Platinum-resistant Recurrence Research Articles

Antibody-Drug Conjugates: The New Treatment Approaches for Ovarian Cancer

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments. However, treatment options for platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC). This approval was based on a Phase II study, which demonstrated its efficacy in such patients. ADCs comprise an antibody, a linker, and a payload, representing new concept agents without precedence. Advanced clinical studies are developing ADCs for patients with OC, targeting solid tumors such as gynecologic cancer. Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. 160 patients. Recruitment is estimated to be completed by 2024 and results may be published by 2027. ClinicalTrials.gov: NCT05044871.

Perioperative outcomes and platinum resistant recurrence in patients undergoing systematic, protocol-based, total parietal peritonectomy during interval cytoreductive surgery for advanced ovarian cancer: results of the TORPEDO study.

The TORPEDO (CTRI/2018/12/016789) is the single-arm, prospective, interventional study evaluating the role of a total parietal peritonectomy (TPP) in patients undergoing interval cytoreductive surgery (iCRS). In this manuscript, we report the perioperative outcomes and platinum resistant recurrence (PRR) in 218 patients enrolled in the study. A TPP was performed in all patients undergoing iCRS irrespective of the residual disease extent. hyperthermic intraperitoneal chemotherapy (HIPEC) was performed as per the clinician's discretion with 75 mg/m² of cisplatin. Maintenance therapy was also used at the discretion of the treating clinicians. From 9th December 2018 to 31st July 2022 (recruitment complete), 218 patients were enrolled at 4 medical centers in India. The median surgical peritoneal cancer index was 14 and a complete gross resection was achieved in 95.8%. HIPEC was performed in 130 (59.6%) patients. The 90-day major morbidity was 17.4% and 2.7% patients died within 90 days of surgery. Adjuvant chemotherapy was delayed beyond 6 weeks in 7.3%. At a median follow-up of 19 months (95% confidence interval [CI]=15.9-35 months), 101 (46.3%) recurrences and 19 (8.7%) deaths had occurred. The median progression-free survival was 22 months (95% CI=17-35 months) and the median overall survival (OS) not reached. Platinum resistant recurrence was observed in 6.4%. The projected 3-year OS was 81.5% and in 80 patients treated before may 2020, it was 77.5%. The morbidity and mortality of TPP with or without HIPEC performed during iCRS is acceptable. The incidence was of PRR is low. Early survival results are encouraging and warrant conduction of a randomized controlled trial comparing TPP with conventional surgery.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) Applied to Platinum-Resistant Recurrence of Ovarian Tumor: A Single-Institution Experience (ID: PARROT Trial)

BackgroundWe aimed to investigate the therapeutic efficacy and safety of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in platinum-resistant recurrence of ovarian cancer and peritoneal carcinomatosis, while our secondary endpoint was to establish any changes in quality of life estimated via the EORTC QLQ-30 and QLQ-OV28 questionnaires.MethodsIn this monocentric, single-arm, phase II trial, women were prospectively recruited and every 28–42 days underwent courses of PIPAC with doxorubicin 2.1 mg/m2 followed by cisplatin 10.5 mg/m2 via sequential laparoscopy.ResultsOverall, 98 PIPAC procedures were performed on 43 women from January 2016 to January 2020; three procedures were aborted due to extensive intra-abdominal adhesions. The clinical benefit rate (CBR) was reached in 82% of women. Three cycles of PIPAC were completed in 18 women (45%), and 13 (32.5%) and 9 (22.5%) patients were subjected to one and two cycles, respectively. During two PIPAC procedures, patients experienced an intraoperative intestinal perforation. There were no treatment-related deaths. Nineteen patients showed no response according to the Peritoneal Regression Grading Score (PRGS) and 8 patients showed minor response according to the PRGS. Median time from ovarian cancer relapse to disease progression was 12 months (95% confidence interval [CI] 6.483–17.517), while the median overall survival was 27 months (95% CI 20.337–33.663). The EORTC QLQ-28 and EORTC QLQ-30 scores did not worsen during therapy.ConclusionsPIPAC seems a feasible approach for the treatment of this subset of patients, without any impact on their quality of life. Since this study had a small sample size and a single-center design, future research is mandatory, such as its application in addition to systemic chemotherapy.

