Metastatic Ovarian Cancer Patients Research Articles

Ecological and evolutionary dynamics to design and improve ovarian cancer treatment.

Ovarian cancer ecosystems are exceedingly complex, consisting of a high heterogeneity of cancer cells. Development of drugs such as poly ADP-ribose polymerase (PARP) inhibitors, targeted therapies and immunotherapies offer more options for sequential or combined treatments. Nevertheless, mortality in metastatic ovarian cancer patients remains high because cancer cells consistently develop resistance to single and combination therapies, urging a need for treatment designs that target the evolvability of cancer cells. The evolutionary dynamics that lead to resistance emerge from the complex tumour microenvironment, the heterogeneous populations, and the individual cancer cell's plasticity. We propose that successful management of ovarian cancer requires consideration of the ecological and evolutionary dynamics of the disease. Here, we review current options and challenges in ovarian cancer treatment and discuss principles of tumour evolution. We conclude by proposing evolutionarily designed strategies for ovarian cancer, with the goal of integrating such principles with longitudinal, quantitative data to improve the treatment design and management of drug resistance. KEY POINTS/HIGHLIGHTS: Tumours are ecosystems in which cancer and non-cancer cells interact and evolve in complex and dynamic ways. Conventional therapies for ovarian cancer inevitably lead to the development of resistance because they fail to consider tumours' heterogeneity and cellular plasticity. Eco-evolutionarily designed therapies should consider cancer cell plasticity and patient-specific characteristics to improve clinical outcome and prevent relapse.

Abstract PO5-18-06: On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit the the in vitro and in vivo action of human PGRN/GP88 has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. The presentation will provide an update on the number of patients enrolled in this on-going phase 1A trial. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-06.

Prognostic marker of red cell distribution width (RDW) correlates with survival outcomes in metastatic ovarian cancer patients

Red cell distribution width (RDW) measures red cells’ size variability. Metastatic ovarian cancer displays poor chemotherapy response without an effective prognostic predictor address. we investigated whether RDW correlates independently with survival outcomes in metastatic ovarian cancer treated by chemotherapy. Subsequently, it has been specified that RDW can be likewise utilized as a prognostic marker of metastatic ovarian cancer patients. Venous blood was collected from each patient in the morning. RDW was obtained directly by the hematology analyzer from 55 patients with metastatic ovarian cancer and were retrospectively analyzed between 2018 and 2022. Survival time was calculated from the date of chemotherapy initiation until the date of death.

Abstract CT240: On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit PGRN/GP88 action in vitro and in vivo has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT240.

Prognostic Role of Vascular Endothelial Growth Factor and Correlation with Oxidative Stress Markers in Locally Advanced and Metastatic Ovarian Cancer Patients

Vascular endothelial growth factor (VEGF) plays an important role in tumor progression in ovarian cancer, but the complex mechanism and interaction with oxidative stress are not fully understood. A prospective study included 52 patients with ovarian adenocarcinoma stage IIIA-IV. Serum VEGF and reactive oxygen species (ROS) such as malondialdehyde and ceruloplasmin were measured. VEGF levels were elevated (mean 1014.7 ± 165 pg/mL), especially in patients with macroscopic residual disease (1058 vs. 810 pg/mL, p = 0.0001). Median progression-free survival (PFS) and overall survival (OS) were 6 and 40 months in patients with a very high VEGF (over 1200 pg/mL), 11 and 48 months in patients with VEGF between 1000-1200 pg/mL, 18 and 84 months in patients with VEGF between 800-1000 pg/mL, and not reached in patients with normal VEGF. Increased VEGF values were associated with a 2.6-fold increased risk of disease progression (HR = 2.60, 95% CI 1.69-3.99), and a 1.4-fold increased risk of death (HR = 1.4, 95% CI 1.15-1.91, p = 0.002). Receiver operator characteristic (ROC) curves were used to validate VEGF as a prognostic factor and the area under the curve (AUC) was 0.814, p = 0.036 for PFS and 0.729, p = 0.043, for OS. There was a positive correlation between VEGF and malondialdehyde, Pearson coefficient of 0.35, p = 0.0001. VEGF and malondialdehyde are important prognostic markers in ovarian cancer, especially in macroscopic residual disease, and there is a positive correlation between angiogenesis and oxidative stress.

Prediction for 2-year mortality of metastatic ovarian cancer patients based on surveillance, epidemiology, and end results database.

