Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities.

BACKGROUND: Non-metastatic castration resistant prostate cancer (M0 CRPC) has seen important developments in drugs and diagnostic tools in the last two years. New hormonal agents have demonstrated improvement in metastasis free survival in M0 CRPC patients and have been approved by regulatory agencies in Brazil. Additionally, newer and more sensitive imaging tools are able to detect metastasis earlier than before, which will impact the percentage of patients staged as M0 CRPC. Based on the available international guidelines, a group of Brazilian urology and medical oncology experts developed and completed a survey on the diagnosis and treatment of M0 CRPC in Brazil. These results are reviewed and summarized and associated recommendations are provided. OBJECTIVE: To present survey results on management of M0 CRPC in Brazil. DESIGN, SETTING, AND PARTICIPANTS: A panel of six Brazilian prostate cancer experts determined 64 questions concerning the main areas of interest: 1) staging tools, 2) treatments, 3) side effects of systemic treatment/s, and 4) osteoclast-targeted therapy. A larger panel of 28 Brazilian prostate cancer experts answered these questions in order to create country-specific recommendations discussed in this manuscript. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on the predefined questions. These answers are the panelists' opinions, not a literature review or meta-analysis. Therapies not yet approved in Brazil were excluded from answer options. Each question had five to seven relevant answers including two non-answers. Results were tabulated in real time. CONCLUSIONS: The results and recommendations presented can be used by Brazilian physicians to support the management of M0 CRPC patients. Individual clinical decision making should be supported by available data, however, for Brazil, guidelines for diagnosis and management of M0 CRPC patients have not been developed. This document will serve as a point of reference when confronting this disease stage.

Spectrum and Clinical Activity of PD-1/PD-L1 Inhibitors: Regulatory Approval and Under Development.

PURPOSE OF REVIEW: The aim of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy. We focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies and future strategies. RECENT FINDINGS: The number of PD-1/PD-L1 inhibitors approved and in studies continues to grow, in different scenarios. Although the first wave of approvals included advanced cancers, localized disease is under growing interest in recent trials and approvals. Several of these agents are migrating from a monotherapy strategy to combinations (especially with targeted agents and chemotherapy). To date, several studies are being conducted for a better understanding of predictive biomarkers, mechanisms of resistance, optimal treatment duration, and immune-related toxicities. This article summarizes the recent history of modern cancer immunotherapy, provides an overview of novel drug-development considerations, and thus, illustrates the opportunities these new generations of immunotherapies represent.

Consensus on the Treatment and Follow-Up for the Nonmetastatic Castration-Resistant Prostate Cancer: A Report From the First Prostate Cancer Consensus Conference for Developing Countries.

PURPOSE: To present a summary of the recommendations for the treatment and follow-up for the biochemical recurrence of castration-resistant prostate cancer (PCa) as acquired through a questionnaire administered at the Prostate Cancer Consensus Conference for Developing Countries. METHODS: A total of 27 questions were identified as relating to this topic. Responses from the clinician were tallied and are presented in percentage format. Topics included the use of imaging in staging, treatment recommendations across different patient scenarios of life expectancy and prostate-specific antigen (PSA) doubling time, and follow-up for nonmetastatic castration-resistant PCa. RESULTS: A consensus agreed that in optimal conditions, positron emission tomography-computed tomography with prostate-specific membrane antigen would be used although in limited resource situations the combined use of CT of the abdomen and pelvic (or pelvic MRI), a bone scan, and a CT of the thorax or chest x-ray was recommended. In cases when PSA levels double in < 10 months, more than 90% of clinicians agreed on the use of apalutamide or enzalutamide, regardless of life expectancy. With a doubling time of more than 10 months, > 54% of experts recommended no treatment independent of life expectancy. More than half of the experts, regardless of resources, recommended follow-up with a physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms. CONCLUSION: The voting results and recommendations presented in this document can be used by physicians to support management for biochemical recurrence of castration-resistant PCa in areas of limited resources. Individual clinical decision making should be supported by available data.

