Recurrent Ovarian Cancer Patients Research Articles

BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines - Place for platinum reinduction.

Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear. (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients. This was a single-institution retrospective analysis. Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment. Statistical significance of differences between and among patients was tested for continuous variables by the Mann-Whitney U-test or the Kruskal-Wallis test; a maximum likelihood Chi-square test was used for categorical variables. Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062). Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.

Hyperthermic intraperitoneal chemotherapy in the treatment of recurrent ovarian cancer: When, and for whom?

The aim of this study is to evaluate the progression-free survival (PFS) of recurrent ovarian cancer (ROC) patients treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). ROC patients who underwent cytoreductive surgery plus HIPEC between 2015 and 2021 were retrospectively evaluated. Patients' demographic information and clinicopathological characteristics including cancer type, histology, platinum status, presence of ascites, type of surgery, complications, chemotherapy history, and disease progression were documented. PFS was calculated using the Kaplan-Meier method. A total of 104 patients with ROC were included. The median age was 57 years and the median follow-up time was 15 months (range: 5-69 months). In Cox regression multivariate analyses, platinum resistance (hazard ratio[HR]: 3.32, 95% confidence interval [CI]: 1.91-5.76, p = 0.00), more than one relapse prior HIPEC (HR: 2.81, 95% CI: 1.65-4.87, p = 0.024), and presence of ascites (HR: 1.88, 95% CI: 1.08-3.26, p = 0.00) were found to be negative prognostic factors for PFS. In subgroup analyses of patients with the first recurrence, the median PFS was 21 months for platinum-sensitive patients and 6 months for platinum-resistant patients (p = 0.032). HIPEC at the time of first platinum-sensitive relapse may lead to favorable PFS in the treatment ROC. However, HIPECas salvage treatment even with R0 cytoreductive surgery does not seem effective.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer

ObjectiveBRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. MethodsThe study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. Results147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. ConclusionGermline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification.

Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.

569P Pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer: Real-life clinical experience

Single agent immune checkpoint inhibitors are largely ineffective in treating recurrent ovarian cancer (OC). In a recently completed phase 2 clinical trial at our institute (NCT02853318), we combined pembrolizumab with anti-VEGF bevacizumab and oral metronomic cyclophosphamide in patients with recurrent ovarian cancer. Our phase 2 trial had a median progression free survival (PFS) of 10.0 months and 25% of the recurrent OC patients had a PFS > 12 months with excellent quality of life. Based on the results of this trial, our center has been using this regimen off label in patients with recurrent gynecologic malignancies, given the limited efficacy of traditional second line chemotherapies in this patient population.

Simplified Selection Criteria for Secondary Cytoreductive Surgery in Recurrent Ovarian Cancer.

Simple SummaryEligibility for secondary cytoreductive surgery (SCS) in ovarian cancer is dependent on multiple confounding factors. In this study, we evaluated the clinical characteristics of 262 patients with recurrent ovarian cancer to assess the impact of SCS on patient survival and establish simplified criteria for the selection of patients who would most likely be benefitted from SCS. We observed that the median survival was significantly longer in the patients who received SCS compared with those who received chemotherapy alone. As for the indication of the surgery, limited regional recurrence (single region or up to three regions with limited carcinomatosis) emerged as the simplified factor that could predict no residual disease after SCS.(1) Background: Multiple confounding factors influence the indications for secondary cytoreductive surgery (SCS) in patients with ovarian cancer (OC). We aimed to identify the factors associated with patients most likely to benefit from SCS. (2) Methods: We retrospectively reviewed the medical records of patients with recurrent ovarian cancer from 2003 to 2021. The potential factors influencing treatment outcomes and survival between patients who received chemotherapy alone and those who received SCS after recurrence were evaluated. (3) Results: Recurrent OC was identified in 262 patients, with a median age of 53 (20–80) years. Of these patients, 87.4% had an initial stage III/IV disease. Eighty-nine (34%) patients received SCS. The median survival was 41.0 (95% confidence interval [CI], 37.4–44.5) months and 88.0 (95% CI, 64.2–111.7) months in the chemotherapy and surgery groups, respectively. A multivariate analysis showed limited regional carcinomatosis (single region or up to three regions with limited carcinomatosis) (p = 0.045) as the only significant factor for predicting no residual disease after SCS. In platinum-sensitive recurrent patients with limited regional recurrence, the complete resection rate was 87.6%. (4) Conclusions: SCS had a significant impact on survival in the selected patient population. Limited regional recurrence (single region or up to three regions with limited carcinomatosis) may be a simple criterion for SCS in platinum-sensitive recurrent OC patients.

