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1.
CA Cancer J Clin ; 69(4): 258-279, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31074865

RESUMEN

Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite-instable, metastatic disease, anti- programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.


Asunto(s)
Neoplasias Endometriales/terapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Procedimientos Quirúrgicos de Citorreducción , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Histerectomía , Escisión del Ganglio Linfático , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/terapia , Pronóstico , Radioterapia Adyuvante , Factores de Riesgo , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/cirugía
2.
Future Oncol ; 19(25): 1709-1714, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37381977

RESUMEN

WHAT IS THIS SUMMARY ABOUT?: Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study. WHAT WERE THE RESULTS?: The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. WHAT DO THE RESULTS MEAN?: The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias Endometriales , Humanos , Femenino , Pacientes , Lenguaje
3.
Br J Cancer ; 124(3): 567-569, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33106582

RESUMEN

Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.


Asunto(s)
Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/patología , Personas Transgénero , Adolescente , Agentes Anticonceptivos Hormonales/administración & dosificación , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/cirugía , Femenino , Humanos , Masculino , Acetato de Noretindrona/administración & dosificación , Neoplasias Ováricas/química , Neoplasias Ováricas/cirugía , Receptores Androgénicos/análisis , Salpingooforectomía
4.
Gynecol Oncol ; 158(2): 467-475, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32507650

RESUMEN

Ovarian germ cell tumors (GCTs) are rare in adults, but are more common in adolescents and young adults. Contemporary management of ovarian GCTs is evolving as collaboration among pediatric, medical, and gynecologic oncologists increases, and studies increasingly incorporate female adult patients. Despite an improved understanding of ovarian GCT, many questions remain. Areas of continued controversy include which stage I ovarian GCTs and immature teratomas can be observed without adjuvant therapy, appropriate risk classification for ovarian GCT, surveillance strategies, and optimal therapy for recurrence. These topics as well as active areas of clinical investigation are discussed.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Teratoma/diagnóstico , Teratoma/terapia
5.
Gynecol Oncol ; 156(2): 488-497, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31630846

RESUMEN

PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Animales , Proteína BRCA1/genética , Proteína BRCA2/genética , Reparación del ADN , Femenino , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Humanos , Neoplasias Ováricas/genética , Ensayos Clínicos Controlados Aleatorios como Asunto
6.
Gynecol Oncol ; 153(3): 471-478, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30935717
7.
Gynecol Oncol ; 154(2): 314-322, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31204078

RESUMEN

OBJECTIVE: Patients with advanced/recurrent epithelial ovarian and uterine cancers have limited treatment options beyond platinum chemotherapy. Both tumor types can express programmed death-ligand 1 (PD-L1), providing a potential therapeutic target for these patients. Here we present data from the ovarian and uterine cancer cohorts of the Phase I atezolizumab monotherapy study (PCD4989g). METHODS: This Phase I, multi-center, first-in-human, open-label, dose-escalation/expansion clinical trial investigated single-agent atezolizumab in cohorts of patients with recurrent epithelial ovarian or uterine cancer. The primary objective was to evaluate the safety and tolerability of single-agent atezolizumab. Anti-tumor activity and preliminary assessment of potential biomarkers were evaluated as secondary and exploratory objectives, respectively. RESULTS: The ovarian and uterine cancer cohorts enrolled 12 and 15 patients, respectively (10 [83%] and 5 [33%], respectively, had PD-L1 ≥ 5% on tumor-infiltrating immune cells). Atezolizumab was generally well tolerated with no new safety signals identified. The safety profiles in both cohorts were consistent with the known profile of atezolizumab monotherapy. Treatment-related adverse events (AEs) were mostly Grade ≤ 2, with no treatment-related Grade ≥ 4 AEs reported. Preliminary anti-tumor activity, with long durations of response, was observed in 2 patients from each cohort (ovarian cancer, 8.1 and 30.6+ months; uterine cancer, 7.3 and 16.6+ months). High microsatellite instability and tumor mutational burden were noted in the responders from the uterine cancer cohort. CONCLUSIONS: Atezolizumab monotherapy was well tolerated in patients with epithelial ovarian or uterine cancer and may have clinical activity warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01375842.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Biomarcadores de Tumor , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1 , Adulto Joven
8.
Int J Gynecol Cancer ; 29(2): 357-364, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30683758

RESUMEN

OBJECTIVE: High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status. METHODS: Whole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis. RESULTS: Combined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed. CONCLUSIONS: Increased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.