To establish prediction models for 2-year overall survival of ovarian cancer patients with metastasis. In total, 4,929 participants from Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into the training set (n = 3,451) and the testing set (n = 1,478). Univariate and multivariable regression were conducted in the training set to identify predictors for 2-year overall survival of metastatic ovarian cancer patients. The C-index was calculated for assessing the performance of the models. The nomogram for the model was plotted. The prediction value of the model was validated in the testing set. Subgroup analysis were performed concerning surgery and chemotherapy status of patients and the metastatic site of ovarian cancer in the testing set. The calibration curves were plotted and the decision curve analysis (DCA) were conducted. At the end of follow-up, 2,587 patients were survived and 2,342 patients were dead within 2 years. The 2-year survival rate was 52.5%. The prediction models were constructed based on predictors including age, radiation, surgery and chemotherapy, CA125, and bone, liver, and lung metastasis. The prediction model for 2-year overall survival of ovarian cancer patients with metastasis showed good predictive ability with the C-index of the model of 0.719 (95% CI: 0.706-0.731) in the training set and 0.718 (95% CI: 0.698-0.737) in the testing set. In terms of patients with bone metastasis, the C-index was 0.740 (95% CI: 0.652-0.828) for predicting the 2-year overall survival of ovarian cancer patients. The C-index was 0.836 (95% CI: 0.694-0.979) in patients with brain metastasis, 0.755 (95% CI: 0.721-0.788) in patients with liver metastasis and 0.725 (95% CI: 0.686-0.764) in those with lung metastasis for predicting the 2-year overall survival of ovarian cancer patients. The models showed good predictive performance for 2-year overall survival of metastatic ovarian cancer patients.

Detection of ESR1 Mutations in Primary Tumors and Plasma Cell-Free DNA in High-Grade Serous Ovarian Carcinoma Patients.

Simple SummaryIn the present study we evaluated the frequency and the clinical relevance of ESR1 mutations in high-grade serous ovarian cancer (HGSOC). Drop-off droplet digital PCR (ddPCR) was first used to screen for ESR1 mutations in primary tumors (formalin-fixed paraffin-embedded, FFPEs) from HGSOC patients and plasma cell-free DNA (cfDNA) samples from advanced and metastatic ovarian cancer patients. We further used the recently developed ESR1-NAPA assay to detect individual ESR1 mutations in drop-off ddPCR-positive samples. We report for the first time the presence of ESR1 mutations in 15% of FFPEs and in 13.8% of plasma cfDNA samples from advanced and metastatic ovarian cancer patients.ESR1 mutations have been recently associated with resistance to endocrine therapy in metastatic breast cancer and their detection has led to the development and current evaluation of novel, highly promising therapeutic strategies. In ovarian cancer there have been just a few reports on the presence of ESR1 mutations. The aim of our study was to evaluate the frequency and the clinical relevance of ESR1 mutations in high-grade serous ovarian cancer (HGSOC). Drop-off droplet digital PCR (ddPCR) was first used to screen for ESR1 mutations in 60 primary tumors (FFPEs) from HGSOC patients and in 80 plasma cell-free DNA (cfDNA) samples from advanced and metastatic ovarian cancer patients. We further used our recently developed ESR1-NAPA assay to identify individual ESR1 mutations in drop-off ddPCR-positive samples. We report for the first time the presence of ESR1 mutations in 15% of FFPEs and in 13.8% of plasma cfDNA samples from advanced and metastatic ovarian cancer patients. To define the clinical significance of this finding, our results should be further validated in a large and well-defined cohort of ovarian cancer patients.

Racial and ethnic disparities in palliative care utilization among gynecological cancer patients