Duration of treatment, treatment adherence, and treatment discontinuations associated with second-line PARP inhibitor or bevacizumab maintenance regimens for recurrent ovarian cancer (338)

Objectives: Maintenance therapy after response to platinum has been shown in clinical trials to prolong progression-free survival in patients with recurrent ovarian cancer. We sought to describe current practice patterns for patients receiving maintenance therapy for recurrent ovarian cancer from real-world usage. Methods: We conducted a retrospective cohort study of US patients >18 years old with recurrent ovarian cancer and commercial or medicare advantage claims data in the Optum Research Database. Patients were required to have at least two diagnoses of ovarian cancer between July 1, 2010, and December 31, 2019, subsequent systemic chemotherapy, and an index second-line maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor or bevacizumab between January 1, 2017, and end of patient follow-up. Patients were followed until death, end of the study, or health plan disenrollment. Treatment duration and adherence were evaluated using descriptive statistics, and a Cox proportional hazards model was used to ascertain the time without dose interruption or discontinuation by the therapy group. Results: A total of 1092 patients met the inclusion criteria and had at least two lines of therapy. Among these, 446 (40.8%) subsequently received PARP inhibitor or bevacizumab maintenance treatment: 38 (8.5%) received rucaparib, 110 (24.7%) niraparib, 114 (25.6%) olaparib, and 184 (41.3%) bevacizumab. Average duration of maintenance treatment was as follows: olaparib, 187.6 (standard deviation [SD]: 178.7) days; bevacizumab, 185.2 (149.2) days; rucaparib, 147.2 (155.4) days; and niraparib, 124.2 (122.9) days. Treatment adherence was similar across all therapies (86-88%). Dose reduction was numerically more common during this time period in the niraparib group (28.2%) than rucaparib (21.1%) or olaparib (20.2%) groups, although the difference in frequency did not reach statistical significance. In a Cox proportional hazards model, niraparib was associated with a significantly shorter dose interruption or discontinuation time than rucaparib (HR: 3.7; p=0.03) (Figure). Olaparib and bevacizumab also had higher HRs for dose interruptions or discontinuations compared with rucaparib, but these estimates were not statistically significant (HR: 1.5; p=0.498 and HR: 1.4; p=0.584, respectively). Conclusions: Less than half of recurrent ovarian cancer patients received maintenance therapy with a PARP inhibitor or bevacizumab. For patients receiving maintenance therapy after a second chemotherapy regimen, while adherence was >86% in all regimens, dose modifications or discontinuation levels varied depending on the treatment received. Niraparib was associated with the shortest time to dose interruption or discontinuation among the agents evaluated. Objectives: Maintenance therapy after response to platinum has been shown in clinical trials to prolong progression-free survival in patients with recurrent ovarian cancer. We sought to describe current practice patterns for patients receiving maintenance therapy for recurrent ovarian cancer from real-world usage. Methods: We conducted a retrospective cohort study of US patients >18 years old with recurrent ovarian cancer and commercial or medicare advantage claims data in the Optum Research Database. Patients were required to have at least two diagnoses of ovarian cancer between July 1, 2010, and December 31, 2019, subsequent systemic chemotherapy, and an index second-line maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor or bevacizumab between January 1, 2017, and end of patient follow-up. Patients were followed until death, end of the study, or health plan disenrollment. Treatment duration and adherence were evaluated using descriptive statistics, and a Cox proportional hazards model was used to ascertain the time without dose interruption or discontinuation by the therapy group. Results: A total of 1092 patients met the inclusion criteria and had at least two lines of therapy. Among these, 446 (40.8%) subsequently received PARP inhibitor or bevacizumab maintenance treatment: 38 (8.5%) received rucaparib, 110 (24.7%) niraparib, 114 (25.6%) olaparib, and 184 (41.3%) bevacizumab. Average duration of maintenance treatment was as follows: olaparib, 187.6 (standard deviation [SD]: 178.7) days; bevacizumab, 185.2 (149.2) days; rucaparib, 147.2 (155.4) days; and niraparib, 124.2 (122.9) days. Treatment adherence was similar across all therapies (86-88%). Dose reduction was numerically more common during this time period in the niraparib group (28.2%) than rucaparib (21.1%) or olaparib (20.2%) groups, although the difference in frequency did not reach statistical significance. In a Cox proportional hazards model, niraparib was associated with a significantly shorter dose interruption or discontinuation time than rucaparib (HR: 3.7; p=0.03) (Figure). Olaparib and bevacizumab also had higher HRs for dose interruptions or discontinuations compared with rucaparib, but these estimates were not statistically significant (HR: 1.5; p=0.498 and HR: 1.4; p=0.584, respectively). Conclusions: Less than half of recurrent ovarian cancer patients received maintenance therapy with a PARP inhibitor or bevacizumab. For patients receiving maintenance therapy after a second chemotherapy regimen, while adherence was >86% in all regimens, dose modifications or discontinuation levels varied depending on the treatment received. Niraparib was associated with the shortest time to dose interruption or discontinuation among the agents evaluated.

