Advanced Ovarian Carcinoma Patients Research Articles

A signature of circulating miRNAs predicts the prognosis and therapeutic outcome of taxane/platinum regimen in advanced ovarian carcinoma patients.

Ovarian carcinoma (OC) is ranked as the eighth most lethal gynecological cancer due to late diagnosis and high recurrence. Existing biomarkers are lacking to predict the recurrence and stratify patients who are likely to benefit from chemotherapy. MicroRNAs (miRNAs/miRs) are persistently present in humans and are capable of predicting treatment outcomes. Thus, the purpose of the study was to assess the potential of circulatory miRNAs to predict the efficacy of OC. Newly diagnosed n = 208 OC patients were administrated neoadjuvant/adjuvant chemotherapy (taxane + platinum) after surgery. Their demographic, gynecologic, clinical parameters, response, and survival were recorded. MiR-27a, miR-182, miR-199a, miR-214, and miR-591 were taken and the expression were analyzed using real-time PCR at different treatment intervals. Further, its prognostic value (Kaplan-Meier, and Cox regression analysis) and diagnostic importance (receiver operating characteristic curve) were validated. The mean age of patients with poorly differentiated (45.2%) serous OC was 48.69 ± 10.38. The majority experienced menarche at ≥ 12 (62.2%) with poor menstrual hygiene (81.8%) and were post-menopausal (69.4%), some were associated with high risk of survival (HR = > 1). MiRNA signature showed three over-expression and two under-expression (miR-27a, miR-182, and miR-214; miR-199a and miR-591) in advanced OC compared to the control (P= < 0.05). Also, a significant difference was detected at each time interval of treatment with the response (P = ≤ 0.001) associated with resistance and overall survival (P = ≤ 0.001) with risk (HR = > 1). ROC analysis showed enhanced the diagnostics accuracy (< 0.001). Our findings indicate that circulating miRNAs might be a potential minimally invasive diagnostic marker for treatment outcome and recurrence in ovarian carcinoma.

BRCA1 and RAD51 methylation impact on outcome in patients with advanced ovarian cancer: A PAOLA-1 ancillary study.

5559 Background: The PAOLA-1/ENGOT-ov25 trial showed that adding olaparib (ola) to maintenance bevacizumab (bev) after first-line therapy led to a progression-free and overall survival benefit in advanced ovarian high-grade carcinoma (AOC) patients with homologous recombination deficiency (HRD) (Myriad MyChoiceR Genomic Instability Score) or BRCA1/2 mutations (BRCAmut). Here, we address the impact of BRCA1 and RAD51C epimutations to improve our understanding of GIS beyond BRCAmut. Methods: BRCA1 and RAD51C methylation analysis was assessed and quantified in pre-treatment biopsies (66%), after neoadjuvant chemotherapy (NACT) (20%) or unknown (14%) from bisulfite converted DNAs using fluorescent methylation specific PCR and methylation specific droplet digital PCR (ddPCR). Methylation status was correlated to clinical data, BRCA1/2 mutations, GIS and HRD scores, PFS (PFS1, PFS2) and OS. R (r-project.org) was used for statistical analysis. Results: Among the 537 patients randomized to maintenance ola + bev and 269 to placebo (pbo) + bev, 348 and 171 were available for methylation analysis. Their baseline molecular and clinical characteristics were well balanced with those of the entire cohort. Promoter methylation was identified in 67 (12.9%) samples for BRCA1 and 25 (4.8%) for RAD51C (4 were methylated on both genes). Methylation and BRCAmut were mutually exclusive except for 3 samples. Mean GIS scores were 62.5 [59.6-65.5]; 59.4 [57.2-61.5]; 54.2 [50.5-57.8]; 23.4 [21.6-25.2] for BRCA1 or RAD51C methylated ( met-tumors), BRCAmut, non-mut/non-met HRD+ ( b-/m-HRD+) and HRP (proficient) tumors respectively. Among met-tumors 92% (66/72) were GIS positive (&gt;42). The mean GIS score of Met-tumors were significantly higher than that of b-/m- HRD+ samples (p=0,009). Benefit of adding ola maintenance to bev was in a similar between patients with met AOC and those with b-/m- HRD+ tumors ( table). Conclusions: Methylated BRCA1/RAD51 tumors are HRD+ and provide to ovarian cancer patients a similar clinical benefit of ola+bev as patients with b-/m- HRD+ tumors. Methylation assessment represents a rapid and cost effective tool; which coupled with BRCA1-2 somatic testing allows the identification of the majority (81%) of HRD+ AOC. Clinical trial information: NCT02477644 . [Table: see text]

