RESUMEN
Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.
Asunto(s)
Carcinoma Epitelial de Ovario , Mutación , Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Femenino , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/patología , Pronóstico , Persona de Mediana Edad , Anciano , ARN Helicasas , Proteínas del Grupo de Complementación de la Anemia de FanconiRESUMEN
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy with poor prognosis and patient survival outcome. Protein kinase D2 (PKD2) belongs to Ca++/calmodulin-dependent serine/threonine kinase family and its aberrant expression is associated with many cellular and physiological functions associated with tumorigenesis including cell proliferation. We show that PKD2 is activated during G2/M cell cycle transition and its catalytic inactivation by small molecule inhibitor CRT0066101 or genetic knockdown caused suppression of EOC cell proliferation followed by a delay into mitotic entry. Our RNASeq analysis of PKD2-inactivated EOC cells revealed significant downregulation of genes associated with cell cycle including Aurora kinase A, a critical mitotic regulator. Mechanistically, PKD2 positively regulated Aurora kinase A stability at both transcriptional and post-translational levels by interfering with the function of Fbxw7, drove G2/M cell cycle transition and EOC cell proliferation. Moreover, pharmacological inhibition of Aurora kinase A by small molecule CD532 or its shRNA-mediated genetic knockdown suppressed EOC cell proliferation, induced G2/M cell cycle arrest and mitotic catastrophe followed by apoptosis. Taken together, our results indicated that PKD2 positively regulates Aurora kinase A during G2/M cell cycle entry and pharmacological targeting of PKD2/Aurora kinase A signalling axis could serve as a novel therapeutic intervention against a lethal pathology like EOC.
Asunto(s)
Aurora Quinasa A , Carcinoma Epitelial de Ovario , Proliferación Celular , Neoplasias Ováricas , Proteína Quinasa D2 , Transducción de Señal , Humanos , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Femenino , Proliferación Celular/efectos de los fármacos , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Pirimidinas/farmacología , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
BACKGROUND: Thymic epithelial tumors (TETs) are rare malignant tumors with limited treatment options. No established second-line treatment regimen is available following the preferred first-line chemotherapy, resulting in unsatisfactory efficacy and poor prognosis for patients with advanced TETs. This study aimed to evaluate the efficacy of small molecule multitarget antiangiogenic inhibitors as well as the prognostic factors for advanced TETs. METHODS: A retrospective study was conducted using data from a real-world database. Clinical information and survival follow-up data were collected from 52 patients with advanced TETs who received small molecule multitarget antiangiogenic inhibitors at Zhejiang Cancer Hospital between August 10, 2016 and August 10, 2022. The short-term efficacy of the treatments, survival time of the patients, and relevant prognostic factors of advanced TETs were analyzed. RESULTS: Out of the 52 patients included in this study, 16 had thymoma and 36 had thymic carcinoma. The 52 patients had an overall response rate of 21.1% and a disease control rate of 94.2%. In addition, the median progression-free survival (PFS) was 8.05 months, and the overall survival (OS) was 25.00 months. Apatinib was given to 33 patients, anlotinib to 15 patients, and sunitinib or lenvatinib to four patients. Only seven patients received antiangiogenic inhibitors as their first-line therapy, 27 patients as their second-line therapy, and 18 patients as third-line or subsequent therapy. Meanwhile, 42 patients received monotherapy with an antiangiogenesis inhibitor, while 10 patients received combination therapy. Univariate analysis indicated that the combined treatment was associated with a superior OS (p = 0.044); multivariate analysis indicated that the combined treatment was an independent prognostic factor for PFS (p = 0.014) and OS (p = 0.012). CONCLUSION: The findings suggest that small molecule multitarget antiangiogenic inhibitors are efficacious as second or post-line treatments as a viable alternative treatment option for patients with advanced TETs.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Estudios Retrospectivos , Neoplasias del Timo/patología , Timoma/patología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
The efficacy of CAR-T cells for solid tumors is unsatisfactory. EpCAM is a biomarker of epithelial tumors, but the clinical feasibility of CAR-T therapy targeting EpCAM is lacking. Here, we report pre- and clinical investigations of EpCAM-CAR-T cells for solid tumors. We demonstrated that EpCAM-CAR-T cells costimulated by Dectin-1 exhibited robust antitumor activity without adverse effects in xenograft mouse models and EpCAM-humanized mice. Notably, in clinical trials for epithelial tumors (NCT02915445), 6 (50%) of the 12 enrolled patients experienced self-remitted grade 1/2 toxicities, 1 patient (8.3%) experienced reversible grade 3 leukopenia, and no higher-grade toxicity reported. Efficacy analysis determined two patients as partial response. Three patients showed >23 months of progression-free survival, among whom one patient experienced 2-year progress-free survival with detectable CAR-T cells 200 days after infusion. These data demonstrate the feasibility and tolerability of EpCAM-CAR-T therapy.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Molécula de Adhesión Celular Epitelial , Linfocitos T , Inmunoterapia/efectos adversos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