Optimum selection criteria for secondary cytoreductive surgery in patients with recurrent ovarian cancer: A multicenter study from the Gynecologic Oncology Research Investigators coLLaborAtion (GORILLA) group (GORILLA 3001) (546)

Objectives: Optimum selection criteria for secondary cytoreductive surgery (SCS) in recurrent ovarian cancer is often dependent on multiple confounding factors. This study aimed to evaluate the treatment outcomes of recurrent ovarian cancer and investigate the factors identifying patients who most likely benefit from the SCS. Methods: We retrospectively reviewed medical records of recurrent ovarian cancer patients from five referral hospitals in Korea from 2010 to 2020. Recurrent characteristics, following treatment methods and potential factors for survivals were evaluated between the chemotherapy and surgery groups. Results: A total of 670 patients with recurrent ovarian cancer were identified. The patient’s median age was 55 years (24-83), and 88.1% of patients had initial stage III/IV disease. Of all patients, 215 (32.1%) received SCS for the disease recurrence. The median survival was 85 months (95% CI: 65.0-105.0) in the chemotherapy group, whereas the median survival time was not reached in the SCS group. Patients who received the SCS were more likely to be young and had no residual disease at primary surgery, platinum-sensitive recurrence, limited regional recurrence (LRR, ≤3 lesions or regional carcinomatosis) with a low rate of ascites (p<0.001, 0.001, 0.001, 0.001, 0.006, respectively). In multivariate cox analysis, residual disease at primary surgery, PFI, recurrent sites, ascites, and SCS were significant prognostic factors for survival. Meanwhile, predicting factor for complete resection after SCS was only recurrent sites (LRR, p<0.001). Conclusions: SCS resulted in significantly favorable survival outcomes in well-selected patients. Platinum-sensitive recurrence with limited regional diseases (< 3 regions or limited carcinomatosis without ascites) can be considered as optimum criteria for SCS in recurrent ovarian cancer. Objectives: Optimum selection criteria for secondary cytoreductive surgery (SCS) in recurrent ovarian cancer is often dependent on multiple confounding factors. This study aimed to evaluate the treatment outcomes of recurrent ovarian cancer and investigate the factors identifying patients who most likely benefit from the SCS. Methods: We retrospectively reviewed medical records of recurrent ovarian cancer patients from five referral hospitals in Korea from 2010 to 2020. Recurrent characteristics, following treatment methods and potential factors for survivals were evaluated between the chemotherapy and surgery groups. Results: A total of 670 patients with recurrent ovarian cancer were identified. The patient’s median age was 55 years (24-83), and 88.1% of patients had initial stage III/IV disease. Of all patients, 215 (32.1%) received SCS for the disease recurrence. The median survival was 85 months (95% CI: 65.0-105.0) in the chemotherapy group, whereas the median survival time was not reached in the SCS group. Patients who received the SCS were more likely to be young and had no residual disease at primary surgery, platinum-sensitive recurrence, limited regional recurrence (LRR, ≤3 lesions or regional carcinomatosis) with a low rate of ascites (p<0.001, 0.001, 0.001, 0.001, 0.006, respectively). In multivariate cox analysis, residual disease at primary surgery, PFI, recurrent sites, ascites, and SCS were significant prognostic factors for survival. Meanwhile, predicting factor for complete resection after SCS was only recurrent sites (LRR, p<0.001). Conclusions: SCS resulted in significantly favorable survival outcomes in well-selected patients. Platinum-sensitive recurrence with limited regional diseases (< 3 regions or limited carcinomatosis without ascites) can be considered as optimum criteria for SCS in recurrent ovarian cancer.

