utilizar dos resultados da detecção da mutação em KRAS como um teste pré-triagem para diagnóstico da MAP.

10598 Background: Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Methods: A cohort of 1,234 unrelated patients with suspicion of hereditary cancer was screened using a validated NGS panel including 20 genes associated with hereditary cancer. Results: One hundred and forty two (8.7%) patients harbouring probably pathogenic or pathogenic mutatations and 9 harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 6.3% (9/142) of patients with pathogenic mutations. All (9/9) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. Conclusions: Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.

Introduction: Much has been discussed about benefits of physical exercise in women who have ended breast cancer treatment, which includes not only the improvement of their quality of life but also a remarkable decreased risk of recurrence. To achieve these benefits, it is important that the parameters for prescribing and monitoring physical activity for this population are well defined, as well as the evaluation of factors that may interfere with the results and the adherence to physical exercises. Objectives: To assess the impact of physical exercise on physical fitness and body composition in women who have ended breast cancer curative treatment and to evaluate the impact of physical exercise on women with binge eating disorder. Methods: This prospective study included 107 women between 18 and 60 years of age shortly after the end of their curative treatment for breast cancer (surgery and/or chemotherapy and/or radiotherapy). The participants, after signing the informed consent form, were motivated to do aerobic exercises, localized muscular strength/resistance, and flexibility exercises. Intervention consisted of sets of physical exercises prescribed to all participants by a physical educator in progressive intensities and volumes over the months, according to their adaptive responses, considering individual capabilities and limitations. All participants were evaluated at entrance for cardiovascular morbidities and oriented how to exercise by their own at their homes. Evaluations including body composition, VO2max, and localized muscle resistance were performed at pre-intervention (basal), after 6 and 9 months of intervention. Results: A total of 78 (72.8%) women adhered to the training program, and 29 (27.2%) chose not to adhere. After 9 months of regular and individualized intervention, adherent women showed significantly better results in all variables of body composition and physical fitness: body mass (-4.38±3.67 kg; p0.05), as well as it was not influenced by breast cancer characteristics (e.g., histology, stage, and molecular subtypes) or treatment (i.e., mastectomy, axillary surgery, chemotherapy, or radiotherapy; p>0.05). Conclusion: Our study shows that individualized programs of self-training sets of physical exercises, remotely guided by a physical education professional, could improve the body composition and physical fitness of women in surveillance after breast cancer, regardless of the history of breast cancer or treatment, showing that it is possible to reduce risk factors associated with breast cancer recurrence and to contribute to a better quality of life for these women.

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)-endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (LC-MS/MS), adherence behavior (Morisky Medication Adherence Scale), and CYP2D6 and other pharmacogene polymorphisms (MALDI-TOF mass spectrometry and real-time PCR). Adherence explained 47% of the variability of tamoxifen plasma concentrations (p

In Brazil, the population in general has little knowledge about genetic risks, as well as regarding the role and importance of the Cancer Genetic Counseling (CGC). The goal of this study was to evaluate cancer-related worry and cancer risk perception during CGC sessions in Brazilian women at-risk for hereditary breast cancer. This study was performed in 264 individuals seeking CGC for hereditary breast cancer. Both cancer-affected and unaffected individuals were included. As results, individuals with and without cancer reported different motivations for seeking CGC and undergoing genetic testing. A correlation was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer. Multivariate analysis showed that educational level, cancer risk discussion within the family, and number of deaths by cancer among first-degree relatives influenced positively the cancer risk perception. In conclusion, the results of this study indicate that cancer-related worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected. CGC has an important role in health education and cancer prevention for its potential of promoting an accurate perception of the risk.

Objetivos: Realizar medidas de educação visando a prevenção em saúde e melhor qualidade de vida, e obter dados através de levantamento epidemiológico que poderão ser fornecidos ao SUS como um modelo de região rural que poderá ser utilizado em outras regiões do país gerando um grande impacto social e economia de recursos federais, estaduais e municipais.Resultados: Juntamente com os questionários e visitas às comunidades estudadas, foram realizadas ações educativas para a prevenção do uso indiscriminado de agrotóxicos, assim como o uso de tabaco e álcool. Vale apena destacar a parceria com diversos outros projetos na região, que possibilitou a oferta de cursos de capacitação EAD e presenciais, assim como a elaboração de material didático sobre o assunto na forma de livros, aulas e organização de espaços virtuais de aprendizagem e de treinamento. Conclusão: O projeto gerou impacto social, com treinamento de professores e crianças nas escolas, além dos agentes de saúde e outros profissionais que atuam na saúde e educação dentro dos municípios. Finalmente, um ponto de grande destaque relacionado às metas do projeto foi a capacitação e formação de pessoas na área de oncogenética e aconselhamento genético, algo inédito para o estado do Espírito Santo.