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BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.
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Neoplasias Ováricas , Vacunas Virales , Humanos , Femenino , Bevacizumab , Estudios Prospectivos , Carcinoma Epitelial de Ovario , Platino (Metal) , Neoplasias Ováricas/tratamiento farmacológico , Microambiente TumoralRESUMEN
BACKGROUND: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS: Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION: NCT3093155.
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Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Neoplasias Peritoneales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Epotilonas , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Trompas Uterinas , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Platino (Metal)/uso terapéuticoRESUMEN
BACKGROUND: Sclerosing stromal tumors (SSTs) are rare benign ovarian tumors that occur in adolescents and young adults. They are often treated with unilateral salpingo-oopherectomy due to concern for malignancy. CASE: A 13-year-old postpubertal female presented with sharp, constant abdominal pain with physical exam concerning for a lower abdominal mass. An ultrasound revealed a 9.7-cm solid, heterogenous left ovarian mass. The abdomen and pelvis CT confirmed the findings and showed a predominantly cystic mass arising from the left adnexa. During surgery, a smooth and distinct mass arising from the left ovary was encountered without abnormal findings in surrounding structures. A cystectomy was performed, and intraoperative findings showed no evidence of malignancy. Based on the lab, imaging, and surgical findings, staging and salpingo-oopherectomy were not pursued. SUMMARY AND CONCLUSION: Given the benign nature of SSTs, it is important to entertain the diagnosis in adolescents presenting with clinically congruent ovarian masses. The minimally invasive approach allows for sparing of the ovary in the adolescent population.
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Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Dolor Abdominal/etiología , Adolescente , Femenino , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/cirugía , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Ultrasonografía , Adulto JovenRESUMEN
BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.
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Neoplasias Endometriales , Inestabilidad de Microsatélites , Anticuerpos Monoclonales Humanizados , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Proyectos Piloto , Estudios ProspectivosRESUMEN
OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. METHODS: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. RESULTS: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01). CONCLUSIONS: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.
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Anticuerpos Monoclonales Humanizados/farmacología , Benzodiazepinas/farmacología , Cistadenocarcinoma Seroso/tratamiento farmacológico , Inmunoconjugados/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzodiazepinas/uso terapéutico , Efecto Espectador/efectos de los fármacos , Línea Celular Tumoral , Cistadenocarcinoma Seroso/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Persona de Mediana Edad , Cultivo Primario de Células , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Neoplasias Uterinas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
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Genotipo , Leiomiosarcoma/genética , Mutación , Fusión de Oncogenes , Neoplasias Uterinas/genética , Animales , Antineoplásicos/uso terapéutico , Femenino , Humanos , Leiomiosarcoma/tratamiento farmacológico , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida/métodos , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológicoRESUMEN
Background: Mortality from ovarian cancer remains high due to the lack of methods for early detection. The difficulty lies in the low prevalence of the disease necessitating a significantly high specificity and positive-predictive value (PPV) to avoid unneeded and invasive intervention. Currently, cancer antigen- 125 (CA-125) is the most commonly used biomarker for the early detection of ovarian cancer. In this study we determine the value of combining macrophage migration inhibitory factor (MIF), osteopontin (OPN), and prolactin (PROL) with CA-125 in the detection of ovarian cancer serum samples from healthy controls. Materials and Methods: A total of 432 serum samples were included in this study. 153 samples were from ovarian cancer patients and 279 samples were from age-matched healthy controls. The four proteins were quantified using a fully automated, multi-analyte immunoassay. The serum samples were divided into training and testing datasets and analyzed using four classification models to calculate accuracy, sensitivity, specificity, PPV, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). Results: The four-protein biomarker panel yielded an average accuracy of 91% compared to 85% using CA-125 alone across four classification models (p = 3.224 × 10-9). Further, in our cohort, the four-protein biomarker panel demonstrated a higher sensitivity (median of 76%), specificity (median of 98%), PPV (median of 91.5%), and NPV (median of 92%), compared to CA-125 alone. The performance of the four-protein biomarker remained better than CA-125 alone even in experiments comparing early stage (Stage I and Stage II) ovarian cancer to healthy controls. Conclusions: Combining MIF, OPN, PROL, and CA-125 can better differentiate ovarian cancer from healthy controls compared to CA-125 alone.