Real-world Efficacy and Safety of Bevacizumab for Advanced or Recurrent Müllerian Cancer: A Single-institutional Experience.

The efficacy and safety of bevacizumab for ovarian cancer have been reported in randomized phase III clinical trials. It is important to gather experience and data in a real-world setting. The objective of the present study was to evaluate the efficacy and safety of bevacizumab for patients with ovarian cancer in a real-world setting. For front-line settings, patients with FIGO stage III-IV ovarian cancer treated using bevacizumab and chemotherapy after debulking surgery (Chemo + Bev group, n=79), in addition to those treated with only chemotherapy after debulking surgery (Chemo group; n=66), at our institute were reviewed retrospectively. For recurrent settings, patients with recurrent ovarian cancers treated with bevacizumab and any chemotherapy were reviewed retrospectively (n=65). In the front-line setting, the disease-free survival was significantly longer in the Chemo + Bev group compared with that in the Chemo group (p=0.021). Hypertension and proteinuria were found to be statistically more frequent in the Chemo + Bev group compared with that in the Chemo group (p=0.002 and p=0.004). In the recurrent setting, in platinum-sensitive patients, the response rate (RR) and the disease control ratio (DCR) were 78.4 and 94.1%, respectively. In platinum-resistant patients, the RR and the DCR were 28.6 and 57.1% respectively. The median progression-free survival was 18.3 and 7.1 months for platinum-sensitive recurrence and platinum-resistant recurrence, respectively. The major ≥ grade 3 adverse event was neutropenia. The present study provided encouraging real-world evidence of the efficacy and safety of bevacizumab for ovarian cancer in real-world.

Comprehensive Genomic Profiling Detects Hereditary Cancers and Confers Survival Advantage in Patients With Gynaecological Cancers.

The clinical benefits of comprehensive genomic profiling (CGP) of tumours in patients with gynaecological cancers remain unknown. We investigated the utility of CGP in assessing patient survival and its efficacy in detecting hereditary cancers in gynaecological patients. We retrospectively analysed the medical records of 104 gynaecological patients who underwent CGP between August 2018 and December 2022. The detection of actionable and accessible genomic alterations and administration of targeted therapy, as recommended by the molecular tumour board (MTB), were assessed. The overall survival (after second-line treatment in cervical and endometrial carcinomas and after platinum-resistant recurrence in ovarian carcinoma) was compared between patients with or without administration of MTB-recommended genotype-matched therapy. Germline findings were assessed using a variant allele frequency-tumour content graph. Among 104 patients, actionable and accessible genomic alterations were observed in 53 patients. Matched therapy was applied in 21 patients, comprising administration of repurposing itraconazole (n=7), immune checkpoint inhibitors (n=7), poly (ADP-ribose) polymerase inhibitors (n=5), and others (n=2). The median overall survival of patients receiving and not receiving matched therapy were 19.3 months and 11.2 months, respectively (p=0.036, hazard ratio=0.48). Among 12 patients with hereditary cancers, 11 patients were previously undiagnosed. Seven patients had hereditary breast and ovarian cancer, and five had other cancer. The implementation of CGP testing prolonged overall survival in gynaecological cancer as well as provided an opportunity for genetic counselling for newly-diagnosed patients with hereditary cancers and their families.