9.
Gynecol Oncol ; 147(3): 672-677, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28927900

RESUMEN

BACKGROUND: Glucocorticoid receptor (GR) has emerged as an important steroid nuclear receptor in hormone dependent cancers, however few data are available regarding a potential role of GR in endometrial cancer. The aim of this study was to investigate expression of GR in primary and metastatic endometrial cancer lesions, and to assess the relationship between GR expression and clinical and histopathological variables and survival. METHODS: Expression of GR was investigated by IHC in 724 primary tumors and 289 metastatic lesions (from 135 patients), and correlations with clinical and histopathological data and survival were explored. RESULTS: Expression of GR was significantly increased in non-endometrioid tumors compared to endometrioid tumors, and was associated with markers of aggressive disease and poor survival both in univariate and multivariate analysis after correcting for age, FIGO stage and histologic grade. Within the subgroups of hormone receptor negative tumors (loss of androgen receptor, estrogen receptor or progesterone receptor) expression of GR was highly significantly associated with poor disease specific survival. There was an overall increase in GR expression from primary to metastatic lesions, and the majority of metastases expressed GR. CONCLUSION: GR expression in primary endometrial cancer is associated with aggressive disease and poor survival. The majority of metastatic endometrial cancer lesions express GR; therefore GR may represent a therapeutic target in the adjuvant therapy of poor prognosis early-stage as well as metastatic endometrial cancer.


Asunto(s)
Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Receptores de Glucocorticoides/biosíntesis , Anciano , Progresión de la Enfermedad , Neoplasias Endometriales/genética , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Transcriptoma
10.
Gynecol Oncol ; 146(1): 153-160, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28456378

RESUMEN

OBJECTIVE: To investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer. METHODS: GR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells. Analyses were performed to evaluate the relationship of GR expression with clinical characteristics, progression-free survival (PFS) and overall survival (OS). RESULTS: GR protein was highly expressed in 133 of 341 (39.0%) tumors from patients who underwent upfront cytoreduction surgery followed by adjuvant chemotherapy. High GR expression was more common in serous tumors (p<0.001), high grade tumors (p<0.001), and advanced stage tumors (p=0.037). Median PFS was significantly decreased in cases with high GR (20.4months) compared to those with low GR (36.0months, HR=1.66, 95% CI 1.29-2.14, p<0.001). GR remained an independent prognostic factor for PFS in multivariate analysis. OS was not associated with GR status. CONCLUSIONS: These data suggest that high GR expression correlates with poor prognosis and support the hypothesis that modulating GR activity in combination with chemotherapy may improve outcomes.


Asunto(s)
Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Receptores de Glucocorticoides/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Pronóstico , Tasa de Supervivencia , Adulto Joven
11.
J Gynecol Oncol ; 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38909640

RESUMEN

OBJECTIVE: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). METHODS: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA (NR3C1) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. RESULTS: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. CONCLUSION: The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

12.
Clin Cancer Res ; 30(9): 1739-1749, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38456660

RESUMEN

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.


Asunto(s)
Compuestos de Anilina , Mutación , Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Piridonas , Pirimidinonas , Sulfonamidas , Proteína bcl-X , Humanos , Femenino , Piridonas/administración & dosificación , Piridonas/efectos adversos , Piridonas/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/uso terapéutico , Pirimidinonas/administración & dosificación , Pirimidinonas/efectos adversos , Anciano , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/genética , Adulto , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , GTP Fosfohidrolasas/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento
13.
Cancer Metastasis Rev ; 31(3-4): 605-13, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22706843

RESUMEN

Host tissue microenvironment plays key roles in cancer progression and colonization of secondary organs. One example is ovarian cancer, which colonizes the peritoneal cavity and especially the omentum. Our research indicates that the interaction of ovarian cancer cells with the omental microenvironment can activate a stress-kinase pathway involving the mitogen-activated protein kinase kinase 4 (MKK4). A combination of clinical correlative and functional data suggests that MKK4 activation suppresses growth of ovarian cancer cells lodged in omentum. These findings prompted us to turn our focus to the cellular composition of the omental microenvironment and its role in regulating cancer growth. In this review, in addition to providing an overview of MKK4 function, we highlight a use for metastasis suppressors as a molecular tool to study cancer cell interaction with its microenvironment. We review features of the omentum that makes it a favorable microenvironment for metastatic colonization. In conclusion, a broader, evolutionary biology perspective is presented which we believe needs to be considered when studying the evolution of cancer cells within a defined microenvironment. Taken together, this approach can direct new multi-dimensional lines of research aimed at a mechanistic understanding of host tissue microenvironment, which could be used to realize novel targets for future research.


Asunto(s)
MAP Quinasa Quinasa 4/fisiología , Metástasis de la Neoplasia/prevención & control , Microambiente Tumoral , Proteínas Supresoras de Tumor/fisiología , Animales , Femenino , Humanos , Metástasis de la Neoplasia/patología , Neoplasias Ováricas/patología
14.
Clin Cancer Res ; 29(22): 4564-4574, 2023 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-37363992

RESUMEN

PURPOSE: This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. PATIENTS AND METHODS: A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). RESULTS: A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. CONCLUSIONS: Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Endometriales , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Colorrectales/patología , Inestabilidad de Microsatélites , Biomarcadores de Tumor/genética , Reparación de la Incompatibilidad de ADN
15.
JAMA Netw Open ; 6(11): e2341165, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37917058

RESUMEN

Importance: Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor. Objective: To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors. Design, Setting, And Participants: The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months. Interventions: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. Main Outcomes and Measures: The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results: The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified. Conclusions And Relevance: In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need. Trial Registration: ClinicalTrials.gov Identifier: NCT02715284.


