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High-grade serous ovarian cancer (HGSOC) and ovarian clear cell carcinoma (CC), are biologically aggressive tumors endowed with the ability to rapidly metastasize to the abdominal cavity and distant organs. About 10% of HGSOC and 30% of CC demonstrate HER2 IHC 3 + receptor over-expression. We evaluated the efficacy of trastuzumab deruxtecan (T-DXd; DS-8201a), a novel HER2-targeting antibody-drug conjugate (ADC) to an ADC isotype control (CTL ADC) against multiple HGSOC and CC tumor models. Eleven ovarian cancer cell lines including a matched primary and metastatic cell line established from the same patient, were evaluated for HER2 expression by immunohistochemistry and flow cytometry, and gene amplification by fluorescence in situ hybridization assays. In vitro experiments demonstrated T-DXd to be significantly more effective against HER2 3 + HGSOC and CC cell lines when compared to CTL ADC (p < 0.0001). T-DXd induced efficient bystander killing of HER2 non-expressing tumor cells when admixed with HER2 3 + cells. In vivo activity of T-DXd was studied in HER2 IHC 3 + HGSOC and CC mouse xenograft models. We found T-DXd to be significantly more effective than CTL ADC against HER2 3 + HGSOC (KR(CH)31) and CC (OVA10) xenografts with a significant difference in tumor growth starting at day 8 (p = 0.0003 for KR(CH)31, p < 0.0001 for OVA10). T-DXd also conferred a survival advantage in both xenograft models. T-DXd may represent an effective ADC against primary and metastatic HER2-overexpressing HGSOC and CC.
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High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.
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Adenocarcinoma , Carcinoma Neuroendocrino , Tumores Neuroendocrinos , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Afatinib , Filogenia , Fosfatidilinositol 3-Quinasas/genética , Mutación , Fosfatidilinositol 3-Quinasa Clase I/genética , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Análisis Mutacional de ADNRESUMEN
PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.
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Imiquimod , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Imiquimod/administración & dosificación , Femenino , Vacunas contra Papillomavirus/administración & dosificación , Adulto , Displasia del Cuello del Útero/inmunología , Displasia del Cuello del Útero/tratamiento farmacológico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Persona de Mediana Edad , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Aminoquinolinas/administración & dosificación , Aminoquinolinas/efectos adversos , Aminoquinolinas/uso terapéutico , Resultado del Tratamiento , Linfocitos T CD8-positivos/inmunología , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Lesiones Precancerosas/inmunología , Clasificación del Tumor , Adulto JovenRESUMEN
Uterine serous carcinoma (USC) is a rare, biologically aggressive variant of endometrial cancer with a high recurrence rate and poor prognosis. HER2 overexpression (3+ positivity) by IHC and/or FISH ERBB2 gene amplification is detected in approximately one-third of patients with USC. Clinical trials incorporating trastuzumab with standard chemotherapy have recently demonstrated improved progression-free and overall survival in advanced-stage or recurrent USC that overexpresses HER2. However, a large number of patients with USC eventually developed resistance to trastuzumab. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload recently approved by the Food and Drug Administration (FDA) for multiple tumor indications. Here, we investigated the in vitro and in vivo efficacy of T-DXd in primary USC cell lines and xenografts with different HER2 expression. T-DXd-induced cell growth suppression in HER2-overexpressing cell lines in vitro, increased early and late apoptosis as assessed by annexin and propidium iodide staining, and, similarly to trastuzumab, T-DXd-induced significant antibody-dependent cellular cytotoxicity in the presence of peripheral blood lymphocytes. While negligible activity was detected against USC cell lines with low HER2 expression, T-DXd demonstrated significant bystander killing against USC tumors with low/negligible HER2 when such cells were admixed with HER2 3+ tumor cells in vitro. T-DXd showed tumor growth suppression in in vivo USC PDX models that overexpress HER2 at 3+ levels, prolonging survival when compared with controls, with minimal toxicity. Future clinical trials are warranted in patients with USC failing trastuzumab treatment.
