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Background: Healthcare workers perform an emotionally exhausting daily work activity, making them prone to occupational hazards, namely psychosocial ones. This study aims to assess the impact of psychosocial risk factors on healthcare workers' mental health. Methods: A cross-sectional study was developed between May and June of 2021 with 479 healthcare workers from Portuguese hospitals. The Depression, Anxiety and Stress Scale was used to assess mental health, and psychosocial risks were assessed through the Health and Work Survey – INSAT. Statistical analysis was performed to identify the psychosocial risk factors related to anxiety, depression, and stress. Subsequently, a multiple linear regression was performed to identify the models that better explained psychosocial risk factors' relationship with anxiety, depression, and stress. Results: Data showed a strong exposure to psychosocial risks. Work pace and intensity, work relationships, and emotional demands stood out with higher global average percentages for yes answers to “exposure and discomfort.” The analysis of the β values and p-values from the multiple linear regression shows that some cross-sectional psychosocial risks are predictors of anxiety and stress dimensions, and other psychosocial risks differ in the two mental health dimensions. However, it is important to highlight that healthcare workers still showed great joy and pleasure in performing their work activities. Conclusion: Support network development in the work environment is needed to prevent healthcare workers' emotional stress and promote their psychological well-being. Therefore, new research is essential to understand the psychosocial risks that affect healthcare workers and assess the less visible effects of work–health relationships., (undefined)

Purpose This study aims to provide a comparative portrait of the profile of men and women in the boardrooms of listed companies (Euronext Lisbon, Portugal) during the first stage of the gender quota law, by comparing the profile of those board members appointed before the mandated quota law and those appointed after it. This study also seeks to contribute to a critical review of the main reservations expressed by some core institutional actors, who initially voiced their concern that it might be difficult to find women in equal conditions to men in terms of their cumulative experience and qualifications to serve as board members. Design/methodology/approach In addition to providing a comparative descriptive analysis of male and female board members’ profiles before and after the mandated gender quota law, an aggregate professional endowments measure (professional endowments Index) is also calculated. Findings The research findings show that, in the first stage of the quota law, men and women appointed as board members after the mandated gender quota law are fundamentally similar in their professional attributes, forming a more homogeneous boardroom than those holding board positions before it. Originality/value This study contributes to the literature on the profile of the men and women serving on the publicly listed company boards in Portugal, by comparing their profiles before and after the mandated gender quota law. This study also fills a gap in the literature, as studies about gender quotas and corporate boards relating to Portugal and Southern European countries in general are still relatively scant. To the best of the authors’ knowledge, this is the first study carried out into the gender quota law on corporate boards in Portugal.

Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer (BC) to downstage the disease. Clinical responses to NACT may vary depending on a few known clinical and biological features, but the diversity of responses to NACT is not fully understood. In this study, 80 women had their metabolite profiles of pre-treatment sera analyzed for potential NACT response biomarker candidates in combination with immunohistochemical parameters using Nuclear Magnetic Resonance (NMR). Sixty-four percent of the patients were resistant to chemotherapy. NMR, hormonal receptors (HR), human epidermal growth factor receptor 2 (HER2), and the nuclear protein Ki67 were combined through machine learning (ML) to predict the response to NACT. Metabolites such as leucine, formate, valine, and proline, along with hormone receptor status, were discriminants of response to NACT. The glyoxylate and dicarboxylate metabolism was found to be involved in the resistance to NACT. We obtained an accuracy in excess of 80% for the prediction of response to NACT combining metabolomic and tumor profile data. Our results suggest that NMR data can substantially enhance the prediction of response to NACT when used in combination with already known response prediction factors.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. ESR1m prevalence has been described as 9-45% in cohorts of ET-resistant metastatic tumors in a variety of publications. We recently reported a prevalence of 25% in a cohort of ER+ breast cancer patients with visceral metastasis. However, the role of ESR1m as a mechanism of resistance to ET used in early-stage disease is not well studied. Neoadjuvant endocrine therapy (NET) is being increasingly explored, not only to allow less extensive surgery but also as a scientific tool, exploring biomarkers to predict outcomes. The preoperative endocrine prognostic index (PEPI) combining Ki67 score, ER Allred score, tumor size, and nodal status after NET is a surrogate of endocrine sensitivity and can identify a subgroup of patients with primary resistance to ET. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer that were primarily resistant to neoadjuvant aromatase inhibitor (AI) therapy. Methods: We followed a prospective cohort of postmenopausal patients with ER+ HER2- stages II-III breast cancer treated with neoadjuvant endocrine therapy (NET). Patients were treated with anastrozole for a recommended period of at least three months. Tumor samples from patients with a pattern of primary endocrine-resistant tumors (defined as a PEPI Score higher than 3) were selected and analyzed for the presence of ESR1m. ESR1m were evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Results: 127 patients were included in the cohort, of which 100 (79%) had completed NET and had surgery. Among these patients, the PEPI Score ranged from 0 to 3 in 70% (70/100), and 30% (30/100) had a PEPI Score of 4 or more and were selected. 23 patients were included in the analysis (6 did not consent or were lost to follow-up, and one was HER2-positive). Patients characteristics are summarized in Table 1. The median duration of NET was 22 weeks. All samples of tumor tissue from the surgical specimens after NET were evaluable. Quantification of DNA extraction and reference gene cycle threshold values confirmed that the material was adequate for the analysis. We compared these findings with a study from our group using the same methodology in patients with advanced disease where ESR1 mutations were detected in 25% (n=32) of patients with visceral metastasis of ER+ breast cancer resistant to endocrine therapy. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET (p 0.01, Fisher´s exact test) Discussion: Growing evidence supports the notion that there are different mechanisms of primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET. Citation Format: Tomas Reinert, Susana Ramalho, Vivian CA Vasconcelos, Leonardo R Silva, Ana Elisa R Silva, Camila A Andrade, Maria Beatriz PL Kraft, Guilherme P Coelho, Jovana Mandelli, Monique Binotto, Cesar Cabello, Geisilene RP Silva, Jose Bines, Carlos H Barrios, Matthew J Ellis, Marcia S Graudenz. ESR1 mutations are not a mechanism of primary resistance to aromatase inhibitors in ER-positive breast cancer treated with neoadjuvant endocrine therapy [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 P2-11-08.

