Relapsed Epithelial Ovarian Cancer Research Articles

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

Impact of Bevacizumab on Clinical Outcomes in Patients With Platinum-resistant Relapsed Ovarian Cancer.

Over the past several decades, new anti-cancer drugs have been developed for the treatment of epithelial ovarian cancer. The development of drugs has led to changes in improving the prognosis of ovarian cancer patients. One of these drugs, bevacizumab, is used for advanced or recurrent ovarian cancer. In this study, we aimed to evaluate survival improvement in patients with platinum-resistant relapsed epithelial ovarian cancer (PR-ROC) after introduction of bevacizumab in real world experience. We retrospectively divided patients with PR-ROC into two groups: bevacizumab plus chemotherapy (BEV-CT group) and chemotherapy alone (CT group). Progression-free survival (PFS), the primary endpoint, between two groups was compared to evaluate whether survival outcomes were improved. In addition, overall survival (OS) was also compared. A total of 154 patients were included in the study: 57 and 97 patients in the BEV-CT and CT groups, respectively. OS was significantly longer in the BEV-CT group than in the CT group. The use of bevacizumab was identified as a favorable prognostic factor for OS. In a subgroup analysis confined to second-line chemotherapy, PFS and OS were statistically different between groups. More patients in the CT group suffered hematologic adverse events of grade 3 or above than patients in the BEV-CT group. In a real-world clinical setting, introduction of bevacizumab led to improvement of OS in patients with PR-ROC with a tolerable toxicity.

Mechanisms of carboplatin- and paclitaxel-dependent induction of premature senescence and pro-cancerogenic conversion of normal peritoneal mesothelium and fibroblasts.

Carboplatin (CPT) and paclitaxel (PCT) are the optimal non-surgical treatment of epithelial ovarian cancer (EOC). Although their growth-restricting influence on EOC cells is well known, their impact on normal peritoneal cells, including mesothelium (PMCs) and fibroblasts (PFBs), is poorly understood. Here, we investigated whether, and if so, by what mechanism, CPT and PCT induce senescence of omental PMCs and PFBs. In addition, we tested whether PMC and PFB exposure to the drugs promotes the development of a pro-cancerogenic phenotype. The results showed that CPT and PCT induce G2/M growth arrest-associated senescence of normal peritoneal cells and that the strongest induction occurs when the drugs act together. PMCs senesce telomere-independently with an elevated p16 level and via activation of AKT and STAT3. In PFBs, telomeres shorten along with an induction of p21 and p53, and their senescence proceeds via the activation of ERK1/2. Oxidative stress in CPT + PCT-treated PMCs and PFBs is extensive and contributes causatively to their premature senescence. Both PMCs and PFBs exposed to CPT + PCT fuel the proliferation, migration, and invasion of established (A2780, OVCAR-3, SKOV-3) and primary EOCs, and this activity is linked with an overproduction of multiple cytokines altering the cancer cell transcriptome and controlled by p38 MAPK, NF-κB, STAT3, Notch1, and JAK1. Collectively, our findings indicate that CPT and PCT lead to iatrogenic senescence of normal peritoneal cells, which paradoxically and opposing therapeutic needs alters their phenotype towards pro-cancerogenic. It cannot be excluded that these adverse outcomes of chemotherapy may contribute to EOC relapse in the case of incomplete tumor eradication and residual disease initiation. © 2023 The Pathological Society of Great Britain and Ireland.

What are the effects of pegylated liposomal doxorubicin (PLD) for women with platinum-sensitive or platinum-resistant relapsed epithelial ovarian cancer?

What are the effects of pegylated liposomal doxorubicin (PLD) for women with platinum-sensitive or platinum-resistant relapsed epithelial ovarian cancer?

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI

ObjectiveTo determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a...

68Ga]Ga-FAPI-04 PET/CT in the evaluation of epithelial ovarian cancer: comparison with [18F]F-FDG PET/CT.