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Research within a gynecologic oncology population has lagged behind the uptake in use of medical cannabis for symptom control. This study seeks to evaluate patient experience with prescribed medical cannabis obtained through licensed dispensaries in women with gynecologic malignancies. A 43-item survey exploring patient experience with medical cannabis was administered to women with gynecologic malignancies who used medical cannabis prescribed by a gynecologic oncologist. Thirty-six eligible patients were approached for consent, and 31 patients returned completed surveys (86%). Ninety-three percent had advanced or recurrent disease; 74% were receiving chemotherapy or immunotherapy. Eighty-three percent reported medical cannabis provided relief from cancer or treatment-related symptoms including decreased appetite (41%), insomnia (41%), neuropathy (41%), anxiety (35%), nausea (29%), joint pain (29%), bone pain (29%), abdominal pain (25%), and depression (19%). Eighty percent of patients reported medical cannabis worked the same or better than other traditional medications for management of their cancer or treatment-related symptoms, and 83% reported medical cannabis had an equivalent or better side effect profile. Of the subset of patients using medical cannabis for pain, 63% reported a reduction in opioid use. Patients perceive that medical cannabis was useful for relief of cancer and treatment-related symptoms, suggesting medical cannabis may be a reasonable alternative or adjunct therapy. Medical cannabis was well tolerated and may have the potential to improve neuropathic pain and decrease opioid use.
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BACKGROUND AND OBJECTIVES: Transversus abdominis plane (TAP) block is a safe and effective type of regional anesthesia technique used in laparoscopic gynecologic surgery to minimize postoperative pain. Our study aimed to compare the analgesic effects of the posterior versus lateral approaches to laparoscopic-assisted TAP block in minimally invasive gynecologic surgery. METHODS: We performed a randomized controlled trial with 82 patients allocated to either posterior (n = 38) or lateral (n = 44) TAP block groups. Laparoscopic-assisted posterior or lateral TAP block was administered using liposomal bupivacaine mixture. All subjects were asked to fill out a questionnaire, which included postoperative pain scores at 6 h, 12 h, 24 h, 48 h, and 72 h, as well as narcotic utilization postoperatively. Both groups were compared for postoperative pain scores, opioid consumption, perioperative, and demographic characteristics. RESULTS: A total of 67 patients were analyzed in our study (n = 33 in posterior arm, n = 34 in lateral arm). Demographic characteristics including race, body mass index, comorbidities, American Society of Anesthesiologists classification, pre-operative diagnosis, complication rates, length of stay, and estimated blood loss were comparable between the two groups. The distribution of different operative procedures was similar between the two groups. There was no statistically significant difference in pain scores at 6 h, 12 h, 24 h, 48 h, and 72 h postoperatively between the two groups. However, patients receiving posterior TAP had a significant reduction in narcotic intake (p = 0.0009). CONCLUSION: Laparoscopic-assisted TAP block is a safe and effective option for regional analgesia in laparoscopic gynecologic surgery. Posterior TAP block may help to reduce narcotic usage postoperatively.
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Músculos Abdominales/inervación , Procedimientos Quirúrgicos Ginecológicos , Laparoscopía , Bloqueo Nervioso/métodos , Dolor Postoperatorio/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/epidemiología , Resultado del TratamientoRESUMEN
OBJECTIVE: Whole-exome-sequencing (WES) studies reported c-MYC gene-amplification and HUWE1 gene deletion/mutations in a significant number of cervical-cancer-patients (CC) suggesting HUWE1/c-MYC pathway as potential therapeutic target. We investigated HUWE1/c-MYC expression in fresh-frozen-CC and the activity of the novel BET inhibitor GS-626510 (Gilead-Science-Inc) against primary WES CC-cultures and CC-xenografts. METHODS: HUWE1 and c-MYC expression were evaluated by qRT-PCR in 23 CC including 12 fresh-frozen-tumor-tissues and 11 primary-cell-lines. c-Myc expression was also evaluated by Western-Blot (WB) and fluorescence-in-situ-hybridization (FISH) in all 11 fully sequenced primary-CC-cell-lines. Primary tumors were evaluated for sensitivity to GS-626510 in-vitro using proliferation and viability-assays. siRNA experiments were used to evaluate the effect of HUWE1 silencing on primary-CC-cell-line growth and sensitivity to GS-626510. Finally, the in-vivo activity of GS-626510 was studied in CC-CVX8-mouse-xenografts. RESULTS: Fresh-frozen-CC and primary-CC-cell-lines overexpressed c-MYC when compared to normal tissues (p = .01). FISH demonstrated amplification of c-MYC in 9/11 (82%) of the primary-CC-cell-lines. Cell-lines with derangements in HUWE1/c-MYC pathway were highly sensitive to GS-626510, with a dose-response decrease in cell proliferation and viability. siRNA silencing of HUWE1 significantly increased c-MYC expression and CC cell-proliferation and enhanced the in-vitro sensitivity to GS-626510. Twice-daily oral doses of GS-626510 were well tolerated in-vivo and highly effective in decreasing tumor-growth (p = .004) and increasing survival (p = .004) of CC-CVX8 xenografts. CONCLUSIONS: Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary-CC-cell-lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted.