BackgroundPalliative care (PC) is recommended for gynecological cancer patients to improve survival and quality-of-life. Our objective was to evaluate racial/ethnic disparities in PC utilization among patients with metastatic gynecologic cancer. MethodsWe used data from the 2016 National Cancer Database (NCDB) and included patients between ages 18–90 years with metastatic (stage III-IV) gynecologic cancers including, ovarian, cervical and uterine cancer who were deceased at last contact or follow-up (n = 124,729). PC was defined by NCDB as non-curative treatment, and could include surgery, radiation, chemotherapy, and pain management or any combination. We used multivariable logistic regression to evaluate racial disparities in PC use. ResultsThe study population was primarily NH-White (74%), ovarian cancer patients (74%), insured by Medicare (47%) or privately insured (36%), and had a Charlson-Deyo score of zero (77%). Over one-third of patients were treated at a comprehensive community cancer program. Overall, 7% of metastatic gynecologic deceased cancer patients based on last follow-up utilized palliative care: more specifically, 5% of ovarian, 11% of cervical, and 12% of uterine metastatic cancer patients. Palliative care utilization increased over time starting at 4% in 2004 to as high as 13% in 2015, although palliative care use decreased to 7% in 2016. Among metastatic ovarian cancer patients, NH-Black (aOR:0.87, 95% CI:0.78–0.97) and Hispanic patients (aOR:0.77, 95% CI:0.66–0.91) were less likely to utilize PC when compared to NH-White patients. Similarly, Hispanic cervical cancer patients were less likely (aOR:0.75, 95% CI:0.63–0.88) to utilize PC when compared to NH-White patients. ConclusionsPC is highly underutilized among metastatic gynecological cancer patients. Racial disparities exist in palliative care utilization among patients with metastatic gynecological cancer.

Economic Burden of Metastatic Ovarian Cancer in a Commercially Insured Population: A Retrospective Cohort Analysis.

Ovarian cancer is the tenth most common type of cancer and the fifth leading cause of cancer death among females in the United States. The majority of incident ovarian cancer cases are diagnosed in individuals aged < 65 years, but limited evidence exists regarding the economic burden of ovarian cancer in this age group. To (a) estimate the annual all-cause direct total cost of metastatic ovarian cancer and (b) compare it to the cost of individuals without cancer in the working age commercially insured U.S. We conducted a retrospective cohort analysis using the IBM MarketScan Commercial Database. Patients were included if they met the following criteria: ≥ 1 medical claim with a secondary malignancy diagnosis in the primary position between January 1, 2011, and December 31, 2015 (earliest date of diagnosis defined as the index date); aged ≥ 18 years on the index date; ≥ 12 months of continuous enrollment before the index date; ≥ 1 month of continuous enrollment after the index date; and ≥ 1 inpatient medical claim or ≥ 2 outpatient medical claims ≥ 30 days apart, with an ovarian cancer diagnosis in any claim position within 60 days before or 30 days after the index date. Patients were excluded if they had ≥ 1 medical claim with a cancer diagnosis except for ovarian cancer in any claim position during the 12-month pre-index period. Controls were randomly selected and matched to metastatic ovarian cancer patients based on age, region, index date, number of months of continuous enrollment after the index date, and propensity score. Annual all-cause direct total costs and ovarian cancer-related direct total costs were estimated and compared for each cohort by using the Kaplan-Meier sample average technique to account for censoring after the index date. 2,991 metastatic ovarian cancer patients and 2,991 matched controls were included in this study. Patients in the metastatic ovarian cancer cohort had a mean (SD) age of 54.4 (8.5) years, and controls had a mean (SD) age of 54.2 (8.4) years. The mean (95% CI) annual all-cause total costs in the 12-month post-index period were $140,124 ($134,025-$146,267) for metastatic ovarian cancer patients and $35,161 ($31,338-$39,529) for controls; the resulting mean (95% CI) difference in annual all-cause total costs was $104,964 ($99,732-$110,042). In comparison with the annual all-cause total costs, the mean (95% CI) annual ovarian cancer-related total costs in the 12-month post-index period were $86,971 ($82,349-$91,508) for metastatic ovarian cancer patients and $0 ($0-$0) for controls. Working age patients with metastatic ovarian cancer have significantly higher costs compared with those without cancer. These findings contribute to the understanding of the burden of illness in a patient population where limited evidence currently exists on the economic consequences of the disease. No outside funding supported this study. The authors have nothing to disclose. This study was presented at the 2019 International Society for Pharmacoeconomics and Outcomes Research Annual Meeting; May 18-22, 2019; New Orleans, LA.

