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BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
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Carcinoma Epitelial de Ovario , Maitansina , Neoplasias Ováricas , Femenino , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Maitansina/administración & dosificación , Maitansina/efectos adversos , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Receptor 1 de Folato/antagonistas & inhibidores , Receptor 1 de Folato/genética , Resistencia a Antineoplásicos/genética , Compuestos de Platino/farmacologíaRESUMEN
OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.
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Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Inmunoconjugados , Maitansina , Neoplasias Ováricas , Trombocitopenia , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Gemcitabina , Neoplasias Ováricas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/etiología , Trompas Uterinas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/etiología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Diarrea/inducido químicamente , Trombocitopenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Maitansina/análogos & derivadosRESUMEN
OBJECTIVE: We aimed to validate whether pathologic response (pR) to neoadjuvant chemotherapy (NACT) using a three-tier chemotherapy response score (CRS) is associated with clinical outcome in ovarian cancer (OC) and could be used as surrogate marker for survival. METHODS: We conducted a retrospective study of OC patients with FIGO stage III/IV disease who received NACT and graded response as no or minimal (CRS 1), partial (CRS 2), or complete/near-complete (CRS 3) pR using tissue specimens obtained from omentum. Uni- and multivariate survival analyses were performed accounting for age, FIGO stage, debulking and BRCA status as well as neoadjuvant use of bevacizumab. RESULTS: CRSs 1, 2 and 3 were found in 41(31%), 62 (47%) and 30 (22%) of the 133 examined cases. Response to NACT was associated with significantly improved progression-free (PFS, p < 0.001) and overall survival (OS, p = 0.011). Complete/ near-complete pathologic response (CRS3) was associated with improved PFS (median 24.8 vs. 12.5 months, unadjusted HR 0.28 [95%CI 0.15-0.54], p < 0.001; adjusted hazard ration (aHR) 0.31 [95% CI 0.14-0.72], p = 0.007) and OS (median 63.3 vs. 32.1 months, unadjusted HR 0.27 [95%CI 0.10-0.68], p = 0.006; aHR 0.32 [95% CI 0.09-1.11], p = 0.072) when compared to no or minimal response (CRS1). CONCLUSIONS: We validate a three-tier CRS for assessment of pathologic response to NACT in OC and demonstrate its prognostic independence of BRCA status or neoadjuvant bevacizumab use. Improving pR rates may be a useful goal of NACT in OC with the expectation of improved survival. The CRS may be a useful endpoint in clinical trials in OC.
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OBJECTIVE: To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. METHODS: This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety. RESULTS: Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff). CONCLUSION: Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ováricas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Femenino , Humanos , Indazoles , Quimioterapia de Mantención , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Piperidinas , Platino (Metal)/uso terapéuticoRESUMEN
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Neoplasias Peritoneales , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/terapia , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Estados UnidosRESUMEN
OBJECTIVE: There is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This study aimed to approach this question by identifying prognostically relevant genes whose prognostic mRNA expression levels correlated with a genomic event. METHODS: Expression microarray and 5-year survival data on 170 ovarian tumors and aCGH data on 45 ovarian cancer cell lines were used to identify amplified/deleted genes associated with prognosis. Three immune-response genes were identified mapping to epigenetically modified chromosome 6p21.3. Genes were searched for roles in epigenetic modification, identifying KANSL1. Genome-wide association studies were searched to identify genetic variants in KANSL1 associated with altered immune profile. Sensitivity to HDAC inhibition in cell lines with KANSL1 amplification/rearrangement was studied. RESULTS: Expression of 196 genes was statistically significantly associated with survival, and expression levels correlated with copy number variations for 82 of them. Among these, 3 immune-response genes (HCP5, PSMB8, PSMB9) clustered together at epigenetically modified chromosome 6p21.3 and their expression was inversely correlated to epigenetic