Asunto(s)
Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales , Humanos , Femenino , Persona de Mediana Edad , Masculino , Recurrencia Local de Neoplasia
16.
Int J Cancer ; 130(3): 509-20, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21351092

RESUMEN

Metastatic dissemination in prostate cancer is often early, but not all cancer cells form clinical metastases. Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model. We hypothesize that MKK4 will specifically inhibit metastatic colonization through impaired proliferation. Three highly metastatic rat prostate cancer cell lines (AT6.1, Mat-Lu and AT3.1) were employed. Stably over-expressing HA-MKK4 or vector control lines were injected into immunocompromised mice. These experiments validated that HA-MKK4 specifically affects metastatic colonization and increases survival. Median survival (days) with HA-MKK4 vs. vector was 42 vs. 28 (p < 0.0001) for AT6.1, 25 vs. 19 (p < 0.0001) for Mat-Lu and 27 vs. 20 (p < 0.0001) for AT3.1. HA-MKK4 suppresses colonization within 14 days post dissemination, after which exponential proliferation resumes. Although overt metastases retain HA-MKK4, it is inactive within these lesions. Nonetheless, metastasis-derived cell lines were shown to retain functional HA-MKK4 and like their parental HA-MKK4 line are suppressed for experimental metastasis formation in vivo. Disseminated AT6.1-HA-MKK4 cells were analyzed and were found to have an alteration in cell cycle. Specifically, there was an accumulation of cells in G1-phase (p = 0.024) and decrease in S-phase (p = 0.037) compared with vector. In multiple prostate cancer lines, HA-MKK4 suppresses an early step in metastatic colonization. These data support a model in which MKK4 activation at the metastatic site causes a cell-cycle arrest, which is eventually overcome despite presence of functional HA-MKK4. Further studies will specifically interrogate the regulation of MKK4 activation within the metastatic microenvironment and the down-stream molecular events critical for metastasis suppression.


Asunto(s)
Puntos de Control del Ciclo Celular , MAP Quinasa Quinasa 4/metabolismo , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Animales , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Fase G1/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , MAP Quinasa Quinasa 4/genética , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Ratas , Carga Tumoral/genética
17.
Eur J Cancer ; 173: 59-70, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35863107

RESUMEN

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference.


Asunto(s)
Tumor del Seno Endodérmico , Neoplasias de Células Germinales y Embrionarias , Neoplasias Ováricas , Teratoma , Adulto , Niño , Conferencias de Consenso como Asunto , Tumor del Seno Endodérmico/tratamiento farmacológico , Tumor del Seno Endodérmico/terapia , Femenino , Humanos , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/terapia , Teratoma/tratamiento farmacológico , Teratoma/terapia
18.
Clin Lung Cancer ; 23(7): e415-e427, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35729005

RESUMEN

BACKGROUND: Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284). MATERIALS AND METHODS: Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety. RESULTS: As of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients. CONCLUSION: Dostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ensayos Clínicos Fase I como Asunto
19.
J Immunother Cancer ; 10(1)2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35064011

RESUMEN

BACKGROUND: Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. METHODS: GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. RESULTS: Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. CONCLUSION: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT02715284.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores de Tumor/metabolismo , Reparación de la Incompatibilidad de ADN/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Inestabilidad de Microsatélites/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Humanos , Persona de Mediana Edad
20.
J Clin Oncol ; 39(14): 1531-1539, 2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33705205

RESUMEN

PURPOSE: Uterine serous carcinoma (USC) is a distinct histologic subtype of endometrial cancer, with molecular characteristics suggesting frequent cell-cycle dysregulation paired with a high level of oncogene-driven replication stress. Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with impaired cell-cycle regulation and high replication stress may be vulnerable to WEE1 inhibition, we conducted this study to assess the activity of adavosertib monotherapy in women with recurrent USC. PATIENTS AND METHODS: This was a single-arm two-stage phase II study with coprimary end points of objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6). Women with recurrent USC were treated with adavosertib monotherapy at a starting dose of 300 mg orally once daily days 1 through 5 and 8 through 12 of a 21-day cycle until disease progression. RESULTS: In 34 evaluable patients, 10 total responses (one confirmed complete response, eight confirmed partial responses, and one unconfirmed partial response) were observed with adavosertib monotherapy, for an ORR of 29.4% (95% CI, 15.1 to 47.5). Sixteen patients were progression-free at 6 months, for a PFS6 rate of 47.1% (95% CI, 29.8 to 64.9). Median PFS was 6.1 months, and median duration of response was 9.0 months. Frequent treatment-related adverse events (AEs) included diarrhea (76.5%), fatigue (64.7%), nausea (61.8%), and hematologic AEs. No clear correlation of clinical activity with specific molecular alterations was observed in an exploratory biomarker analysis. CONCLUSION: Adavosertib monotherapy demonstrated encouraging and durable evidence of activity in women with USC, and further investigation of this agent in this cancer and biomarkers of activity are indicated.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Cistadenocarcinoma Seroso/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/uso terapéutico , Pirimidinonas/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidad , Femenino , Genes BRCA1 , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Pirazoles/efectos adversos , Pirimidinonas/efectos adversos , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidad
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