Conference Presentations by Susana Ramalho
PD2-03: Recurrent functionally diverse in-frame ESR1 gene …ions drive endocrine resistance in bre... more PD2-03: Recurrent functionally diverse in-frame ESR1 gene …ions drive endocrine resistance in breast cancer | Cancer Research Página 1 de 2 Abstract PD2-03: Recurrent functionally diverse in-frame ESR1 gene fusions drive endocrine resistance in breast cancer Abstract Background. We previously reported an alternative ESR1 somatic gain-of-function chromosomal
Papers by Susana Ramalho
The Oncologist, 2022
Background Breast cancer outcomes among patients who use safety-net hospitals in the highly popul... more 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 di...
Scientific Reports, Nov 18, 2021
Herein it was evaluated the impact of PD-L1 immunohistochemical expression and stromal tumor-infi... more Herein it was evaluated the impact of PD-L1 immunohistochemical expression and stromal tumor-infiltrating lymphocyte (sTIL) counts in pretreatment needle core biopsy on response to neoadjuvant chemotherapy (NACT) for patients with breast carcinomas (BC). In 127 paired pre-and post-NACT BC specimens, immunohistochemical expression of PD-L1 was evaluated in stroma and in neoplastic cells. In the same samples sTILs were semi-quantified in tumor stroma. Post-NACT specimens were histologically rated as having residual cancer burden (RCB of any degree), or with complete pathological response (pCR). PD-L1 expression and higher sTIL counts were associated with histological grade 3 BC. PD-L1 expression was also associated with the non-luminal-HER2+ and triple negative immunohistochemical profiles of BC. Pathological complete response was associated with histological grade 3 tumors, and with the non-luminal-HER2+ and triple negative profiles. Additionally, our results support an association between PD-L1 expression and pCR to NACT. It was also observed that there is a trend to reduction of sTIL counts in the post-NACT specimens of patients with pCR. Of note, PD-L1 was expressed in half of the hormone receptor positive cases, a finding that might expand the potential use of immune checkpoint inhibitors for BC patients. Breast cancer is the most common malignancy among women worldwide, excluding non-melanoma skin cancer. This neoplasia accounts for about a third of all cancers and represents the first most frequent cause of death 1. In Brazil, breast cancer has an estimated incidence of 66,280 cases for 2020, and a mortality rate of 17,572 patients in 2018 2. Treatment of breast cancer includes surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy 3-5. Breast cancer is a heterogeneous disease classified into different molecular subtypes 6,7. An
Oncologist, Mar 28, 2022
Background: Breast cancer outcomes among patients who use safety-net hospitals in the highly popu... more 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
Molecular Genetics & Genomic Medicine, May 16, 2019
This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmer... more This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Revista Brasileira de Ginecologia e Obstetrícia, Dec 1, 2019
Objective To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal bre... more Objective To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal breast cancer. Methods A cross-sectional study that included all patients with early or locallyadvanced luminal breast cancer submitted to neoadjuvant chemotherapy between 2013 and 2014. Demographic, clinic and pathologic data were retrieved from patient records. The expressions of the estrogen receptor (ER), the progesterone receptor (PR), and Ki67 were analyzed by immunohistochemistry (IHC). The status of the human epidermal growth factor receptor 2 (HER2) was evaluated by IHC and fluorescent in situ hybridization (FISH). Independent predictors of clinic and pathologic response were evaluated by stepwise logistic regression models and receiver operating characteristic (ROC) curve analysis. Results Out of 298 patients identified, 115 were included in the analysis. Clinical complete response (cCR) was observed in 43.4% of the patients (49/113), and pathologic complete response (pCR) was observed in 7.1% (8/115) of the patients. The independent predictors of cCR were premenopausal status (p < 0.001), low PR expression (50% versus > 50%; p ¼ 0.048), and Ki67 expression ! 14% (versus < 14%; p ¼ 0.01). Patients with cCR were more commonly submitted to breast conserving surgery (34.7% versus 7.8%; p < 0.001). Increasing cutoff points for Ki67 expression were associated with an increase in specificity and a decrease in sensitivity to identify patients with cCR. Conclusion Premenopausal status, lower PR expression and higher Ki67 expression were associated with a higher rate of cCR to neoadjuvant chemotherapy in luminal breast cancer.