Objectives: Addition of carboplatin to standard neoadjuvant chemotherapy (NACT) for triple negative breast cancer (TNBC) remains controversial. There are several randomized trials showing that carboplatin increases the likelihood of achieving pathological complete response (pCR) in TNBC. Patients with TNBC who achieve pCR has been shown to have better disease-free and overall survival. The aim of this study was to asses the impact of adding carboplatin to standard NACT in TNBC in terms of pCR rates and toxicity. Methods:In this cross-sectional study, 252 consecutive patients with primary TNBC who were submitted to neoadjuvant chemotherapy between 2013 and 2018, in a single center, were selected. Patients with biopsy-confirmed TNBC, previously untreated, with clinical stages I-III were included (n=179). Clinical pathological features, pathological response, treatment protocol, and toxicities were analyzed and considered for statistical analysis. Eighty patients treated from 2013 to 2015 received doxorubicin plus cyclophosphamide once every 3 weeks (AC) for four cycles, followed by 12 weeks (wP) or every 3 weeks (P) paclitaxel(AC-T group). Ninety-nine patients, treated from 2015 to 2018 had four cycles of AC followed by wP plus weekly carboplatin (Cb) area under curve (AUC) 1.5-2.0 (AC-TCb group). Pathologic response was determined locally, and pCR was defined as the absence of residual invasive disease with or without ductal carcinoma in situ in the breast and axilla. Results: Data from 179 patients were included in the analysis (AC-T: n=80; AC-TCb: n=99). Patients in AC-TCb group had a median age of 51.7 years vs. 47.4 years in AC-T group, p=0.01. In AC-TCb group 61.6% of patients were postmenopausal vs 43.7% in AC-T group, p=0.03. The distribution of clinical stage in groups AC-TCb and AC-T were as follows: stage I 6.0% vs 0%; stage II 42.4% vs 43.7%; stage III 51.6% vs 56.3%, respectively (p=0.02). In AC-TCbgroup, 34 patients (35.0%) had pCR in comparison to 20 patients (25.0%) on AC-T group (p=0.22). Pathological stage distribution in groups AC-TCb and AC-T were: stage I 24.7% vs 33.7%; stage II 23.7% vs 26.3%; stage III 16.4% vs 15%, respectively (p=0.42). More than 85.0% of patients in AC-TCb group received at least 9 weeks of carboplatin and less than 20.0% required dose reduction due to toxicity.Conclusions: An improved pathological complete response for TNBC patients submitted to standard NACT plus carboplatin was observed. The results are in accordance with previous studies demonstrating that the addition of carboplatin to NACT improves pCR rate in TNBC with a favorable risk to benefit profile. Therefore carboplatin might be a potential component of NACT and should be considered in this context. Distribution of patients with TNBC submitted to NACT with AC-T and AC-TCb according clinical–pathological characteristicsClinical pathological characteristicsAC-T n= 80AC-TCb n=99pMenopausal 0.03yes3561 no4538 Clinical stage 0.02I06 II3542 III4551 Histologic type 0.25IDC8096 others03 Histologic grade 0.86101 22932 35164 Pathological stage 0.42O2034 I2724 II2123 III1216 pCR 0.22yes2034 no6063 Citation Format: Ramalho S, Natal RdA, Cardoso Filho C, Xavier MB, da Silva AER, Silva LR, Vasconcelos V, Reinert T, Coelho GP, Silva GRdP, dos Santos CC. Pathological complete response rates with the addition of carboplatin to standard neoadjuvant chemotherapy in a cohort of real–world patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-16.

Introduction: The Oncotype DX was associated to 14% of adjuvant chemotherapy administration to Hormonal Receptor positive (HR+) and HER2 negative, T1N0 or T2N0 breast cancer patients at Tailor X trial recently published (RS>25) Objective: To describe the adjuvant chemotherapy administration to a Brazilian public hospital for HR+ HER2 negative, T1N0 or T2N0 breast cancer patients. And the estimate the cost effectivity of Oncotype DX in our low income scenary. Materials and Methods:This retrospective cross-sectional study was conducted at the Oncology Division of the Women's Hospital - CAISM of the State University of Campinas (UNICAMP), Brazil. All patient data were found from the hospital records from 2007 to 2009. It was included T1N0 and T2N0 HR+/HER2 negative breast cancer patients. Patients submitted to neoadjuvant treatment were excluded. We calculate the final cost of different types of chemotherapy used and the potential impact to oncotype DX introduction in this scenary. Results: It was found 109 patients records. 66% (72/109) had received adjuvant chemotherapy. 35% (38/109) had AC (X6), 29% (32/109) had CMF (X6) and 2% (2/109) had AC-T (X4). The total cost for chemotherapy scheme were; AC (X6) US$ 346,9; CMF (X6), US$300,6; ACT (X4), US$395,9. The total cost of chemotherapy was US$ 23.596,83 to 72 patients. If we consider 14% (15/109) of adjuvant chemotherapy associate to a Oncotype DX use (Tailor X RS>25), It would reduce adjuvant chemotherapy administration to 15 patients. The chemotherapy cost would be US$ 4588,27. In our scenary, It could save US$ 19.008,56. Nevertheless, the Oncotype Dx cost to Brasil is US$ 3.200,00 for each test. To 109 patients the total cost would be (109 X US$ 3.200,00) US$ 348.800,00. Therefore, the total cost for Oncotype DX program plus adjuvant chemotherapy for our patients would be US$ 348.800,00 + US$ 4.588,27= US$ 353.388,27. While in the real situation we had spent US$ 23.596,83. The total estimate cost would be 15 times more. Conclusion: At the moment, because of the assay high cost and the low cost of the adjuvant chemotherapy to HR+, HER2 negative T1N0 and T2N0, It would be difficult to consider Oncotype DX cost-effective to Brazilian public heath system. Even considering many advantages to spare chemotherapy to this population. Citation Format: Cabello C, de Andrade RN, Cabello TF, Teixeira S, da Costa LS, Ramalho S. Oncotype DX cost effectivity to a Brazilian public hospital [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-15-04.