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Carcinoma , Inmunoconjugados , Neoplasias Uterinas , Femenino , Humanos , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Camptotecina/farmacología , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Carcinoma/tratamiento farmacológicoRESUMEN
Objective: To describe the surgical and oncologic outcomes in surgically treated oldest old women (≥80 years) with endometrioid endometrial cancer as a function of their comorbidities. Methods: In this retrospective cohort study, patients aged 80-99 years who underwent surgical management of stage I endometrioid endometrial cancer between 2006 and 2018 were included. Low- and high-intermediate risk disease was defined using the Gynecologic Oncology Group-99 criteria. The validated, Combined Age-Charlson Comorbidity Index (CA-CCI) was used to quantify comorbidity burden. Logistic regression was used to identify the independent predictors of various surgical and oncologic outcomes. Kaplan-Meier survival analysis was performed to compare survival distributions based on mortality cause and comorbidity status. Results: We identified 64 women who met the eligibility criteria. Median age was 84 years (IQR 80, 94 years). Among oldest old women undergoing a hysterectomy with or without lymph node dissection, women with a CA-CCI score of ≥7 had an 8 times higher risk of postoperative infections compared with oldest old women with a <7 score (95% CI 1.53-48.91, P = 0.015). Women with a CA-CCI score of ≥8 were 45% less likely to survive at 3 years (aRR 0.55, 95% CI 0.004-0.87; P = 0.039) than those with a lower CA-CCI score (three-year overall survival 73% vs 96%). Conclusion: Surgical and oncologic outcomes in oldest old women with early stage endometrioid endometrial cancer are largely determined by comorbidity status. Less comorbid women (CA-CCI score < 8) had a significantly higher five-year survival at 87% than their more comorbid counterparts. Use of age-comorbidity risk scoring such as CA-CCI, preoperative optimization, and careful selection for and counseling of patients about surgical treatment are paramount in providing optimal recovery and survival advantages in the oldest old.
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Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment modality that aims to target the main site of tumor dissemination in ovarian cancer, the peritoneum, by combining the benefits of intraperitoneal chemotherapy with the synergistic effects of hyperthermia all during a single administration at the time of cytoreductive surgery. High-quality evidence currently only supports the use of HIPEC with cisplatin at the time of interval cytoreduction after neoadjuvant chemotherapy for stage III epithelial ovarian cancer. Many questions remain, including HIPEC's role at other timepoints in ovarian cancer treatment, who are optimal candidates, and specifics of HIPEC protocols. This article reviews the history of normothermic and hyperthermic intraperitoneal chemotherapy in ovarian cancer and evidence regarding HIPEC implementation and patient outcomes. Additionally, this review explores details of HIPEC technique and perioperative care, cost considerations, complication and quality of life data, disparities in HIPEC use, and unresolved issues.
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Hipertermia Inducida , Neoplasias Ováricas , Femenino , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Calidad de Vida , Hipertermia Inducida/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Carcinoma Epitelial de Ovario/cirugía , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Procedimientos Quirúrgicos de Citorreducción/métodosRESUMEN
INTRODUCTION: Uterine leiomyosarcomas (uLMS) are rare, highly aggressive tumors. Up to 30% of uLMS may harbor gain of function (GOF) in the MAP2K4 gene, important for tumor cell proliferation, differentiation and metastasis. We investigated the in vivo activity of a novel MAP2K4 inhibitor, PLX8725, against uLMS harboring MAP2K4 gene-amplification. METHODS: Two fully characterized uLMS (i.e., LEY-11 and LEY-16) were grafted into female CB-17/SCID mice. Treatments with control vehicle or PLX8725 (50 mg/kg) were given via oral gavage daily on weekdays for up to 60 days. Tumor volume differences were calculated with two-way ANOVA. Pharmacokinetic (PK) and mechanistic studies of PLX8725 in uLMS PDX models were also performed. RESULTS: Both uLMS tumors evaluated demonstrated GOF in MAP2K4 (i.e., 3 CNV in both LEY-11 and LEY-16). Tumor growth inhibition was significantly greater in both PDX LEY-11 and PDX LEY-16 treated with PLX8725 when compared to controls (p < 0.001). Median overall survival was also significantly longer in both PDX LEY-11 (p = 0.0047) and PDX LEY-16 (p = 0.0058) treatment cohorts when compared to controls. PLX8725 oral treatment was well tolerated, and PK studies demonstrated that oral PLX8725 gives extended exposure in mice. Ex vivo tumor samples after PLX8725 exposure decreased phosphorylated-ATR, JNK and p38, and increased expression of apoptotic molecules on western blot. CONCLUSION: PLX8725 demonstrates promising in vivo activity against PDX models of uLMS harboring GOF alterations in the MAP2K4 gene with tolerable toxicity. Phase I trials of PLX8725 in advanced, recurrent, chemotherapy-resistant uLMS patients are warranted.
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Leiomiosarcoma , Neoplasias Pélvicas , Neoplasias Uterinas , Humanos , Femenino , Animales , Ratones , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Amplificación de Genes , Ratones SCID , Recurrencia Local de Neoplasia/genética , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , MAP Quinasa Quinasa 4/genéticaRESUMEN
OBJECTIVES: Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. METHODS: Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. RESULTS: In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. CONCLUSION: DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS.