Incidence and Prognostic Impact of Deleterious Germline Mutations in Primary Advanced Ovarian Carcinoma Patients.

Data on deleterious variants in genes other than BRCA1/2 remain limited. A retrospective cohort study was performed, including primary OC cases with TruRisk® germline gene panel testing between 2011 and 2020. Patients with testing after relapse were excluded. The cohort was divided into three groups: (A) no mutations, (B) deleterious BRCA1/2 mutations, and (C) deleterious mutations in other genes. A total of 702 patients met the inclusion criteria. Of these 17.4% (n = 122) showed BRCA1/2 mutations and a further 6.0% (n = 42) in other genes. Three-year overall survival (OS) of the entire cohort was significantly longer in patients with germline mutations (85%/82.8% for cohort B/C vs. 70.2% for cohort A, p < 0.001) and 3-year progression-free survival (PFS) only for cohort B (58.1% vs. 36.9%/41.6% in cohort A/C, p = 0.002). In multivariate analysis for the subgroup of advanced-stages of high-grade serous OC, both cohorts B/C were found to be independent factors for significantly better outcome, cohort C for OS (HR 0.46; 95% CI 0.25-0.84), and cohort B for both OS and PFS (HR 0.40; 95% CI 0.27-0.61 and HR 0.49; 95% CI 0.37-0.66, respectively). Germline mutations were detected in a quarter of OC patients, and a quarter of those in genes other than BRCA1/2. Germline mutations demonstrate in our cohort a prognostic factor and predict better prognosis for OC patients.

Efficacy Analysis of Comprehensive Nursing in the Care of Ovarian Carcinoma Treated with Paclitaxel Combined with Nedaplatin.

Objective To determine the effectiveness of comprehensive nursing in the care of ovarian carcinoma (OC) patients treated with paclitaxel (PTX) plus nedaplatin (NDP). Methods The research population comprised 180 advanced OC patients who received treatment in the Shaanxi Cancer Hospital between November 2018 and November 2021. The enrolled cases were assigned to two groups based on different nursing plans: an observation group (OG) with 100 cases treated with comprehensive nursing and a control group (CG) with 80 cases intervened by conventional nursing. Intergroup comparisons were performed to identify statistical significance in terms of the following parameters: serum NGF, TK1, and CA15-3 levels; VAS, SAS, and SDS scores; nursing compliance; incidence of adverse reactions; and nursing satisfaction. Results Compared with CG, OG showed the following: (1) lower posttreatment NGF, TK1, and CA15-3 levels; (2) lower scores of SAS and SDS; (3) higher nursing compliance; and (4) lower incidence of adverse reactions and higher nursing satisfaction after nursing. Conclusions Comprehensive nursing far outperformed conventional nursing in the care of advanced OC patients treated with PTX plus NDP, which is worth popularizing.