RNAseq correlative biomarkers IFIT1B and VSTM5 predict progression free survival and clinical benefit in a multi-site Phase I/II trial of Olaparib and Tremelimumab for gBRCAm recurrent ovarian cancer (LBA 11)

<b>Objectives:</b> Although ovarian cancer is a rational target for immune therapy, immune checkpoint blockade has not demonstrated the efficacy seen in other solid tumors. In preclinical studies, PARP inhibition (PARPi) synergized with CTLA4 immune checkpoint blockade, resulting in durable anti-tumor immunity and long-term survival in ovarian cancer models. This combination was tested in women with germline BRCA1 or BRCA2 mutations (gBRCAm) and recurrent ovarian cancer in a phase I/II clinical trial (NCT0257125). Correlative studies were performed to identify predictive biomarkers of response. <b>Methods:</b> Women with recurrent ovarian cancer, confirmed gBRCAm, and measurable disease were eligible for participation. There were no restrictions on the number or type of prior treatment regimens. Prior PARPi treatment was allowed. Subjects received olaparib at 300mg BID and the CTLA4 antibody tremelimumab at 10mg/kg IV every 4 weeks for six doses followed by maintenance dosing every 12 weeks. Treatment continued for up to two years. The Phase I lead-in allowed dose modifications for toxicity. The phase II component used Simon's 2-stage design based on the primary endpoint of overall response rate. RNAseq was performed on archived formalin-fixed, paraffin embedded pre-treatment tumor samples from 30 subjects, and candidate biomarkers were selected based on differential expression in subjects with and without clinical benefit. <b>Results:</b> Forty-nine patients received study treatment (mean age 56 yrs, range 39-79) at five sites. Twenty-eight subjects had received ≥3 prior chemotherapy regimens, and 29 were previously treated with a PARPi. After 14 patients received the study regimen, the recommended phase 2 schedule for tremelimumab was changed to 10mg/kg infusions every 4 weeks for four doses followed by maintenance dosing every 12 weks due to immune-related adverse events, primarily colitis. Fifty-nine percent of subjects experienced at least one non-hematologic ≥ grade 3 toxicity. Among 44 evaluable patients, the overall response rate was 39%, with a clinical benefit rate of 48%. The median PFS was 3.4 months (95% CI 2.7-6.1). In a curated analysis of interferon response genes, lack of IFIT1B expression was associated with significantly enhanced PFS (median 11.4 vs 2.7 months; log-rank p=0.009; Fig 1). In an unbiased analysis of all genes, VSTM5 was the most differentially expressed marker (AUC=0.852), and lack of VSTM5 expression was significantly associated with PFS (8.12 vs 2.56 months; log-rank p=0.001). <b>Conclusions:</b> The combination of olaparib and tremelimumab achieved durable treatment benefit in a subset of gBRCAm recurrent ovarian cancer patients. Immune toxicity was moderate. Biomarkers based on gene expression in archived tumor samples were associated with clinical benefit. Future studies are needed to assess the utility of these biomarkers to identify candidates for immune therapy.

Randomized phase III trial on trabectedin (ET-743) single agent versus clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal, or fallopian tube cancers of BRCA-mutated or BRCAness phenotype patients (MITO23).

LBA5504 Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.

