RESUMO
OBJECTIVE: Although advanced stage epithelial ovarian cancer is widely considered life-threatening, 17% of women with advanced disease will survive long-term. Little is known about the health-related quality of life (QOL) of long-term ovarian cancer survivors, or how fear of recurrence might affect QOL. METHODS: 58 long-term survivors with advanced disease participated in the study. Participants completed standardized questionnaires to capture cancer history, QOL, and fear of recurrent disease (FOR). Statistical analyses included multivariable linear models. RESULTS: Participants averaged 52.8 years at diagnosis and had survived >8 years (mean:13.5); 64% had recurrent disease. Mean FACT-G, FACT-O, and FACT-O-TOI (TOI) scores were 90.7 (SD:11.6), 128.6 (SD:14.8), and 85.9 (SD:10.2) respectively. Compared to the U.S. population using T-scores, QOL for participants exceeded that of healthy adults (T-score (FACT-G) = 55.9). Overall QOL was lower in women with recurrent vs. non-recurrent disease though differences did not reach statistical significance (FACT-O = 126.1 vs. 133.3, p = 0.082). Despite good QOL, high FOR was reported in 27%. FOR was inversely associated with emotional well-being (EWB) (p < 0.001), but not associated with other QOL subdomains. In multivariable analysis, FOR was a significant predictor of EWB after adjusting for QOL (TOI). A significant interaction was observed between recurrence and FOR (p = 0.034), supporting a larger impact of FOR in recurrent disease. CONCLUSION: QOL in long-term ovarian cancer survivors was better than the average for healthy U.S. women. Despite good QOL, high FOR contributed significantly to increased emotional distress, most notably for those with recurrence. Attention to FOR may be warranted in this survivor population.
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Sobreviventes de Câncer , Neoplasias Ovarianas , Adulto , Humanos , Feminino , Qualidade de Vida/psicologia , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/psicologia , Carcinoma Epitelial do Ovário , MedoRESUMO
OBJECTIVE: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.
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Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Neoplasias Ovarianas , Humanos , Feminino , Peritônio/patologia , Dasatinibe/efeitos adversos , Tubas Uterinas/patologia , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Endométrio/patologia , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismoRESUMO
PURPOSE: Patients with persistent/recurrent cervical cancer following platinum-based chemotherapy have limited therapeutic options. The Gynecologic-Oncology-Group conducted a phase II trial to assess efficacy and tolerability of nivolumab, an immune checkpoint inhibitor, in persistent/recurrent cervical carcinoma. PATIENTS AND METHODS: Key eligibility criteria included persistent/recurrent cervical cancer, failure of prior systemic therapy and ECOG PS 0-1. Nivolumab 3 mg/kg was given IV every 2 wk. until disease progression or intolerable toxicity. Response was assessed every 8 wk. for 6 months and every 12 wk. thereafter. The primary endpoints were objective response as assessed by RECIST 1.1. The study used a 2-stage group sequential design. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1%. RESULTS: Of 26 enrolled patients with persistent/recurrent cervical cancer, 25 were evaluable for response/toxicity with a median age of 45. 36% had ECOG PS of 1, and 100% had received one prior systemic chemotherapy regimen. PD-L1 expression (≥1%) was identified in 77.3% of tumor samples. As of 03/05/19, all patients were off study treatment; median follow-up for survival status was 32 months (range, 2-41.5). There were 21 (84%) patients with a treatment-related adverse event (TRAE) and most were grades 1-2. Six (24%) patients had grade 3 TRAEs with 1 discontinuing nivolumab due to hepatic toxicity. No grade 5 TRAEs occurred, and 2 patients had grade 4 TRAEs. One confirmed partial response (4%; 90% CI, 0.4%-22.9%), duration of response 3.8 months. Thirty-six percent of patients had stable disease (SD) (9/25; 90% CI, 20.2%-54.4%); the median duration of SD was 5.7 months (range, 3.5-12.7). Estimated PFS and OS at 6 months were 16% and 78.4%, respectively. CONCLUSION: Single agent nivolumab exhibited low antitumor activity and an acceptable safety profile in patients with persistent/recurrent cervical cancer previously treated with platinum-based chemotherapy.
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Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Neoplasias do Colo do Útero/imunologia , Adulto JovemRESUMO
OBJECTIVE: Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity. METHODS: From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity. RESULTS: Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71-1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively. CONCLUSIONS: Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches. TRIAL REGISTRATION: NCT00857545.
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Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Carcinoma Epitelial do Ovário/terapia , Neoplasias das Tubas Uterinas/terapia , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Vacinas Conjugadas/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Método Duplo-Cego , Neoplasias das Tubas Uterinas/imunologia , Neoplasias das Tubas Uterinas/patologia , Feminino , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologiaRESUMO
OBJECTIVES: The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients. METHODS: Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated. RESULTS: 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-valueâ¯≤â¯0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-valueâ¯=â¯0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-valueâ¯=â¯0.02) and hazard ratio (HR) for progression of 0.66 (p-valueâ¯=â¯0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables. CONCLUSION: SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.