To compare the efficacy of [68Ga]Ga-FAPI-04 PET/CT in primary or recurrent tumors and metastatic lesions of epithelial ovarian cancer (EOC) with that of fluorine-18 fluorodeoxyglucose ([18F]F-FDG) PET/CT. Forty-nine patients (median age, 57 years; IQR, 51-66 years) with histologically proven primary or relapsed EOC were enrolled. Participants underwent [18F]F-FDG and [68Ga]Ga-FAPI-04 PET/CT. The detection rate, diagnostic accuracy, semiquantitative parameters, tumor staging, and clinical management of the tracers were compared. The diagnostic performance of [18F]F-FDG and [68Ga]Ga-FAPI-04 PET/CT was evaluated and compared using surgical pathology. Differences between methods regarding the peritoneal cancer index (PCI) using preoperative imaging, surgical PCI, and tumor markers (CA125, HE4) were also assessed regarding peritoneal metastases. Among the 49 patients, 28 had primary EOC; 21 had relapsed EOC. [68Ga]Ga-FAPI-04 PET/CT outperformed [18F]F-FDG PET/CT in detecting peritoneal metastases (96.8% vs. 83.0%; p < 0.001), retroperitoneal (99.5% vs. 91.4%; p < 0.001), and supradiaphragmatic lymph node metastases (100% vs. 80.4%; p < 0.001). Compared with [18F]F-FDG, [68Ga]Ga-FAPI-04 showed higher SUVmax for peritoneal metastases (17.31 vs. 13.68; p = 0.026) and retroperitoneal (8.72 vs. 6.56; p < 0.001) and supradiaphragmatic lymph node metastases (6.39 vs. 4.20; p < 0.001). Moreover, [68Ga]Ga-FAPI-04 PET/CT showed higher sensitivity compared with [18F]F-FDG PET/CT for detecting metastatic lymph nodes (80.6% vs. 61.3%; p = 0.031) and peritoneal metastases (97.5% vs. 75.9%; p < 0.001), using surgical pathology as the gold standard. Compared with [18F]F-FDG PET/CT, [68Ga]Ga-FAPI-04 PET/CT led to an upgrade in 14.3% and 33.3% of treatment-naive and relapse participants, resulting in management changes in 10.7% and 19.0% of the patients, respectively. The median PCIFAPI scores were significantly higher than PCIFDG (15 vs. 11; p < 0.001) and positively correlated with CA125 and HE4 levels and surgical PCI. [68Ga]Ga-FAPI-04 PET/CT achieved higher sensitivity than [18F]F-FDG PET/CT in the detection and diagnosis of lymph node and peritoneal metastases, suggesting advantages regarding the preoperative staging of patients with EOC and, thereby, improving treatment decision-making. NCT05034146. Registered February 23, 2021.

Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

The role of minimally invasive surgery in epithelial ovarian cancer treatment: a narrative review.

The aim of this narrative review is to summarize the available evidence on the use of minimal invasive surgery (MIS) in the management of epithelial ovarian cancer (EOC). MIS is currently performed to stage and treat EOC at different stage of presentation. We will evaluate risks and benefits of minimally invasive surgery for early stage EOC treatment, then potential advantages provided by staging laparoscopy in identifying patients suitable for primary cytoreductive surgery (PDS) will be discussed. Finally we will investigate the growing role of MIS in the treatment of advanced EOC after neoadjuvant chemotherapy (NACT) and in the treatment of EOC recurrence. An electronic database search was performed on PubMed, Medline, and Google Scholar for relevant studies up to December 2022. LPS represents a feasible surgical procedure for the staging and treatment in early, advanced and EOC relapse in selected patients treated in high-volume oncological centers by surgeons with adequate experience in advanced surgical procedures. Despite the increasing use of MIS over the last few years, randomized clinical trials are still needed to prove its effectiveness.

Hyperthermic intraperitoneal chemotherapy in platinum-sensitive relapsed epithelial ovarian cancer: The CHIPOR randomized phase III trial.