Frontiers in Oncology, Apr 3, 2020
Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocr... more Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor-positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of ESR1m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy. Methods: We followed a prospective cohort of patients with ER+ HER2-stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of ESR1m. Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET. Reinert et al. ESR1m After Neoadjuvant Endocrine Therapy Discussion: Growing evidence supports the notion that there are different mechanisms for 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.
Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocr... more 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 negati... more 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.
Background. Dysregulation of the estrogen receptor gene (ESR1) is an established mechanism of ind... more 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.
Journal of Clinical Oncology, May 20, 2008
11548 Background: Breast cancer is the most prevalent solid tumor in our practice, a community-ba... more 11548 Background: Breast cancer is the most prevalent solid tumor in our practice, a community-based oncological center in Campinas, SP, Brazil. Our goal was to determine the overall survival (OS) and disease-free survival (DFS) of three subgroups: the ICD, the triple negative (ER negative, PR negative and HER-2 negative) and the IBC. Methods: We retrieved from our database 415 breast cancer patients treated from 1988 to 2006. A total of 318 IDC, 37 TN and 16 IBC cases were reviewed. The log-rank test and Kaplan-Meier analyses were performed. Results: In the IDC subgroup, results of DFS and OS confirmed data from literature and DFS regarding to estrogen receptor and linfonodal status were statistically significant. In 1998 an important improvement was observed in the DFS in the IDC group after the insertion of paclitaxel in the adjuvant chemotherapy regimens at our institution. OS before 1998 was 52% and after 1998 was 74% (p= NS) while DFS was 43% and 70%, respectively (p= 0.01). It was also found that t...
Introduction: The Oncotype DX was associated to 14% of adjuvant chemotherapy administration to Ho... more 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&gt;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&gt;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.
Programa de Pós-Graduação: Tocoginecologia Diagramação e arte-final: Assessoria Técnica do CAISM ... more Programa de Pós-Graduação: Tocoginecologia Diagramação e arte-final: Assessoria Técnica do CAISM (ASTEC) Ramalho, Susana Oliveira Botelho, 1977-R141e Expressão do HER-2 em pacientes brasileiras com carcinoma da mama receptor de estrógeno e progesterona negativo. / Susana Oliveira Botelho Ramalho.
A minha orientadora, Profa. Dra. Sophie Françoise Mauricette Derchain, pela amizade e revisão cui... more A minha orientadora, Profa. Dra. Sophie Françoise Mauricette Derchain, pela amizade e revisão cuidadosa desta tese. Ao meu coorientador, Prof. Dr. Luis Otávio Zanatta Sarian, pelo incentivo e revisão dos artigos. Aos membros da banca de qualificação, Prof Dr.Luiz Carlos Zeferino e Prof. Dr. Jose Barreto Campello Carvalheira que contribuíram para a elaboração final desta tese.
Cancers
Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer ... more 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...
Cancer Research
Objective: To assess the association of MRI BPE and pathological response in women diagnosed with... more 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...