ODALIE Study, a retrospective analysis of a real-life cohort of patients with de novo advanced high grade epithelial ovarian cancer treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab.

e17577 Background: PARP inhibitors (PARPi) demonstrated improvement in progression-free survival (PFS) following a first line platinum-based chemotherapy including bevacizumab for HRD-positive advanced ovarian carcinoma (OC) patients (pts) (PAOLA-1 study). We aimed to describe real-world (rw) clinical outcomes in patients with de novo high grade epithelial advanced ovarian cancer (HGEOC) treated with a first-line platinum- and taxane-based chemotherapy combined with bevacizumab. Methods: Using the Epidemiological Strategy and Medical Economics (ESME) Ovarian Cancer (OC) Data Platform [NCT03275298], a French EHR-derived database centralizing deidentified data of consecutive patients diagnosed and/or treated in 18 French comprehensive cancer centers since 2011, we identified all patients with de novo FIGO stage III/IV HGEOC diagnosed between 01 October 2012 and 31 January 2017, with a documented response to a first-line platinum-based chemotherapy and a maintenance treatment with bevacizumab ( PAOLA-like control group population). Data cut-off was 06 August 2020. Endpoints (overall survival, PFS and time to subsequent treatment) were estimated using the Kaplan-Meier method. Subgroups were analysed according to the BRCA-derived status. Results: Of 10,263 OC cases in the ESME-OC cohort, 382 patients, with a median follow-up of 47.8 months (CI 95% 44.4-49.1), were analysed. Median age was 61 years (q1-q3: 56-68). 290 pts (75.9%) had a FIGO stage III, 361 pts (94.5%) had at least one surgery, 141 (39.1%) and 210 (58.5%) of them had a primary cytoreductive surgery and an interval surgery respectively. BRCA deleterious mutations were present in 72 pts (22.3%). Median progression free survival was 23.2 months (CI 95% 20.9-24.8) in overall population and 25.3 months (CI 95% 19.7-23.8) in BRCA mutated pts, comparable to the control arm of PAOLA-1 when considering the difference in the PFS definition (from first CT versus from randomization in PAOLA study). Estimated 24-months overall survival rate was 45.7% (95% CI: 40.7- 50.7) and 53.9% (95% CI: 42.4 - 65.5) in BRCA mutated pts. Conclusions: Analyses of our large real-world French ESME-OC cohort are powerful tools to confirm clinical outcomes in HGEOC pts. Our data confirmed the reproducibility of the results observed in randomized clinical trials for de novo HGEOC pts with a documented response to a first line with bevacizumab maintenance therapy.

Evaluation of NRS and NPSI pain scores in advanced ovarian carcinoma patients undergoing surgery and first-line chemotherapy

Advanced ovarian cancer (OC) has a high disease manifestation with difficult-to-manage symptoms that limit the patients' functionality. Abdominal pain, difficult chronic pain, and neuropathic pain are among the common discomforts associated with OC and its treatment. Read more at JCTRes.com

746P Real-world clinical outcomes of patients with de novo advanced high-grade epithelial ovarian cancer eligible to niraparib maintenance in France

PARP inhibitors (PARPi) demonstrated improvement in progression-free survival (PFS) following first-line (1L) platinum-based chemotherapy (Pt-CT) for advanced ovarian carcinoma (OC) patients (pts). Here we describe real-world clinical outcomes in pts with de novo high-grade epithelial OC (HGEOC) eligible for niraparib per EMEA approval (PRIMA trial).

Concordance Between Tumor and Germline BRCA Status in High-Grade Ovarian Carcinoma Patients in the Phase III PAOLA-1/ENGOT-ov25 Trial

Abstract Background PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane–based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening. Methods tBRCA was tested on formalin-fixed, paraffin-embedded tumor blocks on 5 French platforms using 2 next-generation sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms. Results From May 2015 to July 2017, tBRCA tests were performed for 1176 screened patients. Only 52 (4.4%) tumor samples were noncontributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range = 8-260). A pathogenic variant was reported in 27.1% tumor samples (319 of 1176 screened patients). tBRCA and gBRCA testing were performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only 1 large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of pathogenic variant (29 of 451) not detected by gBRCA testing. Conclusions tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from poly(ADP-ribose) polymerase inhibitor therapy.