5510 Background: Standard treatment for patients with first platinum-sensitive relapse of epithelial ovarian cancer (EOC) is based on surgery and second-line systemic chemotherapy (CT). The role of hyperthermic intra-peritoneal chemotherapy (HIPEC) remains uncertain. Methods: The CHIPOR multicentric randomized phase III trial (NCT01376752), conducted in 31 institutions, enrolled patients with a first platinum-sensitive relapse (platinum-free interval of ≥6 months) of EOC. Patients were treated with 6 cycles of platinum and taxane based CT ± bevacizumab, and those amenable to a complete cytoreductive surgery at the end of CT were enrolled and randomly assigned to receive HIPEC (cisplatin 75 mg/m² at 41°C for 60 min) or not. Randomization was performed during complete cytoreductive surgery, stratified by center, surgical outcome (no residual disease vs residual &lt;0.25 cm), chemotherapy-free interval before relapse, and PARP inhibitor use (yes vs no). The primary endpoint was overall survival (OS). The target sample size was 404 evaluable patients, providing 80% power at 5% alpha after 268 deaths. Secondary endpoints included progression-free survival (PFS), peritoneal PFS, patient-reported outcomes, safety, and postoperative morbidity and mortality (≤60 days after surgery). Results: Between May 11, 2011, and May 14, 2021, 415 patients were randomized. Baseline characteristics were balanced between treatment arms. At the data cutoff (Jan 8, 2023), with a median follow-up of 6.2 years, 268 patients (65%) had died. Efficacy results are summarized below. Conclusions: HIPEC significantly improves OS and peritoneal PFS of women with first platinum-sensitive relapse of EOC treated with second-line platinum-based CT followed by secondary complete cytoreductive surgery. Ongoing analyses, including patient reported outcome, BRCA status, bevacizumab exposure, and subsequent therapy, will be presented. Clinical trial information: NCT01376752 . [Table: see text]

TEDOVA/GINECO-OV244b/ENGOT-ov58 trial: Neo-epitope based vaccine OSE2101 alone or in combination with pembrolizumab vs best supportive care (BSC) as maintenance in platinum-sensitive recurrent ovarian cancer with disease control after platinum.

TPS5618 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A*02-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 20211). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information NCT04713514. 1. Besse B, Garcia MR, Cobo MA, Quoix E, Madroszyk A, Felip E, et al. LBA47 - Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO): Final results of phase III Atalante-1 randomised trial. Annals of Oncology 2021;32(suppl_5) : S1283-S1346. Clinical trial information: NCT04713514 .

Observation of the therapeutic effect of apatinib in advanced platinum-resistant recurrent epithelial ovarian cancer

BackgroundApatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC).MethodsA retrospective analysis was performed, the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018 were collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the final case data included in this study.ResultsAccording to 1:2 propensity matching, 108 patients were finally taken into account: 36 in the apatinib group and 72 in the control group. The follow-up ended in January 2019, and the median follow-up time was 28 months. In the apatinib group, ORR was 30.56% and DCR was 66.67%, whereas in the control group, ORR was 16.67% and DCR was 44.44%. In the apatinib group, median PFS was 6.0 months (95% CI 3.69–8.31) and median OS was 15.8 months (95% CI 6.99–24.6), while in the control group, median PFS was 3.3 months (95% CI 2.44–4.16) and median OS was 9.2 months (95% CI 6.3–12.06); the difference was statistically significant (P < 0.05). Apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22–0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21–0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence affecting the OS of patients. The main grade 3–4 adverse events in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers, and all adverse events were controllable.ConclusionApatinib was found to be both safe and effective in patients with advanced platinum-resistant relapsed EOC. More in-depth clinical research and applications should be carried out.

Efficacy and safety of apatinib in the treatment of advanced platinum-resistant recurrent epithelial ovarian cancer: A retrospective study.