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Carcinosarcoma , Inmunoconjugados , Neoplasias Ováricas , Humanos , Femenino , Ratones , Animales , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Hibridación Fluorescente in Situ , Receptor ErbB-2/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Línea Celular Tumoral , Trastuzumab/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias Ováricas/patología , Carcinosarcoma/patologíaRESUMEN
INTRODUCTION: Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression. METHODS: In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. RESULTS: HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC50: 2.06 ± 0.33 µM vs. 39.28 ± 30.51 µM, p = 0.0035 for olaparib and 19.42 ± 2.63 nM vs. 235.0 ± 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation. CONCLUSION: The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.
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Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Ribosa/uso terapéutico , Antineoplásicos/uso terapéutico , Ftalazinas/uso terapéutico , Neoplasias Ováricas/patología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Línea Celular TumoralRESUMEN
INTRODUCTION: Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy. Recent data suggest 50% of uLMS may harbor alterations in the ATRX gene and such mutations may confer sensitivity to ataxia-telangiectasia-and-Rad3-related (ATR) kinase inhibitors. We sought to investigate the in vivo activity of Elimusertib (BAY1895344), a novel ATR-inhibitor, against ATRX-mutated uLMS patient-derived xenografts (PDXs). METHODS: Two fully characterized uLMS (i.e., LEY-11 and LEY-16) were grafted into female CB-17/SCID mice. Treatments with control vehicle or BAY1895344 (20 mg/kg dosed twice daily 3 days on 4 days off) were given via oral gavage and tumor measurements as well as weights obtained twice weekly. Tumor volume differences were calculated with a two-way ANOVA. Mechanistic studies were performed ex vivo using BAY1895344 treated uLMS tumor samples by western blot analysis. RESULTS: Both PDX LEY-11 and PDX LEY-16 harboring ATRX gene mutations demonstrated an aggressive behavior in vivo (i.e., control mice were euthanized on average at day 12.5 for PDX LEY-11 and at day 33 for PDX LEY-16). In both tumor models BAY1895344 20 mg/kg dosed with an intermittent oral schedule was able to induce significant growth inhibition compared to vehicle control treatment (p < 0.001 for both LEY-11 and LEY-16) and prolong median overall survival [PDX LEY-11 (12.5 vs. 42 days, p < 0.001) and PDX LEY-16 (33 vs. 60 days, p < 0.001)]. There were not significant changes in weight between treatment and controls. By western blot assays BAY1895344 exposure decreased phosphorylated-ATR and increased expression of apoptotic molecules in LMS PDXs. CONCLUSIONS: BAY1895344 demonstrates promising in vivo activity against biologically aggressive PDX models of uLMS harboring ATRX mutations, with no significant toxicity. Clinical trials of BAY1895344 in uLMS patients are warranted.
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Leiomiosarcoma , Neoplasias Uterinas , Humanos , Femenino , Animales , Ratones , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Ratones SCID , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Mutación , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genéticaRESUMEN
BACKGROUND: Carcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. METHODS: Sensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. RESULTS: Out of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. CONCLUSIONS: Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.
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Antineoplásicos , Ataxia Telangiectasia , Carcinosarcoma , Neoplasias Uterinas , Femenino , Animales , Humanos , Ataxia Telangiectasia/tratamiento farmacológico , Ovario , Proteínas de la Ataxia Telangiectasia Mutada/genética , Línea Celular Tumoral , Antineoplásicos/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Carcinosarcoma/tratamiento farmacológico , Carcinosarcoma/genéticaRESUMEN
INTRODUCTION: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with a poor prognosis. Approximately 30% of USC overexpress HER2/neu, a recognized target for trastuzumab in advanced/recurrent HER2/neu-positive USC. We evaluated the efficacy of the pan-c-erb inhibitor neratinib and the poly (ADP-ribose)-polymerase (PARP) inhibitor olaparib as single agents and in combination against USC cell lines and xenografts. METHODS: In-vitro cell-viability assays with olaparib, neratinib, and olaparib/neratinib were assessed using flow-cytometry based assays against a panel of USC cell lines with high and low HER2/neu expression. Homologous recombination deficiency (HRD) signatures were evaluated as described by Alexandrov et al. (Nature;2020;578:94-101) while downstream signaling affected by neratinib/olaparib exposure was assessed with immunoblotting. Efficacy of single- versus dual-agent inhibition was evaluated in-vivo using two USC-xenografts with 3+ HER2/neu expression. RESULTS: Neratinib was more potent than olaparib in suppression of in-vitro growth of HER2/neu 3+ cell lines (ARK1: p = 0.0047; ARK2: p = 0.0428) while no difference was noted against HER2/neu 1+ tumors (ARK4). Importantly, the combination of olaparib with neratinib synergistically improved tumor suppression compared to either single-agent in vitro. USC cells exposed to olaparib upregulated HER2/neu expression, while neratinib treatment increased PARP activity (ARK1: p < 0.0001; ARK2: p < 0.0001). Single-agent neratinib transiently inhibited in vivo growth of USC xenografts harboring HER2/neu gene amplification (ARK1: p < 0.05; ARK2: p < 0.05). In contrast, the combination of the two inhibitors caused a stronger and durable growth inhibition in both USC xenografts (ARK1: p < 0.05; ARK2: p < 0.05). CONCLUSION: The combination of olaparib and neratinib is active and synergistic against primary HER2/neu + USC. This combination may represent a novel therapeutic option for USC patients with HER2/neu+, homologous recombination-proficient tumors resistant to chemotherapy.