Clinical efficacy and safety of apatinib combined with oral VP-16 for the treatment of advanced ovarian cancer: Preliminary evaluation of a clinical drug regimen

To investigate the clinical efficacy and safety of apatinib in combination with oral VP-16 for the treatment of chemotherapy-resistant advanced ovarian carcinoma. Twenty-seven advanced ovarian carcinoma patients were treated with oral VP-16 chemotherapy combined with oral apatinib mesylate (500 mg/d). CA125, VEGF, and CEA were examined every 3-4 weeks, and tumour changes were monitored by CT every 8-12 weeks. PFS was obtained by follow-up after discharge. For all patients, the ORR (including CR and PR) was 25.0%, and the DCR (including CR, PR and SD) was 75.0%. CEA and CA199 significantly decreased (p&lt;0.05), but the decrease in VEGF was not significant. The average PFS was 5.13 months. The ECOG score had a significant effect on PFS (p&lt;0.05), while there were no significant differences in PFS based on age (p=0.394). The main side effects of this regimen were hypertension, proteinuria, hand-foot syndrome and myelosuppression, which were tolerated by patients after active symptomatic treatment. Apatinib combined with oral VP-16 is an effective regimen for the treatment of chemotherapy-resistant advanced ovarian cancer. This combination therapy should be widely used in clinical practice.

Nano-scavengers for blood biomarker discovery in ovarian carcinoma

The development and implementation of biomarker-based screening tools for ovarian cancer require novel analytical platforms to enable the discovery of biomarker panels that will overcome the limitations associated with the clinically used CA-125.The systematic discovery of protein biomarkers directly from human plasma using proteomics remains extremely challenging, due to the wide concentration range of plasma proteins. Here, we describe the use of lipid-based nanoparticles (NPs) as an ‘omics’ enrichment tool to amplify cancer signals in the blood and to uncover disease specific signatures. We aimed to exploit the spontaneous interaction of clinically-used liposomes (Caelyx®) with plasma proteins, also known as’ protein corona’ formation, in order to facilitate the discovery of previously unreported differentially abundant molecules. Caelyx® liposomes were incubated with plasma samples obtained from advanced ovarian carcinoma patients and healthy donors and corona-coated liposomes were subsequently recovered. Comprehensive comparison between ‘healthy’ and ‘diseased’ corona samples by label-free proteomics resulted in the identification of multiple differentially abundant proteins. Moreover, immunoassay-based validation of selected proteins demonstrated the potential of nanoparticle-platform proposed to discover novel molecules with great diagnostic potential. This study proposes a nanoparticle-enabled workflow for plasma proteomic analysis in healthy and diseased states and paves the way for further work needed to discover and validate panels of novel biomarkers for disease diagnosis and monitoring.

External validation of a 'response score' after neoadjuvant chemotherapy in patients with high-grade serous ovarian carcinoma with complete clinical response

ObjectivesThe chemotherapy response score (CRS) has been developed for measuring response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma. This study aimed to validate the ability of this three-tier scoring...

Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer: An Institutional Experience

Epithelial ovarian cancer is the second most common gynaecological malignancy among Indian women. Primary debulking surgery remains the standard of care in advanced operable ovarian cancer patients, but is associated with morbidity. Neoadjuvant chemotherapy followed by delayed primary cytoreductive surgery may be a better treatment strategy in advanced ovarian cancer. We present our experience of neoadjuvant chemotherapy in advanced ovarian cancer with special emphasis on treatment outcomes. A retrospective analysis of advanced epithelial ovarian carcinoma (stages III and IV) patients treated at the Department of Surgical Oncology at King George’s Medical University, Lucknow, between 2012 and 2016 was done. A total of 128 patients with advanced ovarian carcinoma were treated during this period. Median age at diagnosis was 46 years. Among these patients, 115 underwent surgery, of which 57.4% were optimally cytoreduced. Papillary serous adenocarcinoma was the most common histological subtype (78.1%). Recurrence was seen in 73% of patients, with a median time to recurrence 16 months (range 6.5–37 months). They were managed with second-line chemotherapy and surgery. Median overall survival in this study for optimally cytoreduced stage III patients was 38 months and 17 months for optimally cytoreduced stage IV patients. Median progression-free survival for stage III was 13 months and stage IV was 6 months. Neoadjuvant chemotherapy facilitates surgery in advanced ovarian cancer and helps in assessing chemotherapy responsiveness. It provides an opportunity to modify systemic treatment if there is no response to therapy or disease progression.