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Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Metástase Linfática/genética , Nucleosídeo NM23 Difosfato Quinases/genética , Idoso , Estudos de Casos e Controles , Progressão da Doença , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Endométrio/patologia , Receptores ErbB/genética , Feminino , Humanos , Metástase Linfática/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Intervalo Livre de Progressão , Medição de Risco/métodosRESUMO
OBJECTIVE: Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy. METHODS: In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety. RESULTS: Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (pâ¯>â¯0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36â¯months), was significantly increased in Arm 1 (pâ¯<â¯0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified. CONCLUSION: PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Epotilonas/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/análogos & derivadosRESUMO
OBJECTIVES: The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. METHODS: Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. RESULTS: Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53-3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10-7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04-4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. CONCLUSIONS: A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.
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Carcinoma Endometrioide/classificação , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Carcinoma Endometrioide/patologia , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/genética , Neoplasias do Endométrio/patologia , Feminino , Genes p53 , Humanos , Perda de Heterozigosidade , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Proteínas de Ligação a Poli-ADP-Ribose/genética , Valor Preditivo dos Testes , Risco , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.
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Biomarcadores Tumorais , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/mortalidade , gama-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/terapia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , gama-Sinucleína/genéticaRESUMO
OBJECTIVE: The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). METHODS: Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3+3 phase I dose escalation design with patients receiving intravenous PLD 40mg/m2 (dose level 1 and 2) or 50mg/m2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m2 (dose level 1) or 36mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. RESULTS: Sixteen evaluable patients received a median of 4cycles (range 1-8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR=21.4%; SD=35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. CONCLUSIONS: GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1.
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Doxorrubicina/análogos & derivados , Neoplasias das Tubas Uterinas/terapia , Terapia Genética/métodos , Interleucina-12/genética , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/terapia , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/genética , Feminino , Humanos , Interleucina-12/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Plasmídeos/administração & dosagem , Plasmídeos/genética , Polietilenoglicóis/administração & dosagem , Polietilenoimina/administração & dosagem , Polietilenoimina/análogos & derivadosRESUMO
OBJECTIVES: Ovarian cancer leads to abdominal carcinomatosis and late stage (III/IV) diagnosis in 75% of patients. Three randomized phase III trials have demonstrated that intraperitoneal (IP) chemotherapy improves outcomes in epithelial ovarian cancer. While IP treatment is validated by clinical trials, there is a poor understanding of the mechanism(s) leading to the survival advantage other than the increased concentration of cytotoxic drugs within the tumor microenvironment. A better understanding of this process through analysis of dynamic biomarkers should promote novel approaches that may enhance tumor clearance. We propose this pilot study to confirm the feasibility of collecting serial peritoneal samples from implanted catheters in women receiving IP chemotherapy. We believe these specimens may be used for multiplex analysis to reveal unique biomarker fluctuations when compared to peripheral blood. METHODS: From 13 women participating on GOG 252, 30 whole blood, 12 peritoneal fluid (PF), and 20 peritoneal wash (PW) with 30mL saline were obtained. Samples were requested prior to the first three chemotherapy cycles. Samples were assessed for volume, cell populations, protein, RNA, and miRNA content changes. RESULTS: Median volume for PF was 1.6mL and 3.1mL for PW. PW is a dilution of PF capable of capturing measurable biomarkers. Peritoneal aspirates contain a unique profile of biomarkers distinct from blood. miRNA undergo earlier alteration with chemotherapy than genes. Flow cytometry does not adequately capture biomarker fluctuations. CONCLUSIONS: As a proof of principle study, this trial provides evidence that sampling the peritoneal cavity can be adapted for biomarker analysis.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Líquido Ascítico/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Idoso , Líquido Ascítico/química , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/sangue , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Cateteres de Demora , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente Tumoral/efeitos dos fármacosRESUMO
PURPOSE: To examine the effect of celecoxib on cervical intraepithelial neoplasia 3 (CIN 3). This is a NRG Oncology/Gynecologic Oncology Group study with translational biomarkers. PATIENTS AND METHODS: Patients with CIN 3 were randomized to celecoxib 400mg once daily (67 patients) or placebo (63 patients) for 14-18weeks. The primary outcome measure was histologic regression. A test of equal probabilities of success between two therapies was conducted, using Fisher's Exact Test at alpha=10% and 90% power when the treatment arm boosted the probability of success by 30%. Translational analysis included cervical tissue HPV genotyping, COX-2 expression in biopsies, and serum celecoxib and VEGF levels. RESULTS: In primary analysis, histologic regression was not significantly higher in the celecoxib group (40%) than in the placebo group (34.1%). However, exploratory analyses suggest patients with high serum VEGF levels exhibited greater regression in the celecoxib arm (47.3%) than in the placebo arm (14.3%). Regression rates were similar by treatment group in patients with low VEGF. VEGF levels increased over time in the placebo group, but remained the same in the treatment group. COX-2 expression in cervical biopsies declined from pre-treatment to the end of treatment with celecoxib; it did not change with placebo. CONCLUSIONS: Celecoxib at 400mg once daily for 14-18weeks did not significantly decrease the severity of CIN 3 compared with placebo except, possibly, in subjects with high baseline VEGF. Therefore, serum VEGF levels might identify patients who may benefit from celecoxib or other therapies, personalizing future chemoprevention trials for CIN 3.