e17594 Background: Apatinib is an oral anti-angiogenic drug that mainly targets vascular endothelial growth factor receptor 2 (VEGFR-2) and is widely used in a variety of solid tumours. The purpose of this study is to evaluate the clinical efficacy and safety of apatinib in patients with advanced platinum-resistant relapsed epithelial ovarian cancer (EOC). Methods: This study retrospectively analyzed the clinical data of patients with stage IIIC-IV platinum-resistant relapsed EOC between January 2014 and May 2018. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were reviewed and evaluated. The propensity score matching (PSM) method was used to determine the data included in this study of the final case. Results: This study included 36 patients in the apatinib group and 72 patients in the control group, according to the 1:2 propensity matching. The follow-up ended in January 2019, and the median follow-up time was 28 months. The ORR was 30.56% in the apatinib group and 16.67% in the control group. The DCR in both cohorts was 66.67% and 44.44%, respectively. The median PFS (6.0 vs. 3.3 months) and OS (15.8 vs. 9.2 months) in the apatinib group were significantly longer than that in the control group. In addition, apatinib was more effective than conventional chemotherapy in reducing the risk of PFS [HR 0.40 (95% CI 0.22-0.76), P = 0.0017] and OS [HR 0.40 (95% CI 0.21-0.73), P = 0.002]. Multivariate Cox analysis showed that the course of treatment and decrease in serum CA125 levels are independent risk factors for PFS in patients, while for apatinib, the length of treatment course and the location of the lesion are independent risk factors for recurrence that affects the OS of patients. The most common grade 3/4 toxicities in the apatinib group were hypertension, hand-foot syndrome, and oral mucosal ulcers. Conclusions: Apatinib therapy was an effective treatment for patients with advanced platinum-resistant relapsed EOC. The toxicities were tolerable and manageable.

TEDOVA/GINECO-OV244b/ENGOT-ov58 trial: Neo-epitope based vaccine OSE2101 alone or in combination with pembrolizumab versus best supportive care (BSC) as maintenance in platinum-sensitive recurrent ovarian cancer with disease control after platinum.

TPS5614 Background: Besides PARP inhibitors and bevacizumab, there are no approved maintenance therapies after platinum based chemotherapy for patients with a platinum sensitive relapsed epithelial ovarian cancer (OC). Immune checkpoint inhibitors (ICI) as single agents have limited activity in OC. One attractive strategy is to turn OC from immunogenic “cold” to “hot” tumors via vaccination with tumor-associated antigens (TAAs). OSE2101 is a multiple-neoepitope vaccine restricted to HLA-A2-positive patients (45% of OC patients) targeting 5 TAAs: TP53, MAGE2, MAGE3, CEA and HER2. These neo-epitopes are modified to increase both major histocompatibility complex and the T cell receptor binding affinity. The proof of concept for this approach was recently demonstrated with OSE2101 improving overall survival in a phase III trial in lung cancer progressing after ICI (Besse et al. 2021). The combination of OSE2101 with an ICI may most effectively harness anti-tumor immunity. Methods: TEDOVA is an international randomized open-label, phase II trial evaluating the benefit of maintenance by OSE2101 alone or in combination with PD1 inhibition (pembrolizumab) after platinum based chemotherapy in relapsed OC, previously treated with bevacizumab (if eligible) and a PARP inhibitor (if eligible). Patients (N=180) with CR/PR/SD at the end of chemotherapy are randomized (1:1:2) to: Observation/BSC (Arm A), OSE2101 alone (Arm B), or OSE2101 in combination with pembrolizumab (Arm C). Experimental treatments are continued until progression, or intolerance, for up to 2 years. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, safety, time to subsequent first or second treatment (TTST-1, TTST-2) and overall survival. 180 HLA-A*02 positive patients will be randomized. HLA-A*02 negative patients will be followed in a separate observational cohort. The sample size is calculated to provide 90% power to detect an improvement in PFS for Arm C vs Arm A with a HR of 0.57. Three one-sided Log-rank tests will be considered in a pre-defined sequence: H1: C (OSE2101+pembrolizumab) vs A (BSC); H2: C (OSE2101+pembrolizumab) vs B (OSE2101) and H3: B vs A. The type I error will be α=5%. The type II error will be β=10%. Tests will be one-sided. Status: The TEDOVA/GINECO-OV244b/ENGOT-ov58 trial is currently recruiting. Clinical trial information: NCT04713514.