Este artigo analisa o impacto do novo marco regulatório que entrou em vigor em Portugal em janeiro de 2018, a chamada lei das cotas de gênero, que determina uma composição mais equilibrada de mulheres e homens nos conselhos de administração das empresas cotadas na Bolsa de Valores Euronext Lisbon e das empresas do setor público. O artigo começa por contextualizar o debate sobre a sub-representação de mulheres nos conselhos de administração e sobre o novo marco de políticas com efeito vinculativo, introduzido em vários países da União Europeia (UE) e em Portugal. Examina, em seguida, os dados relativos à representação de homens e mulheres nos conselhos de administração das empresas cotadas em bolsa. Conclui-se que a introdução desta medida legislativa de natureza vinculativa em Portugal acelerou o movimento em direção a uma maior representação das mulheres nos conselhos de administração das empresas cotadas em bolsa, representando um novo impulso ao progresso neste domínio, porém lento, gerado pelos anteriores incentivos que visaram estimular a ação voluntária por parte das próprias empresas e promover medidas de autorregulação. Um dos principais desafios consiste, ainda, na passagem de um maior equilíbrio numérico de gênero para uma igualdade substantiva nos conselhos de administração, aumentando ao mesmo tempo a representação das mulheres em cargos de poder e influência efetiva nos processos decisórios. This paper looks at the impact of the new regulatory framework in Portugal that came into force in January 2018, the so-called gender quota law that relates to the gender composition of the boardrooms of companies listed on the Euronext Lisbon Stock Exchange and in the public sector. It begins by contextualising the debate about the underrepresentation of women on boards and the new binding policy framework that has been introduced in the European Union (EU) and Portugal. The paper then examines the data relating to the representation of men and women on the boards of public listed companies (PLCs). It is concluded that the introduction of binding legal targets in Portugal has accelerated the movement towards a greater representation of women on the boards of PLCs, giving an added impulse to the longstanding, but slow progress generated by the incentives that were designed to encourage voluntary action on the part of the companies themselves, and to promote self-regulatory measures. One of the fundamental challenges lying ahead is to move from a greater numerical gender balance to substantive gender equality in the boardroom, while also increasing the representation of women in positions of power and with influence over decision-making.

Portugal has been described as a singular case in terms of the participation of women in the labour market and work–life balance policies. Unlike the other so-called Southern European countries, where a belated and somewhat slower move away from the male breadwinner model has been found, Portugal stands out from the other EU member states with its relatively high rate of female employment and the prevalence of the dual-earner model based on continuous and fundamentally full-time employment. Moreover, the “early return to full-time work and a gender equality oriented model” calls for a separate analysis of this country’s case. In addition to providing a comprehensive overview of the singularities of Portugal’s employment patterns and work–family articulation policies, this article substantially adds to the existing literature by bringing new analytical angles to the debate. The intention is therefore to shed light on the political discourses that fuelled the policy debate throughout the three decades following Portugal’s transition to democracy, up until the latest and most decisive policy changes. This article also examines the key social actors’ views about the political process sustaining the development of policies in this area and identifies the major players promoting the most progressive legislative advances in the country.

Background Breast cancer outcomes among patients who use safety-net hospitals in the highly populated Harris County, Texas and Southeast Brazil are poor. It is unknown whether treatment delay contributes to these outcomes. Methods We conducted a retrospective cohort analysis of patients with non-metastatic breast cancer diagnosed between January 1, 2009 and December 31, 2011 at Harris Health Texas and Unicamp’s Women’s Hospital, Barretos Hospital, and Brazilian National Institute of Cancer, Brazil. We used Cox proportional hazards regression to evaluate association of time to treatment and risk of recurrence (ROR) or death. Results One thousand one hundred ninety-one patients were included. Women in Brazil were more frequently diagnosed with stage III disease (32.3% vs. 21.1% Texas; P = .002). Majority of patients in both populations had symptom-detected disease (63% in Brazil vs. 59% in Texas). Recurrence within 5 years from diagnosis was similar 21% versus 23%. Median time from diagnosis to first treatment defined as either systemic therapy (chemotherapy or endocrine therapy) or surgery, were comparable, 9.9 weeks versus 9.4 weeks. Treatment delay was not associated with increased ROR or death. Higher stage at diagnosis was associated with both increased ROR and death. Conclusion Time from symptoms to treatment was considerably long in both populations. Treatment delay did not affect outcomes. Impact Access to timely screening and diagnosis of breast cancer are priorities in these populations.

Neoadjuvant endocrine therapy (NET) has been shown to be effective in ER-positive/HER2-negative breast cancer in clinical trials. However, adoption in clinical practice is still limited. Real-world data may provide useful insights into effectiveness, toxicities and quality of care, potentially rendering clinical trial results to the real-world setting. Our purpose was to report real-world data of a cohort of postmenopausal patients submitted to NET. This prospective cohort study evaluated 146 postmenopausal female patients with ER-positive/HER2-negative breast cancer treated with NET at three tertiary hospitals between 2016 and 2018. Clinicopathological information were collected prospectively. Preoperative Endocrine Prognostic Index (PEPI) score was calculated for tumors submitted to at least 16 weeks of NET. Median age was 67 years old, and 87.8% had stage I-II disease. Most tumors had histological grade II (76.1%). Median pretreatment Ki67 expression was 10%. Aromatase inhibitor was used in 99.5% of patients, and median treatment duration was 21.0 weeks. No tumor progressed during NET. Breast-conserving surgery was performed in the majority of patients (63.0%), as well as sentinel lymph-node biopsy (76.7%). Pathological complete response rate was 1.0%. 43 patients (29.5%) had PEPI score 0, and 26% had PEPI scores 4–5. Posttreatment Ki67 median expression was 3.0%, and only five tumors (3.4%) showed marked increase in Ki67 expression during treatment. Seven patients (4.8%) had HER2-positive residual disease, and were treated with adjuvant chemotherapy plus trastuzumab. Our real-world data shows that NET is effective and safe in postmenopausal patients with ER-positive/HER2-negative breast cancer. Postmenopausal status and low-risk luminal tumor features (luminal A-like) should be used as selection criteria to ensure the best results with NET.

