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1.
Gynecol Oncol ; 189: 90-97, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39068739

RESUMEN

OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.


Asunto(s)
Vacunas contra el Cáncer , Carcinoma Epitelial de Ovario , Receptor 1 de Folato , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Neoplasias Ováricas , Humanos , Femenino , Receptor 1 de Folato/inmunología , Persona de Mediana Edad , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/terapia , Anciano , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/terapia , Método Doble Ciego , Adulto , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/efectos adversos , Supervivencia sin Progresión , Anciano de 80 o más Años
2.
Int J Gynecol Cancer ; 34(8): 1119-1125, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38858103

RESUMEN

OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos , Receptor 1 de Folato , Inmunoconjugados , Maitansina , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Receptor 1 de Folato/metabolismo , Persona de Mediana Edad , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Maitansina/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Anciano de 80 o más Años
3.
Cancer Immunol Immunother ; 72(1): 183-191, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35779095

RESUMEN

BACKGROUND: To characterize the safety, immunogenicity, and outcomes of patients with high-grade serous ovarian cancer (HGSOC) in second or greater remission treated with a polyvalent antigen-KLH plus OPT-821 vaccine construct and bevacizumab. METHODS: Patients with recurrent HGSOC were treated with the vaccine plus bevacizumab at our institution from 01/05/2011 to 03/20/2012. Follow-up continued until 03/2021. Blood/urine samples were collected. "Responders" had an immunogenic response to ≥ 3 antigens; "non-responders" to ≤ 2 antigens. RESULTS: Twenty-one patients were treated on study. One developed a dose-limiting toxicity (grade 4 fever). Two (10%) experienced bevacizumab-related grade 3 hypertension. Thirteen (68%) and 16 (84%) of 19 responded to ≥ 3 and ≥ 2 antigens, respectively (Globo-H, GM2, TF cluster Tn, MUC-1). Four of 21 patients were alive > 5 years post-treatment. Responders and non-responders had a median PFS of 4.9 months (95% CI: 2.8-8.1) and 5.0 months (95% CI: 0.7-cannot estimate), respectively; median OS was 30.7 months (95% CI: 16.9-52.0) and 34.2 months (95% CI: 12.8-cannot estimate), respectively. On two-timepoint analysis (baseline, week 17), increased IL-8 exhibited improved PFS (HR as 10-unit increase, 0.43; p = 0.04); increased PDGF exhibited worse OS (HR as 10-unit increase, 1.01; p = 0.02). CONCLUSIONS: This is the longest follow-up of vaccine administration with bevacizumab in patients with ovarian cancer. The vaccine was well tolerated with bevacizumab. Response was not associated with improved survival. On two-timepoint analysis, increased IL-8 was associated with significant improvement in PFS; increased PDGF with significantly worse OS. For all timepoint measurements, cytokine levels were not significantly associated with survival. TRIAL REGISTRATION: NCT01223235.


Asunto(s)
Interleucina-8 , Neoplasias Ováricas , Humanos , Femenino , Bevacizumab/uso terapéutico , Vacunas Combinadas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
5.
Mod Pathol ; 35(1): 117-127, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34561551

RESUMEN

Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.


Asunto(s)
Sarcoma/genética , Neoplasias Uterinas/genética , Anciano , Estudios de Cohortes , Metilación de ADN , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Mutación , Sarcoma/patología , Sarcoma/terapia , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia
6.
Int J Gynecol Cancer ; 32(8): 1017-1024, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35545291

RESUMEN

BACKGROUND: Although immune checkpoint blockade has demonstrated limited effectiveness against ovarian cancer, subset analyses from completed trials suggest possible superior efficacy in the clear cell carcinoma subtype. OBJECTIVE: To describe the outcomes of patients with ovarian clear cell carcinoma treated with immune checkpoint blockade. METHODS: This was a single-institution, retrospective case series of patients with ovarian clear cell carcinoma treated with a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor with or without concomitant cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition between January 2016 and June 2021. Demographic variables, tumor microenvironment, molecular data, and clinical outcomes were examined. Time to treatment failure was defined as the number of days between start of treatment and next line of treatment or death. RESULTS: A total of 16 eligible patients were analyzed. The median treatment duration was 56 days (range 14-574); median time to treatment failure was 99 days (range 27-1568). The reason for discontinuation was disease progression in 88% of cases. Four patients (25%) experienced durable clinical benefit (time to treatment failure ≥180 days). One patient was treated twice with combined immune checkpoint blockade and experienced a complete response each time. All 12 patients who underwent clinical tumor-normal molecular profiling had microsatellite-stable disease, and all but one had low tumor mutation burden. Multiplex immunofluorescence analysis available from pre-treatment biopsies of two patients with clinical benefit demonstrated abundant tumor-infiltrating lymphocytes expressing PD-1. CONCLUSION: Our study suggests a potential role for immune checkpoint blockade in patients with clear cell carcinoma of the ovary. Identification of genetic and microenvironmental biomarkers predictive of response will be key to guide therapy.