Platinum vs non-platinum chemotherapy for platinum-resistant ovarian cancer: A meta-analysis.

e17551 Background: recurrent ovarian cancer (OC) patients with platinum-free interval (PFI) &lt; 6 mo. are usually considered platinum-resistant and treated with non-platinum chemotherapy. However, this practice is not based on proper-conducted randomized trials. Methods: we queried the PubMed database for all full-text articles and abstracts on the treatment of patients with platinum-resistant ovarian cancer (PROC) in 01/01/2000-01/06/2019 timeframe. The PRISMA tool was used to ensure transparent reporting of the results. Inclusion criteria were: 1) histologically confirmed epithelial OC; 2) recurrent disease within 6 months after completion of platinum chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) defined response rate (RR) and assessment criteria. Proportion meta-analysis (random-effect model) and beta-regression were conducted to assess the impact of platinum agents on response rate as well as significance of other variables. In the beta-regression model response rate was a dependent variable, while platinum agents (yes or no), used non-platinum drugs and method of response assessment were independent variables. Statistical analysis was dose with meta and betareg packages of R software. Results: we identified 7156 articles and screened them for title and abstract, 157 studies for further analysis. Efficacy of non-platinum- and platinum-based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively. In meta-proportion random-effect model RR among patients treated with platinum-based and non-platinum chemotherapy RR was 36% (95% CI 30-41; I2 = 62%) and 16% (95% CI 14-19; I2= 70%) respectively. Multiple beta-regression model is presented in the Table below. For sensitivity analysis various regression models were made with different subsets of the trials and additional variables (including year of the trial, percentage of serous subtype of OC and median of prior therapy lines). Platinum was the strongest predictor of response in every developed model. Conclusions: this meta-analysis shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents. These results support recent ESMO-ESGO consensus on treatment of recurrent ovarian cancer and randomize trials are required to refine the role of platinum in early relapsed OC.[Table: see text]

Cancer stem cell assay for identification of effective treatments for platinum-resistant recurrent ovarian cancer.

e17584 Background: Disease recurrence and progression of ovarian cancer is a common event, which is accompanied by the development of platinum-resistant or refractory disease. The presence of chemo-resistant cancer stem cells (CSCs) contributes to tumor propagation, maintenance, and treatment resistance of this difficult to treat disease. The choice of appropriate chemotherapy is critical to the management of advanced epithelial ovarian cancer. We developed a CSCs assay (ChemoID) that identifies the most effective chemotherapy for individual patients from a panel of FDA-approved chemotherapies. Methods: Ascites or interventional radiology biopsies were collected under physician order from 85 consecutive patients affected by 3rd relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, if needed. Our study assessed the correlation of the ChemoID test results to treatment outcomes independently of other biomarkers. A retrospective chart analysis and review of CT and PET scans were performed to determine patients’ outcomes for tumor response, progression-free survival (PFS), and overall survival (OS). Results: We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the ChemoID drug response assay had an improvement in their median PFS and OS when compared to historical median PFS and OS and/or when compared to patients who could not receive high cell kill chemotherapies (PFS low cell kill 3.5 months vs. high cell kill 12.0 months; OS low cell kill 6.0 months vs. high cell kill 15.0 months). Conclusions: The current evidence strongly suggests that the ChemoID assay predicted the effectiveness of specific therapies, as well as improved outcomes for patients treated with assay-sensitive therapies.

An effective AKT inhibitor-PARP inhibitor combination therapy for recurrent ovarian cancer

BackgroundAlthough the use of PARP inhibitor has received considerable amount of attention in ovarian cancer, PARP inhibitor resistance still emerges with disease progression. PI3K/AKT pathway inhibitors have been proposed to synergize with PARP inhibition to slow tumor growth, but the exact molecular mechanisms are still elusive.MethodsUtilizing tumor samples from recurrent EOC patients with platinum resistance and prior PARP inhibitor use, Mini PDX and PDX models were established to study the anti-tumor effect of AKT inhibitor (LAE003) and LAE003/PARP inhibitor (Olaparib) in combination. Five ovarian cancer cell lines were treated with Olaparib or LAE003 or in combination in vitro. Cell viability and apoptosis rate were measured after the treatments. Combination index by the Chou–Talalay was used to evaluate in vitro combination effect of Olaparib and LAE003. The protein expression level of PARP1 and PAR was measured by Western blot in cell lines and by immunohistochemistry in PDX tumor tissues.ResultsTumor cells from two out of five platinum-resistant ovarian cancer patients previously treated with PARP inhibitor were sensitive to AKT inhibition in Mini-PDX study. Inhibition of AKT further increased the response of tumor cells to Olaparib in a PDX model derived from a recurrent platinum-resistant ovarian cancer patient. Additive anti-proliferation effect of LAE003 and Olaparib was also observed in three ovarian cancer cell lines with high PARP1 protein level. Interestingly, mechanism study revealed that AKT inhibition decreased PARP enzyme activity as measured by PAR level and/or reduced PARP1 protein level in the tumor cell lines and PDX tumor tissues, which may explain the observed combined anti-tumor effect of LAE003 and Olaparib.ConclusionCollectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients.