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Isoxazoles/farmacología , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Adulto , Anciano , Animales , Línea Celular Tumoral , Femenino , Humanos , Imidazoles/farmacología , Hibridación Fluorescente in Situ , Ratones , Persona de Mediana Edad , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/biosíntesis , Ubiquitina-Proteína Ligasas/genética , Neoplasias del Cuello Uterino/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
PURPOSE: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002. PATIENTS AND METHODS: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints. RESULTS: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; P = 0.041). Toxicity was not different between arms. CONCLUSIONS: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cistadenocarcinoma Seroso/terapia , Neoplasias Endometriales/terapia , Recurrencia Local de Neoplasia/terapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidad , Procedimientos Quirúrgicos de Citorreducción , Esquema de Medicación , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/mortalidad , Endometrio/patología , Endometrio/cirugía , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Supervivencia sin Progresión , Receptor ErbB-2/análisis , Receptor ErbB-2/metabolismo , Análisis de Supervivencia , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversosRESUMEN
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2- tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.
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BACKGROUND: Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated with the active metabolite of irinotecan (SN-38). We evaluated the efficacy of SG against biologically aggressive CS. METHODS: Trop-2 expression was evaluated in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flow-cytometry. One Trop-2 low/negative (SARARK14) and two Trop-2 positive (SARARK4, SARARK9) cell-lines were tested in cell-viability assays . The in vivo antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression. RESULTS: Strong/diffuse staining was seen in 30% (3/10) of FFPE tumors and 33% (3/9) of primary CS cell lines. Trop-2 positive cell-lines (SARARK4, SARARK9) showed higher sensitivity to SG in vitro when compared to Trop-2 low/negative (SARARK14) cell lines. In xenografts, twice-weekly intravenous administration of SG for three weeks showed a significant tumor growth inhibition when compared to control, to ADC control and to the naked AB (p=0.004, p=0.007 and p=0.0007, respectively). SG significantly improved overall survival at 90 days when compared to control groups (p<0.0001). CONCLUSION: SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.
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Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with IC50 values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.
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Adenocarcinoma/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos de Neoplasias/metabolismo , Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Carcinoma de Células Escamosas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Inmunoconjugados/uso terapéutico , Neoplasias del Cuello Uterino/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Neoplasias/genética , Antineoplásicos/farmacología , Camptotecina/farmacología , Camptotecina/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Inmunoconjugados/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genéticaRESUMEN
Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell-surface antigen-2 (Trop-2) - a cell-surface glycoprotein highly expressed in many epithelial tumors - and delivers the active metabolite of irinotecan SN-38 to Trop-2-positive tumor cells. We evaluated Trop-2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiated EC cell lines and xenografts. Trop-2 expression was assessed in 143 formalin-fixed-paraffin-embedded tumors and seven primary tumor cell lines by immunohistochemistry and flow cytometry, respectively. Cell viability of primary tumor cell lines was assessed following exposure to SG, or control antibodies. Antibody-dependent cell cytotoxicity (ADCC) against Trop-2-positive and Trop-2-negative EC cell lines was measured in vitro using 4-h chromium release assays. A Trop-2-positive EC xenograft model was used to determine the in vivo activity of SG. Moderate-to-strong staining was detected in 84% (120/143) of EC samples, whereas 43% (3/7) of the primary EC cell lines tested overexpressed Trop-2. EC cell lines overexpressing Trop-2 were significantly more sensitive to SG compared to control ADC (P = 0.014 and P = 0.005). Both SG and the unconjugated parental antibody hRS7 mediated high ADCC against Trop-2-positive cell lines. Moreover, SG induced significant bystander killing of Trop-2-negative tumors cocultured with Trop-2-positive tumors. In the xenograft model, intravenous administration of SG twice weekly for three weeks was well tolerated and demonstrated impressive tumor growth inhibition against poorly differentiated, chemotherapy-resistant EC xenografts (P = 0.011). In summary, SG is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing Trop-2. These findings warrant future clinical trials.