Background: Access to medical care vary across the world and is related to different health systems with an impact in recurrence.Objective: To evaluate disparities in breast cancer(BC) diagnosis and treatment between public and private services in southwest Brazil and at two public safety net hospitals in Houston, Texas.Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at the four hospitals in Brazil and two health centers in US were included. All statistical analyses were performed in R studio software, and p Table 1. Clinical and demographic characteristics of the patientsCharacteristicsPublic (%), n=967Private (%), n=274pDiscovery of BC By patient530 (54.8)92 (33.5) Routine exam87 (9)109 (39.8) Screening mammography270 (27.9)23 (8.4) Other80 (8.3)50 (18.3) . Considering the interval in weeks: symptoms to diagnosis, diagnosis to first treatment (either surgery or neoadjuvant chemotherapy), diagnosis to first systemic treatment, diagnosis to surgical treatment and diagnosis to radiotherapy were longer in public patients (24.1 vs. 8.7; 11.1 vs. 3.5; 18.6 vs. 9.8; 16.9 vs. 5.6; 51.4 vs. 26.1; p Table 2. Delay disparities between public and private health system PublicPrivatepSymptoms to diagnosis Number of patients575146 Time (weeks)24.1 (0.4-104.9)8.7 (0.0-43.7) In multivariate analysis, PHS (HR 1.72; 95% CI 1.34-1.88; p adj=0.003), presence of symptoms (HR 2.29; 95% CI 1.39-3.78; p adj=0.001), clinical stage III (HR 1.62; 95% CI 1.35-1.93; p adj Citation Format: NematiShafaee M, Natal RA, Ramalho S, Dória MT, Conz L, Cabello V, Pavanello M, Mano MS, Linck RDM, Batista LS, Pedro EP, Bines J, de Paula BH, Zucca-Matthes G, Bondy ML, Ellis MJ, Podany E, Debord L, Makawita S, Stewart K, Cabello C. Impact of delay in breast cancer diagnosis and treatment according to health insurance status in southwest Brazil and Houston, Texas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-15.

Background: Delays in diagnosis and treatment is associated with recurrence. Access to medical care in public health systems (PHS) may vary across Southwest Brazil and Houston, Texas. Objective: To evaluate disparities in breast cancer (BC) diagnosis and treatment between public services in southwest Brazil and at a public safety net hospital in Houston, Texas. Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at thefour hospitals in Brazil and two health centers in US were included. All statistical analyses was performed in R studio, and p Table 1. Clinical and demographic characteristics of the patientsCharacteristicsBrazil (%), n=778US (%), n=189pDiscovery of BC By patient443 (56.9)87 (46) Routine exam82 (10.5)5 (2.7) Screening mammography207 (26.6)63 (33.4) Other46 (6)34 (17.9) . Considering the interval in weeks: symptoms to diagnosis, diagnosis to first systemic therapy and diagnosis to radiotherapy were longer in Brazil PHS patients (24.4 vs. 22.8; 18.9 vs. 16.1 and 51.8 vs. 47.8 p Table 2. Delay disparities in public health system between Brazil and US BrazilUSpSymptoms to diagnosis Number of patients473102 Time (weeks)24.4 (0.5-102.6)22.8 (0.1-124.8) However, considering the interval in weeks: diagnosis to first treatment (either surgery or neoadjuvant chemotherapy) and diagnosis to surgical treatment were shorter in Brazil PHS patients (10.8 vs. 12.2 and 16.4 vs. 19.2, p Citation Format: Ramalho S, Dória MT, Natal RA, Conz L, Cabello V, Pavanello M, Cabello C, Mano MS, Linck RD, Batista LS, Pedro EP, Bines J, de Paula BH, Zucca-Matthes G, Ellis MJ, Podany E, Debord L, Makawita S, Stewart K, NematiShafaee M, Bondy ML. Impact of delay in breast cancer diagnosis and treatment in public health according to nationality: Brazil vs US [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-16.

// Luis Felipe Sallum 1 , Liliana Andrade 2 , Susana Ramalho 1 , Amanda Canato Ferracini 3 , Rodrigo de Andrade Natal 4 , Angelo Borsarelli Carvalho Brito 5 , Luis Otavio Sarian 1 and Sophie Derchain 1 1 Department of Obstetrics and Gynecology, State University of Campinas, Campinas, Faculty of Medical Sciences, Campinas, Sao Paulo, Brazil 2 Department of Pathology, University of Campinas, Campinas, Faculty of Medical Sciences, Campinas, Sao Paulo, Brazil 3 Program in Medical Sciences, State University of Campinas, Campinas, Faculty of Medical Sciences, Campinas, Sao Paulo, Brazil 4 Laboratory of Investigative and Molecular Pathology, State University of Campinas, Campinas, Faculty of Medical Sciences, Campinas, Sao Paulo, Brazil 5 Laboratory of Cancer Genetics, State University of Campinas, Campinas, Faculty of Medical Sciences, Campinas, Sao Paulo, Brazil Correspondence to: Sophie Derchain, email: fsallum@unicamp.br Keywords: cystadenocarcinoma; serous; diagnoses; survival; prognosis; Pathology Received: September 28, 2017 Accepted: February 12, 2018 Epub: February 19, 2018 Published: March 23, 2018 ABSTRACT Objective: To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53 and p16 in low- (LGSOCs) and high-grade serous ovarian carcinomas (HGSOCs). Results: HGSOC had a significantly higher proportion of advanced stage disease, higher CA125 levels, higher proportion of post-surgery residual disease and higher recurrence or disease progression. WT1 was expressed in 71.4% of LGSOCs and in 57.1% of HGSOCs ( p = 0.32). Focal and/or complete absence of p53 expression with negative p16 expression was found in 90.5% of LGSOCs, in contrast to the 88.1% of HGSOCs with diffuse or complete absence of p53 expression with positive p16 expression (

Introduction: Breast cancer is the most common malignant neoplasm affecting the female gender (besides non-melanoma skin cancer). It is a heterogenous disease with different phenotypic subtypes; the most common subtype is the luminal-like, which presents poor response to neoadjuvant chemotherapy. If patients with positive axilla at diagnosis are submitted to surgery, axillary dissection must be carried out, which is a surgery with major morbidities; however, if the patients are treated with neoadjuvant chemotherapy and develop negative axillary disease, they can avoid axillary dissection. Objective: to assess axillary response to neoadjuvant therapy in patients with cT1-3 cN1-2 luminal-like breast cancer. The secondary objectives were to assess the association between the axillary response to neoadjuvant chemotherapy according to: tumor replication marker (Ki67), estrogen and progesterone receptors (ER and PR), tumor histological grade, according to the Nottingham classification, tumor size (cT), level of axillary compromise (cN1, cN2 or cN3), chemotherapy scheme, luminal subtype and epidemiological variables (age, BMI, menopause status). Method: reconstituted cohort including female patients diagnosed with invasive breast cancer stage cT1-3 cN1-2 M0 at physical or ultrasound examination, who received neoadjuvant chemotherapy. Axillary compromise can be assumed. The patients were followed-up at the ambulatory of Clinical Oncology and Mastology at CAISM UNICAMP. A convenience sample was used. Statistical analysis: Statistical analysis will be carried out using the Statistical Package for the Social Sciences, version 22.0 (SPSS). Correlations between categorical variables will be analyzed with the chi-square test. Differences between means will be verified using Student’s t-test. Nonparametric tests will be used according to necessity. All tests will be bicaudal, with 5% as the threshold of statistical significance. Results: One hundred and forty three cases were included, respecting the inclusion criteria. Of these, 2.8% evolved with pathological complete response per se (pCR); 5.6%, with pCR in the breast; and 23.1%, with axillary pCR. The lower the axillary compromise at diagnosis, the higher the frequency of axillary pCR (cN1 26.7%, cN2-3 11.1% - p=0.049). The smaller the residual lesion in the breast after chemotherapy (ycT), the higher the chances of axillary pCR (ycT0 28.8%, ycT1 38.5%, ycT2 9.7%, ycT3-4 0 cases – p=0.042). The anthropometric, immunohistochemical and anatomopathological parameters did not present statistical relevance. Conclusion: Patients with luminal-like breast cancer and axillary compromise at diagnosis may benefit from avoiding dissection in about 20% of the time if treated with neoadjuvant chemotherapy, so this therapeutic strategy should be considered in these cases.