Hrd in ovarian cancer: Defined today, evolving for the future.

e18052 Background: Homologous Recombination Repair (HRR) gene mutations result in Homologous Recombination Deficiency (HRD) associated with increased risk of high grade serous ovarian (HGOC) cancer and subsequent response to PARP inhibitors (PARPi). Traditionally, HRD has been determined by testing for germline and/or somatic BRCA1/2 mutations. Today, a growing number of HRR gene mutations are known to result in HRD and genomic instability, thus being a suitable target for PARPi. Therapy response to PARPi is highest in BRCA-mutant followed by HRD+/non-BRCA-mutant HGOC. Today, no standard HRD testing methods exist, causing confusion for physicians, and leading to poor outcomes for missed PARPi eligible patients. Thus, there is need to understand HRD testing utilization and methods in HGOC to inform best practices and optimize HRD testing in the clinic. Methods: We assessed the testing landscape for determining HRD status in ovarian cancer using a data set of 8,400 newly diagnosed and metastatic ovarian cancer patients in the US from Q3-2018 through Q2-2019 identified from Diaceutics’ proprietary Global Diagnostic Index (GDI). Analysis of real-world BRCA1/2 and NGS associated testing data and laboratory profile mapping exercise of 82 US labs was carried out using Diaceutics proprietary methods and data sources to evaluate BRCA1/2 and/or HRD germline/somatic testing rates, test availability, and test panel HRR gene composition. Results: Overall, germline mutation testing rates were 3x greater than somatic testing rates. Excluding BRCA1/2, 67 labs offered comprehensive solid tumor NGS panels capable of measuring HRD with varied HRR gene target composition. Across 34 labs, 5 HRR genes were commonly found on panels: PALB2, ATM, BARD1, BRIP1 and CHEK2. 3 labs currently offering panels explicitly intended for HRD determination only include BRCA1/2 and at least one genomic instability marker (loss of heterozygosity, large-scale state transitions or telomeric allelic imbalance). Conclusions: Lack of standardized HRD panels and low testing rate identifying patients with somatic mutations in BRCA1/2 and other HRR genes is leading to poorer outcomes for missed patients eligible for PARPi’s. As clinical evidence linking HRD status with PARPi efficacy grows in ovarian as well as prostate and pancreatic cancer, Diaceutics recommends organizations such as ASCO, CAP or AMP establish defined universal HRD testing panels including relevant somatic/germline HRR genes and BRCA1/2 as well as genomic instability markers and educate stake holders aiding harmonization and ultimately, better treatment outcomes.

BRCA1/2 and multigene panel testing among metastatic breast, pancreas, prostate, and ovarian cancer patients.

e13160 Background: Given the availability of targeted therapies such as PARP inhibitors, patients with metastatic breast, pancreas, prostate, and ovarian cancer are recommended to have germline genetic testing for hereditary cancer syndromes. Completion of genetic testing among this population is understudied. Methods: We performed a retrospective study of 548 patients with stage 4 breast, pancreas, prostate, and ovarian cancer at diagnosis from January 2013-December 2017 identified in the New York Presbyterian Hospital Tumor Registry at Columbia University Irving Medical Center. Data on socio-demographics, clinical factors, and genetic testing completion and results were collected from the medical record. We conducted descriptive statistics. Results: Our study population had a median age of 66 years (range, 23-97) at diagnosis; 61% female; 50% non-Hispanic white/22% Hispanic/15% non-Hispanic black/5% Asian/7% other; 33% private insurance/16% Medicaid/44% Medicare/7% unknown insurance. Primary cancer was 24% breast, 8% ovary, 61% pancreas, and 7% prostate. Only 38 patients were seen by a genetic counselor (7%) and only 50 (9%) had genetic testing performed. Among those who underwent germline testing, 92% had multigene panel testing (median number of genes tested 13.5, range 2-74). Pathogenic variants were detected in 6 patients (12%), of which 4 had a BRCA1/2 mutation, and 26% had a variant of uncertain significance (VUS). Conclusions: We found that only a small percentage of metastatic breast, pancreas, prostate, and ovarian cancer patients underwent genetic testing. Further research is necessary to identify the barriers to genetic testing uptake in metastatic cancer patients. BRCA1/2 and multigene panel testing has important implications in this patient population not only for treatment decisions, but also to increase cascade testing in unaffected family members who may be at risk for malignancy in the future.

Real life efficacy and safety data of bevacizumab-based front line treatment in advance or metastatic ovarian cancer patients: Focus on patients with malignant ascites—A phase IV study.