Asunto(s)
Carcinoma , Receptor de Muerte Celular Programada 1 , Carcinoma/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor , Ovario , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Microambiente Tumoral
7.
Mod Pathol ; 34(8): 1570-1587, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33772212

RESUMEN

Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher's exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.


Asunto(s)
Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/patología , Mesonefroma/genética , Mesonefroma/patología , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Mutación
8.
Gynecol Oncol ; 157(1): 214-221, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31959492

RESUMEN

OBJECTIVE: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. METHODS: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. RESULTS: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). CONCLUSIONS: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Infusiones Parenterales , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos
9.
Int J Gynecol Cancer ; 30(12): 1915-1921, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33106271

RESUMEN

OBJECTIVE: Although trials of neoadjuvant chemotherapy in ovarian cancer use 3 neoadjuvant cycles, real-world practice varies. We sought to evaluate the influence of increasing pre-operative cycles on survival, accounting for surgical outcomes. METHODS: We identified 199 women with newly diagnosed ovarian cancer recommended for neoadjuvant chemotherapy who underwent interval debulking surgery from July 2015 to December 2018. Non-parametric tests were used to compare clinical characteristics by neoadjuvant cycles. The Kaplan-Meier method was used to estimate differences in progression-free and overall survival. The log-rank test was used to assess the relationship of covariates to outcome. RESULTS: The median number of neoadjuvant cycles was 4 (range 3-8), with 56 (28%) women receiving ≥5 cycles. Compared with those receiving 3 or 4, women with ≥5 neoadjuvant cycles received fewer or no post-operative cycles (p<0.001) but had no other differences in clinical factors (p>0.05). Complete gross resection rates were similar among those receiving 3, 4, and ≥5 neoadjuvant cycles (68.5%, 70%, and 71.4%, respectively, p=0.96). There were no significant differences in progression-free or overall survival when comparing 3 versus 4 neoadjuvant cycles. However, more cycles (≥5 vs 4) were associated with worse progression-free survival, even after adjustment for BRCA status and complete gross resection (HR 2.20, 95% CI 1.45 to 3.33, p<0.001), and worse overall survival, even after adjustment for histology, response on imaging, and complete gross resection rates (HR 2.78, 95% CI 1.37 to 5.63, p=0.016). The most common reason for receiving ≥5 cycles was extent of disease requiring more neoadjuvant chemotherapy. CONCLUSIONS: Despite maximal cytoreduction, patients receiving ≥5 neoadjuvant cycles have a poorer prognosis than those receiving 3-4 cycles. Future studies should focus on reducing surgical morbidity and optimizing novel therapies in this high-risk group.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Procedimientos Quirúrgicos de Citorreducción , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Nivolumab/administración & dosificación , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Polietilenglicoles/administración & dosificación , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia
10.
Int J Gynecol Cancer ; 30(10): 1554-1561, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32522770