Background As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non‐mucinous luminal tumors, taking into account their clinical and pathological features. Methods 48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors. Results CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history. Conclusion Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

ObjectiveThe purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival.MethodsFor this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and β-catenin expression was assessed using tissue microarray-based immunohistochemistry.ResultsWomen with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and β-catenin did not differ between LGSOC and HGSOC (P = 0.12 and P = 1.00, respectively). The clinicopathological features and the response to platinum-based chemotherapy did not differ according to the BRCA1, Ki67, and β-catenin expression in either group. In HGSOC, only International Federation of Gynecology and Obstetrics stage was independently associated with poor survival (PFS and OS).ConclusionsKi67 expression was significantly higher in HGSOC. BRCA1 and β-catenin expression did not differ between LGSOC and HGSOC samples. BRCA1, Ki67, and β-catenin expression was neither related to clinicopathological features, response to platinum-based chemotherapy, nor survival. Only International Federation of Gynecology and Obstetrics stage remained associated with poor survival in women with HGSOC.

Background Breast cancer with pathological non-complete response (non-pCR) after neoadjuvant chemotherapy (NAC) has a worse prognosis. Despite Neo-Bioscore has been validated as an independent prognostic model for breast cancer submitted to NAC, non-pCR carcinoma was not assessed in this setting. Methods This is a retrospective trial that included women with localized breast cancer who underwent NAC and had non-pCR carcinoma in surgical specimen between 01/01/2013 to 12/31/2015 with a three-year follow-up. Survival analysis was performed by Kaplan-Meier estimator and hazard ratio (HR) set by log-rank test for the primary and secondary endpoints, respectively Disease-Free Survival (DFS) and Overall Survival (OS). According to Neo-Bioscore, the proposed prognostic model named Clustered Neo-Bioscore was classified into low (0–3), low-intermediate (4–5), high-intermediate (6) and high (7) risk. The prognostic accuracy for recurrence risk was assessed by time-dependent receiver operating characteristic (time-ROC) methodology. Multivariate Cox regression assessed the menopausal status, histological grade, Ki-67, estrogen receptor, HER2, tumor subtype, pathological and clinical stages. Confidence interval at 95% (CI95%) and statistical significance at set 2-sided p-value less than 0.05 were adopted. Results Among the 310 women enrolled, 267 patients (86.2%) had non-pCR carcinoma presenting size T3/T4 (63.3%), node-positive axilla (74.9%), stage III (62.9%), Ki-67 ≥ 20% (71.9%) and non-luminal A (78.3%). Non-pCR carcinoma presented worse DFS-3y (HR = 3.88, CI95% = 1.18–11.95) but not OS-3y (HR = 2.73, CI95% = 0.66–11.40). Clustered Neo-Bioscore discerned the recurrence risk for non-pCR carcinoma: low (DFS-3y = 0.86; baseline), low-intermediate (DFS-3y = 0.70; HR = 2.61), high-intermediate (DFS-3y = 0.13, HR = 14.05), and high (DFS-3y = not achieved; HR = 22.19). The prognostic accuracy was similar between Clustered Neo-Bioscore and Neo-Bioscore (0.76 vs 0.78, p > 0.05). Triple-negative subtype (HR = 3.6, CI95% = 1.19–10.92) and pathological stages II (HR = 5.35, CI95% = 1.19–24.01) and III (HR = 6.56, CI95% = 1.29–33.32) were prognoses for low-intermediate risk, whereas pathological stage III (HR = 13.0, CI95% = 1.60–106.10) was prognosis for low risk. Conclusions Clustered Neo-Bioscore represents a novel prognostic model of non-pCR carcinoma undergoing NAC with a more simplified and appropriate score pattern in the assessment of prognostic factors. Electronic supplementary material The online version of this article (10.1186/s12885-019-5812-0) contains supplementary material, which is available to authorized users.

Objective: There is insufficient information on predictors of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast carcinoma that also presented clinical complete response (cCR) evaluated in breast, axilla and breast and axilla. Methods: This retrospective study included 310 women with breast carcinoma who received NAC from 1/1/13 to 12/31/15 with follow-up until 8/31/16. The factors analyzed to predict pCR and cCR were menopausal status, Ki67, estrogen receptor, histologic grade, molecular subtype, tumor size, axilla status, and stage. Results: The cCR/pCR rates were 53.2/16.5% (breast), 76.3/36.8% (axilla) and 50.6/13.9% (breast and axilla). Molecular subtype and HER2-positive were independent predictors to confirm pCR in women with cCR, mainly triple negative (TN) in breast (OR 22.81, 95% CI 7.13–72.96) and breast and axilla (OR 36.06, 95% CI 8.77–148.26), but not in axilla. Ki67 ≥50% expression was predictor of cCR in breast (OR 2.00, 95% CI 1.31–3.06) and breast and axilla (OR 1.67, 95% CI 1.10–1.45). Conclusion: TN subtype and HER2-positive were the main independent predictors of pCR in women who also had cCR to NAC in breast and breast and axilla, but none was predictor in axilla. The Ki67 ≥50% was the independent predictor of cCR in breast and breast and axilla.