5562 Background: The standard of care for Epithelial Ovarian cancer (EOC) is the combination of a taxane plus a platinum compound (TC) whereas the addition of bevacizumab (bev) to this regimen (TC-bev) has been shown to improve the PFS. Patients (pts) with ascites have more aggressive disease and less overall survival. The aim of the study was to evaluate the safety of the TC/bev regimen in the real life clinical practice. Methods: A multi-center observational study, approved by the ethics committees of the participating centers, including 314 pts with stage III/IV EOC, was conducted (11.2011-06.2014) in Greece. Two independent cohorts, with similar clinico-pathologic characteristics, were treated with front-line TC (n = 109) or TC/bev (n = 205) according to the physician’s choice. 83 (40.5%) and 40 (36.7%) in the TC/bev and TC groups presented with ascites. Results: Disease control was achieved in 90.7% and in 78.9% of patients treated with TC/bev and TC, respectively (p = 0.003). Pts with ascites treated with TC/bev experienced a better overall response rate (ORR) (68.7% Vs 55%) and less progression disease (PD) compared to patients receiving TC (13.2% Vs 30.8%). The median PFS in all pts was 21.5mo and 12.4mo (p &lt; 0.001) and median PFS in ascites pts was 18.1mo and 10.3mo in the TC/bev and TC cohort , respectively (p &lt; 0.001). The median OS was not reached in the TC/bev group and it was 36.9mo in the TC group, ( p = 0.059) while in the ascites pts also has not reached and it is 22.5m, respectively ( p = 0.023). The 3 year survival rate in all pts was 59.4% and 50.4% and in ascites pts was 55.3% and 30% in the TC/bev and TC respectively. Neutropenia was the most common grade 3/4 adverse event in 16.6% and 9.1% in TC/bev- and TC- treated patients ( p = 0.072) with no other adverse events &gt; 5%. Conclusions: These real life data demonstrate that the combination of TC/bev represents an active and well tolerated regimen offering survival benefit in patients with stage III/IV EOC and especially in patients with ascites. Additional larger prospective studies are required to confirm these observations. Clinical trial information: NCT01982500.

Abstract P3-16-02: Voice of cancer patient: Analysis of breast cancer patients' experience with PARP inhibitors

Abstract Background: Many breast and ovarian cancer patients have germline or somatic mutations in BRCA 1&amp;2 genes. These proteins are important for repairing double-strand DNA breaks by homologous recombinational repair. In patients who have mutations in these genes, PARP is the major alternative for repairing single-strand DNA breaks. PARP inhibitors (PARPi) inhibit PARP, thereby causing cell death by accumulation of damaged DNA in cells. Many PARPi, including Olaparib, have been approved and used in treatment of metastatic ovarian cancer patients with BRCA 1&amp;2 mutation. Recently, Olaparib was also approved by the FDA for treatment of metastatic breast cancer patients with germline BRCA 1&amp;2 mutation, and many other PARPi are in clinical trial. In this study we analyzed breast cancer patients' awareness, use and experience with PARPi s. Many patients share their experiences on online forums which contain millions of freely shared messages. These can be used to analyze patient concerns and experiences. However, this data is unstructured and difficult to analyze. We used our automated system VoCP, that uses techniques from Big Data Science and Artificial Intelligence (deep learning, topic modeling, information retrieval, and natural language processing) to analyze these messages. Methods: We collected 15.13 million unique messages by 987,189 users from 37 unrestricted cancer forums that provide clinically relevant information. We built custom ontologies for breast cancer, various PARPi, chemotherapy and side effects, and then used our automated system VoCP to extract relevant information from these messages. Results: We found 1,536 breast cancer patients discussing PARPi. 459 patients mentioned use of PARPi whereas 706 patients shared the information about PARPi and 196 inquired about them. 176 patients mentioned that they were planning to use PARPi. 76 patients using PARPi mentioned having BRCA 1 or 2 mutation and 1 patient mentioned CHEK 2 mutation. 91 patients mentioned having triple negative cancer. 212 patients mentioned being treated on clinical trial and 10 mentioned being off trial. 162 patients mentioned use of chemotherapy with PARPi and 40 mentioned use of PARPi as single agent. Specific PARPi: 47 mentioned Olaparib, 104 mentioned Valiparib, &amp; Talazoparib, 6 rucaparib and 4 Niraparib. Most patient just mentioned “PARP inhibitor.” Some patients mentioned iniparib on clinical trial. Side effects were reported by 60 patients. These include: · Nausea: 14 · Fatigue: 15 · GI side effect: 7 · Thrombocytopenia: 5 · Anemia: 2 · Neutropenia: 2 · Neuropathy: 5 · Insomnia:2 99 patients mentioned PARPi were “effective,” 21 mentioned they were “somewhat effective” and 36 mentioned they were “ineffective.” 144 patient expressed positive sentiments, 30 patients expressed negative sentiments and 16 patients expressed neutral sentiment for PARPi. Conclusion: · There is increasing awareness and curiosity for PARPi in breast cancer patients as more patients are being tested for BRCA and other mutations. · Among the users, PARPi are generally associated with low toxicity and positive sentiments. · VoCP reliably provides meaningful insights from the patient's point of view; it also gives insight into unmet needs where more resources and research should be focused. Citation Format: Aggarwal S, Sharma R, Singh M, Aggarwal A. Voice of cancer patient: Analysis of breast cancer patients' experience with PARP inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-16-02.