Involvement of Cancer Stem Cells in Chemoresistant Relapse of Epithelial Ovarian Cancer Identified by Transcriptome Analysis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite the initial resection and chemotherapeutic treatment, relapse is common, which leads to poor survival rates in patients. A primary cause of recurrence is the persistence of ovarian cancer stem cells (OCSCs) with high tumorigenicity and chemoresistance. To achieve a better therapeutic response in EOC relapse, the mechanisms underlying acquired chemoresistance associated with relapse-initiating OCSCs need to be studied. Transcriptomes of both chemosensitive primary and chemoresistant relapse EOC samples were obtained from ICGC OV-AU dataset for differential expression analysis. The upregulated genes were further studied using KEGG and GO analysis. Significantly increased expression of eighteen CSC-related genes was found in chemoresistant relapse EOC groups. Upregulation of the expression in four hub genes including WNT3A, SMAD3, KLF4, and PAX6 was verified in chemoresistant relapse samples via immunohistochemistry staining, which confirmed the existence and enrichment of OCSCs in chemoresistant relapse EOC. KEGG and GO enrichment analysis in microarray expression datasets of isolated OCSCs indicated that quiescent state, increased ability of drug efflux, and enhanced response to DNA damage may have caused the chemoresistance in relapse EOC patients. These findings demonstrated a correlation between OCSCs and acquired chemoresistance and illustrated potential underlying mechanisms of OCSC-initiated relapse in EOC patients. Meanwhile, the differentially expressed genes in OCSCs may serve as novel preventive or therapeutic targets against EOC recurrence in the future.

Disulfiram Transcends ALDH Inhibitory Activity When Targeting Ovarian Cancer Tumor-Initiating Cells.

Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. EOC recurrence is considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs compared to adherent EOC cells in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit to broader pathway inhibition by disulfiram. NCT-505 and NCT-506 are isoenzyme-specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with both the NCTs and disulfiram, the viability of TICs versus adherent cells, sphere formation, and cell death in our in vitro relapse model were measured and compared in EOC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus adherent cells, while no consistent trend was observed when the cells were treated with the NCTs. Disulfiram also affected the expression of proteins associated with NFκB signaling. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that the broader cellular effects of disulfiram are more suitable as a therapeutic to eradicate TICs from tumors and prevent EOC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCT-505 and -506 has increased our understanding of the mechanism of action of disulfiram. Further elucidation of the mechanism of disulfiram has the potential to reveal additional targets to treat EOC TICs and prevent disease recurrence.

Combination microRNA-based cellular reprogramming with paclitaxel enhances therapeutic efficacy in a relapsed and multidrug-resistant model of epithelial ovarian cancer

Most advanced-stage ovarian cancer patients, including those with epithelial ovarian cancer (EOC), develop recurrent disease and acquisition of resistance to chemotherapy, leading to limited treatment options. Decrease in Let7b miRNA levels in clinical ovarian cancer has been associated with chemoresistance, increased proliferation, invasion, and relapse in EOC. We have established a murine EOC relapsed model by administering paclitaxel (PTX) and stopping therapy to allow for tumor regrowth. Global microRNA profiling in the relapsed tumor showed significant downregulation of Let7b relative to untreated tumors. Here, we report the use of hyaluronic acid (HA)-based nanoparticle formulation that can deliver Let7b miRNA mimic to tumor cells and achieve cellular programming both in vitro and in vivo. We demonstrate that a therapeutic combination of Let7b miRNA and PTX leads to significant improvement in anti-tumor efficacy in the relapsed model of EOC. We further demonstrate that the combination therapy is safe for repeated administration. This novel approach of cellular reprogramming of tumor cells using clinically relevant miRNA mimic in combination with chemotherapy could enable more effective therapeutic outcomes for patients with advanced-stage relapsed EOC.

Salvage chemotherapy and maintenance therapy with poly adenosine diphosphate-ribose polymerase inhibitors for bevacizumab-resistant relapse of epithelial ovarian cancer