Neoadjuvant chemotherapy in advanced epithelial ovarian cancer: An institutional experience.

e17044 Background: Epithelial ovarian cancer is the second most common gynecological malignancy among Indian women. Primary debulking surgery remains the standard of care in advanced operable ovarian cancer patients, but is associated with morbidity. Neoadjuvant chemotherapy followed by delayed primary cytoreductive surgery maybe a better treatment strategy in advanced ovarian cancer. We present our experience of neoadjuvant chemotherapy in advanced ovarian cancer with special emphasis on treatment outcomes. Methods: A retrospective analysis of advanced epithelial ovarian carcinoma (Stage IIIc and IV) patients treated at the Department of Surgical Oncology at King George’s Medical University, Lucknow between 2012 and 2017 was done. Results: A total of 151 patients with advanced ovarian carcinoma were treated during this period. Median age at diagnosis was 46 years. Among these patients, 137 underwent surgery, of which 59.1% were optimally cytoreduced. Papillary serous adenocarcinoma was the most common histological subtype (76.1%). Recurrence was seen in 79.3% patients, with a median time to recurrence 17 months (range 6.5 - 39 months). They were managed with second line chemotherapy and surgery. Median overall survival in this study for optimally cytoreduced stage III patients was 39 months and 18 months for optimally cytoreduced stage IV patients. Median progression free survival for stage III was 12 months and stage IV was 6 months. Conclusions: Neoadjuvant chemotherapy facilitates surgery in advanced ovarian cancer and helps in assessing chemotherapy responsiveness. It provides an opportunity to modify systemic treatment if there no response to therapy or disease progression.

Peritoneal NK cells are responsive to IL-15 and percentages are correlated with outcome in advanced ovarian cancer patients.

The demonstration that ovarian carcinoma (OC) is an immunogenic disease, opens opportunities to explore immunotherapeutic interventions to improve clinical outcome. In this regard, NK cell based immunotherapy could be promising as it has been demonstrated that OC cells are susceptible to killing by cytokine-stimulated NK cells. Here, we evaluated whether percentage, phenotype, function and IL-15 responsiveness of ascites-derived natural killer (NK) cells is related to progression-free survival (PFS) and overall survival (OS) of advanced stage OC patients. Generally, a lower percentage of NK cells within the lymphocyte fraction was seen in OC ascites (mean 17.4 ± 2.7%) versus benign peritoneal fluids (48.1 ± 6.8%; p < 0.0001). Importantly, a higher CD56+ NK cell percentage in ascites was associated with a better PFS (p = 0.01) and OS (p = 0.002) in OC patients. Furthermore, the functionality of ascites-derived NK cells in terms of CD107a/IFN-γ activity was comparable to that of healthy donor peripheral blood NK cells, and stimulation with monomeric IL-15 or IL-15 superagonist ALT-803 potently improved their reactivity towards tumor cells. By showing that a higher NK cell percentage is related to better outcome in OC patients and NK cell functionality can be boosted by IL-15 receptor stimulation, a part of NK cell immunity in OC is further deciphered to exploit NK cell based immunotherapy.