modification gene KANSL1. KANSL1 is amplified/rearranged in ovarian cancer, associated with lymphocyte profile, a biomarker for response to HDAC inhibition, and may drive expression of immune-response genes. CONCLUSION: This study identifies 82 genes with prognostic relevance and genomic alteration in ovarian cancer. Among these, immune-response genes have correlated expression which is associated with 5-year survival. KANSL1 may be a master gene altering immune-response gene expression at 6p21.3 and drive response to HDAC inhibitors. Future research should investigate KANSL1 and determine whether targeting it alters the immune profile of ovarian cancer and improves survival, HDAC inhibition, and/or immunotherapy response.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/terapia , Recurrencia Local de Neoplasia/epidemiología , Proteínas Nucleares/genética , Neoplasias Ováricas/terapia , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/mortalidad , Línea Celular Tumoral , Quimioterapia Adyuvante/métodos , Variaciones en el Número de Copia de ADN , Metilación de ADN/inmunología , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Epigénesis Genética/inmunología , Femenino , Estudios de Seguimiento , Amplificación de Genes/inmunología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Estudio de Asociación del Genoma Completo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Ovariectomía , Pronóstico , Piridinas/farmacología , Piridinas/uso terapéuticoRESUMEN
OBJECTIVE: To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. METHODS: Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model. RESULTS: Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05). CONCLUSION: The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
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Carcinoma Epitelial de Ovario/tratamiento farmacológico , Indoles/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Administración Oral , Anciano , Área Bajo la Curva , Proteína BRCA1 , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indoles/farmacocinética , Persona de Mediana Edad , Platino (Metal)RESUMEN
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypesâhigh-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.
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Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Adenocarcinoma de Células Claras , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/epidemiología , Carcinoma Epitelial de Ovario/terapia , Femenino , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/terapiaRESUMEN
PURPOSE: To assess the safety, feasibility, and efficacy of percutaneous thermal ablation (TA) in the treatment of metastatic gynecologic (GYN) tumors. MATERIALS AND METHODS: A study cohort of 42 consecutive women (mean age, 59. years; range, 25-78 years) with metastatic GYN tumors (119 metastatic tumors) treated with radiofrequency (n = 47 tumors), microwave (n = 47 tumors), or cryogenic (n = 30 tumors) ablation from over 2,800 ablations performed from January 2001 to January 2019 was identified. The primary GYN neoplasms consisted of ovarian (27 patients; 77 tumors; mean tumor diameter [MTD], 2.50 cm), uterine (7 patients; 26 tumors; MTD, 1.89 cm), endometrial (5 patients; 10 tumors; MTD, 2.8 cm), vaginal (2 patients; 5 tumors; MTD, 2.40 cm), and cervical (1 patient; 1 tumor; MTD, 1.90 cm) cancers. In order of descending frequency, metastatic tumors treated by TA were located in the liver or liver capsule (74%), lungs (13%), and peritoneal implants (9%). Single tumors were also treated in the kidneys, rectus muscle, perirectal soft tissue (2.5%), and retroperitoneal lymph nodes (1.6%). All efficacy parameters of TA and definitions of major and minor adverse events are categorized by the latest Society of Interventional Radiology reporting standards. RESULTS: The median follow-up of treated patients was 10 months. After the initial ablation, 95.6% of the patients achieved a complete tumor response confirmed by contrast-enhanced magnetic resonance imaging or computed tomography. On surveillance imaging, 8.5% of the ablated tumors developed local progression over a median follow-up period of 4.1 months. Five of 8 tumors with local recurrence underwent repeated treatment over a mean follow-up period of 18 months, and 4 of 5 tumors achieved complete eradication after 1 additional treatment session that resulted in a secondary efficacy of 80%. The overall technique efficacy of TA was 96.2% over a median follow-up period of 10 months. CONCLUSIONS: TA was safe and effective for the local control of metastatic GYN tumors in the lungs, abdomen, and pelvis, with an overall survival rate of 37.5 months and a local progression-free survival rate of 16.5 months, with only 4.8% of treated patients experiencing a major adverse event.