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Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Carcinoma Endometrioide/tratamiento farmacológico , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Inmunoconjugados/farmacología , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos , Antineoplásicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunohistoquímica , Irinotecán/metabolismo , Ratones , Ratones SCID , Análisis de Matrices Tisulares , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. METHODS: We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. RESULTS: Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p <0.05). Both SG and hRS7 mediated ADCC in Trop2+ USC cell-lines while no cytotoxicity was detected against Trop-2- cells. SG induced significant bystander killing of Trop-2- tumors when admixed with Trop-2+ tumors. SG caused growth-inhibition and increased survival in SG treated mice harboring Trop-2+ xenografts when compared to controls (p <0.05). CONCLUSIONS: SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.
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Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Neoplasias/inmunología , Camptotecina/análogos & derivados , Moléculas de Adhesión Celular/inmunología , Inmunoconjugados/farmacología , Neoplasias Uterinas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos de Neoplasias/biosíntesis , Camptotecina/inmunología , Camptotecina/farmacología , Moléculas de Adhesión Celular/biosíntesis , Línea Celular Tumoral , Cistadenocarcinoma Seroso , Femenino , Citometría de Flujo , Humanos , Inmunoconjugados/inmunología , Inmunohistoquímica , Ratones , Ratones SCID , Terapia Molecular Dirigida , Distribución Aleatoria , Análisis de Matrices Tisulares , Neoplasias Uterinas/inmunología , Neoplasias Uterinas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Secuenciación del Exoma , Mutación , Receptor ErbB-2/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapia , Animales , Línea Celular Tumoral , Terapia Combinada , Variaciones en el Número de Copia de ADN , Femenino , Xenoinjertos , Humanos , Polimorfismo de Nucleótido Simple , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVES: Cervical cancer (CC) remains a major health problem worldwide. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutics in ovarian cancer. We explored the preclinical in vitro and in vivo activity of olaparib against multiple primary whole exome sequenced (WES) CC cells lines and xenografts. METHODS: Olaparib cell-cycle, apoptosis, homologous-recombination-deficiency (HRD), PARP trapping and cytotoxicity activity was evaluated against 9 primary CC cell lines in vitro. PARP and PAR expression were analyzed by Western blot assays. Finally, olaparib in vivo antitumor activity was tested against CC xenografts. RESULTS: While none of the cell lines demonstrated HRD, three out of 9 (33.3%) primary CC cell lines showed strong PARylation activity and demonstrated high sensitivity to olaparib in vitro treatment (cutoff IC50 valuesâ¯<â¯2⯵M, pâ¯=â¯0.0012). Olaparib suppressed CC cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (pâ¯<â¯0.0001). Olaparib activity in CC involved both PARP enzyme inhibition and trapping. In vivo, olaparib significantly impaired CC xenografts tumor growth (pâ¯=â¯0.0017) and increased overall animal survival (pâ¯=â¯0.008). CONCLUSIONS: A subset of CC primary cell lines is highly responsive to olaparib treatment in vitro and in vivo. High level of PARylation correlated with olaparib preclinical activity and may represent a useful biomarker for the identification of CC patients benefitting the most from PARPi.
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Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/enzimología , Adulto , Animales , Apoptosis/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones SCID , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: To determine if the use of an intrauterine manipulator is associated with an increased incidence of pseudovascular invasion on pathologic evaluation of hysterectomy specimens for endometrial cancer and to assess the possible implications of pseudovascular space invasion in the treatment of endometrial cancer. METHODS: We performed a retrospective cohort study of patients with early stage (I/II) endometrial cancer who underwent minimally invasive surgical staging. The following data were abstracted: race, body mass index, grade, age, stage, histology, presence or absence of lymphovascular space invasion (LVSI), peritoneal cytology, and adjuvant treatment. Slides were blindly reviewed by a gynecologic pathologist. RESULTS: Of the104 patients meeting eligibility criteria, 74 cases were reviewed in detail (the study was terminated early based on the results of an interim analysis). Patients in the no-manipulator group were older (P = .02) and had a higher stage 1B/II (P = .01) than patients in the manipulator group. No difference was found in the incidence of pseudovascular invasion between the manipulator and the no-manipulator groups (P = .86). Subgroup analysis showed no association of pseudovascular invasion with tumor grade (P = .79). Five patients were identified to have pseudovascular invasion misdiagnosed as true LVSI-4 had endometrioid and 1 had serous histology. Of these, 3 were in the manipulator group. Two received adjuvant radiotherapy which they not have gotten, absent reported lymphovascular invasion. CONCLUSION: The use of a uterine manipulator does not appear to increase the rate of pseudovascular invasion in our limited data set. Misdiagnosis of pseudovascular invasion as LVSI can result in risk migration of patients with potential for harm from unwarranted adjuvant therapy.