Appropriate Selection of PARP Inhibitors in Ovarian Cancer.

Poly-ADP-ribose polymerase inhibitors (PARPi) are a class of anti-cancer drugs that target DNA repair pathways and have shown promising efficacy in patients with ovarian cancer in recent clinical trials. To date, there have been 9 FDA PARPi approvals/indications in ovarian cancer since 2014, highlighting the importance of this class of agents in the treatment of ovarian cancer. BRCA1/2-mutated tumors or other forms of homologous recombination deficient (HRD) tumors are particularly susceptible to PARP inhibition and have seen the greatest benefits of improvement in response rate and progression-free survival (PFS) in clinical trials. Patients with homologous recombination-proficient tumors also receive benefit, especially when a nice response to paltinum is noted, but to a lesser extent. PARP inhibitors now have FDA approval and indications in first-line and recurrent maintenance, and treatment. PARP inhibitor use as maintenance therapy in the front-line setting is now considered the standard of care in patients with BRCA1/2 mutations based on the SOLO-1/GOG-3004/ENGOT study. PARP inhibitors are also recommended per ASCO guidelines in all patients with ovarian cancer as front-line maintenance therapy based on the PRIMA/ENGOT-OV26/GOG-3012 trial. The combination of PARP inhibitor, olaparib, and the anti-angiogenesis inhibitor bevacizumab is also approved as maintenance therapy after front-line chemotherapy treatment in patients with HRD tumors and is an option for patients who have initiated bevacizumab with their chemotherapy treatment. PARPi are also FDA approved and can be utilized as a treatment in third-line and beyond in recurrent ovarian cancer patients with BRCA1/2 mutations and HRD tumors. In this review, we will cover in detail when PARP inhibitor use is appropriate in ovarian cancer, as well as the various clinical factors to take into consideration when selecting a PARP inhibitor regimen.

Efficacy of non‑platinum chemotherapy in platinum‑resistant ovarian cancer: a meta‑analysis

Background: Recurrent ovarian cancer (OC) patients with platinum‑free interval (PFI) &lt; 6 mo. are usually considered platinum‑resistant and treated with non‑platinum based chemotherapy. There is a lack of evidence to compare various non‑platinum therapeutic options in patients with platinum‑resistant ovarian cancer (PROC). We conducted meta‑analysis to assess efficacy of various therapeutic options in PROC patients. This article aimed to compare non‑platinum therapeutic regimens.Methods: We queried the PubMed database for full‑text articles and abstracts on the treatment of PROC patients (01/01/2000–01/06/2019 timeframe). Inclusion criteria were: 1) epithelial ovarian cancer; 2) recurrent disease ≤ 6 mo. after platinum‑based chemotherapy; 3) standard therapy with platinum‑ or non‑platinum agents; 4) no targeted therapy, investigational agents or non‑platinum doublets; 5) reported response rate (RR) and assessment criteria. Proportion meta‑analysis (random‑effect model) and beta‑regression were conducted to assess efficacy of various options. Statistical analysis was dose with meta and betareg packages of R software.Results: We identified 7156 articles and screened them for title and abstract, 157 studies were left for further analysis. Efficacy of non‑platinum‑ and platinum‑based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively, only the latter were included in this analysis. In meta‑proportion random‑ effect model RR among patients treated with taxanes, etoposide, doxorubicin/PLD, topotecan and gemcitabine were 27 % (95 % CI 0.21–0.34), 19 % (95 % ДИ 0.13–0.27), 15 % (95 % CI 0.11–0.19), 13 % (95 % CI 0.10–0.18) and 10 % (95 % CI 0.07–0.14), respectively. Multiple beta‑regression model accounting for response assessment method, number of prior therapy lines and other factors confirmed the results.Conclusions: Taxanes monotherapy may be the most effective therapeutic option for patients who are not candidates for platinum‑based chemotherapy.