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Técnicas de Ablación , Neoplasias de los Genitales Femeninos/cirugía , Cirugía Asistida por Computador , Técnicas de Ablación/efectos adversos , Técnicas de Ablación/mortalidad , Adulto , Anciano , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Neoplasias de los Genitales Femeninos/diagnóstico por imagen , Neoplasias de los Genitales Femeninos/mortalidad , Neoplasias de los Genitales Femeninos/patología , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Supervivencia sin Progresión , Estudios Retrospectivos , Cirugía Asistida por Computador/efectos adversos , Cirugía Asistida por Computador/mortalidad , Factores de TiempoRESUMEN
Identifying patients who respond to immune checkpoint blockade (ICB) is a significant challenge in oncology. While PD-L1 expression by immunohistochemistry (IHC) is the current diagnostic gold standard for patient selection, it nevertheless does not capture all patients who may respond to ICB. Recent gene expression studies in high-grade serous ovarian carcinoma have defined an immunoreactive molecular subtype that has a measurable difference in patient survival compared with non-immunoreactive subtypes, but no studies have yet demonstrated its impact on predicting response to ICB. As a step toward establishing the predictive value of gene expression classifiers in ICB, we assessed the relationship between PD-L1 IHC and molecular subtypes of ovarian epithelial cancer. This was done by analyzing a total of 93 tissue specimens from patients with stage III and IV disease, and comparing PD-L1 IHC with gene expression by Agilent microarrays using TCGA-defined subtypes. We showed that ovarian tumors with elevated IHC PD-L1 expression are most strongly associated with immunoreactive subtype as compared with other molecular subtypes, reaching statistical significance against differentiated (Dunn's test, 33.39, p = 0.0003) and mesenchymal (39.63, p < 0.0001) subtypes. Comparing PD-L1 scoring with CPS vs. TPS showed similar trends, but with stronger correlation strength when using CPS (Kruskal-Wallis, H = 27.52, p < 0.0001), as opposed to TPS (H = 25.04, p < 0.0001). Interestingly, while PD-L1 gene expression by microarray was significantly increased in the immunoreactive subtype (H = 20.25, p = 0.0002), it showed a positive but relatively poor correlation to IHC. Overall, the results demonstrate potential value in use of the molecular classifier to select patients for ICB, pending further studies that assess its ability to predict treatment outcomes. In the future, integration of cellular, protein, and genomic biomarkers in the tumor and tumor microenvironment may improve current methods of predicting treatment response.
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Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Neoplasias Ováricas , Antígeno B7-H1/biosíntesis , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inmunohistoquímica/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , TranscriptomaRESUMEN
PURPOSE OF REVIEW: To summarize recently discovered PARP inhibitor resistance mechanisms and highlight the clinical relevance of these findings to date. RECENT FINDINGS: A predominant mechanism of acquired PARP inhibitor resistance in homologous recombination-deficient cancers is the acquisition of homologous recombination proficiency as a consequence of secondary genetic or epigenetic events, such as secondary mutations in BRCA1 or BRCA2, or reversal of BRCA1 promoter methylation that restores homologous recombination and leads to PARP inhibitor resistance. Multiple other potential mechanisms of acquired resistance to PARP inhibitors including loss of DNA end resection inhibition (53BP1/REV7/RIF1/Sheldin) or DNA replication fork protection (PTIP/EZH2), but also increased drug efflux or induction of a reversible senescent or mesenchymal cell state have been described in ovarian cancer models. However, only few of these mechanisms have been identified in clinical samples. SUMMARY: Multiple adaptive responses following PARP inhibitor treatment have been identified. Further research is needed to better understand what role these mechanisms play for clinical PARP inhibitor resistance and how these mechanisms may render ovarian cancer cells susceptible to subsequent novel combination therapies.
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Carcinoma Epitelial de Ovario/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Animales , Proteína BRCA1/efectos de los fármacos , Proteína BRCA2/efectos de los fármacos , Femenino , Recombinación Homóloga/efectos de los fármacos , Humanos , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Immune checkpoint blockade (ICB) is a promising area of cancer therapeutic research. Therapies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) mechanism of tumor immune evasion have resulted in durable responses in many difficult-to-treat tumor types. While these inhibitors are being actively investigated in clinical trials for ovarian cancer, most patients fail to respond to initial treatment with immune therapy. This review focuses on biomarkers for predicting response to treatment, and discusses clinical trials using ICB for recurrent ovarian cancer. RECENT FINDINGS: While PD-L1 detection by immunohistochemistry (IHC) is approved as a companion or complementary diagnostic in some cancers, there are many limitations with its use as a predictive marker. Recent research has explored biomarkers beyond PD-L1 that assess for somatic mutations, immune cell infiltrate, and gene signatures. SUMMARY: With improved understanding of the tumor microenvironment and genomic classifications of ovarian tumors, new diagnostics and biomarkers that supplement conventional IHC may help predict response to therapy.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Neoplasias Ováricas/tratamiento farmacológico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/patología , Microambiente Tumoral/genéticaRESUMEN
OBJECTIVES: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6â¯months (range 4.3-69â¯months). CONCLUSIONS: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.