Gab2 plays a carcinogenic role in ovarian cancer by regulating CrkII

ObjectiveTo detect the expression of Growth factor binding protein 2 associated binding protein 2 (Gab2) and CT10 regulator of kinase II (CrkII) in ovarian cancer and analyze their clinical significance. To explore the effects of Gab2 and CrkII on the biological behavior of ovarian cancer cells. To analyze the possible molecular mechanism of Gab2 in the development of ovarian cancer.MethodsImmunohistochemistry was used to detect the expression of Gab2 and CrkII in ovarian cancer. Chi square test was used to analyze the correlation between Gab2, CrkII and clinical parameters. Using Cox regression model to evaluate the risk factors affecting the prognosis. To analyze the correlation between Gab2, CrkII and survival rate by Kaplan–Meier. Cell experiments were preformed to explore the effects of Gab2 and CrkII on the biological behavior of cells. The interaction between Gab2 and CrkII was explored by immunoprecipitation.ResultsImmunohistochemistry revealed that high expression of Gab2 and CrkII in ovarian cancer. Patients with high expression of Gab2 or CrkII had higher International Federation of Gynecology and Obstetrics (FIGO) stage, grade and platinum-resistance recurrence. Multivariate analysis showed that Gab2 and CrkII were independent prognostic factors. Kaplan–Meier curve showed that the higher Gab2 and CrkII were, the poor prognosis the patients had. We observed that the overexpression of Gab2 and CrkII promoted the proliferation, metastasis and reduced chemosensitivity of cells. Conversely, the knockdown of Gab2 and CrkII resulted in the opposite results. In CrkII-knockdown cells, we found that Gab2 mediates biological behavior through CrkII.ConclusionsThe expression of Gab2 and CrkII increase in ovarian cancer. The higher expression of Gab2 and CrkII predict the poor prognosis of patients. Gab2 and CrkII promote the proliferation and migration and reduce the chemosensitivity of cells. Gab2 regulates the biological behaviors of ovarian cancer cells through CrkII.

Ovarian high-grade serous carcinoma cells with low SMARCA4 expression and high SMARCA2 expression contribute to platinum resistance.

Platinum resistance is a major obstacle to the treatment of ovarian cancer and is correlated with poor clinical outcomes. Intratumor heterogeneity plays a key role in chemoresistance. Recent studies have emphasized the contributions of genetic and epigenetic factors to the development of intratumor heterogeneity. Although the clinical significance of multi-subunit chromatin remodeler, switch/sucrose nonfermenting (SWI/SNF) complexes in cancers has been reported, the impacts of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4/subfamily A, member 2 (SMARCA4/A2) expression patterns in human cancer tissues have not been fully elucidated. Here, we show that low expression of SMARCA4 and high expression of SMARCA2 are associated with platinum resistance in ovarian high-grade serous carcinoma (HGSC) cells. We used fluorescence multiplex immunohistochemistry (fmIHC) to study resected specimens; we examined heterogeneity in human HGSC tissues at the single-cell level, which revealed that the proportion of cells with the SMARCA4low /SMARCA2high phenotype was positively correlated with clinical platinum-resistant recurrence. We used stable transfection of SMARCA2 and siRNA knockdown of SMARCA4 to generate HGSC cells with the SMARCA4low /SMARCA2high phenotype; these cells had the greatest resistance to carboplatin. Bioinformatics analyses revealed that the underlying mechanism involved in substantial alterations to chromatin accessibility and resultant fibroblast growth factor (FGF) signaling activation, MAPK pathway activation, BCL2 overexpression, and reduced carboplatin-induced apoptosis; these were confirmed by in vitro functional experiments. Furthermore, in vivo experiments in an animal model demonstrated that combination therapy with carboplatin and a fibroblast growth factor receptor (FGFR) inhibitor promoted cell death in HGSC xenografts. Taken together, these observations reveal a specific subpopulation of HGSC cells that is associated with clinical chemoresistance, which may lead to the establishment of a histopathological prediction system for carboplatin response. Our findings may facilitate the development of novel therapeutic strategies for platinum-resistant HGSC cells. © 2023 The Pathological Society of Great Britain and Ireland.

PD-L1 and MHC Class I Expression in High-grade Ovarian Cancers, Including Platinum-resistant Recurrences Treated With Checkpoint Inhibitor Therapy.