Angiogenesis significantly influences the carcinogenesis of thymic epithelial tumors (TET). Both thymomas and thymic carcinoma (TC) overexpress VEGF-A and VEGFR-1 and -2. This review aims to provide an appraisal of the use of anti-angiogenics in the treatment of TET. The literature research identified 16 studies that were deemed eligible for further analysis. Seven studies assessed the clinical efficacy of sunitinib and five studies the use of apatinib and/or anlotinib. The multicenter Japanese phase II REMORA trial investigated the efficacy of lenvatinib, which is a multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The objective response rate was 38% (25.6-52%), which is the highest documented in TET that progressed after first-line chemotherapy. Anti-angiogenic agents may be useful in the treatment of TET, which are not amenable to curative treatment. Their toxicity profile seems to be acceptable. However, angiogenesis inhibitors do not appear to have a major influence on either thymomas or TC, although multikinase inhibitors may have some effect on TC. The current evidence suggests that the most active agent is lenvatinib, whereas sunitinib could be proposed as an acceptable second-line therapy for TC. Further research concerning the combination of immune checkpoint inhibitors with anti-angiogenic drugs is warranted.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Timoma/tratamiento farmacológico , Timoma/patología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Sunitinib/uso terapéutico , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Estudios Multicéntricos como AsuntoRESUMEN
Recent advances in epithelial ovarian cancer research have led to a shift in treatment strategy from the traditional 'organ-centric' to a personalized tumor biology-based approach. Nevertheless, we are still far behind an individualized approach for cytoreductive surgery in advanced ovarian cancer; the gold standard of primary treatment in combination with systemic agents. The impact of tumor biology on treatment sequence is still understudied. It is obvious, that response to platinum-based therapy is crucial for the success of neoadjuvant chemotherapy. While high-grade serous and endometrioid tumors are commonly characterized by an excellent response, other subtypes are considered poor responders or even resistant to platinum. Undoubtedly, neoadjuvant chemotherapy may filter poor responders, but to date, we still do not have appropriate alternatives to platinum-based chemotherapy in the neoadjuvant and first-line setting and 'adjusting' systemic treatment in cases of poor response to neoadjuvant chemotherapy remains elusive. Primary cytoreduction is still considered the gold standard for fit patients with operable tumor dissemination patterns, especially for those ovarian cancer subtypes that show poor response to platinum. Of note, even in high-grade serous ovarian cancer, approximately 20% of tumors are platinum resistant and the benefit of neoadjuvant chemotherapy in this subgroup is limited. Interestingly, these tumors are associated with the mesenchymal molecular subtype, which in turn correlates with high risk for residual disease after cytoreductive surgery and is characterized by the worst survival outcome among high-grade ovarian cancers. This leads to the question, how to best tailor surgical radicality at the onset of patients' presentation to avoid associated morbidity and with a moderate benefit. Here, we give an overview of recent advances of interaction between tumor biology and surgery in ovarian cancer.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/cirugía , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Terapia Neoadyuvante , Biología , Procedimientos Quirúrgicos de Citorreducción , Quimioterapia AdyuvanteRESUMEN
OBJECTIVE: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. METHODS: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared. RESULTS: We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. CONCLUSIONS: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Femenino , Humanos , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carboplatino , Neoplasias Ováricas/patología , Supervivencia sin Enfermedad , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Paclitaxel , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de NeoplasiasRESUMEN
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias del Timo , Humanos , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Inmunoterapia/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
Epithelial ovarian cancers (EOCs) are a heterogeneous group of tumors with different molecular and clinical features. In past decades, few improvements have been achieved in terms of EOC management and treatment efficacy, such that the 5-year survival rate of patients remained almost unchanged. A better characterization of EOCs' heterogeneity is needed to identify cancer vulnerabilities, stratify patients and adopt proper therapies. The mechanical features of malignant cells are emerging as new biomarkers of cancer invasiveness and drug resistance that can further improve our knowledge of EOC biology and allow the identification of new molecular targets. In this study, we determined the inter and intra-mechanical heterogeneity of eight ovarian cancer cell lines and their association with tumor invasiveness and resistance to an anti-tumoral drug with cytoskeleton depolymerization activity (2c).