RESUMEN

INTRODUCTION: Delays from primary surgery to chemotherapy are associated with worse survival in ovarian cancer, however the impact of delays from neoadjuvant chemotherapy to interval debulking surgery is unknown. We sought to evaluate the association of delays from neoadjuvant chemotherapy to interval debulking with survival. METHODS: Patients with a diagnosis of stage III/IV ovarian cancer receiving neoadjuvant chemotherapy from July 2015 to December 2017 were included in our analysis. Delays from neoadjuvant chemotherapy to interval debulking were defined as time from last preoperative carboplatin to interval debulking >6 weeks. Fisher's exact/Wilcoxon rank sum tests were used to compare clinical characteristics. The Kaplan-Meier method, log-rank test, and multivariate Cox Proportional-Hazards models were used to estimate progression-free and overall survival and examine differences by delay groups, adjusting for covariates. RESULTS: Of the 224 women, 159 (71%) underwent interval debulking and 34 (21%) of these experienced delays from neoadjuvant chemotherapy to interval debulking. These women were older (median 68 vs 65 years, P=0.05) and received more preoperative chemotherapy cycles (median 6 vs 4, P=0.003). Delays from neoadjuvant chemotherapy to interval debulking were associated with worse overall survival (HR 2.4 95% CI 1.2 to 4.8, P=0.01), however survival was not significantly shortened after adjusting for age, stage, and complete gross resection, HR 1.66 95% CI 0.8 to 3.4, P=0.17. Delays from neoadjuvant chemotherapy to interval debulking were not associated with worse progression-free survival (HR 1.55 95% CI 0.97 to 2.5, P=0.062). Increase in number of preoperative cycles (P=0.005) and lack of complete gross resection (P<0.001) were the only variables predictive of worse progression-free survival. DISCUSSION: Delays from neoadjuvant chemotherapy to interval debulking were not associated with worse overall survival after adjustment for age, stage, and complete gross resection.


Asunto(s)
Carcinoma Epitelial de Ovario/terapia , Procedimientos Quirúrgicos de Citorreducción/estadística & datos numéricos , Terapia Neoadyuvante/estadística & datos numéricos , Neoplasias Ováricas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Supervivencia sin Progresión , Estudios Retrospectivos , Factores de Tiempo
11.
Gynecol Oncol ; 155(1): 51-57, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31421916

RESUMEN

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC), yet little is known about their effects on subsequent treatment. Preclinical studies suggest immunotherapy may enhance response to chemotherapy. We sought to evaluate the impact of ICIs on subsequent therapies and survival in recurrent OC. METHODS: A retrospective review was conducted to identify women with recurrent OC who received ICI from 01/2013 to 5/2017 and ≥1 subsequent treatment. Treatment duration after ICI was calculated using time-to-event analysis. Kaplan-Meier survival analysis and Cox proportional hazards models were used to calculate overall survival (OS) from first treatment after ICI and to assess survival differences by clinical benefit from ICI, defined by long (≥24 weeks) versus short (<24 weeks) ICI treatment duration. RESULTS: Of 79 evaluable women identified, 66 (84%) had platinum-resistant OC. Median age at diagnosis was 57 years. Median time from diagnosis to ICI was 39.7 months, with median of 4 prior treatments (range, 1-12). Median number of treatments after ICI was 2 (range, 1-8). Median duration of first-line treatment after ICI was 3.7 months (95% CI, 2.9-6.0) and declined with each subsequent line. The most common therapies after ICI were taxanes, platinum-based regimens, and pegylated liposomal doxorubicin. Bevacizumab was used in 47 women (59%). Median OS after ICI was 18.3 months (95% CI, 11.8-22.7) and did not differ between long versus short ICI. CONCLUSIONS: In this heavily pretreated population of patients with recurrent OC, therapies after ICI resulted in promising survival, suggesting that ICI may improve efficacy of subsequent chemotherapy.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Bevacizumab/administración & dosificación , Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , New York/epidemiología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Adulto Joven
12.
Future Oncol ; 14(2): 123-136, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29098867

RESUMEN

Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Resistencia a Antineoplásicos/genética , Inmunoconjugados/uso terapéutico , Maitansina/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Femenino , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/inmunología , Humanos , Inmunoconjugados/inmunología , Maitansina/uso terapéutico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Platino (Metal)/efectos adversos , Platino (Metal)/uso terapéutico
13.
Gynecol Oncol ; 147(3): 621-625, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28969913

RESUMEN

OBJECTIVE: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). METHODS: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. RESULTS: The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39). CONCLUSIONS: We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy.