WOS, 2018
Orientadores: Sophie Françoise Mauricette Derchain, Luis Otávio Zanatta SarianTese (doutorado) - ... more Orientadores: Sophie Françoise Mauricette Derchain, Luis Otávio Zanatta SarianTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: o carcinoma seroso de alto grau de ovário (CSAGO) é uma doença heterogênea que apresenta alta mortalidade. Inicialmente a maioria das mulheres responde à quimioterapia com platina, porém rapidamente muitas se tornam resistentes à droga e evoluem com recidiva e óbito. O maior conhecimento das vias responsáveis pelos mecanismos de invasão e metástase em mulheres com CSAGO poderá ajudar na identificação de biomarcadores prognósticos e desenvolvimento de novas terapias alvos. A transição epitélio-mesenquimal (TEM) é um importante processo celular relacionado com invasão e metástases. Alguns componentes proteicos tais como o receptor tirosino quinase, discoidin domain receptor 2 (DDR2), atuando na via extracelular signal-regulated kinase 1/2 (ERK1/2), e o co-ativador transcricional yes-associated protein (YAP), atuando na via Hippo, estão associados a TEM. Nessas vias, os microRNAs, tais como miR-182, miR-96 e miR-9 estão descritos como reguladores pós-transcricionais. Objetivo: avaliar a expressão do DDR2, do YAP e dos miR-182, miR-96 e miR-9 em blocos de parafina de mulheres com CSAGO, e sua associação com características clínicas, do tumor, resposta à platina e sobrevida. Métodos: foram incluídas 63 mulheres com CSAGO estádios III e IV, submetidas à quimioterapia com platina de 1996 até 2013 e acompanhadas até 2016 no Hospital da Mulher Prof. Dr. José Aristodemo Pinotti, Brasil. Todas tinham blocos de parafina e dados clínicos completos no prontuário. A expressão do DDR2 e do YAP foram avaliados por imunoistoquímica em lâminas de microarranjo de tecido (TMA) e os microRNAs foram avaliados por reação em cadeia da polimerase quantitativa em tempo real (qRT-PCR). Para comparação entre a expressão do DDR2 e da YAP com idade, nível sérico de CA125, estádio, doença residual pós-cirurgia e resposta à platina foram utilizados os testes de Mann-Whitney e Fisher. A sobrevida livre de progressão (SLP) e a sobrevida global (SG) foram calculadas por regressão de Cox. As curvas de SLP e SG foram estimadas pelo método Kaplan-Meier e comparadas pelo teste Log-Rank. A expressão dos níveis de miR e do DDR2 e YAP foram comparadas pelo teste t. Resultados: a expressão citoplasmática do DDR2 foi alta em 8 (13,7%) mulheres. Não houve associação entre expressão do DDR2 e idade, estádio, CA125, doença residual pós-cirurgia e resposta à quimioterapia baseada em platina. A SLP foi significativamente pior nas mulheres cujos tumores apresentaram alta expressão de DDR2 (p = 0,03), mas não a SG (p=0,49). O nível de expressão do miR-182 foi menor no grupo com alta expressão de DDR2 (p<0,001), mas não o nível de expressão do miR-96 (p=0,067). Alta expressão nuclear do YAP com baixa expressão citoplasmática foi encontrada em 15 (24,5%) mulheres. Não houve associação entre a expressão do YAP e características da doença ou evolução das mulheres. O nível de expressão do miR-9 não se associou com a expressão do YAP. Conclusões: baixos níveis de expressão do miR-182 foram associados com alta expressão do DDR2 a qual se relacionou com pior SLP. Esses achados sugerem que a via de sinalização ERK1/2 foi relevante para a TEM desses CSAGO. O papel da Hippo permaneceu indeterminadoAbstract: 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 with relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help the identification of prognostic biomarkers and 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 extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo pathway, 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 of HGSOC, and its association with clinical pathological characteristics, platinum response and survival. Methods: 63 women with HGSOC stages III and IV, who underwent platinum-based chemotherapy from 1996 until 2013, followed up until 2016 at 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…
The FASEB Journal, Apr 1, 2016
IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly rel... more IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly related with platinum resistance. Parameters of collagen can be used as potential new prognostic biomar...
Breast Cancer Research and Treatment, 2021
Neoadjuvant endocrine therapy (NET) has been shown to be effective in ER-positive/HER2-negative b... more 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.
Journal of Clinical Oncology, 2019
e20700 Background: Palliative systemic therapy is the primary approach for stage IV non-small cel... more 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-surv...
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