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1.
Gynecol Oncol ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33934848

RESUMO

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.

2.
Int J Gynecol Cancer ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931498

RESUMO

OBJECTIVE: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab. METHODS: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m2) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints. RESULTS: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported. CONCLUSIONS: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors. TRIAL REGISTRATION NUMBER: EudraCT 2012-003043-29; NCT01706120.

3.
Lancet Oncol ; 22(5): 632-642, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862001

RESUMO

BACKGROUND: In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. METHODS: SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. FINDINGS: Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. INTERPRETATION: The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. FUNDING: AstraZeneca and Merck Sharp & Dohme.

4.
J Clin Oncol ; : JCO2100306, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33891472

RESUMO

PURPOSE: To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). METHODS: This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1-positive populations. RESULTS: Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1-positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). CONCLUSION: Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.

5.
Int J Gynecol Cancer ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893147

RESUMO

INTRODUCTION: Several biomarkers have been proposed for the detection of recurrences in adult-type granulosa cell tumors of the ovary. Here we validate the value of inhibin B in detecting recurrences and investigate its role in guiding follow-up examinations and treatment strategies in postmenopausal patients with ovarian adult-type granulosa cell tumors. METHODS: Data from 140 patients with a diagnosis of adult-type granulosa cell tumor of the ovary referred to the European Institute of Oncology of Milan from January 1996 to March 2016 were retrospectively collected. Among these, we selected data from 47 postmenopausal women for whom serial inhibin B measurements and related imaging examinations were performed according to the follow-up program, with a total of 315 serum inhibin B samples, together with the corresponding clinical examination, and 180 imaging examinations, confirming the presence or absence of macroscopic disease. RESULTS: At a cut-off of 7 pg/mL, inhibin B levels were significantly correlated with the presence/absence of disease (p<0.01), with a sensitivity of 98.8% (95% confidence interval (CI) 95.8% to 99.9%) and a specificity of 88.9% (95% CI 82.6% to 93.5%). Further, inhibin B was positively correlated with the size of the lesion, and levels were significantly higher in patients with larger lesions also at a cut-off size of 3 cm (total diameter). Logistic regression showed that 15.6 pg/mL, 44.6 pg/mL, and 73.6 pg/mL inhibin B corresponded to 25%, 50%, and 75% probability of having an abnormal computer tomography scan, respectively. CONCLUSIONS: Our results confirmed that inhibin B is a sensitive and specific marker for adult-type granulosa cell tumors of the ovary that may be used during follow-up for detection of recurrences. Moreover, it could guide clinicians in the decision regarding when to perform imaging, avoiding redundant interventional tests in the absence of clinical suspicion.

6.
Radiother Oncol ; 154: 327-353, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33712263

RESUMO

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.


Assuntos
Neoplasias do Endométrio , Guias como Assunto , Radioterapia (Especialidade) , Consenso , Neoplasias do Endométrio/radioterapia , Europa (Continente) , Feminino , Humanos , Fatores de Risco
7.
Virchows Arch ; 478(2): 153-190, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33604759

RESUMO

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.


Assuntos
Carcinoma/terapia , Neoplasias do Endométrio/terapia , Oncologia/normas , Biomarcadores Tumorais/genética , Biópsia/normas , Carcinoma/genética , Carcinoma/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Medicina Baseada em Evidências/normas , Feminino , Humanos , Técnicas de Diagnóstico Molecular/normas , Estadiamento de Neoplasias/normas , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Resultado do Tratamento
8.
Lancet Oncol ; 22(2): 267-276, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33539744

RESUMO

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carboplatina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem
9.
Int J Gynecol Cancer ; 31(1): 12-39, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33397713

RESUMO

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

10.
Int J Gynecol Cancer ; 31(4): 617-622, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33318079

RESUMO

BACKGROUND: Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity. PRIMARY OBJECTIVE: To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months. TRIAL DESIGN: The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1. PRIMARY ENDPOINT: The primary endpoint for this study is progression free survival. SAMPLE SIZE: Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023. TRIAL REGISTRATION: Clinicaltrials.gov NCT03598270.

11.
Int J Cancer ; 148(1): 170-177, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32856727

RESUMO

We investigated the occurrence and management of therapy-related hematological disorders (tr-HDs) in women with epithelial ovarian cancer (EOC) exposed to poly-ADP-ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr-HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr-HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow-up, the actual risk of tr-HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.

13.
J Natl Cancer Inst ; 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33372675

RESUMO

BACKGROUND: PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane-based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening. METHODS: tBRCA was tested on FFPE tumor blocks on 5 French platforms using 2 Next-Generation Sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms. RESULTS: From May 2015 to July 2017, tBRCA tests were performed for 1,176 screened patients. Only 52 (4.4%) tumor samples were non-contributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range =8-260). A pathogenic variant (PV) was reported in 27.1% tumor samples (319 of 1,176 screened patients). tBRCA and gBRCA testing were both performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only one large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of PV (29 of 451) not detected by gBRCA testing. CONCLUSIONS: tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from PARPi therapy.