Asunto(s)
Antineoplásicos , Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Línea Celular Tumoral , Neoplasias Ováricas/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Biomarcadores de Tumor/metabolismoRESUMEN
The vacuolar ATPase H+ transporting V1 subunit B1 (ATP6V1B1) belongs to the family of ATP6Vs, which functions to transport hydrogen ions. The expression of ATP6V1B1 and associated clinicopathological features have been linked to various cancers; however, its role in epithelial ovarian cancer (EOC) has remained to be explored. The present study aimed to unveil the function, molecular mechanisms and clinical significance of ATP6V1B1 in EOC. The mRNA levels of ATP6V1 subunits A, B1 and B2 in EOC tissues were determined using data from the Gene Expression Profiling Interactive Analysis database and RNA sequencing. Protein levels of ATP6V1B1 were evaluated through immunohistochemistry staining of EOC, borderline, benign and normal epithelial tissues. The association between ATP6V1B1 expression and clinicopathological features and prognosis of patients with EOC was analyzed. Furthermore, the biological role of ATP6V1B1 in ovarian cancer cell lines was also assessed. RNA sequencing and public dataset analyses revealed elevated ATP6V1B1 mRNA levels in EOCs. High ATP6V1B1 protein levels were also observed in EOC compared with those of borderline and benign tumors and nonadjacent normal epithelial tissues. High ATP6V1B1 expression was associated with the serous cell type, advanced International Federation of Gynecology and Obstetrics stage, high/advanced tumor grade, elevated serum cancer antigen 125 levels and platinum resistance (P<0.001, P<0.001, P=0.035, P=0.029 and P=0.011, respectively). High expression levels of ATP6V1B1 were also associated with poor overall and diseasefree survival (P<0.001). Knockdown of ATP6V1B1 decreased cancer cell proliferation and colonyforming abilities (P<0.001) in vitro by inducing cell cycle arrest in G0/G1 phase. Significant upregulation of ATP6V1B1 was observed in EOC and the prognostic significance and association with chemotherapy resistance of ATP6V1B1 in EOC was demonstrated, rendering it an EOCrelated biomarker for prognostic evaluation and chemotherapy resistance, as well as a potential therapeutic target for patients with EOC.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , ATPasas de Translocación de Protón Vacuolares , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , ARN Mensajero/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).
Asunto(s)
Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Antígeno Ca-125 , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carboplatino , Paclitaxel , Doxorrubicina , Polietilenglicoles , Recurrencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Thymic epithelial tumors (TETs) are a rare group of malignancies arising from the thymus. Surgery remains the foundation of treatment for patients with early-stage disease. Limited treatment options are available for the treatment of unresectable, metastatic, or recurrent TETs and are associated with modest clinical efficacy. The emergence of immunotherapies in the treatment of solid tumors has generated significant interest in understanding their role in TET treatment. However, the high rates of comorbid paraneoplastic autoimmune disorders, particularly in thymoma, have tempered expectations regarding the role of immune-based therapies. Clinical studies of immune checkpoint blockade (ICB) in thymoma and thymic carcinoma have revealed higher frequencies of immune-related adverse events (IRAEs) and limited efficacy. Despite these setbacks, the growing understanding of the thymic tumor microenvironment and systemic immune system has advanced the understanding of these diseases and provided opportunities for novel immunotherapy modalities. Ongoing studies are evaluating numerous immune-based treatments in TETs with the goal of improving clinical efficacy and mitigating IRAE risk. This review will provide insight into the current understanding of the thymic immune microenvironment, outcomes of previous ICB studies, and review treatments currently being explored for the management of TET.
Asunto(s)
Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Timoma/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Inmunoterapia/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microambiente TumoralRESUMEN
The optimal pharmaceutical regimen for advanced thymic epithelial tumors (TETs) remains controversial when first-line chemotherapy fails. This retrospective study aims to evaluate the efficacy and safety of anlotinib treatment for patients with relapsed and refractory TETs. Patients with progressive disease after failure of platinum-based chemotherapy were enrolled in this study. Anlotinib was orally taken once a day at an initial dose of 12 mg (10 mg when body weight <60 kg). The cycle was repeated every 3 weeks (2 weeks of treatment followed by 1-week rest). Objective response rate (ORR) and progression-free survival (PFS) were recorded as primary endpoints. There were 50 patients enrolled in this study from October 2018 to June 2021 at a median age of 50 (range 23-79) years old. Patients with thymoma and thymic carcinoma were 33 (66%) and 17 (34%), respectively. The ORR in thymoma and thymic carcinoma patients were 33% (11/33) and 41% (7/17), respectively. The median PFS (mPFS) was 7 (95% CI, 5.9-10.2) months in thymoma patients and 6 (95% CI, 4.6-9.3) months in the thymic carcinoma group. Eleven patients experienced dose reduction due to toxicities, among whom, eight patients discontinued treatment even after dose reduction. Six patients with thymoma showed myasthenia gravis deterioration during treatment, and two of them died of myasthenia gravis crisis. Anlotinib is active in patients with advanced TETs refractory to routine chemotherapy. Prescription of anlotinib to patients with myasthenia gravis should be made cautiously.