Prognostic implications of histological tumor regression (Böhm's score) in patients receiving neoadjuvant chemotherapy for high grade serous tubal & ovarian carcinoma

ObjectivePrimary objective of this study was to determine prognostic significance of Bohm's histopathological regression score in patients who received neoadjuvant chemotherapy (NACT) for treatment of high grade serous (HGS) tubal & ovarian carcinoma. MethodsThis was a retrospective cohort study of patients who received NACT between 2010 and 2015. The 3 point histopathological regression score of Böhm was used to classify chemotherapy response. Survival outcomes between the 3 different subgroups was analysed and compared with standard clinico-pathological variables using the Cox proportional hazards model and log-rank test. ResultsStudy cohort comprised 111 patients. Chemotherapy response score (CRS) 3 was observed in 47 (42.4%) and CRS 1and CRS 2 in 22 (19.8%) and 42 (37.8%) women respectively. Women with CRS score of 1 and 2 combined showed a three-fold increased risk of progression on both univariate and multivariate assessment (HR 3.54; C.I 2.19–5.72, p < 0.001). The median overall survival for patients with CRS 1 was 34 months, CRS 2 was 30 months and 47 months for CRS 3. CRS 1 and 2 combined was the only variable that held significance in prediction of reduced overall survival on multivariate assessment (HR 3.26, C.I 1.91–5.54, p 0.0006). CRS 1 and 2 were also associated with 5.15-fold increased risk of relapse within 6 months of completion of chemotherapy (Odds ratio OR 5.15, C.I 0.07–0.47, p - 0.002). ConclusionCRS is an independent prognosticator of survival and reliable predictor of relapse within 6 months in advanced high grade serous tubal and ovarian carcinoma patients receiving NACT.

Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: A Single-Institution Experience and a Review of the Literature

Objectives: The aim of this study was to evaluate the role of neoadjuvant chemotherapy (NACT) in advanced ovarian carcinoma patients unable to undergo a complete resection during primary debulking surgery. Methods: From February 2005 to October 2015, all consecutive cases of advanced-stage epithelial ovarian carcinoma at the University of Bari were retrospectively recorded. Of them, patients treated with NACT were collected. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors of survival. Results: Seventy-eight women with advanced-stage epithelial ovarian carcinoma were treated with NACT. On univariate analysis, age (p = 0.003), CA-125 serum level (0.001), response to NACT (p < 0.0001), stage of disease (p = 0.011) and optimal debulking surgery (p < 0.0001) were found to be important prognostic factors related to survival. However, on multivariate analysis, age, response to NACT, CA-125 serum level and optimal debulking surgery remained as independent poor prognostic factors for survival. The median overall and disease-free survival were 31 and 12 months, respectively. Conclusions: NACT does not compromise survival in patients with stage IIIC and IV ovarian cancer compared to patients treated with primary surgery. Prospective randomized trials comparing NACT to conventional treatment are needed to determine the quality of life and cost/benefit outcomes for women presenting advanced epithelial ovarian cancer.

Altretamine in advanced pretreated epithelial ovarian carcinoma patients: Experience from a center in north India

BackgroundAltretamine has been approved for the treatment of ovarian cancer around four decades back. But still this agent is not used widely by medical oncologists in the view of controversial results reported in literature. AimThe aim of this study was to assess the anti-tumor activity (time to treatment failure) and toxicity profile of altretamine. MethodsPatients of advanced ovarian carcinoma were included in this study that had undergone surgery, failed at least one chemotherapy regimen and completed at least one month of altretamine (150mg/m2/day for 14 consecutive days of a 28 day cycle with prophylactic anti-emetic agents). ResultsA total of 13 patients were evaluated. The median age at presentation was 55 years (46–83 years) and performance status ECOG I 8/13 (61.6%); ECOG II 2/13 (15.4%); ECOG III 3/13 (23.1%). 7.7% of patients (1/13) failed to respond to one chemotherapy regimen; 46.2% (6/13) to two CT regimen; 15.4% (2/13) to three CT regimen, and 30.8 (4/13) to four CT regimens. 0 patient showed complete response (CR), 2 partial response (PR), 7 had stable disease (SD). This led to overall disease control rate (CR+PR+SD) of 9/13 (69%) patients. The median time of treatment failure was 8.17 months (95% CI 6.87–9.47). In hematological toxicity only one patient (1/13) 7.7% had grade II anemia. No patient had significant neutropenia/thrombocytopenia. ConclusionAltretamine demonstrates meaningful prolongation of lifetime to disease progression in advanced pretreated carcinoma ovary patients with favorable toxicity profile.