Immune-modulating therapies targeting the programmed cell death-1/programmed cell death ligand-1 (PD-L1) immunosuppressive system have been used successfully in many solid tumor types. There is evidence that biomarkers such as PD-L1 and major histocompatibility complex (MHC) class I help identify candidates for anti-programmed cell death-1/PD-L1 checkpoint inhibition, though the evidence is limited in ovarian malignancies. PD-L1 and MHC Class I immunostaining was performed on pretreatment whole tissue sections in 30 cases of high-grade ovarian carcinoma. The PD-L1 combined positive score was calculated (a score of ≥1 is considered positive). MHC class I status was categorized as an intact or subclonal loss. In patients who received immunotherapy, drug response was assessed using RECIST criteria. PD-L1 was positive in 26 of 30 cases (87%; combined positive score: 1 to 100). Seven of 30 patients showed subclonal loss of MHC class I (23%), and this occurred in both PD-L1 negative (3/4; 75%) and PD-L1 positive (4/26; 15%) cases. Only 1 of 17 patients who received immunotherapy in the setting of a platinum-resistant recurrence responded to the addition of immunotherapy, and all 17 died of disease. In the setting of recurrent disease, patients did not respond to immunotherapy regardless of PD-L1/MHC class I status, suggesting that these immunostains may not be effective predictive biomarkers in this setting. Subclonal loss of expression of MHC class I occurs in ovarian carcinoma, including in PD-L1 positive cases, suggesting that the 2 pathways of immune evasion may not be mutually exclusive and that it may be important to interrogate MHC class I status in PD-L1 positive tumors to identify additional immune evasion mechanisms in these tumors.

Combination therapy of oral cyclophosphamide and bevacizumab for patients with recurrent ovarian and peritoneal cancer

Chemotherapy for patients with recurrent cancer aims to obtain survival benefits, relieve symptoms, and improve quality of life. We used oral cyclophosphamide and bevacizumab (BEV) combination therapy in recurrent ovarian and peritoneal cancer cases, where standard chemotherapy was infeasible. Subsequently, we evaluated the safety and efficacy of this treatment. Between August 2014 and June 2020, patients received the following regimen: oral cyclophosphamide 50 mg daily and intravenous cyclic BEV 15 mg/kg every 3 weeks. Data from 2 facilities were retrospectively analyzed. Twenty-two patients were enrolled (20 with ovarian cancer and two with peritoneal cancer). The median follow-up period and age were 18.9 months (range, 5.0-51.5) and 60 years (range 37-81), respectively. Sixteen patients had platinum resistance. The median number of previous chemotherapy regimens was 2.5 (range 0-5). The median implementation cycle was five (range 2-14). Eighteen patients discontinued treatment due to side effects (3 patient) and disease progression (15 patient). Grade 2 toxicities included neutropenia (1 patient), proteinuria (1 patient), hypertension (2 patient), and esophagitis (1 patient). Two patients had complete response and one had a partial response. Five patients had stable disease. The response rate in platinum-sensitive recurrence was 33.3%, and 7.1% in platinum-resistant recurrence, and a clinical benefit was found in 8 (36.3%) patients. The median PFS and overall survival from cyclophosphamide and BEV initiation was 5.3 months (range, 0.8-23.5) and 9.2 months (range, 4.8-51.5), respectively. The combination of oral cyclophosphamide and BEV does not have a high response rate, but is well-tolerated and can be used safely in patients who are difficult to treat after second-line chemotherapy. Data from 2 facilities were retrospectively analyzed.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601

ObjectiveTo determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin.MethodsROLANDO was a single-arm...

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

ObjectivesWe aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution.MethodsNext-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancer patients with RAD51D germline mutations.ResultsRAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45–69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%). 92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months.For patients who received PARPis for 2nd line maintenance treatment (n = 5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months.Nine patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classified as platinum-sensitive recurrence (PSR), and only 1 patient was classified as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%.ConclusionsRAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.

Comparison of treatment outcomes between first-line chemotherapy with or without bevacizumab for advanced ovarian, fallopian tube, and primary peritoneal cancer (Tohoku gynecologic cancer unit: TGCU-RS001 study).

Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit. The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events. The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15months, respectively (P = 0.0002), and the median overall survival was not reached and 49months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group. Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

Platinum resistant recurrence and early recurrence in a multi-centre cohort of patients undergoing interval cytoreductive surgery for advanced epithelial ovarian cancer.