Asunto(s)
Miastenia Gravis , Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Timoma/tratamiento farmacológico , Timoma/patología , Estudios Retrospectivos , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias Glandulares y Epiteliales , Neoplasias del Timo , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/patología , Timoma/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Platino (Metal)/uso terapéuticoRESUMEN
BACKGROUND: Thymic epithelial tumors (TETs) are rare thoracic malignancies with no standard second-line treatment. Tumor angiogenesis is closely associated with the pathogenesis and invasiveness of TETs. Anlotinib is a small-molecule multitarget tyrosine kinase inhibitor (TKI) which inhibits tumor angiogenesis and tumor cell proliferation. Published studies have demonstrated the promising clinical effect of multitarget TKIs sunitinib and lenvatinib in previously treated TETs. However, TKIs have a high incidence of adverse events (AEs). OBJECTIVE: In this study, we investigated the clinical efficacy and safety of anlotinib in previously treated TET patients. METHODS: We collected clinical data of 22 patients from Shandong Cancer Hospital and Institute between October 2018 and March 2022. These patients were diagnosed with advanced TETs and received at least the first-line (1st-line) treatment. We analyzed the clinical effects between anlotinib monotherapy and anlotinib combination therapy in the second-line (2nd-line) or anlotinib treatment in different lines. RESULTS: These 22 patients included 18 cases of thymic carcinoma (TC) and 4 cases of thymoma (T). 68.2% of patients were males, and the median age was 53 years. Fourteen patients (63.6%) received anlotinib monotherapy and 8 patients (36.4%) received anlotinib combination therapy. The objective response rate (ORR) was 9.1% in the overall patients. The median progression-free survival (PFS) in the overall population was 12 months (14 months for T and 9 months for TC), and the median overall survival (OS) was 24 months (survival was not reached for T and was 24 months for TC). The incidence of AEs was 50%, most of them were grades I and II, and the incidence of grades III and IV AEs was 9%. CONCLUSION: This is the first study reporting the clinical effect of anlotinib in previously treated TETs patients. The survival data indicate that the efficacy of anlotinib is superior to sunitinib and lenvatinib. Our results suggest that anlotinib is a promising treatment option for previously treated TET patients and its toxicity is tolerable. More research and patents are needed in the future to explore better options for the diagnosis and treatment of TETs.
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Neoplasias Glandulares y Epiteliales , Patentes como Asunto , Masculino , Humanos , Persona de Mediana Edad , Femenino , Sunitinib , Estudios Retrospectivos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
INTRODUCTION: To explore differences in surgical complexity, chemotherapy administration, and treatment delays between younger and older Danish patients with epithelial ovarian cancer (EOC). MATERIALS AND METHODS: We included a nationwide cohort diagnosed with EOC from 2013 to 2018. We described surgical complexity and outcomes, the extent of chemotherapy and treatment delays stratified by age (<70 and ≥ 70 years), and surgical modality (primary, interval, or no debulking surgery). RESULTS: In total, we included 2946 patients. For patients with advanced-stage disease, 52% of the older patients versus 25% of the younger patients did not undergo primary debulking surgery (PDS) or interval debulking surgery (IDS). For patients undergoing PDS or IDS, older patients underwent less extensive surgery and more often had residual disease after surgery >0 cm compared to younger patients. Furthermore, older patients were less often treated with chemotherapy. Older patients had PDS later than younger. We did not find any differences between age groups concerning treatment delays. Two-year cancer-specific survival differed significantly between age groups regardless of curatively intended treatment. DISCUSSION: This study demonstrates that older patients are treated less actively concerning surgical and oncological treatment than younger patients, leading to worse cancer-specific survival. Older patients do not experience more treatment delays than younger ones.