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Cistadenocarcinoma Seroso , Neoplasias Uterinas , Línea Celular Tumoral , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Ftalazinas , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Quinolinas , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly(ADP-ribose)-polymerase inhibitors (PARPi) are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome-sequencing (WES) data from a cohort of fresh tumor samples of ovarian (OCS) and uterine carcinosarcoma (UCS), primary cell lines and xenografts to investigate the role for olaparib in CSs. METHODS: WES data from 73 CS samples (48 UCS and 25 OCS) were analyzed for HRD signatures. Olaparib activity was evaluated using cell-viability, cell-cycle, apoptosis and cytotoxicity assays against primary CS cell lines. Olaparib antitumor activity was tested in vivo against HRD CS xenografts. RESULTS: Signature-3 (i.e. HRD-related signature) was identified in 60% of OCS (15 of 25) vs 25% of UCS (12 of 48) (p = 0.005). CS cell lines harboring Signature-3/HRD (3 OCS/1 UCS) were significantly more sensitive to olaparib when compared to HRP cell lines (5 UCS/1 OCS) [mean IC50 ± SEM = 2.94 µM ± 0.07 vs mean ± SEM = 23.3 µM ± 0.09, (p = 0.02), respectively]. PARPi suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused more apoptosis in HRD vs HRP primary tumors (p < 0.0001). In vivo, olaparib significantly impaired HRD CS xenografts tumor growth (p = 0.0008) and increased overall animal survival (p < 0.0001). CONCLUSIONS: OCS and UCS cell lines harboring HRD signature-3 were significantly more sensitive to olaparib in vitro and in vivo when compared to HRP CS. Clinical studies with PARPi in CS patients with a dominant signature 3 (HRD-related) are warranted.
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Carcinosarcoma , Neoplasias Ováricas , Adenosina Difosfato/uso terapéutico , Animales , Carcinosarcoma/tratamiento farmacológico , Carcinosarcoma/genética , Línea Celular Tumoral , Femenino , Recombinación Homóloga , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ovario/patología , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas , Ribosa/uso terapéuticoRESUMEN
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
In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS. Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo.
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Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Reparación del ADN por Recombinación/genética , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológicoRESUMEN
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: To evaluate financial toxicity and assess its risk factors among patients with gynecologic cancers. METHODS: This is a cross sectional study that included 2 survey tools, as well as patient demographics, disease characteristics, and treatment regimen. Financial toxicity is measured by validated Comprehensive Score for Financial Toxicity (COST) tool. Participants were also asked to complete a 55-question-survey on attitudes and perspectives surrounding cost of care. Descriptive statistics was used to report patient demographics. Spearman's rank correlation was calculated to assess the relation between financial toxicity and patient/disease related variables. Graphpad Prism Software Version 8.0 was used for analyses. RESULTS: A total of 50 patients with various gynecologic malignancies were enrolled. Median COST score was 20.5 (range, 1-33). Sixty-five percent of the patients reported being in debt due to their cancer care and 4% filed bankruptcy. Correlation analysis showed that COST score was correlated with age (r=-0.3, p=0.028), malignancy type (r=0.3, p=0.039) and income (r=0.3, p=0.047). Ovarian cancer patients had significantly less financial toxicity (median COST score=23) when compared to patients with other gynecologic malignancies (median COST score=17, p=0.043). When scores were dichotomized into low (score ≥22) and high toxicity (score <22), 58% (29/50) of the patients were noted to have high financial toxicity. Enrollment to a clinical trial did not significantly alleviate financial burden. CONCLUSION: Financial toxicity is a significant burden even among highly insured gynecologic oncology patients. Age, malignancy type and income were correlated with high financial burden.
Asunto(s)
Estrés Financiero , Neoplasias de los Genitales Femeninos , Costo de Enfermedad , Estudios Transversales , Femenino , Humanos , Encuestas y CuestionariosRESUMEN
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.