Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 82
Filtrar
1.
Med ; 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39151421

RESUMEN

BACKGROUND: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. METHODS: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. FINDINGS: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-ß, and ß-catenin signaling. CONCLUSIONS: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. FUNDING: This investigator-initiated trial was funded by Merck.

2.
Nat Commun ; 15(1): 7312, 2024 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-39181865

RESUMEN

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI's robust and consistent performance.


Asunto(s)
Perfilación de la Expresión Génica , Neoplasias , Transcriptoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Perfilación de la Expresión Génica/métodos , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Análisis de la Célula Individual/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Análisis por Conglomerados
3.
Nat Rev Clin Oncol ; 21(11): 781-800, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39198622

RESUMEN

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape.


Asunto(s)
Neoplasias Endometriales , Humanos , Neoplasias Endometriales/terapia , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Estadificación de Neoplasias
4.
Med ; 5(6): 487-489, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38878765

RESUMEN

In locally advanced cervical cancer (LACC), the benefit of PD-1 blockade was unknown. In KEYNOTE-A18, Lorusso et al.1 compared the efficacy and safety of adding pembrolizumab to chemoradiation in LACC and demonstrated favorable outcomes. Given multiple approved indications of pembrolizumab in cervical cancer, strategies for optimal integration into management will be needed to maximize overall survival.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Quimioradioterapia/métodos , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto
5.
Gynecol Oncol ; 188: 120-124, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38945019

RESUMEN

OBJECTIVES: Malignant large bowel obstruction (LBO) is a frequent complication affecting women with gynecologic cancers and is an indication for emergent surgery. However, the life expectancy and subsequent medical care utilization are unknown. We sought to estimate overall survival (OS) following colostomy and describe subsequent healthcare utilization among patients with advanced gynecologic malignancies. METHODS: We conducted a retrospective analysis of patients with advanced gynecologic cancers who underwent colostomy with palliative intent due to LBO at our institution between March 2014 and January 2023. Summary statistics were used to describe the clinical and demographic characteristics of the study population. OS was estimated using the Kaplan-Meier method, and we defined healthcare utilization at the end-of-life using criteria published by the National Quality Forum. RESULTS: A total of 78 patients were included. The median age at the time of surgery was 61 (range: 34-83), and most patients had recurrent ovarian, fallopian tube, or primary peritoneal cancer (n = 51, 65.4%), followed by cervical cancer (n = 16, 20.5%), and uterine cancer (n = 10, 12.8%). The median Charlson comorbidity index was 3 and median postoperative length of stay was five days (range: 1-26). The median follow-up for all patients was 4.5 months (range: 0.07-46.2), and the median OS was 4.5 months (95% CI: 2.9-6.0), including 12 patients (15.4%) with <30-day OS and 21 (26.9%) with <60-day OS. In the last 30 days of life, 62.7% of patients were re-admitted to the hospital, 53.0% were seen in the emergency department, and 18.5% were admitted to an intensive care unit. CONCLUSIONS: A significant proportion of patients died within 60 days of surgery, and many had high healthcare utilization at the end of life.


Asunto(s)
Colostomía , Neoplasias de los Genitales Femeninos , Obstrucción Intestinal , Cuidados Paliativos , Humanos , Femenino , Obstrucción Intestinal/cirugía , Obstrucción Intestinal/etiología , Anciano , Cuidados Paliativos/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Anciano de 80 o más Años , Adulto , Neoplasias de los Genitales Femeninos/cirugía , Cuidado Terminal/métodos
6.
iScience ; 27(5): 109801, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38726365

RESUMEN

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

7.
Clin Cancer Res ; 30(14): 2986-2995, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38687597

RESUMEN

PURPOSE: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. EXPERIMENTAL DESIGN: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model. RESULTS: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis. CONCLUSIONS: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.


Asunto(s)
Neoplasias de los Genitales Femeninos , Mutación , Humanos , Femenino , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Femeninos/mortalidad , Persona de Mediana Edad , Anciano , Adulto , Proteínas Proto-Oncogénicas p21(ras)/genética , Genómica/métodos , Pronóstico , Biomarcadores de Tumor/genética , Proteínas ras/genética , Proteínas de Unión al ADN , Factores de Transcripción
8.
Med ; 5(4): 311-320.e3, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38471508

RESUMEN

BACKGROUND: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity. METHODS: In this phase 1b study, registered at Clinical. TRIALS: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). FINDINGS: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. CONCLUSIONS: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. FUNDING: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).


