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1.
N Engl J Med ; 388(23): 2145-2158, 2023 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-36972026

RESUMEN

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Recurrencia Local de Neoplasia , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Reparación de la Incompatibilidad de ADN , Método Doble Ciego , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos
2.
Int J Gynecol Cancer ; 34(7): 1041-1050, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38950925

RESUMEN

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.


Asunto(s)
Indazoles , Neoplasias Ováricas , Piperidinas , Supervivencia sin Progresión , Humanos , Femenino , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Piperidinas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano
3.
Int J Gynecol Cancer ; 33(11): 1807-1811, 2023 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-37813479

RESUMEN

BACKGROUND: Endometrial carcinomas can be classified into four molecular subgroups - mismatch repair deficient (MMRd), p53 abnormal (p53abn), polymerase-ϵ (POLE) ultramutated, and 'no specific molecular profile' (NSMP). Retrospective data imply that the response to adjuvant therapies may depend on the molecular subgroup. These findings emphasize the need for adjuvant therapy trials where patients are randomized to treatment arms separately within each molecular subgroup. PRIMARY OBJECTIVE: The PErsonalized TReatment for Endometrial Carcinoma (PETREC) trial clarifies the value of molecular classification in the determination of adjuvant therapies of high-intermediate risk and early-stage high-risk endometrial carcinoma. STUDY HYPOTHESIS: Compared with vaginal brachytherapy, the utilization of whole pelvic radiotherapy may result in improved outcomes for either MMRd or NSMP high-intermediate risk carcinomas. Early-stage high-risk p53abn and nonendometrioid carcinomas are postulated to gain benefits from chemoradiotherapy, as opposed to chemotherapy alone. POLE ultramutated carcinomas harboring high-intermediate or high-risk clinicopathologic features are speculated to have favorable prognosis without any adjuvant therapy. TRIAL DESIGN: This prospective, multicenter, phase 3 trial compares the efficacy of vaginal brachytherapy vs whole pelvic radiotherapy in high-intermediate risk MMRd and NSMP molecular subgroups, and chemotherapy vs chemoradiotherapy in early-stage high-risk p53abn subtype and nonendometrioid carcinomas. Eligible women who consent to participation in the trial are randomly allocated (1:1) to treatment arms. MAJOR INCLUSION/EXCLUSION CRITERIA: Women with stages I-II molecular integrated high-intermediate risk or high-risk endometrial carcinoma will be included. PRIMARY ENDPOINT: The primary endpoint is the 5 year cumulative incidence of disease recurrence. SAMPLE SIZE: A total sample size of 294 patients (49 subjects in each treatment arm of the three subgroups intended for randomization) was estimated to be sufficient. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed in 2025, and follow-up will be completed in 2030. TRIAL REGISTRATION: NCT05655260.


Asunto(s)
Carcinoma , Neoplasias Endometriales , Humanos , Femenino , Finlandia , Estudios Retrospectivos , Medicina de Precisión , Estudios Prospectivos , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Neoplasias Endometriales/patología , Carcinoma/patología
4.
Acta Obstet Gynecol Scand ; 102(3): 240-245, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36645194

RESUMEN

INTRODUCTION: The long-term risk of cancer among first-degree relatives of ovarian cancer patients, especially their offspring, is of apparent clinical importance. Risks caused by known inherited factors such as BRCA1 or BRCA2 pathogenic variants are well established, but these account for only about 15% of ovarian cancer cases. Less is known about the possible familial risks of sporadic ovarian cancers. MATERIAL AND METHODS: Using registry data, we conducted a retrospective cohort study with a total of 6501 first-degree relatives of 559 epithelial ovarian cancer patients. We studied the occurrence of overall cancer and cancer in specific sites known or suspected to be associated with ovarian cancer (breast, cervix, colon, endometrium, lung and trachea, skin melanoma, ovary, pancreas, prostate, rectum, and stomach). RESULTS: The overall number of cancers was not increased among the first-degree relatives of epithelial ovarian cancer patients during the up to 48 years of follow up. Among female relatives, the standardized incidence ratio for ovarian cancer was 1.92 (95% CI 1.27-2.79), mostly explained by a 2.30-fold (95% CI 1.46-3.45) risk among the patients' sisters. There was a decreasing trend in the standardized incidence ratio for ovarian cancer among patients' sisters by increasing age of the index patient. CONCLUSIONS: In our study cohort, we did not observe an increase in the overall cancer risk among the first-degree relatives of epithelial ovarian cancer patients in comparison with the general population. The risk for ovarian cancer, however, was increased. Current recommendations suggest prophylactic removal of the fallopian tubes and ovaries only with identified inherited risk factors. Our results emphasize the role of genetic counseling and testing, particularly in young ovarian cancer patients and their close female relatives.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Femenino , Humanos , Masculino , Carcinoma Epitelial de Ovario/epidemiología , Carcinoma Epitelial de Ovario/genética , Estudios de Cohortes , Estudios de Seguimiento , Genes BRCA1 , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Estudios Retrospectivos , Factores de Riesgo , Susceptibilidad a Enfermedades
5.
Gynecol Oncol ; 165(3): 478-485, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35397919

