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PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.
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PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.
Subject(s)
Indazoles , Ovarian Neoplasms , Piperidines , Humans , Female , Indazoles/adverse effects , Indazoles/administration & dosage , Piperidines/administration & dosage , Piperidines/adverse effects , Piperidines/therapeutic use , Middle Aged , Aged , Ovarian Neoplasms/drug therapy , Adult , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Isoquinolines/administration & dosage , Isoquinolines/adverse effects , Isoquinolines/therapeutic use , Maintenance ChemotherapyABSTRACT
OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.
Subject(s)
Indazoles , Ovarian Neoplasms , Piperidines , Progression-Free Survival , Humans , Female , Indazoles/therapeutic use , Indazoles/administration & dosage , Piperidines/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/mortality , Middle Aged , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Adult , AgedABSTRACT
We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.
Subject(s)
Chromosomes, Human, Pair 7 , DNA Copy Number Variations , ErbB Receptors , Ovarian Neoplasms , Humans , Female , ErbB Receptors/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovarian Neoplasms/drug therapy , Middle Aged , Chromosomes, Human, Pair 7/genetics , Prospective Studies , Aged , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Adult , Retroelements/genetics , Phenotype , Drug Resistance, Neoplasm/genetics , Endogenous Retroviruses/genetics , Loss of HeterozygosityABSTRACT
Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.
Subject(s)
Biomarkers, Tumor , Drug Resistance, Neoplasm , Endonucleases , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/blood , Ovarian Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Endonucleases/genetics , Middle Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Aged , DNA-Binding Proteins/genetics , DNA-Binding Proteins/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Estrogen Receptor alpha/genetics , Adult , Prognosis , Disease Progression , Gene Expression Regulation, Neoplastic , Platinum/therapeutic useABSTRACT
Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.
Subject(s)
Clonal Hematopoiesis , DNA Damage , Mutation , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Middle Aged , Aged , Carboplatin/pharmacology , Adult , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Protein Phosphatase 2CABSTRACT
The aim of this survey was to increase the knowledge on the characteristics and health concerns of long-term survivors (LTS; survival > 5 years) after ovarian cancer in order to tailor follow-up care. This international survey was initiated by the NOGGO and was made available to members of ENGOT and GCIG. The survey is anonymous and consists of 68 questions regarding sociodemographic, medical (cancer) history, health concerns including distress, long-term side effects, and lifestyle. For this analysis, 1044 LTS from 14 countries were recruited. In total, 58% were diagnosed with FIGO stage III/IV ovarian cancer and 43.4% developed recurrent disease, while 26.0% were receiving cancer treatment at the time of filling in the survey. LTS who survived 5-10 years self-estimated their health status as being significantly worse than LTS who survived more than 10 years (p = 0.034), whereas distress also remained high 10 years after cancer diagnosis. Almost half of the cohort (46.1%) reported still having symptoms, which were mainly lymphedema (37.7%), fatigue (23.9%), pain (21.6%), polyneuropathy (16.9%), gastrointestinal problems (16.6%), and memory problems (15.5%). Almost all patients (94.2%) regularly received follow-up care. Specialized survivorship care with a focus on long-term side effects, lifestyle, and prevention should be offered beyond the typical five years of follow-up care.
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OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.
Subject(s)
Endometrial Neoplasms , Paclitaxel , Humans , Female , Paclitaxel/adverse effects , Treatment Outcome , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/etiology , Progression-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. METHODS: The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. RESULTS: Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. CONCLUSIONS: ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.
Subject(s)
Endometrial Neoplasms , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , Mice , Animals , Female , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Caspase 1/genetics , Caspase 1/metabolism , Caspase 1/pharmacology , Mice, Nude , Pyroptosis , Cisplatin/pharmacology , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Glycolysis , Tumor Microenvironment , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , Phosphate-Binding Proteins/pharmacology , Pore Forming Cytotoxic Proteins/metabolism , ERRalpha Estrogen-Related ReceptorABSTRACT
Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDL receptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P = .005), 29 months (P = .005), and 25 months (P = .001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P = .002), 19 months in stroma (P = .004), and 19 months in both cell types combined (P = .01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications.