Asunto(s)
Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Neoplasias Peritoneales , Neoplasias del Cuello Uterino , Humanos , Femenino , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Neoplasias de los Genitales Femeninos/inducido químicamente , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/inducido químicamente , Neoplasias del Cuello Uterino/inducido químicamente , Teorema de Bayes , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inducido químicamente
9.
J Immunother Cancer ; 12(2)2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38309721

RESUMEN

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture. METHODS: Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers. CONCLUSIONS: TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma Ductal Pancreático , Neoplasias Colorrectales , Neoplasias Pulmonares , Neoplasias Ováricas , Neoplasias Pancreáticas , Humanos , Femenino , Persona de Mediana Edad , Linfocitos Infiltrantes de Tumor , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Interleucina-2/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo
10.
Cancer Biomark ; 39(4): 289-298, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38250760

RESUMEN

High grade epithelial ovarian carcinoma is an aggressive tumor. Treatment includes platinum therapy, however it recurs in most patients due to therapy resistance. In this project, we study the immunohistochemical (IHC) expression of five potential biomarkers/prognostic markers in high grade epithelial ovarian carcinoma: EGFR, HLA-G, CD70, c-MET, and NY-ESO1. A cohort of 274 patients is used. We compare the IHC expression with age, stage, ascites status, family history of cancer, disease free survival (DFS) and overall survival (OS). EGFR expression is significantly correlated with family history and worse OS. HLA-G is associated with worse OS. To confirm the results of EGFR and HLA-G, a second separated cohort of 248 patients is used. Positive EGFR expression again shows worse OS, while HLA-G expression has worse prognostic trend. CD70 has a worse OS trend. C-MET and NY-ESO1 do not have any clinical correlations. EGFR can potentially serve as target in future clinical immune therapy trials.


Asunto(s)
Antígenos de Neoplasias , Biomarcadores de Tumor , Carcinoma Epitelial de Ovario , Receptores ErbB , Antígenos HLA-G , Proteínas de la Membrana , Neoplasias Ováricas , Proteínas Proto-Oncogénicas c-met , Humanos , Femenino , Biomarcadores de Tumor/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptores ErbB/metabolismo , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/mortalidad , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Pronóstico , Antígenos de Neoplasias/metabolismo , Antígenos HLA-G/metabolismo , Anciano , Adulto , Clasificación del Tumor , Inmunohistoquímica , Anciano de 80 o más Años
11.
Cancer ; 130(3): 400-409, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-37864520

RESUMEN

BACKGROUND: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. METHODS: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. RESULTS: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. CONCLUSIONS: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias de los Genitales Femeninos , Inmunoglobulina G , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
12.
Cancer ; 130(7): 1061-1071, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38009662

RESUMEN

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ováricas , Humanos , Femenino , Teorema de Bayes , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Ováricas/tratamiento farmacológico
13.
Med ; 4(11): 755-760, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37951209

RESUMEN

Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Neoplasia Residual , Neoplasias Ováricas/tratamiento farmacológico , Carcinoma Epitelial de Ovario/terapia
14.
Gynecol Oncol Rep ; 50: 101296, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37920829

RESUMEN

As Immune checkpoint inhibitors are being expanded for use in gynecologic malignancies, rare immune-related adverse events are more frequently being reported. Here we describe a 63-year-old with Stage IIIB mismatch repair deficient uterine adenocarcinoma who underwent six cycles of carboplatin and paclitaxel with partial response but persistent disease. She was then started on single agent pembrolizumab. After six cycles of pembrolizumab, she developed bilateral vision changes and was diagnosed with posterior scleritis. Pembrolizumab was held and she was treated with oral prednisone, with rapid resolution of symptoms. One month after completion of prednisone, vision changes were again reported and she was restarted on a longer oral prednisone course. She then underwent definitive surgical management consisting of a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with final pathology of benign endometrial hyperplasia. She has completed her steroid course without any symptoms. Given her complete pathologic response, she was subsequently placed into surveillance and is currently without evidence of disease. Prompt recognition and treatment of this rare immune-related adverse event led to the prevention of potential permanent, debilitating outcomes.