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Celecoxib/uso terapêutico , Displasia do Colo do Útero/sangue , Displasia do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/sangue , Adolescente , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Celecoxib/sangue , Ciclo-Oxigenase 2/sangue , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/virologiaRESUMO
PURPOSE: Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. METHODS: Tumors were collected as part of the GOG 210 clinical trial "Molecular Staging of Endometrial Cancer" where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. RESULTS: Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p=0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p<0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p<0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177-3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096-3.696). CONCLUSION: In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted.
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Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Idoso , Carcinoma Endometrioide/patologia , Estudos de Coortes , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Neoplasias do Endométrio/patologia , Éxons , Feminino , Humanos , Estimativa de Kaplan-Meier , Estadiamento de NeoplasiasRESUMO
BACKGROUND: The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS: Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS: Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION: In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.
Assuntos
Antineoplásicos/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Epotilonas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Carcinossarcoma/química , Carcinossarcoma/radioterapia , Progressão da Doença , Intervalo Livre de Doença , Epotilonas/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Taxa de Sobrevida , Tubulina (Proteína)/análise , Moduladores de Tubulina/uso terapêutico , Neoplasias Uterinas/química , Neoplasias Uterinas/radioterapiaRESUMO
OBJECTIVE: This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). METHODS: Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age≥18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity. RESULTS: Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively. CONCLUSION: Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.
Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Leiomiossarcoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Azepinas/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento , Taxa de SobrevidaRESUMO
PURPOSE: Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. METHODS: Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21days for 6cycles. Pharmacokinetics of both agents were evaluated in cycle 1. RESULTS: Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose-limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5mg/m2), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5mg/m2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n=21) was 19% (1 complete, 3 partial). Cmax and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. CONCLUSION: IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Bortezomib/sangue , Bortezomib/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/sangue , Carboplatina/farmacocinética , Carcinoma Epitelial do Ovário , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Parenterais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Adulto JovemRESUMO
OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.
Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , MicroRNAs/biossíntese , Recidiva Local de Neoplasia/genética , Receptor Notch2/biossíntese , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Recidiva Local de Neoplasia/metabolismo , Receptor Notch2/genéticaRESUMO
PURPOSE: A simple measure to predict chemotherapy tolerance in elderly patients would be useful. We prospectively tested the association of baseline Instrumental Activities of Daily Living (IADL) score with ability to complete 4 cycles of first line chemotherapy without dose reductions or >7days delay in elderly ovarian cancer patients. PATIENTS AND METHODS: Patients' age ≥70 along with their physicians chose between two regimens: CP (Carboplatin AUC 5, Paclitaxel 135mg/m2) or C (Carboplatin AUC 5), both given every 3weeks either after primary surgery or as neoadjuvant chemotherapy (NACT) with IADL and quality of life assessments performed at baseline, pre-cycle 3, and post-cycle 4. RESULTS: Two-hundred-twelve women were enrolled, 152 selecting CP and 60 selecting C. Those who selected CP had higher baseline IADL scores (p<0.001). After adjusting for age and PS, baseline IADL was independently associated with the choice of regimen (p=0.035). The baseline IADL score was not found to be associated with completion of 4 cycles of chemotherapy without dose reduction or delays (p=0.21), but was associated with completion of 4 cycles of chemotherapy regardless of dose reduction and delay (p=0.008) and toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17% (OR: 0.83; 95%CI: 0.72-0.96; p=0.013) for each additional activity in which the patient was independent. After adjustment for chemotherapy regimen, IADL was also associated with overall survival (p=0.019) for patients receiving CP. CONCLUSION: Patients with a higher baseline IADL score (more independent) were more likely to complete 4 cycles of chemotherapy and less likely to experience grade 3 or higher toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologiaRESUMO
PURPOSE: Racial genetic admixture (RGA), a measure to account for ancestral genetic background that correlates with individual's racial classification, could provide insights on causation of racial disparity in endometrial cancer (EC). Our objective is to evaluate the association of RGA with EC outcomes. METHODS: EC patients enrolled onto the GOG-210 protocol were eligible. A randomized subcohort stratified by stage and self-reported race/ethnicity of black or white was used. Genotyping was performed using custom-selected Ancestry Informative Markers to calculate individual admixture estimates of African and European ancestral background. RESULTS: A total of 149 patients were evaluated (self-reported race: 70 black & 79 white). Mean RGA for African ancestry for self-reported black patients was 0.65 (range 0.04-0.86); while mean RGA for European ancestry for self-reported white patients was 0.77 (range 0.12-0.88). Progression-free survival (PFS) analysis using proportional hazards models stratified by stage and race revealed that each 0.10 increase in African ancestry was associated with worse PFS with hazard ratio (HR) of 1.11 (95% CI 0.90-1.37). Each 0.10 increase in European RGA was associated with improved PFS with HR of 0.86 (95% CI 0.69-1.07). Using tertiles of African RGA showed increasing risk of progression of death with increasing African RGA (with 0-5% as reference), HR (95% CIs) for top two tertiles are: 6%-66%: 1.38 (0.64, 2.97), and 67%-86%: 2.27 (0.74, 6.95). CONCLUSION: RGA demonstrated a trend with PFS in self-reported black and white patients with EC. Patients with increased levels of African ancestry showed a trend towards worse survival after stratifying by stage/race.