1146P - Durability of clinical benefit in metastatic epithelial ovarian cancer patients treated with pegilodecakin monotherapy or in combination with platinum plus taxane-based chemotherapy

1146P - Durability of clinical benefit in metastatic epithelial ovarian cancer patients treated with pegilodecakin monotherapy or in combination with platinum plus taxane-based chemotherapy

A phase Ib study evaluating the safety and tolerability of durvalumab in combination with eribulin in patients with HER2-negative metastatic breast cancer and recurrent ovarian cancer.

TPS3116Background: Recent studies have revealed only modest responses to single-agent immune checkpoint blockade in metastatic breast cancer (MBC) and recurrent ovarian cancer (ROC) patients as com...

Plasma-Activated Medium Inhibites Metastatic Activities Of Ovarian Cancer Cells In Vitro Via Repressing Mapk Pathway

Ovarian cancer is among the most malignant gynecologic cancers since peritoneal dissemination often occurs at the diagnosis of these patients. The 5-year survival rate is less than 50%. Recently, non-equilibrium atmospheric pressure plasma (NEAPP) has been introduced in medical field. We have already demonstrated the cytotoxic effect of the direct plasma exposure to ovarian cancer cells. However, it is difficult to expose cancer cells to plasma gas intraperitoneally. Thus, we established the system of plasma-activated medium (PAM) to treat ovarian cancer indirectly instead of a direct exposure to plasma [1]. In our previous works, it was demonstrated that PAM significantly inhibited proliferation ability of ovarian cancer cells, with fibroblast cells remaining unaffected though. Both in vitro and in vivo study had confirmed the cytotoxic effect of PAM to ovarian cancer. However, it still remains unknown whether PAM can affect metastasis of ovarian cancer cells, which is the fatal problem of ovarian cancer patients [2]. In this study, we tried to investigate PAM’s anti-metastasis effect in vitro and the underneath mechanism. Firstly, we performed wound-healing and transwell assay on ES2, one of ovarian cancer cell lines. We found that the cell migration and invasion abilities were significantly inhibited by PAM. Secondly, we established a co-culture system by seeding ES2 cells onto monolayer of peritoneal mesothelial cells, which models the initial step of ovarian cancer cells metastasis in human peritoneal cavity, and it was found that PAM significantly repressed ES2 cells to implant onto mesothelial cells. Moreover, mechanism study showed both mRNA and protein levels of MMP-9 were inhibited by PAM. And PAM significantly inhibited the phosphorylation of JNK1/2 MAPK and p38 MAPK (figure 1), which indicated that inhibition of MMP-9 was dependent on MAPK pathway [3]. In summary, it is indicated in this work that PAM presents efficient inhibitory effect towards ovarian cancer cells metastasis in vitro. Moreover, PAM’s anti-metastasis effect is implemented by repressing the activation MAPK pathway, resulting in de-activation of downstream target MMP-9, thus leading to suppression of cell migration and invasion. In the near future, it might be a new clinical strategy for metastatic ovarian cancer patients to choose PAM therapy via intaperitoneal treatment. Download : Download high-res image (86KB) Download : Download full-size image Fig. 1

Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges.

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.