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Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Neoplasias Endometriales/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inestabilidad de Microsatélites , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. FINDINGS: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9-16·2) versus 5·4 months (5·1-5·6; 0·32 [0·24-0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3-11·4) versus 5·4 months (5·3-5·5; 0·36 [0·30-0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). INTERPRETATION: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. FUNDING: Clovis Oncology.
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Indoles/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/terapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Anciano , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Internacionalidad , Quimioterapia de Mantención/métodos , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Medición de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the relationship between molecular subtype, intraperitoneal (IP) disease dissemination patterns, resectability, and overall survival (OS) in advanced high-grade serous ovarian cancer (HGSOC). METHODS: Patients undergoing primary surgery for stage III-IV HGSOC at Mayo Clinic from 1994 to 2011 were categorized into three IP disease dissemination patterns: upper abdominal or miliary; lower abdominal; and pelvic. Residual disease was defined as 0 (RD0), 0.1-0.5, 0.6-1.0, or >1â¯cm. Molecular subtypes were derived from Agilent 4x44k tumor mRNA expression profiles and categorized as mesenchymal (MES) or non-mesenchymal (non-MES). RESULTS: Operative and molecular data was available for 334 patients. Median OS was shorter in patients with MES compared to non-MES subtypes (34.2 vs 44.6â¯months; Pâ¯=â¯0.009). Patients with MES subtype were more likely to have upper abdominal/miliary disease compared to non-MES subtype (90% vs. 72%, Pâ¯<â¯0.001). For patients with upper abdominal/miliary disease, complete resection (RD0) was less common in MES compared to non-MES subtypes (11% vs. 27%, Pâ¯=â¯0.004). On multivariable analysis, RD was the only factor associated with OS (Pâ¯<â¯0.001). In patients with upper abdominal/miliary disease, though less commonly achieved, RD0 improved survival irrespective of molecular subtype (median OS of 69.2 and 57.9â¯months for MES and non-MES subtype). CONCLUSIONS: Our results support a paradigm in which molecular subtype is an important driver of dissemination pattern; this in turn impacts resectability and ultimately survival. Consequently mesenchymal subtype is associated with much lower rates of complete resection, though RD0 remains the most important independent predictor of survival.
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Cistadenocarcinoma Seroso/clasificación , Cistadenocarcinoma Seroso/mortalidad , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/mortalidad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer. RECENT FINDINGS: The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38. Both cleavable and noncleavable linkers are currently being investigated in clinical trials. A number of novel target antigens are currently being validated in ongoing clinical trials including folate receptor alpha, mesothelin, CA-125, NaPi2b, NOTCH3, protein tyrosine kinase-like 7, ephrin-A4, TROP2, CEACAM5, and LAMP1. For most ADCs currently in clinical development, dose-limiting toxicities appear to be unrelated to the targeted antigen but more tightly associated with the payload. Rational drug design involving optimization of the antibody, the linker and the conjugation chemistry is aimed at improving the therapeutic index of new ADCs. SUMMARY: Antibody-drug conjugates can increase the efficacy and decrease the toxicity of their payloads in comparison with traditional cyctotoxic agents. A better and quicker translation of recent scientific advances in the field of ADCs into rational clinical trials for patients diagnosed with ovarian, endometrial or cervical cancer could create real improvements in tumor response, survival and quality of life for our patients.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Terapia Molecular Dirigida , Animales , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Aprobación de Drogas , Diseño de Fármacos , Drogas en Investigación/efectos adversos , Drogas en Investigación/uso terapéutico , Femenino , Neoplasias de los Genitales Femeninos/metabolismo , Neoplasias de los Genitales Femeninos/mortalidad , Humanos , Inmunoconjugados/efectos adversos , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/tendencias , Tasa de Supervivencia , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. FINDINGS: 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. INTERPRETATION: In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. FUNDING: Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.