Subject(s)
Cystadenocarcinoma, Serous , Fallopian Tube Neoplasms , Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/pathology , Prognosis , Cystadenocarcinoma, Serous/pathology , Progression-Free Survival , Fallopian Tube Neoplasms/pathology , Receptors, LDL/therapeutic useABSTRACT
The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.
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BACKGROUND: Surgery is the backbone of early-stage ovarian cancer (OC) management. However, in practice, there is disagreement about the extent of surgical staging and whether additional adjuvant treatment should be provided. As omitting relevant diagnostic or therapeutic procedures might lead to undertreatment, we aimed to structurally investigate treatment practice in addition to prognostic factors in a multicentre series of patients (pts) diagnosed with early-stage OC. PATIENTS: Within this retrospective, multicentre study, medical records of 379 pts who had undergone surgery for suspected early-stage OC between January 2014 and March 2020 were analysed. RESULTS: Of the 379 patients, 292 had pT stage 1a-2a and had complete data on the extent of surgical staging. At least one surgical step was omitted in 100 pts (34.2%). Complete surgical staging (n = 192; (65.8%)) was more often performed in high-grade serous OC and was independent of the healthcare level of the hospital where the initial diagnosis was made. Missing to take peritoneal biopsies was associated with reduced relapse-free-survival in incompletely staged, pT1 cases (p = 0.03). About every second patient (46.7%) with a final stage lower than FIGO IIB and treated with adjuvant chemotherapy received combination chemotherapy. BRCA1 and BRCA2 testing was only performed in a subset of pts, and mutations were detected in 18% (14/79) and 9% (7/85) pts, respectively. CONCLUSIONS: This study helps to increase our understanding of early-stage OC treatment and prognosis. In addition to treating patients in compliance with current guidelines, the need for BRCA testing should also be considered for early-stage OC.
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PURPOSE: For patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis. METHODS: Blood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state. RESULTS: Maximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples. CONCLUSION: A total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.
Subject(s)
Antineoplastic Agents , Kidney Failure, Chronic , Ovarian Neoplasms , Humans , Female , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/chemically induced , Antineoplastic Agents/adverse effects , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Renal Dialysis , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Dialysis Solutions/therapeutic use , Phthalazines/adverse effectsABSTRACT
PURPOSE: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC). METHODS: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573. RESULTS: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment. CONCLUSION: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.
Subject(s)
Leukopenia , Ovarian Neoplasms , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial/drug therapy , Leukopenia/chemically induced , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/etiology , Platinum/pharmacology , Topotecan/therapeutic useABSTRACT
PURPOSE: In recent years the tumor microenvironment and its interaction with the tumor has emerged into research focus with increased attention to the composition of Tumor-infiltrating lymphocytes. We wanted to quantify the composition of Regulatory T cells (Tregs) and T helper 17 cells (Th17 cells) and their prognostic impact in high-grade serous tubo-ovarian carcinoma. METHODS: Tregs and Th17 cells were determined by immunohistochemical analysis of CD25 FoxP3 and RORγt, respectively on tissue microarrays of a cohort of 222 patients with reviewed histology and available clinical data. Expression was analyzed with Qupath for quantification and integration with clinical data enabled calculation of prognostic impact. For validation FOXP3 and RORC mRNA expression levels from 502 patients with HGSC in publicly available datasets were evaluated. RESULTS: An average percentage of 0.93 Tregs and of 0.06 Th17 cells was detected per cells in overall tissue. Optimal cut-offs were determined and higher Tregs were associated with a better overall survival in stroma (p = 0.006), tumor area (p = 0.0012) and overall tissue (p = 0.02). After accounting for well-known prognostic factors age at diagnosis, residual tumor and FIGO stage, this association remained significant for stromal Tregs with overall survival (p = 0.02). Survival analysis for Th17 cells revealed no significant association with survival rates. Moreover, lower Th17/Treg ratios had a positive impact on patient overall survival (p = 0.025 tumor, p = 0.049 stroma and p = 0.016 overall tissue). CONCLUSION: Our results outline a positive prognostic effect for higher Tregs but not for Th17 in high grade serous tubo-ovarian carcinoma.