Breast cancer (BC) is the second most prevalent type of cancer worldwide and the most common among women. Also, BC shows different subtypes and patterns of chemotherapy response. Moreover, BC recurrence pattern is not well knowledge. But, genetic variants can alter drug pharmacokinetics and pharmacodynamics with an impact in treatment outcome. In many drugs in use, drug carriers act on drug absorption, distribution and elimination. ABCB1 encodes the P-glycoprotein – membrane transport protein – responsible for the cellular efflux of drugs, xenobiotics, cellular metabolites and anticancer agents, being crucial in response to chemotherapy. Our aim was to determine whether C1236T (rs1128503) and G2677 T/A (rs2032582) variants in the ABCB1 were associated with recurrence and survival in patients with BC, with invasive ductal carcinoma, treated with anthracycline-based chemotherapy. The study enrolled 146 patients with BC and 609 healthy control subjects. Genotyping in BC cases was performed by allele-specific PCR. The disease-free survival and overall survival analysis was performed by SPSS software. The χ2, Fisher's exact, univariate and multivariate logistic regression tests were performed by SAS software. ABCB1 variants were in accordance to Hardy-Weinberg equilibrium [P-value>.05]: (C1236T) CC = 57(39.1%), CT = 64(43.8%), TT = 25(17.1%); (G2677 T/A) GG = 69(47.3%), GA = 63(43.1%), AA = 10(6.8%), GT = 2(1.4%), AT = 2(1.4%) in the group including patients with BC. However, in healthy controls concerning the G2677 T/A variant, the ABCB1 variant is not in accordance with the Hardy-Weinberg equilibrium [P-value .05). Also, the Kaplan-Meier analysis of disease-free survival and overall survival regarding ABCB1 variants did not show statistical significance (P-value>.05). In our sample of patients with BC treated with anthracycline-based chemotherapy, ABCB1 variants were not associated with recurrence, disease-free survival and overall survival.

e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Implementing best sustainability solutions that enable improved energy efficiency and overall environmental performance to the building were the assumptions of the project ReHabitar in Marvao (Portugal), promoting sustainability and taking into account technical and economic feasibility of the solutions, without forgetting the social vector. In the case of a building in ruins, the aim of the intervention was the rehabilitation of the building giving it the flexibility and versatility of spaces for multipurpose use of didactic nature, culture and leisure, and another use for temporary housing. The project is characterised by its innovative character in the rehabilitation and recovery of rural areas on a collective basis, keeping the identity of the place and making it attractive and accessible to the local community. The sustainability of the project was acknowledged due to the performance of every environmental aspect, the excellence levels of awareness and education for sustainability, and the high stand...

Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HRþ) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemo-therapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2þ) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HRþ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field. RESUMO O câncer de mama é o mais comum, e a principal causa de mortalidade por câncer em mulheres de todo o mundo. Os tumores com receptor hormonal (RH) positivo representam o tipo mais comum desta doença. O benefício e as taxas de resposta à quimioterapia neoadjuvante variam de acordo com a expressão de RH, sendo mais baixa nos tumores luminais em comparação com tumores HER2 positivos ou triplo-negativos. A hormonioterapia neoadjuvante, uma opção para pacientes selecionados com tumores RH positivo localmente avançados, apresenta melhor perfil de tolerabilidade e segurança, e está associada com benefícios adicionais, como baixo custo e fácil acesso. Estes fatores são relevantes, uma vez que 70% das mortes por câncer de mama acontecem em mulheres de países pobres ou em desenvolvimento. Além disso, a hormonioterapia neoadjuvante vem sendo explorada como uma ferramenta científica, ao possibilitar o estudo de biomarcadores que podem predizer desfechos tanto para pacientes individuais quanto para ensaios clínicos em adjuvância. Este artigo de revisão detalha o conhecimento atual e as evidências mais relevantes sobre hormonioterapia neoadjuvante em câncer de mama, assim como perspectivas futuras nesta área.

Mathematical models, namely the flow boundary conditions, as well as the detail of the bounding geometry, can highly influence the computed flow field. In this work, an anatomically realistic portion of cerebral vasculature with a saccular aneurysm, and its geometric idealisation, are considered. The importance of the geometric description, namely including the side branches or modelling them as holes in the main vessel, is studied. Several approaches to prescribe the outflow boundary conditions at the side branches are analysed, including the traction-free condition, zero velocity (hence neglecting the side-branch), and the coupling with simple zero-dimensional and one-dimensional models. Results of the effects of outflow boundary modelling choice on computed haemodynamic parameters are used to identify appropriateness of the models based on the physical interpretation. Estimated range of error-bars associated to outflow boundary model choice and the level of geometric details are presented for patient-specific computational haemodynamics, and can serve as invitation for future studies. The zero-dimensional and one-dimensional models are shown to provide good representations of the side branches in the case of the clipped geometry.

Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal translocation event in a patient presenting with aggressive, endocrine therapy resistant estrogen receptor (ER) positive disease, producing an in-frame fusion gene consisting of N-terminal ESR1 and the C-terminus of the Hippo pathway coactivator YAP1 (ESR1-YAP1). We recently identified another ESR1 fusion through RNA sequencing (RNA-seq) in advanced stage ER+ disease from a chest wall recurrence in a male patient that was refractory to multiple lines of treatment. Two examples of fusions discovered in primary breast cancer samples include ESR1 fused in-frame to C-terminal sequences from NOP2 (ESR1-NOP2), identified in a resistant cohort from a RNA-seq screen focused on 81 primary breast cancers from aromatase inhibitor clinical trials, and a second ESR1 fusion, fused in-frame to the entire coding sequence of POLH (ESR1-POLH), that was identified from RNA-seq analysis of 728 Cancer Genome Atlas breast samples. This current study extends our previous characterization of ESR1-YAP1 by comparing functional and pharmacological properties of these three additional ESR1 gene fusion events of both early stage and advanced breast cancers. Methods. In vitro and in vivo experiments were conducted to test ESR1 fusions to induce therapeutic resistance, and metastasis. The transcriptional and binding properties of each fusion was also examined. Pharmacological inhibition with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was utilized to assess drug sensitivity in ESR1 fusion containing breast cancer cells and in a patient derived xenograft (PDX) model expressing ESR1-YAP1 (WHIM18). Results. The YAP1 and PCDH11x fusions conferred estrogen-independent and fulvestrant-resistant growth. Immunohistochemistry revealed significantly higher numbers of ER+ cells in lungs of mice xenografted with T47D cells expressing the YAP1 and PCDH11x fusions compared to YFP control, NOP2 and POLH fusions. Results from ChIP-seq and microarray studies suggest that these two fusions promote proliferation and metastasis through genomic action by binding estrogen response elements (ERE) and subsequent gene activation. We thereby define these fusions as “canonical” fusions compared to “non-canonical” NOP2 and POLH fusions, which demonstrated dramatically decreased genomic binding ability. The non-canonical fusions induced genes associated with basal-like breast cancer and promoted HER2, EGFR, and MAPK gene expression signatures in contrast to genes associated with cell cycle/proliferation induced by canonical fusions. The proliferative ability of canonical fusion-containing ER+ cells was inhibited by Palbociclib in a dose-dependent manner. In vivo WHIM18 tumors in mice fed with Palbociclib-containing chow demonstrated significantly reduced tumor volume, growth rate, and weight compared to tumors in mice on control chow. Conclusions. In-frame ERE activating canonical fusions occur in end-stage drug resistant advanced breast cancer and can be added to ESR1 point mutations as a class of recurrent somatic mutation that may cause acquired resistance. Growth induced by these fusions can be antagonized by Palbociclib and is potentially clinically helpful. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Cao J, Chan DW, He X, Kosaka Y, Schmidt C, Matsunuma R, Haricharan S, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Chen X, Perou CM, Creighton CJ, Maher C, Ellis MJ. Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-03.