Abstract OT3-01-06: A phase I/IIa study of the whole-cell vaccine BriaVax™ in metastatic or locally recurrent breast cancer patients (NCT00095862)

Abstract BACKGROUND: BriaVax™ (formerly SV-BR-GM-1) is a breast cancer cell line transfected to release GM-CSF. Under FDA BB-IND 10312, the vaccine was tested in 3 metastatic breast, 1 metastatic ovarian cancer patients refractory to previous therapy. Patients received 20 million viable cells ID at 4 sites 48-72 hours after low-dose cyclophosphamide, 300 mg/m2 . Mean cell count was 22.8 x10^6 (18.8-27.6). Mean viability was 90.6%, (84-94%). Interferon-alpha (10,000 u) was injected into each inoculation site after 48 and 96 hrs. The protocol permitted 3 inoculations at 2 week intervals, then, if not showing clearly progressive disease, 3 more inoculations monthly. All patients were stable after 3 injections (2 months). However, Pt A002 enjoyed complete tumor regression of a progressing lung metastasis and near-complete response of multiple breast lesions (see below). Nonetheless, she relapsed widely 3 months after finishing the sixth and final injection per protocol. After obtaining FDA permission inoculations resumed. All metastases, including CNS, again showed prompt but subtotal regression after 3 immunizations (see Wiseman C and Kharazi A; The Breast Journal 2006). Toxicity was minimal and the overall survival of the 4 patients was 35 months. TRIAL DESIGN: 9 patients will be accrued, toxicity (and also response) will be reviewed; unless there are prohibitive serious adverse events, 15 more patients will then be accrued. ELIGIBILITY: Inclusion Criteria: Patients must have histological confirmation of breast cancer with recurrent and/or metastatic lesions via investigational site. Patients with new or progressive breast cancer metastatic to brain will be eligible if they meet other conditions. Patients must be 18 years of age or older, have expected survival of at least 4 months, adequate performance status (ECOG 0-2). Patients may be maintained on hormonal therapy provided there is clear evidence of tumor progression and have provided written informed consent. Exclusion Criteria: Concurrent or recent chemotherapy (within 3 weeks), XRT within 3 weeks, may have had immunotherapy in the past (off within 3 weeks), or general anesthesia/major surgery (within 3 weeks). Patients must have recovered from all known or expected toxicities from previous treatment and passed a treatment-free “washout” period of 3 weeks before starting this program (8 weeks for persons receiving nitrosourea or mitomycin). History of clinical hypersensitivity to GM-CSF, interferon, yeast, beef, or to any components used in the preparation of the experimental vaccine. Additional criteria to be provided on request. SPECIFIC AIMS: To evaluate the number, frequency, duration, and relation of toxicity events to BriaVax™ (formerly designated as SV-BR-1-GM), as defined by CTCAE and additional tests; to evaluate tumor response and durability; to assess immune responses to vaccine; to archive blood and urine for future analysis; to measure quality of life with the SF-36 questionnaire. For further information, call the BriaCell Corporate Office (US) at 888-485-6340 Acknowledgments: Dr. Gerhard Bauer, Dr. Saeid Babaei, the St. Vincent Medical Center, and Dr. George Peoples for advice and guidance. Citation Format: Wiseman CL, Lacher M. A phase I/IIa study of the whole-cell vaccine BriaVax™ in metastatic or locally recurrent breast cancer patients (NCT00095862) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-01-06.

Trends in hospice discharge, documented inpatient palliative care services and inpatient mortality in ovarian carcinoma

ObjectiveTo investigate the trends in discharge to hospice, documented inpatient palliative care services, and inpatient mortality in metastatic ovarian cancer (mOvCa) patients. MethodsPatients≥18years with mOvCa and a non-elective admission between January 1, 2006 and December 31, 2011 were identified from the National Inpatient Sample (NIS). The primary outcome of interest was the temporal trend in the annual proportion of hospitalizations for mOvCa where discharge destination was hospice. Secondary outcomes included temporal trend of inpatient mortality and documented palliative care services. Multivariable logistic regression models were used to ascertain independent factors predictive of hospice discharge and documented palliative services across the clusters of hospitals. ResultsA total of 106,203 non-elective hospitalizations were identified. The rate of hospice discharge increased from 9.2% in 2004 to 11.1% in 2011 (ptrend<0.001). Similarly, the rate of documented palliative care services increased from 2.7% in 2004 to 10.4% in 2011 (ptrend<0.001). The inpatient mortality decreased from 9.6% in 2004 to 7.4% in 2011 (ptrend<0.001). In a subset of hospitalizations with extreme risk of dying, 22% were discharged to hospice and 11% received documented palliative care services. One fifth of the patients who died in the hospital received documented palliative care services. ConclusionsThe use of hospice as a discharge destination and documented palliative care services is relatively low but appears to be increasing over time for mOvCa patients. Monitoring this data is vital to plan educational programs regarding palliative care approaches in this at-risk population.