Subject(s)
Ovarian Neoplasms , T-Lymphocytes, Regulatory , Humans , Female , Prognosis , T-Lymphocytes, Regulatory/pathology , Th17 Cells/metabolism , Th17 Cells/pathology , Ovarian Neoplasms/pathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Tumor MicroenvironmentABSTRACT
BACKGROUND: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC). PATIENTS AND METHODS: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups. RESULTS: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence. CONCLUSIONS: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC.
Subject(s)
Breast Neoplasms , Ovarian Neoplasms , Humans , Female , Retrospective Studies , Mutation , Treatment Outcome , Ovarian Neoplasms/genetics , Ovarian Neoplasms/surgeryABSTRACT
RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro studies have linked RGS2 suppression to chemoresistance in HGSOC, but in situ data are still missing. In this study, we characterized the expression of RGS2 and its relation to prognosis in HGSOC on the protein level by immunohistochemistry in 519 patients treated at Charité, on the mRNA level in 299 cases from TCGA and on the single-cell level in 19 cases from publicly available datasets. We found that RGS2 is barely detectable on the mRNA level in both bulk tissue (median 8.2. normalized mRNA reads) and single-cell data (median 0 normalized counts), but variably present on the protein level (median 34.5% positive tumor cells, moderate/strong expression in approximately 50% of samples). Interestingly, low expression of RGS2 had a negative impact on overall survival (p = 0.037) and progression-free survival (p = 0.058) on the protein level in lower FIGO stages and in the absence of residual tumor burden. A similar trend was detected on the mRNA level. Our results indicated a significant prognostic impact of RGS2 protein suppression in HGSOC. Due to diverging expression patterns of RGS2 on mRNA and protein levels, posttranslational modification of RGS2 is likely. Our findings warrant further research to unravel the functional role of RGS2 in HGSOC, especially in the light of new drug discovery.
ABSTRACT
BACKGROUND: To evaluate the diagnostic value of adding human epididymis protein 4 (HE4), cancer antigen 125 (CA125) and risk of malignancy algorithm (ROMA) to ultrasound for detecting ovarian cancer in patients with a pelvic mass. METHODS: This was a prospective, observational, multicenter study. Patients aged > 18 years who were scheduled to undergo surgery for a suspicious pelvic mass had CA125 and HE4 levels measured prior to surgery, in addition to a routine transvaginal ultrasound scan. The diagnostic performance of CA125, HE4 and ROMA for distinguishing between benign and malignant adnexal masses was assessed using receiver operating characteristic (ROC) analysis and the corresponding area under the curve (AUC). RESULTS: Of 965 evaluable patients, 804 were diagnosed with benign tumors and 161 were diagnosed with ovarian cancer. In late-stage ovarian cancer, CA125, HE4 and ROMA all had an excellent diagnostic performance (AUC > 0.92), whereas in stage I and II, diagnostic performance of all three biomarkers was less adequate (AUC < 0.77). In the differential diagnosis of ovarian cancer and endometriosis, ROMA and HE4 performed better than CA125 with 99 and 98.1% versus 75.0% sensitivity, respectively, at 75.4% specificity. CONCLUSIONS: ROMA and HE4 could be valuable biomarkers to help with the diagnosis of ovarian cancer in premenopausal patients in order to differentiate from endometriosis, whereas CA125 may be more adequate for postmenopausal patients.