Asunto(s)
Bevacizumab/efectos adversos , Hipertensión/inducido químicamente , Hipertensión/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Casos y Controles , Femenino , Quinasa 4 del Receptor Acoplado a Proteína-G/genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Calicreínas/genética , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Proteína Quinasa Deficiente en Lisina WNK 1/genética
14.
Gynecol Oncol ; 147(2): 402-407, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28843653

RESUMEN

PURPOSE: To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. METHODS: Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥25% of cells with ≥2+ staining intensity). Patients received mirvetuximab soravtansine at 6mg/kg once every 3weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. RESULTS: Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4months). CONCLUSION: Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Receptor 1 de Folato/biosíntesis , Inmunoconjugados/administración & dosificación , Maitansina/análogos & derivados , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma Epitelial de Ovario , Femenino , Receptor 1 de Folato/inmunología , Humanos , Inmunoconjugados/efectos adversos , Maitansina/administración & dosificación , Maitansina/efectos adversos , Persona de Mediana Edad , Terapia Molecular Dirigida
15.
Int J Gynecol Cancer ; 26(2): 255-60, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26745694

RESUMEN

OBJECTIVE: The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS AND MATERIALS: Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks. Treatment continued until disease progression or adverse events (AEs) prohibited further therapy. Common Terminology Criteria for AEs v3.0 was used to grade AEs. The primary endpoint was tumor response. The study was conducted with a Simon 2-stage design with 12 and 23 patients planned in the first and second stage, respectively. The study was designed to distinguish between 10% and 30% responding with types 1 and 2 error of 0.10. RESULTS: Twelve patients were treated on study, with median exposure to iniparib of 7.5 weeks. The median number of previous chemotherapeutic regimens was 7. Treatment-related AEs (≥10%) included asthenia (83.3%), constipation (25%), diarrhea (25%), nausea (25%), abdominal pain (16.7%), and decreased hemoglobin (16.7%). All treatment-related AEs were grades 1 or 2 with the following 2 exceptions: 1 grade 3 diarrhea and 1 grade 3 hypertension. One patient had stable disease lasting 2 cycles; the remaining 11 patients had progressive disease. The study did not proceed to second stage enrollment. CONCLUSIONS: Iniparib did not show significant activity in this heavily pretreated ovarian cancer population, all of whom had BRCA1 or BRCA2 mutations.


Asunto(s)
Benzamidas/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Carcinoma/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Persona de Mediana Edad
16.
Gynecol Oncol ; 139(2): 236-41, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26404183

RESUMEN

OBJECTIVE: Ovarian clear cell carcinomas (OCCCs) are rare, and uncertainty exists as to the optimal treatment paradigm and validity of the FIGO staging system, especially in early-stage disease. METHODS: We performed a retrospective cohort study of all OCCC patients diagnosed and treated at Memorial Sloan Kettering Cancer Center between January 1996 and December 2013. Progression-free survival (PFS) and overall survival (OS) were calculated by stage and race, and comparisons were made using the log-rank test. Statistical significance was set at p<0.05. Type and duration of treatment were also recorded. RESULTS: There were 177 evaluable patients. The majority of patients were stage I at diagnosis (110/177, 62.2%). Of these, 60/110 (54.6%) were stage IA, 31/110 (28.2%) were stage IC on the basis of rupture-only, and 19/110 (17.3%) were stage IC on the basis of surface involvement and/or positive cytology of ascites or washings. Patients with stage IA and IC based on rupture-only had similar PFS/OS outcomes. Patients with stage IC based on surface involvement and/or positive cytology had a statistically significant decrement in PFS/OS. Stage was an important indicator of PFS/OS, while race was not. CONCLUSIONS: OCCC often presents in early stage. Women with stage IA OCCC have excellent prognosis, and future studies should explore whether they benefit from adjuvant chemotherapy. Women with IC OCCC need further staging clarification, as surgical rupture alone affords better prognosis than surface involvement and/or positive cytology. Women with advanced OCCC have poor survival and are often chemotherapy resistant/refractory. New treatment paradigms are needed.


Asunto(s)
Adenocarcinoma de Células Claras/patología , Neoplasias Ováricas/patología , Ovario/lesiones , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Ovariectomía/efectos adversos , Pronóstico , Estudios Retrospectivos , Rotura/etiología , Tasa de Supervivencia
17.
Clin Cancer Res ; 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39405335

RESUMEN

PURPOSE: Survival of patients with metastatic sarcoma remains poor, and there is pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multi-receptor tyrosine kinase inhibitor targeting tumor vasculature, has immunomodulatory activity that contributes to its antitumor effects. Therefore we hypothesized that combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma. METHODS: This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts A: leiomyosarcoma, B: undifferentiated pleomorphic sarcoma (UPS), C: vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), D: synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and E: bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response and safety. RESULTS: Forty-six patients were evaluable for the primary endpoint which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%,respectively). There were 7 partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade, and Grade 3 or higher, occurred in 50/51 (98%) and 29/51 (57%) of patients respectively. CONCLUSIONS: We observed durable responses in MPNST, synovial sarcoma and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.