SUMMARY RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective., In Brief Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor., Graphical Abstract

Objective: To assess the association of MRI BPE and pathological response in women diagnosed with stage II/III breast cancer submitted to NAC. Methods: This observational and cross-sectional retrospective study was performed in consecutive women who underwent NAC and had MRI exams before and after chemotherapy. The MRI was done before and after 2 weeks of completing NAC. BPE was classified according to ACR-BIRADS 5th edition. The type of BPE before NAC, its changes and the relationship to total pathologic complete response (TpCR) were evaluated. Data were paired with patient age, size on MRI before and after NAC, features of clinical response according to the RECIST criteria, tumor grade and immunohistochemical (IHC) subtypes. MRI assessment included amount of fibroglandular tissue, symmetry of BPE and measurement of tumor at the longest diameter. All images were blinded reviewed by a radiologist. We used for the changes of the BPE the Bowker symmetry test or the McNemar test and to analyze the factors related to the clinical and pathologic responses, logistic regression analysis. The level of significance adopted was 5% (p Table 1. Multivariate Analysis related to TpCR (n=71).VariableCategoryP-ValueO.R.*CI 95% O.R.*Tumor Size on MR pre-MAC (cm) 0.1710,8590.691-1.068Luminal subtypeLuminal B (ref.)---1.00--- Luminal A0.3120.450.10-2.11 HER2pos/ Luminal B HER20.0055.781.71-19.58 Triple negative0.0493.271.01-10.64Age (years) 0.3870.9820.942-1.023Nottingham grade1 (ref.)---1.00--- 20.0817.830.78-79.16 30.0967.100.71-71.31BPE pre-NAC (S or A)Asymmetric (ref.)---1.00--- Symmetric0.3273.030.33-27.76BPE pre-NAC affected breastMinimal (ref.)---1.00--- Mild0.8120.860.24-3.09 Moderate0.3711.890.47-7.64 Marked0.5911.570.30-8.17BPE pre-NAC contralateral breastMinimal (ref.)---1.00--- Mild0.7130.790.22-2.81 Moderate0.2502.330.55-9.77 Marked0.4701.880.34-10.43BPE ChangeSame/increased (ref.)---1.00--- Reduction0.0263.011.14-7.96* OR (Odds Ratio) = Risk ratio to pCR; (n=26 pCR, n=7 DpCR, n=31 PR e n=7 ED, where Total pCR is pathological complete response (without invasive and DCIS in the breast and axilla) DpCR is pathological response with just DCIS, PR is partial response and ED is stable disease – we haven't progression disease). CI 95% OR = Confidence interval of 95% to risk ratio. Ref.: reference level. Proportional risk models. Conclusion: BPE reduction was significantly associated with TpCR. Nevertheless, patterns of BPE pre-NAC have no association with pathological response. Citation Format: Teixeira SRC, Camargo HSAd, Ramalho S, Natal R, Machado HdC, Camargo MMAd, Azevedo J, Arruda MdS, Negrão EMS, Almeida NR, Teixeira AL, Cabello V, Cabello C. Breast cancer and magnetic resonance imaging (MRI): Background parenchymal enhancement (BPE) predicting response to neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-09.

Background. Dysregulation of the estrogen receptor gene (ESR1) is an established mechanism of inducing endocrine therapy resistance. We previously discovered a chromosomal translocation event generating an estrogen receptor gene fused in-frame to C-terminal sequences of YAP1 (ESR1-YAP1) that contributed to endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer models. This study compares functional, transcriptional, and pharmacological properties of additional ESR1 gene fusion events of both early stage (ESR1-NOP2) late stage (ESR1-YAP1 and ESR1-PCDH11x) breast cancers to gain a better understanding of therapeutic resistance and metastasis. Understanding the role of ESR1 fusions in inducing metastasis is critical, since the primary cause of death in breast cancer patients is through metastasis to distant sites. Methods. RNA-seq screens identified ESR1 fusions from early and late stage, endocrine therapy resistant breast tumor samples. Functional experiments were conducted using ER+ breast cancer cell lines, xenograft, and PDX models to test the ability of ESR1 fusions to induce therapeutic resistance and metastasis. ChIP-seq and RNA-seq were performed to examine transcriptional properties and differential gene expression induced by the fusions which directed subsequent pharmacological experiments with a CDK4/6 inhibitor. Results. ESR1-YAP1 and ESR1-PCDH11x promoted estrogen-independent and fulvestrant-resistant growth in vitro and induced greater tumor growth and increased metastatic capacity to the lungs of xenografted mice. In contrast, the ESR1-NOP2 fusion was sensitive to low estrogen conditions in vitro, and did not promote tumor growth. RNA-seq profiling revealed E2F targets pathway as the most highly enriched pathway induced by the ESR1 fusions. IHC revealed higher levels of pRb in ESR1-YAP1 and ESR1-PCDH11x xenograft tumors and subsequent CDK4/6 inhibition completely blocked tumor growth in an ESR1-YAP1 PDX model. Integrating RNA-seq with ChIP-seq data, we discovered a set of EMT and metastasis genes bound by all ESR1 fusions and WT-ER, but whose expression was strongly and uniquely up-regulated only by the ESR1-YAP1 and ESR1-PCDH11x fusions. These studies also revealed gained sites bound only by the ESR1-YAP1 and ESR1-PCDH11x fusions, not bound by WT-ER nor ESR1-NOP2. Genes mapping to these sites have a role in metastatic biology and were highly up-regulated by the YAP1 and PCDH11x fusions, potentially mediated by long range transcriptional activation. Conclusion. ESR1-YAP1 and ESR1-PCDH11x are driver fusions that occur in drug-resistant, advanced stage breast cancer and are a new class of recurrent somatic mutation that can cause acquired endocrine therapy resistance, yet can be treated with CDK4/6 inhibition. These driver fusions also confer increased metastatic ability through their ability to drive expression of genes that contribute to EMT and metastasis. In contrast, ESR1-NOP2 did not produce functional protein and appears to be a passenger event. These studies may provide pre-clinical rationale for targeting ESR1 translocated breast tumors, since the presence of an ESR1 driver fusion places a patient in a therapeutic category where none of the currently available endocrine therapies are likely to be effective. Citation Format: Lei JT, Shao J, Zhang J, Iglesia M, Chan DW, Cao J, Anurag M, Singh P, Haricharan S, Kavuri SM, Matsunuma R, Schmidt C, Kosaka Y, Crowder R, Hoog J, Phommaly C, Goncalves R, Ramalho S, Rodrigues-Peres RM, Lai W-C, Hampton O, Rogers A, Tobias E, Parikh P, Davies S, Ma C, Suman V, Hunt K, Watson M, Hoadley KA, Thompson A, Perou CM, Creighton CJ, Maher C, Ellis MJ. ESR1 gene fusions drive endocrine therapy resistance and metastasis in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-03.

Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mortality. Initially most women respond to platinum chemotherapy, but rapidly many become resistant to the drug and progress to relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help in the identification of prognostic biomarkers and in the development of new target therapies. The epithelial-mesenchymal transition (EMT) is an important cellular process related to invasion and metastasis. Some protein components such as the receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), acting on the signal-regulated kinase 1/2 (ERK1/2) extracellular pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo, are associated with EMT. In such pathways, microRNAs, such as miR-182, miR-96, and miR-9 are described as post-transcriptional regulators. Objective: To evaluate the expression of DDR2, YAP and miR-182, miR-96 and miR-9 in formalin-fixed, paraffin-embedded blocks with HGSOC, and its association with clinical, tumor, platinum response, and survival characteristics. Methods: 63 women with HGSOC stages III and IV, who underwent platinum chemotherapy from 1996 until 2013, followed up until 2016 at the Women's Hospital Prof. Dr. José Aristodemo Pinotti, Brazil, were included. All women had paraffin blocks and complete clinical data on the chart. DDR2 and YAP expression were assessed by immunohistochemistry on tissue microarray (TMA) slides and the microRNAs were evaluated by real-time polymerase chain reaction (rtPCR). For the comparison of DDR2 and YAP expression with age, CA125 serum level, post-surgery residual stage disease, and platinum response, Mann-Whitney and Fisher tests were used. Progression-free survival (PFS) and overall survival (OS) were calculated by Cox regression. The PFS and OS curves were estimated by the Kaplan-Meier method and compared by the Log-Rank test. Expression of miR and DDR2 and YAP levels were compared by the t-test. Results: DDR2 expression was high in 8 (13.7%) women. There was no association between DDR2 expression and age, stage, CA125, residual post-surgery disease, and response to platinum-based chemotherapy. PFS was significantly worse in women whose tumors had high DDR2 expression (p=0.03), but not OS (p=0.49). MiR-182 level expression was lower in the group with high DDR2 expression (p Conclusions: Low levels of miR-182 expression were associated with high expression of DDR2, which was associated with poorer DFS. These findings suggest that the ERK1/2 signaling pathway was relevant to the EMT of these HGSOCs. The role of Hippo remained indeterminate. Citation Format: Susana Oliveira Ramalho, Luis Otávio Sarian, Rodrigo Natal, Liliana Andrade, Amanda Ferracini, Marina Pavanello, Cassio Cardoso Filho, Sophie Derchain. Prognostic evaluation of components associated with epithelium-mesenchymal transition in women with serous carcinoma of high ovary grade [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B16.

Agradecimentos: Este trabalho foi financiado pela Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2009/17097-1 Resumo: Comparar a distribuição das pacientes segundo os subtipos clínico-patológicos de carcinomas de mama luminais like segundo o consenso de St. Gallen 2011 e 2013. Foram selecionadas 142 pacientes com carcinoma invasivo da mama que eram positivas para receptor de estrógeno, diagnosticadas e tratadas no estado de São Paulo, região Sudeste do Brasil. A expressão dos receptores de estrógeno, progesterona (RP) e Ki-67 foi avaliada por imunoistoquímica em microarranjo de tecidos. A expressão de HER-2 foi avaliada por hibridização fluorescente in situ. Observamos que 29 casos classificados como luminais A na classificação de St. Gallen 2011 eram luminais B na classificação de 2013. Dentre os 65 casos luminais B like da classificação de 2013, além dos 29 (45%) casos que migraram, observamos 15 casos (20%) com Ki-67 >14% e pelo menos 20% das células coradas; e 21 casos (35%) com Ki-67 >14% e RP positivo em mais de 20% das células coradas. Comparando a distribuição das pacientes com carcinomas luminais da mama segundo a classificação de St. Gallen 2011 e 2013 observamos que houve um aumento no número de carcinomas da mama luminais B like. Consequentemente, estima-se um aumento nas indicações de quimioterapia adjuvante e no custo do tratamento Abstract: To compare the distributions of patients with clinical-pathological subtypes of luminal B-like breast cancer according to the 2011 and 2013 St. Gallen International Breast Cancer Conference Expert Panel. We studied 142 women with breast cancer who were positive to estrogen receptor and had been treated in São Paulo state, southeast Brazil. The expression of the following receptors was assessed by immunohistochemistry: estrogen, progesterone (PR) and Ki-67. The expression of HER-2 was measured by fluorescent in situ hybridization analysis in tissue microarray. There were 29 cases of luminal A breast cancers according to the 2011 St. Gallen International Breast Cancer Conference Expert Panel that were classified as luminal B-like in the 2013 version. Among the 65 luminal B-like breast cancer cases, 29 (45%) were previous luminal A tumors, 15 cases (20%) had a Ki-67 >14% and were at least 20% PR positive and 21 cases (35%) had Ki-67 >14% and more than 20% were PR positive. The 2013 St. Gallen consensus updated the definition of intrinsic molecular subtypes and increased the number of patients classified as having luminal B-like breast cancer in our series, for whom the use of cytotoxic drugs will probably be proposed with additional treatment cost FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Aberto

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent “outliers” (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.