Adjuvant chemotherapy combined with bevacizumab, an angiogenesis inhibitor, can improve the survival of advanced epithelial ovarian cancer (EOC), but relapse during bevacizumab maintenance therapy may occur. Despite poly adenosine ribose-polymerase (PARP) inhibitors were shown to achieve remission in the relapsed patients upon salvage chemotherapy and long-term maintenance, there is little evidence on their efficacy or criteria for selecting bevacizumab-resistant recurrent EOC patients who would benefit from PARP inhibitors. In this single-center, retrospective, case-series study, we evaluated the efficacy, safety and selection criteria for salvage chemotherapy followed by PARP inhibitors in bevacizumab-resistant EOC patients who recurred during bevacizumab maintenance. The primary endpoint was post-progression survival (PPS), and the secondary endpoints were progression-free survival (PFS) and safety. In all, the data of 49 EOC patients, most of whom were graded as stage III (91.8%) with high-grade serous histology (81.6%), were assessed. They were classified into three groups based on platinum-free interval (PFI) and response to salvage chemotherapy: platinum-based chemotherapy followed by PARP inhibitors, platinum-based chemotherapy followed by non-PARP inhibitors, and non-platinum-based chemotherapy. Survival analysis showed the median PFS and median PPS for the platinum-based chemotherapy followed by PARP inhibitors group were 326 and 771 days, which were significantly longer than the other groups. The highly platinum-sensitive relapse (PSR) group (PFI &gt;12 months) achieved prolonged PPS, while there was no relationship between the clinical status on salvage chemotherapy and response to PARP inhibitors. Adverse events during PARP inhibitor led to withdrawal and dose reduction in &gt;40% of patients; however, no patients discontinued the drugs. Altogether, the study results showed that maintenance therapy using PARP inhibitor was effective and feasible for patients selected based on platinum sensitivity from bevacizumab-resistant relapsed EOC. PFI after adjuvant chemotherapy could predict bevacizumab-resistant EOC patients’ response to PARP inhibitors, which might be effective despite therapeutically insufficient salvage chemotherapy.

Analysis of PARP inhibitors induced anemia in advanced and relapsed epithelial ovarian cancer

Objective: To explore the clinical features of poly ADP-ribose polymerase (PARP) inhibitor-related anemia in advanced and relapsed epithelial ovarian cancer (EOC). Methods: Patients diagnosed with advanced or relapsed EOC and treated with PARP inhibitor at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 to October 2020 were accrued. The data included PARP inhibitors, treatment details, and lab tests before treatment and during treatment were collected and the clinical characteristics of PARP inhibitor-related anemia were analyzed. Results: (1) A total of 98 patients with a median age of 56.5 years old (30-82 years old) were enrolled in this study. All patients were treated with PARP inhibitor (65 cases of olaparib, 17 cases of niraparib, and 16 cases of fluzoparib). The median treatment duration was 37.5 weeks (4-119 weeks). (2) The anemia rate was 40% (39/98), including 5% (5/98) of grade Ⅰ, 14% (14/98) of grade Ⅱ, 11% (11/98) of grade Ⅲ, and 9% (9/98) of grade Ⅳ. Fourteen patients with pre-treatment grade Ⅰ anemia had a higher rate of anemia events than the 80 patients without pre-treatment anemia, 7/14 vs 35% (28/80; χ2=4.281, P=0.039). (3) The median anemia occurrence time was 7.0 weeks (1-52 weeks), including 41% (16/39) of anemia cases occurred in 1-4 weeks, 26% (10/39) occurred in 5-8 weeks, 13% (5/39) occurred in 9-12 weeks, 3% (1/39) occurred in 13-16 weeks, 10% (4/39) occurred in 17-20 weeks, 8% (3/39) occurred ≥21 weeks. At the time of the lowest hemoglobulin tested, the median value of mean corpuscular volume (MCV) was 106 fl,which was higher than the up limit of normal range (100 fl), 74% (29/39) of anemia patients had an elevated MCV level; the median value of mean corpuscular hemoglobin (MCH) was 36 pg, 54% (21/39) of anemia patients had an elevated MCH level; the median value of mean corpuscular hemoglobin concentration (MCHC) was 320 g/L, 69% (27/39) of anemia patients had a higher MCHC level; 92% (36/39) of anemia patients had a normal level of serum iron; 79% (31/39) of anemia patients had a normal level of transferrin. 74% (29/39) of the anemia patients were macrocytic orthochromatic anemia. (4) Among the 39 patients with anemia, 20 patients (51%, 20/39) withhold the treatment of PARP inhibitor due to grade Ⅲ or Ⅳ anemia, including 10 patients (50%, 10/20) who resumed the PARP inhibitor treatment by suppling iron, folate, and vitamin B12. The median stopping time of PARP inhibitor was 5.5 weeks (2-10 weeks), while the other 10 patients terminated the PARP inhibitor treatment for not recovering from severe anemia. Conclusions: One of the common adverse effects of PARP inhibitors is anemia, which mostly happened in the first 3 months of treatment. In the treatment of EOC, PARP inhibitor-related anemia mainly manifest as macrocytic orthochromatic anemia, and most patients with normal serum iron and transferrin.