14.
Clin Epigenetics ; 12(1): 180, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228781

RESUMO

BACKGROUND: The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host's epigenome is largely unexplored. RESULTS: Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77-0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities. CONCLUSIONS: These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.

16.
Gynecol Oncol ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33077259

RESUMO

OBJECTIVE: advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial. METHODS: Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used. RESULTS: Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12-2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17-0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14-3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage. CONCLUSIONS: Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse.

17.
Genome Med ; 12(1): 94, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33121525

RESUMO

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The remaining uncertainty on its originating tissue has hampered the discovery of molecular oncogenic pathways and the development of effective therapies. METHODS: We used an approach based on the retention in tumors of a DNA methylation trace (OriPrint) that distinguishes the two putative tissues of origin of HGSOC, the fimbrial (FI) and ovarian surface epithelia (OSE), to stratify HGSOC by several clustering methods, both linear and non-linear. The identified tumor subtypes (FI-like and OSE-like HGSOC) were investigated at the RNAseq level to stratify an in-house cohort of macrodissected HGSOC FFPE samples to derive overall and disease-free survival and identify specific transcriptional alterations of the two tumor subtypes, both by classical differential expression and weighted correlation network analysis. We translated our strategy to published datasets and verified the co-occurrence of previously described molecular classification of HGSOC. We performed cytokine analysis coupled to immune phenotyping to verify alterations in the immune compartment associated with HGSOC. We identified genes that are both differentially expressed and methylated in the two tumor subtypes, concentrating on PAX8 as a bona fide marker of FI-like HGSOC. RESULTS: We show that: - OriPrint is a robust DNA methylation tracer that exposes the tissue of origin of HGSOC. - The tissue of origin of HGSOC is the main determinant of DNA methylation variance in HGSOC. - The tissue of origin is a prognostic factor for HGSOC patients. - FI-like and OSE-like HGSOC are endowed with specific transcriptional alterations that impact patients' prognosis. - OSE-like tumors present a more invasive and immunomodulatory phenotype, compatible with its worse prognostic impact. - Among genes that are differentially expressed and regulated in FI-like and OSE-like HGSOC, PAX8 is a bona fide marker of FI-like tumors. CONCLUSIONS: Through an integrated approach, our work demonstrates that both FI and OSE are possible origins for human HGSOC, whose derived subtypes are both molecularly and clinically distinct. These results will help define a new roadmap towards rational, subtype-specific therapeutic inroads and improved patients' care.

18.
Eur J Cancer ; 139: 59-67, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32977221

RESUMO

BACKGROUND: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. METHODS: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). RESULTS: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. CONCLUSIONS: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.

19.
Eur J Cancer ; 139: 149-168, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32992154

RESUMO

BACKGROUND: Uterine sarcomas are very rare tumours with different histotypes, molecular features and clinical outcomes; therefore, it is difficult to carry out prospective clinical trials, and this often results in heterogeneous management of patients in the clinical practice. AIM: We planned to set up an Italian consensus conference on these diseases in order to provide recommendations on treatments and quality of care in our country. RESULTS: Early-stage uterine sarcomas are managed by hysterectomy + bilateral salpingo-oophorectomy according to menopausal status and histology; lymphadenectomy is not indicated in patients without bulky nodes, and morcellation must be avoided. The postoperative management is represented by observation, even though chemotherapy can be considered in some high-risk patients. In early-stage low-grade endometrial stromal sarcoma and adenosarcomas without sarcomatous overgrowth, hormonal adjuvant treatment can be offered based on hormone receptor expression. In selected cases, external beam radiotherapy ± brachytherapy can be considered to increase local control only. Patients with advanced disease involving the abdomen can be offered primary chemotherapy (or hormonal therapy in the case of low-grade endometrial stromal sarcoma and adenosarcoma without sarcomatous overgrowth), even if potentially resectable in the absence of residual disease in order to test the chemosensitivity (or hormonosensitivity); debulking surgery can be considered in patients with clinical and radiological response. Chemotherapy is based on anthracyclines ± ifosfamide or dacarbazine. Palliative radiotherapy can be offered for symptom control, and stereotactic radiotherapy can be used for up to five isolated metastatic lesions. CONCLUSIONS: Treatment of uterine sarcoma should be centralised at referral centres and managed in a multidisciplinary setting.

20.
Clin Sarcoma Res ; 10: 17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32874547

RESUMO

Background: Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers. Methods: In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017. Results: A total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regimen, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30-0.80; P = 0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed. Conclusions: DFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemotherapy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS.

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