RESUMEN

OBJECTIVE: To compare survival rates of surgically treated advanced epithelial ovarian cancer patients before and after a programmatic change in surgical approach from standard surgery towards ultra-radical surgery. METHODS: 247 patients with FIGO stage IIIB-IV ovarian, tubal, and primary peritoneal carcinoma were operated during 2013-2019 either by primary or interval cytoreduction in Tampere University Hospital, Finland. Group 1 (n = 122) patients were operated during 2013 and February 2016. Group 2 patients (n = 125) were operated between March 2016 and March 2019, when a systematic change in surgical approach towards more extensive surgery was implemented. RESULTS: The complete resection (R0) rate increased significantly from 17.2% (21/122) to 52.0% (65/125) within the study period (p < 0.001). The median progression-free survival (PFS) was 15.6 months vs 19.3 months (p = 0.037), and the median overall survival (OS) was 33.5 months vs 54.5 months in Groups 1 and 2, respectively (p = 0.028). Median OS for stage III patients in Group 1 was 36.1 months (95% CI 27.4-44.8) but could not be reached in Group 2 (p = 0.009). In Stage IV patients, OS was 32.0 months (16.4-47.7) and 39.3 months (24.8-53.8) in Group 1 and 2, respectively (p = 0.691). Multivariable Cox regression analysis revealed that OS was independently affected by the amount of residual tumor and complication grade. CONCLUSIONS: The change of surgical approach towards maximal surgical effort improved both progression-free and overall survival. The survival benefit was unquestionable for stage III patients but did not reach statistical significance in stage IV patients.


Asunto(s)
Neoplasias Ováricas , Carcinoma Epitelial de Ovario/patología , Procedimientos Quirúrgicos de Citorreducción/métodos , Femenino , Humanos , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Estudios Retrospectivos , Centros de Atención Terciaria
6.
J Pathol ; 250(2): 159-169, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31595974

RESUMEN

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Familia de Aldehído Deshidrogenasa 1/metabolismo , Antineoplásicos/farmacología , Cistadenocarcinoma Seroso/patología , Células Madre Neoplásicas/patología , Neoplasias Ováricas/patología , Retinal-Deshidrogenasa/metabolismo , Aurora Quinasas/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/métodos , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Terapia Molecular Dirigida/métodos , Clasificación del Tumor , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Pronóstico , Esferoides Celulares/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Células Tumorales Cultivadas/efectos de los fármacos
7.
Acta Obstet Gynecol Scand ; 100(9): 1722-1729, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33797081