BackgroundAggressive locoregional therapies like hyperthemic intraperitoneal chemotherapy(HIPEC) and total parietal peritonectomy(TPP) have been used to delay recurrence in patients with advanced ovarian cancer undergoing interval cytoreductive surgery(CRS). The aim of this retrospective study was to evaluate the incidence of platinum resistant recurrence (PRR) and early recurrence (ER)(recurrence within 6 months and 1 year of the last dose of platinum based therapy, respectively) in patients undergoing interval CRS. The secondary goal was to study impact of each of these therapies on PRR and ER.MethodsOne-hundred and fifty-three patients undergoing interval CRS from July 2018 to June 2020 were included. The surgical strategy was to perform a TPP in which the entire parietal peritoneum is resected irrespective of the disease extent or a selective parietal peritonectomy (SPP) in which only the peritoneum bearing visible residual disease is resected. The use of HIPEC was at the discretion of the treating oncologists.ResultsThe median surgical PCI was 15 [range, 0-37]. A CC-0 resection was obtained in 119 (77.7%) and CC-1 in 29 (18.9%) patients. Eighty-one (53%) patients had a TPP and 72 (47%) had SPP. HIPEC was performed in 98(64%) patients. Bevacizumab maintenance was administered to 31(19.6%) patients. No patients received PARP inhibitors during first-line therapy. PRR was observed in 8(5.2%) patients and ER in 30(19.6%). The respective incidences of PRR and ER were 4.9% and 16% in the TPP group, 4.1% and 23.6% in the SPP group, 9% and 20% in the no-HIPEC group and 3% and 19.3% in the HIPEC groups. On multivariate analysis, CC-0(p=0.014) resection and HIPEC(p=0.030) were independent predictors of a low ER. All patients with PR and 70% with ER had peritoneal recurrence with or without extra-peritoneal sites of recurrence.ConclusionsThe incidence of PRR and ER in this cohort was low as compared to historical data. This low incidence could be attributed to the use of aggressive locoregional therapies like TPP and HIPEC. In future, studies should be conducted to confirm these findings and evaluate the potential additive benefit of TPP and HIPEC coupled together as well as their combination with maintenance therapies.

Efficacy and Safety of Platinum Rechallenge in Patients With Platinum-resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer: A Multicenter Retrospective Study.

Ovarian cancer diagnosed with platinum-resistant recurrence has very poor prognosis and single-agent chemotherapy with no cross-resistance to prior chemotherapy is recommended for its treatment. In this study, we retrospectively evaluated the efficacy and safety of platinum rechallenge therapy for once diagnosed with platinum-resistant ovarian cancer who had a platinum-free interval (PFI) of at least 6 months. The study included 49 patients who received platinum rechallenge therapy for ovarian, fallopian tube or primary peritoneal cancer who were once diagnosed with platinum-resistant recurrence between January 2010 and March 2021 and evaluated the efficacy and safety of this treatment. In addition, patient background factors were identified, and independent prognostic factors for progression-free survival (PFS) and overall survival (OS) were investigated. A complete response was noted in 7 cases, partial response in 21, stable disease in 9, and progressive disease in 10. The response and disease control rates were 55% and 76%, respectively. The median PFS and OS were 8.5 months and 35.8 months, respectively. The independent prognostic factor was PFI for OS, and there was no independent prognostic factor for PFS. Seven patients discontinued chemotherapy owing to serious adverse events, including one patient with treatment-related death. Platinum rechallenge therapy for patients with platinum-resistant recurrence did not cause previously unreported adverse events, and the adverse events were manageable. In addition, high response and disease control rates were observed, as well as long-term OS. Platinum rechallenge therapy for platinum-resistant ovarian cancer may be a viable treatment option.

Recurrent of ovarian cancer with lymph node involvement: surgery or chemotherapy? Retrospective cohort study