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.

PURPOSE: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

Consensus on the Treatment and Follow-Up for Metastatic Castration-Resistant Prostate Cancer: A Report From the First Global Prostate Cancer Consensus Conference for Developing Countries (PCCCDC).

PURPOSE: To present a summary of the recommendations for the treatment and follow-up for metastatic castration-resistant prostate cancer (mCRPC) as acquired through a questionnaire administered to 99 physicians working in the field of prostate cancer in developing countries who attended the Prostate Cancer Consensus Conference for Developing Countries. METHODS: A total of 106 questions out of more than 300 questions addressed the use of imaging in staging mCRPC, treatment recommendations across availability and response to prior drug treatments, appropriate drug treatments, and follow-up, and those same scenarios when limited resources needed to be considered. Responses were compiled and the percentages were presented by clinicians to support each response. Most questions had five to seven relevant options for response including abstain and/or unqualified to answer, or in the case of yes or no questions, the option to abstain was offered. RESULTS: Most of the recommendations from this panel were in line with prior consensus, including the preference of a new antiandrogen for first-line therapy of mCRPC. Important aspects highlighted in the scenario of limited resources included the option of docetaxel as treatment preference as first-line treatment in several scenarios, docetaxel retreatment, consideration for reduced doses of abiraterone, and alternative schedules of an osteoclast-targeted therapy. CONCLUSION: There was wide-ranging consensus in the treatment for men with mCRPC in both optimal and limited resource settings.

Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer.

Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3].HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5].In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127].In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8-10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1.This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.

Consensus on diagnosis and management of non-metastatic castration resistant prostate cancer in Brazil: focus on patient, selection, treatment efficacy, side effects and physician's perception according to patient comorbidities

ABSTRACT Background: Non-metastatic castration resistant prostate cancer (M0 CRPC) has seen important developments in drugs and diagnostic tools in the last two years. New hormonal agents have demonstrated improvement in metastasis free survival in M0 CRPC patients and have been approved by regulatory agencies in Brazil. Additionally, newer and more sensitive imaging tools are able to detect metastasis earlier than before, which will impact the percentage of patients staged as M0 CRPC. Based on the available international guidelines, a group of Brazilian urology and medical oncology experts developed and completed a survey on the diagnosis and treatment of M0 CRPC in Brazil. These results are reviewed and summarized and associated recommendations are provided. Objective: To present survey results on management of M0 CRPC in Brazil. Design, setting, and participants: A panel of six Brazilian prostate cancer experts determined 64 questions concerning the main areas of interest: 1) staging tools, 2) treatments, 3) side effects of systemic treatment/s, and 4) osteoclast-targeted therapy. A larger panel of 28 Brazilian prostate cancer experts answered these questions in order to create country-specific recommendations discussed in this manuscript. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on the predefined questions. These answers are the panelists' opinions, not a literature review or meta-analysis. Therapies not yet approved in Brazil were excluded from answer options. Each question had five to seven relevant answers including two non-answers. Results were tabulated in real time. Conclusions: The results and recommendations presented can be used by Brazilian physicians to support the management of M0 CRPC patients. Individual clinical decision making should be supported by available data, however, for Brazil, guidelines for diagnosis and management of M0 CRPC patients have not been developed. This document will serve as a point of reference when confronting this disease stage.

Expression of Sara2 human gene in erythroid progenitors.

A human homologue of Sar1, named Sara2, was shown to be preferentially expressed during erythropoiesis in a culture stimulated by EPO. Previous studies, in yeast, have shown that secretion-associated and Ras-related protein (Sar1p) plays an essential role in protein transport from the endoplasmic reticulum to the Golgi apparatus. Here, we report the molecular analysis of Sara2 in erythroid cell culture. A 1250 bp long cDNA, encoding a 198 amino-acid protein very similar to Sar1 proteins from other organisms, was obtained. Furthermore, we also report a functional study of Sara2 with Real-time quantitative PCR analysis, demonstrating that expression of Sara2 mRNA increases during the initial stages of erythroid differentiation with EPO and that a two-fold increase in expression occurs following the addition of hydroxyurea (HU). In K562 cells, Sara2 mRNA was observed to have a constant expression and the addition of HU also up-regulated the expression in these cells. Our results suggest that Sara2 is an important gene in processes involving proliferation and differentiation and could be valuable for understanding the vesicular transport system during erythropoiesis.