Assuntos
Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/genética , Idoso , População Negra , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , População BrancaRESUMO
OBJECTIVE: The aim of the study was to determine the differential expression patterns of the wingless-type (Wnt) pathway inhibitors Dkk3 (Dickkopf 3), SFRP1 (secreted frizzled-related protein 1), and SFRP4 in normal müllerian tissue and endometrial endometrioid adenocarcinoma specimens. METHODS: Messenger RNA (mRNA) and protein levels of the Wnt pathway inhibitors Dkk3, SFRP1, and SFRP4 were evaluated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. A total of 87 human tissue specimens were obtained from 60 women who participated in Gynecologic Oncology Group protocol 210. Twenty-seven normal müllerian tissues, 32 early-stage, and 28 advanced-stage endometrial endometrioid cancer specimens were analyzed. RESULTS: Median age for this cohort was 60 years, with median body mass index of 32 kg/m. There was a difference in Dkk3 protein expression between normal müllerian tissues and primary endometrial endometrioid adenocarcinoma samples (P = 0.05). There was down-regulation of Dkk3, SFRP1, and SFRP4 mRNA expression in patients with high-grade disease (P = 0.08, 0.06, and 0.05, respectfully). Furthermore, a decrease in SFRP1 and SFPR4 mRNA expression was noted in patients with a diagnosis of locoregional and distant disease recurrence. Lastly, a trend toward decreased progression-free survival in patients with low Dkk3, SFRP1, and SFRP4 mRNA expression levels was noted. CONCLUSIONS: Wnt pathway inhibitor (Dkk3, sFRP1, and/or sFRP4) expression was down-regulated in patients with high-grade disease and was associated with locoregional and distant disease recurrence. Despite sample size (power) limitations, these results support previous preclinical studies and may suggest a therapeutic role for Wnt signaling in endometrial cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Idoso , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Quimiocinas , Estudos de Coortes , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas , Via de Sinalização WntRESUMO
OBJECTIVE: Participation of minority populations in clinical trials is paramount to understanding and overcoming cancer racial disparities. The goal of this project is to evaluate minority participation in published GOG clinical trials. METHODS: GOG publications from 1985 to 2013 were reviewed. Minority enrollment was stratified by tumor site, type of study, and year published. Based on Centers of Disease Control and Prevention (CDC) age-adjusted incidence for race, expected and observed ratios of racial participation were calculated. RESULTS: A total of 445 GOG publications involving 67,568 patients were reviewed. Racial breakdown was provided in 170 studies (38%) for a total of 45,259 patients: 83% White (n=37,617); 8% Black (n=3,686), and 9% Other (n=3,956). The majority of studies were Ovarian (n=202) and Phase 2 (n=290). When evaluating the quartiles of publication year, a steady decline in the proportion of Black patients enrolled was seen. Race was not reported in any publication prior to 1994. Compared to years 1994-2002, a 2.8-fold lower proportion of black enrollment was noted in years 2009-2013 (16% and 5.8%, respectively; p<0.01). Utilizing CDC age-adjusted incidence, observed enrollment of Black patients onto GOG clinical trials was significantly less than expected enrollment. Observed Black enrollment was 15-fold lower than expected for ovarian trials, 10-fold lower for endometrial, 4.5-fold for cervix, and 5.2-fold for sarcoma (each p<0.001). CONCLUSIONS: Based on age-adjusted incidence, observed enrollment of Black patients was lower than expected enrollment onto GOG studies. Despite national emphasis on minority enrollment on clinical trials, fewer Black patients were enrolled over time.