Aim. To give a comparative analysis of long-term results of treatment of patients after surgical treatment in combination with systemic chemotherapy with a control group of patients who received only second-line chemotherapy without surgical treatment for recurrent ovarian cancer (OC) with lymph node (LN) involvement, as well as the search of prognostic factors that favorably affect progression-free survival (PFS) and overall survival (OS).&#x0D; Materials and methods. The retrospective analysis included patients under the age of 75 after surgical treatment or after only second-line chemotherapy without surgery for isolated recurrence in the LN or a combined form of recurrence of OC at Blokhin National Medical Research Center of Oncology from 2005 to 2020. All patients had previously received combined treatment for primary OC. Exclusion criteria: absence of LN involvement in the recurrence of OC, primary multiple malignant tumors, relapses of non-epithelial ovarian tumors, the presence of concomitant pathology in the decompensation phase and lack of information about the treatment received for the recurrence of OC and the date of subsequent progression, death or last observation. The primary endpoint of the study is PFS and the secondary endpoint is OS.&#x0D; Results. The final analysis included 214 patients, who were subsequently divided into 2 main groups: the study group consisted of patients (n=123; 57.5%) who underwent repeated cytoreduction + systemic chemotherapy, and the control group included patients (n=91; 42.5%) who received only second-line chemotherapy. In the general population of patients, the median platinum-free interval was 14.0 months. Platinum-sensitive recurrence of OC developed in 88.3% (189/214) of patients, and platinum-resistant recurrence was observed in 11.7% (25/214) of cases. In the study group, complete repeated cytoreduction was achieved in 70.7% (87/123) of patients, and incomplete in 29.3% (36/123) of patients. All 91 patients in the control group received second-line chemotherapy in the planned volume. The vast majority of patients underwent second-line platinum-containing chemotherapy 87.9% (188/214) of patients. The median follow-up was 33.0 (range 0.7174.0) months. Long-term results in the complete cytoreduction group were significantly higher median PFS and OS were 30.0 months and 87.0 months, respectively, however, in the incomplete cytoreduction group, long-term results were statistically significantly worse: median PFS and OS were 10.0 months and 29.0 months versus 12.0 months and 36.0 months, respectively, in the control group of patients. Surgical treatment in combination with chemotherapy for platinum-resistant recurrence of OC did not improve long-term results of treatment: the median PFS was the same in both groups 7.0 months, and the median OS was 24.0 months versus 21.0 months in the control group (p=0.372).&#x0D; Conclusion. Only complete repeated cytoreduction in combination with systemic chemotherapy leads to an improvement in long-term results of treatment compared with incomplete cytoreduction and only second-line systemic chemotherapy. Incomplete repeated cytoreduction, despite combination with systemic chemotherapy, worsens the prognosis and does not improve the results of drug therapy alone in patients with platinum-sensitive recurrence of OC. Combined treatment (surgery + chemotherapy) for platinum-resistant recurrence of OC does not improve long-term results of treatment.

36P Factors associated with platinum resistance in ovarian cancer patients receiving neoadjuvant chemotherapy

36P Factors associated with platinum resistance in ovarian cancer patients receiving neoadjuvant chemotherapy