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Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Platino (Metal)/farmacología , Anciano , Antineoplásicos/farmacología , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial de Ovario , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal/genética , Humanos , Agencias Internacionales , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/química , Pronóstico , Estudios Prospectivos , Terapia Recuperativa , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To investigate the association between intraperitoneal (IP) disease dissemination patterns, residual disease (RD), surgical complexity, and molecular subtypes in advanced high-grade serous ovarian cancer (HGSOC). METHODS: 741 patients with operable stage III-IV HGSOC undergoing primary debulking surgery at Mayo Clinic from 1994 to 2011 were categorized into four mutually exclusive IP disease dissemination patterns: upper abdominal (60%), miliary (16%), lower abdominal (15%), and pelvic (9%). Surgical complexity was classified as high, intermediate, or low; RD status was defined as 0, 0.1-0.5, 0.6-1.0, or >1cm; molecular subtype assignments were derived from expression profiling of tumors from 334 patients. RESULTS: Patients with either miliary or upper abdominal dissemination patterns were less likely to achieve RD0 compared to patients with pelvic and lower abdominal dissemination patterns (25% vs. 9% and 62%, each P<0.001) despite higher surgical complexity (39% vs. 6% and 20%, each P<0.001). Among the subset with molecular subtype data, patients with mesenchymal subtype of tumors were more likely to have upper abdominal or miliary dissemination patterns compared to patients with differentiated, proliferative, or immunoreactive subtypes (90% vs. 77%, 70%, 69%, respectively, P<0.05). CONCLUSIONS: IP disease dissemination patterns are associated with RD, surgical complexity, and tumor molecular subtypes. Patients with upper abdominal or miliary dissemination patterns are more likely to have mesenchymal HGSOC and in turn achieve lower rates of complete resection. This provides a plausible model for how the biologic behavior of molecular subtypes is manifest in disease and oncologic outcomes.
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Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Anciano , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasia Residual , Cavidad Peritoneal/patologíaRESUMEN
OBJECTIVE: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments. RESULTS: In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile.
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Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Indoles/uso terapéutico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial de Ovario , Femenino , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
OBJECTIVES: We report single-institution clinical outcomes of women treated with stereotactic ablative radiotherapy (SABR) for oligometastatic or progressive gynecological malignancies. MATERIALS AND METHODS: From 2009 to 2015, 47 lesions from 28 patients were treated with SABR and retrospectively analyzed. All patients had oligometastatic (93%) or oligoprogressive (7%) disease. Primary cancer diagnoses were 15 ovarian, 8 endometrial, 2 cervical, 2 vaginal, and 1 uterine carcinosarcoma. Treatment was delivered using a median of 5 fractions to a median total dose of 40 Gy. Targets were grouped by treatment site and assessed for response using Response Evaluation Criteria in Solid Tumors v1.1. Mean biologically effective dose and pre-SABR tumor size were compared with response. Progression-free survival (PFS) was determined using Kaplan-Meier analysis, and toxicity outcomes were graded using Common Terminology Criteria for Adverse Events version 4.03. RESULTS: Median follow-up was 12.8 months. Target locations were 17% liver, 21% lung, 17% paraaortic node, 26% other node, and 19% pelvic soft tissue. After treatment, 34% of targets were stable (SD), 32% had a partial response (PR), 17% had a complete response (CR), and 17% had progressive disease (PD). No failures occurred in lung or nodal targets. Mean ± standard deviation pre-SABR tumor diameter was 24 ± 22 mm. There was a significant difference in mean size between lesions that had a favorable (SD, PR, and CR) versus unfavorable response (PD) (17.2 vs 57.6 mm, P = 0.0044). Lesions that responded favorably were also more likely to have received a higher biologically effective dose (79.0 vs 59.6 Gy, P = 0.027). Median PFS was 10.8 months, and 1 patient experienced grade 3 toxicity. CONCLUSIONS: The SABR is a safe and effective local treatment modality in patients with oligometastatic gynecological disease. Distant progression remains the primary mode of failure in this patient population. In carefully selected patients, a combination of systemic treatment and SABR may offer long-term PFS.