15.
Nat Med ; 29(6): 1550-1562, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37248301

RESUMEN

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos Infiltrantes de Tumor , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Inmunoterapia , Microambiente Tumoral
16.
Cancer ; 129(11): 1672-1680, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36930815

RESUMEN

BACKGROUND: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer. METHODS: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival. RESULTS: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42-0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002-14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high-grade serous carcinoma. CONCLUSIONS: tbNGS often yields clinically relevant information. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools. PLAIN LANGUAGE SUMMARY: Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Estudios Retrospectivos , Neoplasias Ováricas/patología , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento
17.
J Immunother Precis Oncol ; 6(1): 10-18, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36751659

RESUMEN

Introduction: We aimed to identify clinical, pathologic, and treatment factors that are predictive of response and survival in patients with cervical cancer referred to phase I clinical trials. Methods: Patients with cervical cancer who received at least one dose of a phase I investigational agent at our institution between 2014 and 2022 were included. The log-rank test was used to analyze differences in progression-free survival (PFS) and overall survival (OS), and multivariable regression analysis was performed. Results: We included 65 patients with a median age of 41 years (range, 20-74), 3 prior therapies (range, 1-7), and 67.7% squamous carcinoma. The rate of distant metastasis at trial entry was 84.6%. The most common molecular alterations included PIK3CA (46.5%), PD-L1+ (46.2%), EPH (30.0%), and CREBBP (23.1%); 23.1% had received a prior checkpoint inhibitor. Phase I trials were for immunotherapy (58.5%) or targeted therapy (41.5%). The rate of biomarker matching was 21.5%. For all patients, median PFS was 3.6 months (95% CI, 2.0-5.2) and OS was 9.3 months (95% CI, 7.0-10.6). Factors at study entry associated with worse survival were presence of bone metastasis (PFS 1.6 vs 4.4 months: hazard ratio [HR], 2.8; p = 0.001; OS 3.8 vs 10.0 months: HR, 3.9; p < 0.0001) and absolute lymphocyte count below 1000/µL (PFS 1.8 vs 5.2 months: HR, 2.9; p = 0.0004; OS 7.0 vs 10.6 months: HR, 3.2; p = 0.0009). Factors associated only with worse OS were absolute neutrophil count above 4700/µL, hemoglobin below 10.5 g/dL, and smoking status. Grade 3+ treatment-related adverse events were seen in 16.9% of cases. Conclusion: Bone metastasis and absolute lymphocyte count below normal range at phase I study entry portend poor survival in patients with recurrent or metastatic cervical cancer.

18.
Gynecol Oncol ; 167(3): 483-489, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36229264

RESUMEN

BACKGROUND: Gynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era. METHODS: Patterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up. RESULTS: Of the 124 patients included, anatomic subsites were vulvar (n = 82, 66%), vaginal (n = 34, 27%), or cervical (n = 8, 6%). Primary tumor was resected for 85% (n = 106) with surgical nodal evaluation for 60% (n = 75). Systemic therapy, most commonly immune checkpoint inhibitors (ICI, 58% systemic therapy), was used to treat all except one unresectable patient (17/18) and 33% (35/106) of resectable patients. Seven patients received neoadjuvant ICI. Fourteen patients received adjuvant radiation therapy to the pelvis (RT, 13% of those undergoing resection). With a median follow-up of 45 months, 100 patients (81%) recurred. Four-year actuarial outcomes were: 46% local control, 53% nodal control, 36% distant metastasis-free survival, 17% disease-free survival, 49% melanoma-specific survival and 48% overall survival. Mitotic rate > 10/mm2, nodal involvement and non-vulvar anatomic subsite were associated with poor outcomes. Patients treated after 2016 did not have significantly better outcomes than those treated earlier. CONCLUSIONS: Patients with GTM continue to have poor outcomes in the contemporary therapeutic era with particularly notable poor local disease control relative to other mucosal melanoma subtypes. More effective oncologic therapy is needed.


Asunto(s)
Melanoma , Recurrencia Local de Neoplasia , Humanos , Femenino , Melanoma/terapia , Melanoma/patología , Supervivencia sin Enfermedad , Supervivencia sin Progresión , Progresión de la Enfermedad , Estudios Retrospectivos
19.
Cancers (Basel) ; 14(15)2022 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-35954359

RESUMEN

Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33-0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15-0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27-0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study.

20.
Cancers (Basel) ; 14(15)2022 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-35892848

RESUMEN

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...