Phase I trials of antitumour agents: fundamental concepts.

Phase I trials are an important step in the development of new drugs. Because of the advancing knowledge of cancer's molecular biology, these trials offer an important platform for the development of new agents and also for patient treatment. Therefore, comprehension of their peculiar terminology and methodology are increasingly important. Our objectives were to review the fundamental concepts of phase I designs and to critically contextualise this type of study as a therapeutic option for patients with refractory cancer.

Bevacizumab as first-line therapy in advanced non-small-cell lung cancer: a brazilian center experience.

OBJECTIVES: Bevacizumab has been approved by the US Food and Drug Administration as a first-line therapy for metastatic non-small-cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel. A single Latin American center experience was reviewed to determine the safety and efficacy of adding bevacizumab to first-line chemotherapy in a local population. METHODS: We retrospectively identified patients with non-squamous NSCLC treated with bevacizumab plus chemotherapy combinations as first-line chemotherapy between July 1, 2006, and January 30, 2011, at Sirio Libanes Hospital in Sao Paulo, Brazil. We collected data on patient characteristics, treatment combinations, toxicities, response to treatment, and survival. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier analysis, and prognostic factors were identified by the Cox regression model. RESULTS: A total of 56 patients were included in the final analysis (median age 62.4 years; 70% male). In 35 patients (62.5%), bevacizumab was combined with carboplatin and paclitaxel, and in 16 patients (28.6%), it was combined with pemetrexed and carboplatin. The response rate evaluated by the reference clinical team reached 74.5%, the median PFS was 5.3 months, and the median OS was 14.8 months. In multivariate analysis, use of maintenance therapy was the only predictive factor for OS (hazard ratio 6.85, 95% confidence interval 2.94-15.22). No treatment-related deaths were identified, and the overall incidence of grade 3-4 non-hematologic toxicities was 16%. CONCLUSION: Our results confirm the efficacy and safety data of bevacizumab first-line combinations for NSCLC in a Brazilian population.

Autoimmune features caused by dengue fever: a case report.

Dengue virus is the most important mosquito-borne viral disease in the world. Co-circulation of the four types of dengue viruses and expansion of dengue epidemic gave rise to infection enhancement and a big expansion of clinical aspects of the disease. Herein we report a case of a 25-year-old white woman with dengue fever and numerous associated autoimmune features. Our patient had proteinuria, an extensive right pleural effusion, a thin pericardial effusion and ascites. She had a low C3 level and positive antinuclear antibody; cryoglobulins were also positive. The numerous autoimmune features of this patient were a diagnostic challenge, since she was a young woman and could be easily mistaken for a rheumatologic patient in a newly open disease. Dengue infection probably was a triggering event causing an abnormal immune response. Therefore, dengue should be suspected in patients with hematological disorders and autoimmune features in endemic regions or those who have travelled to those regions.

Autoimmune features caused by dengue fever: a case report

Dengue virus is the most important mosquito-borne viral disease in the world. Co-circulation of the four types of dengue viruses and expansion of dengue epidemic gave rise to infection enhancement and a big expansion of clinical aspects of the disease. Herein we report a case of a 25-year-old white woman with dengue fever and numerous associated autoimmune features. Our patient had proteinuria, an extensive right pleural effusion, a thin pericardial effusion and ascites. She had a low C3 level and positive antinuclear antibody; cryoglobulins were also positive. The numerous autoimmune features of this patient were a diagnostic challenge, since she was a young woman and could be easily mistaken for a rheumatologic patient in a newly open disease. Dengue infection probably was a triggering event causing an abnormal immune response. Therefore, dengue should be suspected in patients with hematological disorders and autoimmune features in endemic regions or those who have travelled to those regions.