Izkušnje z zdravilom olaparib pri zdravljenju recidivnega epitelijskega raka jajčnikov z mutacijami v genih BRCA 1 in BRCA 2

Introduction: Olaparib is used as maintenance oral therapy of patients with BRCA 1/2 mutated relapsed epithelial ovarian cancer.Aim of study: To evaluate the safety and efficacy of olaparib in treatment of patients with BRCA 1/2 mutated relapsed epithelial ovarian cancer.Methods: Retrospective analysis of patients with BRCA 1/2 mutated relapsed epithelial ovarian cancer treated with olaparib at the Institute of Oncology Ljubljana in the period from 1st november 2015 to 31th december 2020. The end points of the study were safety and efficacy (progression-free survival, overall survival). The study was approved by our institutional ethics board.Results: In the observed period, a total of 88 patients with BRCA 1/2 mutated relapsed epithelial ovarian cancer were treated with olaparib. Median age of patients was 60 years. Majority of patients (61%) had 1st relapse of the disease. Majority of patients (74%) had germline BRCA 1 gene mutation. Majority of patients (85%) had at least one adverse event during olaparib treatment. The most common adverse events (all grades) were: nausea (59%), fatigue (59%), anemia (25%), dispepsia (14%), diarrhea (11%), dysgeusia (10%), neutropenia (6%) and arrhythmia (1%). Severe adverse events (grade 3/4) had 10% of patients: anemia 9%, nausea 1%. Median follow up was 40 months. Median progression-free survival was 14,3 months, median overall survival was 20,4 months. Progression-free survival was in correlation to the type of BRCA gene mutation: 80% of patients with somatic BRCA 1/2 gene mutation were progression-free, 55% of patients with germline BRCA 2 gene mutation were progression-free, while 32% of patients with germline BRCA 1 gene mutation were progression-free (p=0,021). The type fo BRCA 1/2 gene mutation did not correlate with overall survival.

Survival impact of extended cycles of second-line chemotherapy in platinum-sensitive relapsed ovarian cancer patients with residual tumor after six cycles

BackgroundTo determine if extended chemotherapy improves survival outcomes in patients with platinum-sensitive relapsed epithelial ovarian cancer (EOC) who have residual disease after six cycles of second-line chemotherapy.MethodsIn this study, 135 EOC patients who experienced platinum-sensitive recurrence after primary treatment between 2008 and 2018, and had a residual tumor ≥0.5 cm (detected on CT scans) after completing six cycles of second-line, platinum-based chemotherapy, were retrospectively reviewed. Based on the number of main therapy cycles (second-line chemotherapy), we divided patients into an extended group (>6 cycles, n = 52) or a standard group (6 cycles, n = 83) and compared patient characteristics and survival outcomes between these groups.ResultsThe extended group had a shorter platinum-free interval after primary treatment than the standard group (median, 11.0 vs. 13.1 months; P = 0.018). Secondary debulking surgery was less frequently performed in the standard group (1.9% vs. 19.3%; P = 0.003). After six chemotherapy cycles, the extended and standard groups showed similar serum CA-125 levels (P = 0.122) and residual tumor sizes (P = 0.232). There was no difference in overall survival (OS) between the groups (P = 0.382), although the extended group had significantly worse progression-free survival (PFS) than the standard group (median, 13.9 vs. 15.1 months; P = 0.012). Multivariate analyses revealed that platinum-free interval was an independent prognostic factor for PFS and OS, but extended chemotherapy was not (PFS: HR, 1.25; 95% CI, 0.84–1.85; P = 0.279; and OS: HR, 1.36; 95% CI, 0.72–2.56; P = 0.342). We observed consistent results in the subset of patients who did not undergo secondary debulking surgery.ConclusionsMore than six cycles of platinum-based chemotherapy might not improve survival outcomes in patients with platinum-sensitive recurrent EOC who had a residual tumor ≥0.5 cm after six cycles of second-line chemotherapy.