RESUMO
Knockout of ERß in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERß plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERß agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERß and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERß expression, but, on treatment longer than 8 mo, ERß was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERß agonists together with abiraterone should be considered as a treatment that might sustain expression of ERß and offer some benefit to patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptor beta de Estrogênio/agonistas , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androstenos/farmacologia , Androstenos/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Biópsia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Estudos de Coortes , Receptores ErbB/metabolismo , Receptor beta de Estrogênio/metabolismo , Finasterida/farmacologia , Finasterida/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Knockout , Gradação de Tumores , Nitrilas/farmacologia , Nitrilas/uso terapêutico , PTEN Fosfo-Hidrolase/metabolismo , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Fitoestrógenos/farmacologia , Fitoestrógenos/uso terapêutico , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismoRESUMO
PURPOSE: The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC. METHODS: Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy. RESULTS: Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months. CONCLUSIONS: In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.
Assuntos
Gencitabina , Neoplasias Pancreáticas , Humanos , Afatinib/efeitos adversos , Desoxicitidina , Paclitaxel , Albuminas , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
INTRODUCTION: S-1 has been shown to be an effective adjuvant treatment option for East Asian patients who underwent gastrectomy for stage II/III gastric cancer. We conducted a phase I/II study to evaluate the feasibility, tolerability, and efficacy of administering S-1 in the adjuvant setting after R0-resection of adenocarcinoma of the stomach and esophagogastric junction (EGJ) in Caucasian patients. METHODS: In this single-cohort, open-label, phase I/II trial, we enrolled patients with locally advanced adenocarcinoma of the stomach or EGJ having undergone R0-resection with or without neoadjuvant treatment. One treatment cycle consisted of oral S-1 (30 mg/m2 bid) for 14 days. Cycles were repeated every 3 weeks for 18 cycles (54 weeks). Primary endpoint was feasibility and tolerability. Safety was evaluated according to the Common Toxicity Criteria Adverse Events (CTCAE) version 4.0. Secondary endpoints were 1-year relapse-free survival (RFS) rate, RFS, and overall survival (OS). RESULTS: Between October 2015 and February 2018, 32 patients were enrolled in 12 German centers, and 30 started adjuvant study treatment. Seventeen patients completed all 18 cycles. Two patients terminated study treatment early due to adverse events (AEs), 7 due to patient's or investigator's decision, and 4 due to recurrence or distant metastasis during adjuvant therapy. Dose levels were reduced to 25 mg/m2 in 9 patients and to 20 mg/m2 in 1 patient. Of patients completing all 18 cycles, 5 did so with reduced dosage of S-1. Documented grade ≥3 AEs were neutropenia, diarrhea, vomiting, polyneuropathy, palmar-plantar erythrodysaesthesia, and rash. Serious AEs were observed in 7 patients. Median RFS was 32.2 months. One-year RFS rate was 77%. Data on OS were still premature at the end of the study. CONCLUSION: Adjuvant treatment with S-1 for 1 year is a feasible and safe treatment option for Caucasian patients diagnosed with gastric adenocarcinoma or cancer of the EGJ after R0-resection.
Assuntos
Adenocarcinoma , Combinação de Medicamentos , Junção Esofagogástrica , Estudos de Viabilidade , Gastrectomia , Ácido Oxônico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Tegafur/uso terapêutico , Tegafur/administração & dosagem , Masculino , Ácido Oxônico/uso terapêutico , Ácido Oxônico/administração & dosagem , Pessoa de Meia-Idade , Feminino , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Adenocarcinoma/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Idoso , Quimioterapia Adjuvante , Adulto , Resultado do Tratamento , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidadeRESUMO
BACKGROUND AND OBJECTIVE: With the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunichLMU molecular tumor board (MTB). PATIENTS AND METHODS: In this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation. RESULTS: In total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF-mutations and FGFR2-fusions). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment. CONCLUSIONS: In line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients.
Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Humanos , Estudos Retrospectivos , Medicina de Precisão , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/terapia , Neoplasias do Sistema Biliar/patologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
BACKGROUND: Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery. METHODS: This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy. RESULTS: Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events. CONCLUSIONS: In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Calicreínas/sangue , Recidiva Local de Neoplasia/terapia , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/terapia , Acetato de Abiraterona/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Quimiorradioterapia Adjuvante/métodos , Intervalo Livre de Doença , Esquema de Medicação , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Prednisona/administração & dosagem , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Fatores de TempoRESUMO
BACKGROUND: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. PATIENTS AND METHODS: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. RESULTS: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. CONCLUSION: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
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Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona/uso terapêutico , Androstenos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dasatinibe/efeitos adversos , Humanos , Masculino , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Distribuição Aleatória , Sunitinibe/uso terapêutico , Resultado do Tratamento , Microambiente TumoralRESUMO
INTRODUCTION: Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer. AREAS COVERED: The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database. EXPERT OPINION: Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.
Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.
RESUMO
BACKGROUND: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition. PATIENTS AND METHODS: We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry. RESULTS: Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively). CONCLUSION: Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way. TRIAL REGISTRATION: ClinicalTrials.gov NCT01254864.
Assuntos
Acetato de Abiraterona/uso terapêutico , Antagonistas de Androgênios/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Receptores Androgênicos/química , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Curva ROCRESUMO
Prostate cancer commonly affects older men, with one out of five patients being diagnosed at 75 years or older. Elderly patients are more likely to have reduced performance and nutritional status, increased comorbidities, polypharmacy, and altered host-dependent pharmacokinetics and pharmacodynamics. Moreover, elderly patients are often underrepresented in clinical trials, mainly because of comorbidities and decline in performance status. The International Society of Geriatric Oncology recommends management of elderly patients according to fitness and personal preference, rather than chronological age. Since androgen signaling has a nodal role in prostate cancer progression, androgen-targeting agents remain the mainstay of systemic therapy for this disease. However, the potential benefit of these treatments may be compromised by toxicity, especially in elderly patients. Hence, management decisions require evidence-based consideration of both potential benefits and risks on an individualized basis. Furthermore, especially elderly patients should undergo geriatric screening and must be actively monitored during treatment to detect adverse events early and prevent complications. A personalized and vigilant approach could provide the elderly patient with the optimal benefits of existing and emerging prostate cancer treatments, while sparing them the risks of excessive toxicity and avoiding overtreatment.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Antagonistas de Androgênios/efeitos adversos , Comorbidade , Descoberta de Drogas , Avaliação Geriátrica , Serviços de Saúde para Idosos , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
With rising survival rates of patients with congenital heart disease (CHD), functional health variables have become the key aspect in treatment evaluation. The effectiveness of various treatment options on the health-related quality of life (HRQoL) and the objectively measured exercise capacity as peak oxygen uptake (VO2 peak) remains rather unclear and hence, its investigation is the primary aim of this study. Data from 1014 patients (≥14-years-old, various CHD) were retrospectively reviewed. The patients had completed at least twice the SF-36 questionnaire on HRQoL prior to a cardiopulmonary exercise test. Each patient was assigned to 1 of 4 treatment groups (i.e., surgery, catheter intervention, drug therapy, and surveillance) according to the received treatment between the baseline and the follow-up examination. After 4.0 ± 2.2 years of follow-up, patients with surgery and catheter intervention showed an increase in the physical summary score of HRQoL as compared to the other treatment groups (p <0.001). This effect remained also significant in a multivariable model accounting for anthropometric and baseline data. No significant differences in the mental summary score of HRQoL and the VO2 peak were evident between the different treatment groups in the multivariable model. No significant correlation was found between the changes in HRQoL and VO2 peak over time. In conclusion, despite insignificant changes in aerobic capacity, adolescents and adults with CHD report better physical HRQoL following surgery and catheter intervention compared to the other treatment options. HRQoL and exercise capacity need to be considered concurrently in the evaluation of adolescents and adults with CHD.
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Terapia por Exercício/métodos , Tolerância ao Exercício/fisiologia , Cardiopatias Congênitas/psicologia , Qualidade de Vida , Adolescente , Adulto , Idoso , Teste de Esforço , Feminino , Seguimentos , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Estudos Retrospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
Intrathoracic neurofibromas are relatively uncommon in patients with neurofibromatosis. They are usually asymptomatic and may be discovered incidentally. We present the case of a 51-year-old, African American man with neurofibromatosis type 1 who underwent coronary revascularization. Intraoperatively, numerous neurofibromas were discovered, one of which was attached to the left internal mammary artery. The procedure was uncomplicated despite the challenging intraoperative findings. Special considerations in the management of patients with neurofibromatosis undergoing cardiac surgery are discussed, including risks, preoperative imaging and the importance of excision of suspicious tumors.