18.
Int J Gynecol Cancer ; 23(5): 923-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23698798

RESUMEN

OBJECTIVE: It is well documented that recurrence after pelvic exenteration remains high (up to 50%), and patients may require a prolonged period of recuperation following this aggressive surgery. We conducted a retrospective review to evaluate the feasibility of administering adjuvant chemotherapy after pelvic exenteration for gynecologic malignancies. METHODS: We reviewed the medical records of patients with any gynecologic cancer who underwent exenterative surgery between January 2005 and February 2011 at our institution. Patients were referred for postexenteration adjuvant chemotherapy based on surgeon's discretion and/or presence of high-risk features: positive margins, positive lymph nodes, and/or lymphovascular space invasion. Suitability for chemotherapy was assessed by a gynecologic medical oncologist. Regimens consisted of 4 to 6 cycles of platinum-based doublet chemotherapy. Chemotherapy-related toxicities were assessed using the Common Terminology Criteria for Adverse Events version 4. RESULTS: We identified 42 patients who underwent pelvic exenteration during the study period. Eleven (26%) were referred for adjuvant chemotherapy. Three (27%) of the 11 patients did not receive chemotherapy because of delayed postoperative recovery or physician choice. Seven (88%) of the remaining 8 patients completed all scheduled chemotherapy. Grade 2 toxicities or greater were documented in 6 patients (75%), the most common being neutropenia, neuropathy, and fatigue. Median follow-up time was 25 months (range, 6-56 months). The 3-year progression-free and overall survival rates of the 8 patients who received chemotherapy were 58% (95% confidence interval, 18%-84%) and 54% (95% confidence interval, 13%- 83%), respectively. CONCLUSIONS: The administration of adjuvant chemotherapy is feasible for a select group of patients after pelvic exenteration for gynecologic malignancies. Our results need to be interpreted with caution because of the small and heterogeneous cohort of patients included.


Asunto(s)
Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Exenteración Pélvica , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/cirugía , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/mortalidad , Neoplasias de los Genitales Femeninos/cirugía , Humanos , Irinotecán , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Topotecan/administración & dosificación , Gemcitabina
19.
J Clin Oncol ; 41(13): 2436-2445, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36716407

RESUMEN

PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Bevacizumab/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Receptor 1 de Folato/uso terapéutico , Inmunoconjugados/efectos adversos , Antineoplásicos/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adenosina Difosfato Ribosa/uso terapéutico
20.
Cancer ; 118(20): 5078-83, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-22437824

RESUMEN

BACKGROUND: Dermatologic adverse events stemming from anticancer therapies have become an increasingly frequent clinical problem. Inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, have been associated with a high rate of skin eruptions, but their clinical and histopathologic characteristics have not been explored. METHODS: A retrospective analysis of patients who were referred to the Dermatology Service for diagnosis and management of rash in the setting of therapy with the mTOR inhibitors everolimus and temsirolimus was performed. The parameters that were studied included the time to onset, clinical presentation at the time of dermatologic evaluation, associated symptoms, evolution, results of microbiologic studies, concomitant medications, the need for dose reduction and/or treatment interruption because of rash, and routine histopathology. RESULTS: In total, 13 patients were analyzed. Most rashes were mild (grade 1; 31%) and moderate (grade 2; 54%) in severity, and grade 3 rashes were observed only in 2 patients (15%). The trunk was the most frequently affected region (77%), with the scalp (23%), face (38%), neck (54%), and extremities (69%) also commonly involved. Erythematous papules and pustules constituted the predominant primary lesion morphology (62%). No unique or uniform histopathologic reaction pattern was observed. The most common reaction pattern was that of a mixed, spongiotic interface and perivascular dermatitis, which was observed in 7 of 11 patients (63%). CONCLUSIONS: Although mTOR inhibitors may commonly induce erythematous papules and pustules, they are associated with a spectrum of lesion morphologies and a variety of histopathologic findings. Further clinicohistologic correlation studies are needed.


Asunto(s)
Antineoplásicos/efectos adversos , Exantema/inducido químicamente , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Everolimus , Exantema/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sirolimus/efectos adversos
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