The impact of secondary cytoreductive surgery in platinum sensitive recurrent ovarian cancer treated with upfront neoadjuvant chemotherapy and interval debulking surgery

ObjectiveThe aims of the present study were to assess the oncological outcomes of platinum-sensitive recurrent ovarian cancer patients undergoing secondary cytoreduction (SCS) after treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) at diagnosis and to compare the performance of different selection models in these patients. MethodsRetrospective, observational, single-center cohort study including patients with platinum-sensitive recurrent epithelial ovarian cancer with abdominal/inguinal/cardiophrenic disease between November 2012 and November 2020. Patients were selected as surgical candidates with PET/CT-scan and with diagnostic laparoscopy. Results272 patients were included in the study. Of these, 165 (60.7%) patients were treated with PDS at diagnosis and 107 (39.3%) with IDS. SCS was performed in 178 (65.4%) cases, with complete gross resection achieved in 155/178 (87.1%). No progression-free survival (PFS) difference was demonstrated when patients treated with PDS were compared with those treated with NACT+IDS at first diagnosis (median 21 versus 21 months; p = 0.684); no post-recurrence survival (PRS) difference was evident between the two groups (median 81 versus 77 months, respectively; p = 0.574). Current selection models to candidate patients to SCS adequately performed in patients treated with IDS at diagnosis, as well as in the PDS group, with combination of PET/CT-scan and laparoscopy being an accurate tool in prediction of no gross residual disease at SCS in this pre-selected population. ConclusionsPatients with platinum-sensitive recurrent epithelial ovarian cancer treated with NACT/IDS as primary treatment have similar post-recurrence survival outcomes of those treated with PDS. Current models to select patients for SCS can be safely applied to IDS patients.

Oncolytic viral therapy engenders a clinical response in a recurrent ovarian cancer patient.

Platinum-resistant ovarian cancer frequently develops in response to multiple lines of chemotherapy, whereupon the disease becomes relatively intractable and clinical recourse is limited. We document a 58-year-old, advanced-stage, platinum-resistant ovarian cancer patient who previously failed numerous cytotoxic and targeted therapy regimens. She was referred to our gynecologic oncology service with a California (CA)-125 of 3194 U/mL and underwent a modified vaccinia virus coinciding with an Institutional Review Board-approved clinical trial. Following the oncolytic therapy and cycle 8 chemotherapy, the patient's CA-125 declined to 440 U/mL; a computerized tomography scan of the abdomen and pelvis revealed a partial response to therapy. The favorable clinical benefit encountered in our case study indicates that the combination of oncolytic viral therapy and chemotherapy should be considered as a therapeutic option for heavily pretreated ovarian patients.

Survival in recurrent ovarian cancer patients before and after the bevacizumab era: an observational single-centre study

A retrospective observational study was carried out in Baskent University School of Medicine, Ankara, Turkey. Recurrent ovarian cancer patients treated between 2007 and 2017 were divided into two groups according to their bevacizumab status. The primary endpoints were overall survival (OS) and safety. Three hundred and ninety-six patients enrolled in this study, 200 (50.5%) received bevacizumab while 196 (49.5%) patients never received bevacizumab. The median follow-up time was 48.2 and 47.6 months, respectively. The 5-year OS was 61% and 46%, respectively (p=.007). In multivariate analysis, only platinum-sensitivity (HR: 3.75, 95% CI: 3.0–5.32; p<.001) was identified as independent prognostic factors. In subgroup analyses according to platinum status, bevacizumab did not affect the 5 year OS in platinum sensitive patients (64% versus 68% p=.28) but increased survival in platinum resistant patients (36% versus 44%, p=.00). The rate of grade III–IV haematologic toxicities was 13.7% in the bevacizumab group and 11% in the other group (p=.6). Impact Statement What is already known on this subject? Bevacizumab increases the progression-free survival in platinum-sensitive and resistant recurrent ovarian cancer patients without changing overall survival. What do the results of this study add? Bevacizumab did not affect OS in platinum sensitive recurrent ovarian cancer patients however improved OS in platinum resistant patients with mild toxicity. What are the implications of these findings for clinical practice and/or further research ? This study emphasised the crucial role of bevacizumab in the treatment of recurrent ovarian cancer patients.

DO HIGH PRE-OPERATIVE CA-125 LEVELS PREDICT EARLY RECURRENCE IN PATIENTS WITH HIGH-GRADE EPITHELIAL OVARIAN CANCER ?