Determinação da frequência de polimorfismos de cyp2d6 em mulheres brasileiras e revisão de literatura / Determination of the frequency of CYP2D6 polymorphisms in Brazilian women and literature review

O tamoxifeno (TMX),consagrado como terapia padrão no tratamento de pacientes portadoras de câncer de mama com receptores hormonais positivos, é convertido por metabolização primária e secundária no metabólito endoxifeno, que apresenta afinidade muito maior pelos receptores hormonais e é o maior responsável pelos efeitos antitumorais desta droga. A biotransformação do TMX em endoxifeno é dependente da subunidade 2D6 do citocromo P-450 (CYP2D6), cujo gene apresenta inúmeros polimorfismos que reduzem a atividade metabólica dessa via biológica, resultando em menores níveis de seu produto ativo e, possivelmente, da resposta terapêutica ao uso do TMX. Objetivo: O objetivo deste estudo foi determinar a frequência dos polimorfismos CYP2D6*3, *4, *5, *6 e *10 e dos fenótipos de metabolização da droga TMX em pacientes portadoras de câncer de mama atendidas pelos autores no Centro de Oncologia do Hospital Sírio Libanês (HSL), além de revisar os dados sobre este tema disponíveis na literatura. Métodos: Amostras de sangue periférico de 30 pacientes foram enviadas a laboratório de referência para pesquisa dos polimorfismos descritos de CYP2D6 pela técnica de reação em cadeia da polimerase e digestão por enzimas de restrição (PCR-RFLP). Resultados: Os resultados mostraram heterozigose para polimorfismo CYP2D6*4 e *10 em 33 e 38% das mulheres, respectivamente. Utilizando a classificação de fenótipos de metabolização de TMX previamente descrita determinamos que 27% das mulheres avaliadas foram categorizadas com perfil de metabolização intermediária da droga, e 3% como metabolizadoras pobres, as quais, segundo dados atuais, parecem estar duas vezes mais sujeitas a desenvolverem recorrência de câncer de mama durante tratamento com TMX. Foi documentada uma elevada e inesperada prevalência de heterozigose do polimorfismo *10 na população estudada. Conclusões: Estudos prospectivos estão em andamento, visando definir o papel do perfil dos polimorfismos de CYP2D6 na escolha...

Tamoxifen (TMX), established as standard therapy in treating patients with breast cancer with hormone receptor positive, is converted by metabolism in primary and secondary metabolite endoxifeno, which has much higher affinity for hormone receptors and is most responsible the antitumor effects of this drug. Biotransformation of TMX in endoxifeno 2D6 is dependent on the subunit of cytochrome P-450 (CYP2D6), whose gene has many polymorphisms that reduce the metabolic activity of this biological pathway, resulting in lower levels of its active product, and possibly therapeutic response to use of TMX. Objective: The objective of this study was to determine the frequency of CYP2D6 polymorphisms * 3, * 4, * 5, * 6 and * 10 and phenotypes of drug metabolizing TMX in patients with breast cancer treated by the authors at the Centre for Oncology Syrian Lebanese Hospital (HSL), and review the data on this subject available in the literature. Methods: Blood samples from 30 patients were sent to reference laboratory for research of CYP2D6 polymorphisms described the technique of polymerase chain reaction and restriction enzyme digestion (PCR-RFLP). Results: Results showed heterozygosity for polymorphic CYP2D6 * 4 and * 10 in 33 women and 38% respectively. Using the classification of phenotypes of metabolism of TMX described previously determined that 27% of the women studied were categorized with a profile of intermediate metabolites of the drug, and 3% as poor metabolizers, which, according to current data seem to be two times more likely to develop recurrence of breast cancer during treatment with TMX. It was documented and an unexpected high prevalence of heterozygous * 10 polymorphism in the population. Conclusions: Prospective studies are underway, aimed at defining the role of the profile of CYP2D6 polymorphisms on the choice of strategy hormonal therapy in women with breast cancer.