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Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Estadificación de Neoplasias , Quimioterapia Adyuvante , Terapia Neoadyuvante , Procedimientos Quirúrgicos de Citorreducción , DinamarcaRESUMEN
INTRODUCTION: High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. A lack of effective and tolerable therapeutic options and nonspecific symptoms at presentation with advanced stage of disease are among the challenges in the management of the disease. AREAS COVERED: An overview of ovarian cancer, followed by a discussion of the current therapeutic regimes and challenges that arise during and after the treatment of EOC. We discuss different formats of antibody therapeutics and their usage in targeting validated targets implicated in ovarian cancer, as well as three emerging novel proteins as examples recently implicated in their contribution to adaptive resistance in ovarian cancer. EXPERT OPINION: Antibody therapeutics allow for a unique and effective way to target proteins implicated in cancer and other diseases, and have the potential to radically change the outcomes of patients suffering from ovarian cancer. The vast array of targets that have been implicated in ovarian cancer and yet the lack of effective therapeutic options for patients further stresses the importance of discovering novel proteins that can be targeted, as well as predictive biomarkers that can inform the stratification of patients into treatment-specific populations.
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Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológicoRESUMEN
BACKGROUND: Failure to respond to treatment in epithelial ovarian cancer can often be attributed to platinum-based chemotherapy resistance. However, the possible mechanisms or candidate biomarkers associated with platinum resistance are yet to be elucidated, even though many researchers have performed related studies. METHODS: We performed RNA sequencing of clinical specimens obtained from patients with platinum-sensitive or resistant epithelial ovarian cancer (EOC). Furthermore, various bioinformatics approaches, including spatial analysis of functional enrichment, were used to identify key regulators and associated underlying mechanisms of platinum resistance in EOC. RESULTS: Through RNA-sequencing, we identified 263 differentially expressed genes (98 upregulated and 165 downregulated) and subjected them to Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, which were characterized to the traditional platinum-resistant characteristics. Subsequently, the gene interaction network and module analysis by spatial analysis of functional enrichment software demonstrated protein kinase C and casein kinase substrate in neurons 3 (PACSIN3) as the only upregulated hub gene, and neurotensin (NTS) and KIAA0319 as downregulated hub genes in platinum-resistant EOC. We selected PACSIN3 for further analysis because it has not been studied in relation to response to platinum-based chemotherapy. PACSIN3 was significantly upregulated in ovarian cancer cells compared to immortalized human ovarian surface epithelial cells. In addition, cisplatin-induced apoptosis was measured in PACSIN3 knockout OVCA433 and BRCA-mutated EOC cell line, SNU251, by a fluorescence-activated cell sorting-based Annexin-V/propium iodide double staining assay, which revealed a significant increase in apoptosis. CONCLUSIONS: Taken together, the present study presents PACSIN3 as a promising predictive biomarker associated with platinum resistance, especially in BRCA-mutated epithelial ovarian cancers.
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Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Biología Computacional , Caseínas/genética , Caseínas/uso terapéutico , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Análisis de Secuencia de ARN , Biomarcadores , Neuronas/metabolismoRESUMEN
A standard treatment for advanced thymic epithelial tumors (TETs) after initial treatment remains unavailable to date. Targeted immune checkpoint inhibitors (ICIs) of the programmed cell death-1 (PD-1) pathway may produce objective responses in TETs, notably thymic carcinoma. Findings of clinical trials suggested ICIs are a practical choice. However, the risk of severe immuno-related adverse events is higher in TETs. Concerning histologic subtypes, thymomas are more frequently associated with autoimmune disorders than carcinomas, so close monitoring is needed for thymomas. In this article, we describe four cases of fatal toxicity caused by anti-PD-1 therapy in TETs. Four patients with metastatic thymomas or carcinoma difficult to treat with first-line standard chemotherapy were treated with the anti-PD-1 drug pembrolizumab or sintilimab. The association of PD-1 inhibitors with a high proportion of severe immuno-related adverse events in TETs necessitates attentive monitoring during treatment.
Thymic epithelial tumors are the most common malignancy of the anterior mediastinum in adults, with the occurrence of approximately 1.5 cases/million. Surgery is usually the treatment of choice. However, treatment options for advanced disease are poorly understood, and data are limited. Several studies have assessed the objective responses of immune checkpoint inhibitors in patients with advanced thymic epithelial tumors. Anti-cancer immunity also increases the risk of developing adverse events related to immunotherapy. Some patients can experience lethal toxicity. This article presents four cases of developing severe adverse events to exercise caution in prescribing these agents for thymic epithelial tumor, in particular thymoma.
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Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológicoRESUMEN
Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a shortterm fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, crossresistance and association with progressionfree survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatmentnaive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Crossresistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.