RESUMEN

INTRODUCTION: Hysterectomy has been one of the most common surgical procedures in women in Finland. We studied the population-based trends of hysterectomy and its indications from 1986 to 2017. MATERIAL AND METHODS: A retrospective population-based cohort was created from the Care Register for Health Care by identifying women who had a hysterectomy from 1986 to 2017 and calculating the number of women from the Digital and Population Data Services Agency. We estimated the number and incidence of hysterectomy by period and age as well as by indication. We considered the primary diagnosis at the time of surgery as the indication of hysterectomy. RESULTS: The number of hysterectomies increased from 7492 procedures in 1986 to 12 404 procedures in 1998, and reduced substantially after that to 5971 procedures in 2017, the turning point being in 1999. The incidence rate of hysterectomy has decreased on average by 2.5% annually from 432.6 per 100 000 women in 1998-2001 to 224.5 per 100 000 women in 2014-2017. The median age at the time of hysterectomy has increased from 51 years in 1998-2001 to 55 years in 2014-2017. The cumulative burden of hysterectomy by age of 60 years has nearly halved from the first 4-year period (23%) to the last (12%). After 2010, the most common indication has been genital prolapse and incontinence, whereas earlier it was uterine fibroids. CONCLUSIONS: The number and incidence of hysterectomies have fluctuated during the observation period 1986-2017 and decreased considerably during the past 17 years in Finland. This is probably a result of the availability of hormonal and other conservative treatment options for bleeding disorders and uterine fibroids. As hysterectomy practically removes the risk for endometrial cancer, the change in hysterectomy incidence over time emphasizes the importance of correcting endometrial cancer incidence according to hysterectomy incidence.


Asunto(s)
Histerectomía/tendencias , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Enfermedades de los Genitales Femeninos/epidemiología , Enfermedades de los Genitales Femeninos/cirugía , Humanos , Incidencia , Leiomioma/epidemiología , Leiomioma/cirugía , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Neoplasias Uterinas/epidemiología , Neoplasias Uterinas/cirugía , Adulto Joven
9.
Future Oncol ; : 1-18, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38990090

RESUMEN

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

10.
Oncology ; 94(4): 233-242, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29324448

RESUMEN

OBJECTIVE: The aim of this study was to characterize the expression of hydroxysteroid (17ß) dehydrogenase type 12 (HSD17B12), an enzyme involved in the synthesis of arachidonic acid (AA), in ovarian cancer, and to study its coexpression with its upstream and downstream enzymes in the AA pathway, namely elongation of very long chain fatty acids protein 5 (ELOVL5) and cyclooxygenase-2 (COX-2), respectively. MATERIALS AND METHODS: Samples from benign and malignant ovarian neoplastic lesions were immunohistochemically stained with HSD17B12, ELOVL5, and COX-2. The staining intensities were quantified with the QuantCenter program, and the results were confirmed with visual inspection. Statistical significances were calculated with the Student t test, the Mann-Whitney test, linear regression, or ANOVA. RESULTS: The expression of the HSD17B12, ELOVL5, and COX-2 enzymes increased according to the grade of the endometrioid ovarian adenocarcinomas. In contrast, in serous adenocarcinomas, staining with ELOVL5 was constantly weak, whereas the expression of HSD17B12 and COX-2 increased with the grade or FIGO stage of the cancer, respectively. CONCLUSIONS: The expression of HSD17B12 increased along with the severity of ovarian cancer, and the expression mimicked COX-2 expression and intensity. This further suggests the involvement of HSD17B12 in AA production, and its coexpression with COX-2 indicates a role for the enzyme in the increased prostaglandin production during ovarian cancer progression.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Adenocarcinoma/enzimología , Ciclooxigenasa 2/metabolismo , Neoplasias Ováricas/enzimología , Acetiltransferasas/metabolismo , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Elongasas de Ácidos Grasos , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/patología , Adulto Joven
11.
Eur J Nucl Med Mol Imaging ; 45(7): 1224-1232, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29476227

RESUMEN

OBJECTIVE: To evaluate the predictive potential of total metabolic tumor volume (MTV) reduction during neoadjuvant chemotherapy (NACT) with 18F-FDG-PET/CT in an advanced FIGO stage III/IV epithelial ovarian cancer (EOC) patient cohort. METHODS: Twenty-nine primarily inoperable EOC patients underwent 18F-FDG-PET/CT before and after NACT. The pre- and post-NACT total MTV, in addition to the percentage MTV reduction during NACT, were compared with primary therapy outcome and progression-free survival (PFS). ROC-analysis determined an optimal threshold for MTV reduction identifying patients with progressive or stable disease (PD/SD) at the end of primary therapy. A multivariate analysis with residual tumor (0/>0), FIGO stage (III/IV) and MTV reduction compared to PFS was performed. The association between MTV reduction and overall survival (OS) was evaluated. RESULTS: The median pre- and post-NACT total MTV were 352 cm3 (range 150 to 1322 cm3) and 51 cm3 (range 0 to 417 cm3), respectively. The median MTV reduction during NACT was 89% (range 24% to 100%). Post-NACT MTV and MTV reduction associated with primary therapy outcome (MTV post-NACT p = 0.007, MTV reduction p = 0.001) and PFS (MTV post-NACT p = 0.005, MTV reduction p = 0.005). MTV reduction <85% identified the PD/SD patients (sensitivity 70%, specificity 78%, AUC 0.79). In a multivariate analysis, MTV reduction (p = 0.002) and FIGO stage (p = 0.003) were statistically significant variables associated with PFS. MTV reduction during NACT corresponded to OS (p = 0.05). CONCLUSION: 18F-FDG-PET/CT is helpful in NACT response evaluation. Patients with total MTV reduction <85% during NACT might be candidates for second-line chemotherapy and clinical trials, instead of interval debulking surgery.


Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico por imagen , Terapia Neoadyuvante , Tomografía Computarizada por Tomografía de Emisión de Positrones , Carga Tumoral , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/terapia , Femenino , Fluorodesoxiglucosa F18 , Humanos , Persona de Mediana Edad , Imagen Multimodal , Tomografía de Emisión de Positrones , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
12.
Gynecol Oncol ; 149(1): 173-180, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29486992

RESUMEN

OBJECTIVE: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. METHODS: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. RESULTS: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P<0.001) of dying of EEC compared to the low-risk group. CONCLUSIONS: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities.


Asunto(s)
Asparaginasa/metabolismo , Autoantígenos/metabolismo , Carcinoma Endometrioide/metabolismo , Neoplasias Endometriales/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Asparaginasa/biosíntesis , Asparaginasa/genética , Autoantígenos/biosíntesis , Autoantígenos/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Supervivencia sin Enfermedad , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Análisis de Matrices Tisulares , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética
13.
Br J Cancer ; 116(4): 455-463, 2017 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-28118323

RESUMEN

BACKGROUND: Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. METHODS: Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). RESULTS: Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. CONCLUSIONS: Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Platino/uso terapéutico , Tamoxifeno/uso terapéutico , Carboplatino/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación , Calidad de Vida
14.
Tumour Biol ; 39(2): 1010428317691189, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28218038

RESUMEN

Primary chemotherapy treatment response monitoring in advanced epithelial ovarian cancer (EOC) is currently based on CT-imaging and serum CA125 values. Serum HE4 profile during first line chemotherapy has not been previously studied. We evaluated the HE4 profile during first line chemotherapy after primary (PDS) and interval debulking surgery (IDS). In total, 49 FIGO stage III/IV EOC patients were included in the study. 22 patients underwent PDS and 27 patients neoadjuvant chemotherapy (NACT) followed by IDS. Serial HE4 and CA125 serum samples were taken during first line chemotherapy. The association of postoperative tumor markers to surgery outcome, primary therapy outcome and progression free survival (PFS) were determined. The lowest HE4 and CA125 values during chemotherapy were compared to primary therapy outcome and PFS. The postoperative HE4 was associated to residual tumor after surgery (p = 0.0001), primary therapy outcome (p = 0.004) and PFS (p = 0.03) in all patients (n = 40). The postoperative CA125 was associated to PFS after IDS (n = 26, p = 0.006), but not after PDS. In multivariate analysis with FIGO stage (III/IV), residual tumor (0/>0) and postoperative CA125, the postoperative HE4 was the only statistically significant prognostic variable predicting PFS. Both HE4 and CA125 nadir corresponded to primary therapy outcome (HE4 p < 0.0001, CA125 p < 0.0001) and PFS (HE4 p = 0.009, CA125 p < 0.0001). HE4 is a promising candidate for EOC response monitoring. In our study, the performance of HE4 in response monitoring of first line chemotherapy was comparable to that of CA125. Of the postoperative values, only HE4 was statistically significantly associated to primary therapy outcome.


Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Proteínas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Ca-125/sangre , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Femenino , Fluorodesoxiglucosa F18 , Humanos , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Tomografía Computarizada por Tomografía de Emisión de Positrones , Cuidados Posoperatorios , Radiofármacos , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP
16.
Clin Chem ; 62(10): 1390-400, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27540033

RESUMEN

BACKGROUND: Measurement of serum cancer antigen 125 (CA125) is the standard approach for epithelial ovarian cancer (EOC) diagnostics and follow-up. However, the clinical specificity is not optimal because increased values are also detected in healthy controls and in benign diseases. CA125 is known to be differentially glycosylated in EOC, potentially offering a way to construct CA125 assays with improved cancer specificity. Our goal was to identify carbohydrate-reactive lectins for discriminating between CA125 originating from EOC and noncancerous sources. METHODS: CA125 from the OVCAR-3 cancer cell line, placental homogenate, and ascites fluid from patients with cirrhosis were captured on anti-CA125 antibody immobilized on microtitration wells. A panel of lectins, each coated onto fluorescent europium-chelate-doped 97-nm nanoparticles (Eu(+3)-NPs), was tested for detection of the immobilized CA125. Serum samples from high-grade serous EOC or patients with endometriosis and healthy controls were analyzed. RESULTS: By using macrophage galactose-type lectin (MGL)-coated Eu(+3)-NPs, an analytically sensitive CA125 assay (CA125(MGL)) was achieved that specifically recognized the CA125 isoform produced by EOC, whereas the recognition of CA125 from nonmalignant conditions was reduced. Serum CA125(MGL) measurement better discriminated patients with EOC from endometriosis compared to conventional immunoassay. The discrimination was particularly improved for marginally increased CA125 values and for earlier detection of EOC progression. CONCLUSIONS: The new CA125(MGL) assay concept could help reduce the false-positive rates of conventional CA125 immunoassays. The improved analytical specificity of this test approach is dependent on a discriminating lectin immobilized in large numbers on Eu(+3)-NPs, providing both an avidity effect and signal amplification.


Asunto(s)
Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Inmunoensayo/métodos , Lectinas/química , Nanopartículas/química , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Ováricas/sangre , Adulto , Biomarcadores de Tumor/química , Antígeno Ca-125/química , Carcinoma Epitelial de Ovario , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven
17.
Gynecol Oncol ; 140(1): 29-35, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26515076

RESUMEN

OBJECTIVE: The aim of this study was to examine the relationship between the reduction of maximum standardized uptake values (SUVmax) in 18F-FDG-PET/CT to histopathological changes obtained with neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (EOC). We wanted to evaluate whether 18F-FDG-PET/CT is useful for identifying patients who will not respond to NACT and would therefore benefit from second-line chemotherapy instead of interval debulking surgery (IDS). METHODS: Twenty-six primarily inoperable EOC patients treated with NACT were enrolled in this study. 18F-FDG-PET/CT imaging was performed before diagnostic laparoscopy and after three to four NACT cycles. The relationship between the decrease in omental SUVmax from before to after NACT with omental histopathological response was examined in samples taken from the corresponding anatomical sites during IDS. Patients were divided into three groups according to chemotherapy-induced histopathological changes. Serum CA125 and HE4 halftimes during NACT as well as Ki-67 antigen expression in IDS samples were determined. RESULTS: The median omental SUVmax change during NACT was -64% (range-16% to -84%), and it was associated with histopathological response (p=0.004, OR 0.9, CI 0.84-0.97). A SUVmax decrease of less than 57% identified histopathological non-responders. Progression-free survival (PFS) differed between the poor, moderate and good histopathological response groups (0.9 year vs. 1.2 years vs. 1.4 years, respectively, p=0.05). The SUVmax change was not associated with PFS. CONCLUSION: 18F-FDG-PET/CT was able to identify patients who would not respond to NACT. To obtain a histopathological response in EOC, a substantial metabolic response in 18F-FDG-PET/CT is necessary.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/análisis , Neoplasias Glandulares y Epiteliales/diagnóstico por imagen , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/tratamiento farmacológico , Radiofármacos/análisis , Anciano , Carcinoma Epitelial de Ovario , Quimioterapia Adyuvante , Femenino , Humanos , Modelos Estadísticos , Imagen Multimodal/métodos , Terapia Neoadyuvante , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/cirugía , Compuestos Organoplatinos/administración & dosificación , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Tomografía de Emisión de Positrones/métodos , Análisis de Regresión , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos
18.
Gynecol Oncol ; 137(3): 529-37, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25858696