40P Exome sequencing analysis of primary and recurrent ovarian carcinomas

BackgroundOvarian carcinomas (OCs) are highly sensitive to platinum-based therapy, however most of OCs eventually relapse. This study aimed to compare genomic profiles in primary vs. recurrent OCs.MethodsPrimary, recurrent and normal tissue triplets obtained from 15 patients were subjected to exome sequencing. The comparison included 1) spectrum of driver mutations [Tamborero et al., 2018; PMID: 29592813]; 2) tumor mutation burden (TMB); 3) HRD score [Telli et al., 2016; PMID: 26957554]; 4) mutational signatures [Degasperi et al., 2020; PMID: 32118208].ResultsAll driver mutation present in primary tumors remained in the genome through the treatment course. One or several new driver somatic mutations emerged in 6/15 (40%) recurrent lesions. These alterations involved RB1 and ELAC2 (n = 1), TNC (n = 1), TRIO and IKBKB (n = 1), PAX5 and CDH10 (n = 1), SOX9 (n = 1), ABCB4 and EEF1A1 (n = 1) genes. Recurrent tumors demonstrated small but statistically significant increase of TMB as compared to primary lesions (4.7 vs. 3.9 per megabase, p = 0.01). HRD demonstrated high degree of similarity within primary/recurrent tumor pairs. PLATINUM mutation signature was characteristic for platinum-sensitive relapses, but not for platinum-resistant recurrences or chemonaive tumors (p = 0.02).ConclusionsHRD score remains stable through the treatment history. PLATINUM mutation signature reflects not only the mere fact of prior exposure to platinum-based therapy, but also the efficacy of this therapeutic regimen.Legal entity responsible for the studyThe authors.FundingRussian Science Foundation, grant 21-75-30015.DisclosureAll authors have declared no conflicts of interest. BackgroundOvarian carcinomas (OCs) are highly sensitive to platinum-based therapy, however most of OCs eventually relapse. This study aimed to compare genomic profiles in primary vs. recurrent OCs. Ovarian carcinomas (OCs) are highly sensitive to platinum-based therapy, however most of OCs eventually relapse. This study aimed to compare genomic profiles in primary vs. recurrent OCs. MethodsPrimary, recurrent and normal tissue triplets obtained from 15 patients were subjected to exome sequencing. The comparison included 1) spectrum of driver mutations [Tamborero et al., 2018; PMID: 29592813]; 2) tumor mutation burden (TMB); 3) HRD score [Telli et al., 2016; PMID: 26957554]; 4) mutational signatures [Degasperi et al., 2020; PMID: 32118208]. Primary, recurrent and normal tissue triplets obtained from 15 patients were subjected to exome sequencing. The comparison included 1) spectrum of driver mutations [Tamborero et al., 2018; PMID: 29592813]; 2) tumor mutation burden (TMB); 3) HRD score [Telli et al., 2016; PMID: 26957554]; 4) mutational signatures [Degasperi et al., 2020; PMID: 32118208]. ResultsAll driver mutation present in primary tumors remained in the genome through the treatment course. One or several new driver somatic mutations emerged in 6/15 (40%) recurrent lesions. These alterations involved RB1 and ELAC2 (n = 1), TNC (n = 1), TRIO and IKBKB (n = 1), PAX5 and CDH10 (n = 1), SOX9 (n = 1), ABCB4 and EEF1A1 (n = 1) genes. Recurrent tumors demonstrated small but statistically significant increase of TMB as compared to primary lesions (4.7 vs. 3.9 per megabase, p = 0.01). HRD demonstrated high degree of similarity within primary/recurrent tumor pairs. PLATINUM mutation signature was characteristic for platinum-sensitive relapses, but not for platinum-resistant recurrences or chemonaive tumors (p = 0.02). All driver mutation present in primary tumors remained in the genome through the treatment course. One or several new driver somatic mutations emerged in 6/15 (40%) recurrent lesions. These alterations involved RB1 and ELAC2 (n = 1), TNC (n = 1), TRIO and IKBKB (n = 1), PAX5 and CDH10 (n = 1), SOX9 (n = 1), ABCB4 and EEF1A1 (n = 1) genes. Recurrent tumors demonstrated small but statistically significant increase of TMB as compared to primary lesions (4.7 vs. 3.9 per megabase, p = 0.01). HRD demonstrated high degree of similarity within primary/recurrent tumor pairs. PLATINUM mutation signature was characteristic for platinum-sensitive relapses, but not for platinum-resistant recurrences or chemonaive tumors (p = 0.02). ConclusionsHRD score remains stable through the treatment history. PLATINUM mutation signature reflects not only the mere fact of prior exposure to platinum-based therapy, but also the efficacy of this therapeutic regimen. HRD score remains stable through the treatment history. PLATINUM mutation signature reflects not only the mere fact of prior exposure to platinum-based therapy, but also the efficacy of this therapeutic regimen.

MiR-320b and miR-320d as Biomarkers to Predict and Participate in the Formation of Platinum Resistance in Ovarian Cancer Patients.

Patients with ovarian cancer who receive platinum-based chemotherapy typically develop platinum resistance, which leads to tumor recurrence and mortality. Therefore, finding the underlying mechanisms and biomarkers is critical. A total of 51 platinum-resistant and 70 platinum-sensitive ovarian cancer patients were enrolled in this study. We examined the GSE131978 dataset in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus database for differentially expressed long non-coding RNAs and messenger RNAs (mRNAs) between platinum-resistant and platinum-sensitive patients and completed a microRNA chip analysis. After filtering by Pearson correlation analysis, the competitive endogenous RNA (ceRNA) networks were subsequently constructed. Then, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology enrichment analyses about mRNAs in ceRNA networks were accomplished. More crucially, we demonstrated the differentially expressed microRNAs using quantitative real-time PCR and fluorescence in situ hybridization. The feasibility of microRNAs as biomarkers to predict platinum resistance and tumor recurrence was assessed using the receiver operating characteristic curve and survival analysis. MiR-320b and miR-320d exhibited high area under the curve values of 0.757 and 0.702, respectively. In our study, ceRNA networks including miR-320b and miR-320d probably provided novel insights for platinum resistance in ovarian cancer patients.