Abstract IA25: Mechanisms of protective tumor immunity

Abstract Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, suggesting that further Treg inhibition might increase the frequency of clinical responses. Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice. The clinical translation of these therapeutic strategies to Phase I testing in humans is underway. The detailed analysis of patients achieving sustained clinical benefits from irradiated, autologous GM-CSF secreting tumor cell vaccines and CTLA-4 antibody blockade also affords a rich opportunity to identify antigens associated with immune-mediated tumor destruction and to delineate mechanisms of therapeutic immunity. In this regard, we have identified antibodies against a panel of secreted and cell surface proteins that play important roles in tumor development and immune evasion. Isolation of the rare, antigen-specific memory B cells directed towards these important targets provides new opportunities for developing human monoclonal antibodies for cancer immunotherapy. Citation Format: Glenn Dranoff. Mechanisms of protective tumor immunity. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA25.

Abstract PL07-03: Mechanisms of protective tumor immunity.

Abstract Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, suggesting that further Treg inhibition might increase the frequency of clinical responses. Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice. The clinical translation of these therapeutic strategies to Phase I testing in humans is underway. The detailed analysis of patients achieving sustained clinical benefits from irradiated, autologous GM-CSF secreting tumor cell vaccines and CTLA-4 antibody blockade also affords a rich opportunity to identify antigens associated with immune-mediated tumor destruction and to delineate mechanisms of therapeutic immunity. We elucidated several of the molecular pathways that underlie these antitumor effects, including the NKG2D system and multiple secreted/or cell surface proteins that contribute to tumor promoting inflammation. The therapy-induced antibodies manifest functional activity in vitro, antagonizing tumor cell survival, invasive potential, and angiogenesis. These findings support a key role for humoral immunity in tumor destruction, and highlight interest in more detailed characterization of the antitumor B cell repertoire in vaccinated patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-03. Citation Format: Glenn Dranoff. Mechanisms of protective tumor immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL07-03.

Upper abdominal procedures in advanced stage ovarian or primary peritoneal carcinoma patients with minimal or no gross residual disease: An analysis of Gynecologic Oncology Group (GOG) 182

PurposeTo examine the utility of upper abdominal procedures (UAPs) performed in a cohort of optimally cytoreduced patients with advanced stage epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and identify potential areas where aggressive surgery may impact survival. Patients and methodsWe reviewed 2655 patients enrolled in Gynecologic Oncology Group (GOG) 182 who had complete resection (CR) or minimal residual (MR) disease <1cm. Demographic, pathologic, surgical, and outcome data were collected. UAPs included diaphragm stripping or resection, liver resection, splenectomy, pancreatectomy, and porta hepatis surgery. Effect of UAP and CR on PFS/OS was assessed by Kaplan–Meier and proportional hazards methods. ResultsFour-hundred eighty-two patients (18.1%) underwent a total of 590 UAPs. There were 351 (13.1%) diaphragm surgeries, 112 (4.2%) liver surgeries, 108 (4%) splenectomies, 12 (0.5%) pancreatectomies, and 7 (0.2%) porta hepatis surgeries. Comparing patients who did not have UAPs to patients who had UAPs, the PFS was 18.2months (mos) and 14.8mos (p<0.01) and OS was 49.8mos v. 43.7mos (p=0.01), respectively. However, in the multivariable analysis this survival benefit did not remain (PFS HR=1.03, 95% CI 0.91–1.15; OS HR=0.92, 95%CI 0.81–1.04). The OS of the 141 patients who had an UAP and achieved CR compared to the 341 patients who had an UAP with MR was 54.6 compared to 40.4mos (p=0.0005). ConclusionsUAP procedures should only be performed when CR is attainable. A significant proportion of patients with MR were left with diaphragmatic disease that could potentially be completely resected.