RESUMEN

OBJECTIVE: For endometrial carcinoma, prognostic stratification methods do not satisfactorily identify patients with adverse outcome. Currently, histology, tumor grade and stage are used to tailoring surgical treatment and to determine the need for adjuvant treatment. Low-risk patients are not considered to require adjuvant therapy or staging lymphadenectomy. For patients with intermediate or high risk, some guidelines recommend tailoring adjuvant treatment according to additional negative prognostic factors. Our objective was to evaluate the biomarker potential of the ASRGL1 protein in endometrial carcinoma. METHODS: Using The Human Protein Atlas (www.proteinatlas.org), the l-asparaginase (ASRGL1) protein was identified as an endometrial carcinoma biomarker candidate. ASRGL1 expression was immunohistochemically evaluated with an extensively validated antibody on two independent endometrial carcinoma cohorts (n=229 and n=286) arranged as tissue microarrays. Staining results were correlated with clinical features. RESULTS: Reduced expression of ASRGL1, defined as <75% positively stained tumor cells, was significantly associated with poor prognosis and reduced disease-specific survival in endometrioid endometrial adenocarcinoma (EEA). In multivariate analysis the hazard ratios for disease-specific survival were 3.55 (95% CI=1.10-11.43; p=0.003) and 3.23 (95% CI=1.53-6.81; p=0.002) in the two cohorts, respectively. Of the 48 cases with Grade 3 Stage I tumor all disease-related deaths were associated with low ASRGL1 expression. CONCLUSIONS: Loss of ASRGL1 in EEA is a powerful biomarker for poor prognosis and retained ASRGL1 has a positive impact on survival. ASRGL1 immunohistochemistry has potential to become an additional tool for prognostication in cases where tailoring adjuvant treatment according to additional prognostic factors besides grade and stage is recommended.


Asunto(s)
Asparaginasa/biosíntesis , Autoantígenos/biosíntesis , Biomarcadores de Tumor/biosíntesis , Carcinoma Endometrioide/enzimología , Neoplasias Endometriales/enzimología , Anciano , Asparaginasa/deficiencia , Carcinoma Endometrioide/patología , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Endometriales/patología , Femenino , Humanos , Inmunohistoquímica , Pronóstico , Estudios Retrospectivos
20.
Tumour Biol ; 35(12): 12389-95, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25190018

RESUMEN

Human epididymis protein 4 (HE4) is a novel tumour marker in epithelial ovarian cancer (EOC). Data on its profile and predictive potential for subsequent outcome after neoadjuvant chemotherapy (NACT) are still under investigation. The aim of this study was to compare CA125 and HE4 profiles with radiologic response after NACT and to evaluate their potential as predictors of clinical outcome in a primarily inoperable EOC patient cohort. Twenty-five EOC patients of high-grade subtype (HGSC) treated with NACT were enrolled in the study. Serum HE4 and CA125 samples were taken at the time of diagnosis and before interval debulking surgery (IDS). Pre-NACT and pre-IDS HE4 and CA125 and their percentage changes were compared with NACT response seen on CT and surgical outcome in IDS. We also evaluated the biomarkers' abilities to predict platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). All 25 patients were considered inoperable in laparoscopy at the time of diagnosis. HE4 and CA125 changes during NACT did not correlate with the changes seen on CT. Surgical outcome in IDS was associated with pre-IDS biomarker values but not with those taken before diagnosis. In IDS, 87 % had <1-cm residual tumour. In patients with HE4 change >80 and <80 % during NACT, the median OS was 3.38 and 1.60 years (p = 0.01), respectively. Serum HE4 is a promising additional tool when evaluating advanced HGSC patient's response to NACT. It may be helpful when deciding whether to proceed to IDS or to second-line chemotherapy.


Asunto(s)
Biomarcadores de Tumor , Antígeno Ca-125/sangre , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Proteínas/metabolismo , Carcinoma Epitelial de Ovario , Quimioterapia Adyuvante , Cistadenocarcinoma Seroso/sangre , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Femenino , Estudios de Seguimiento , Humanos , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Pronóstico , Resultado del Tratamiento , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP
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