Ponte Academic JournalAug 2022, Volume 78, Issue 8 DO HIGH PRE-OPERATIVE CA-125 LEVELS PREDICT EARLY RECURRENCE IN PATIENTS WITH HIGH-GRADE EPITHELIAL OVARIAN CANCER ?Author(s): Nilufer Bulut ,Tanju KapaganJ. Ponte - Aug 2022 - Volume 78 - Issue 8 doi: 10.21506/j.ponte.2022.8.8 Abstract:Background CA-125 is used as a marker in the diagnosis, treatment, and follow-up of ovarian cancers. High CA-125 levels indicate a high tumor burden, large ascites volume, and advanced stage. In the present study, the predictive value of CA-125 for the prognosis of ovarian cancer patients was determined. Materials-Methods The data of 173 patients diagnosed with ovarian cancer between 2009 and 2021 were analyzed retrospectively. CA-125 values before primary treatment were recorded. All patients underwent neoadjuvant chemotherapy or primary tumor surgery. Patients with normal CA-125 values at the end of treatment, and those with residual tumor, were followed up until the first recurrence. Disease-free and overall survival were analyzed. Results According to the preoperative CA-125 values, the disease-free survival time before treatment in patients with CA-125 levels of 0–40, 41–120, and &gt; 121 U/ml was 73, 59.8, and 54 months, respectively; the differences were not statistically significant (p = 0.174). Patients with a ≥ 3-fold increase in their CA-125 value at recurrence had shorter overall survival (0–40 U/ml: 86 months; 41–120 U/ml: 60 months; &gt; 121 U/ml: 54 months; p = 0.025). For patients without residual tumor after surgery, overall survival was 61 months, but it was significantly shorter (38 months) in those with residual tumor &gt; 1 cm (p=0.001). Conclusion Levels of the tumor marker CA-125 are used to determine the response to treatment, residual tumor, and disease recurrence in ovarian cancer patients. Although elevated CA-125 levels alone do not contribute to the prognosis, patients with values 3-fold higher than before treatment had shorter overall survival. Download full text:Check if you have access through your login credentials or your institution Username Password

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Management of Advanced Ovarian Cancer. A Literature Review

The rationale behind the use of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery is the association between pharmacological activity of chemotherapy delivered to the peritoneal cavity with the enhanced cytotoxic effect of hyperthermia. Data on the efficacy of HIPEC in the primary debulking surgery (PDS) setting are still controversial and limited by the small sample size of most of the studies, the inclusion of different treatment settings and chemotherapy regimens. Among the ongoing prospective trials, only the OVHIPEC-2 trial is investigating exclusively patients submitted to PDS ± HIPEC with cisplatin 100 mg/m22 and results are expected by 2026. On the interval debulking surgery (IDS) setting high quality data are coming from the result of the OVHIPEC-1 trial, which demonstrated a survival advantage of nearly 4 months in median progression-free survival (PFS) (14.2 months vs. 10.7 months; p = 0.003) and almost 12 months in median overall survival (OS) (45.7 months vs. 33.9 months; p = 0.02) for HIPEC treated patients (cisplatin 100 mg/m22) compared to no-HIPEC group, with comparable morbidity. However, due to some criticisms raised to the results of OVHIPEC-1 trial, the ESMO-ESGO guidelines recommended not to consider HIPEC as standard therapy until results from ongoing randomized control trials (RCTs) are provided. On the contrary, for the National Comprehensive cancer network (NCCN) guidelines HIPEC can be considered at the time of IDS. Similarly, data supporting the role of HIPEC in association with surgery in case of recurrent disease appear to be controversial in terms of patients and selection and intraperitoneal chemotherapy regimen. Indeed, despite the positive results coming from a prospective randomized trial, they appear to be biased by the inclusion of both platinum sensitive and resistant disease and the lack of information on PFS. Those results are in contrast with data coming from another prospective trial, which failed to demonstrate a survival gain of recurrent ovarian cancer patients treated with secondary cytoreductive surgery + HIPEC with carboplatin (800 mg/m22 for 90 min) compared to women submitted to cytoreduction only. Again, in this subgroup of patients data of ongoing RCTs are awaited to assess the impact on survival of HIPEC administration in case of recurrent disease.