Relapsed Ovarian Cancer Research Articles

Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells.

Simple SummarySOX2, OCT4, and NANOG are enriched in ovarian cancer spheroids and correlate with tumor-initiating cell markers, CD117 and ALDH/CD133. SOX2, relative to OCT4 or NANOG, is a stronger indictor of chemoresistance, tumor-initiation, and recurrent disease. Including SOX2 in evaluation of ovarian cancer TICs may improve reliability of TIC markers and our understanding of mechanisms of relapse.The identification of tumor-initiating cells (TICs) has traditionally relied on surface markers including CD133, CD44, CD117, and the aldehyde dehydrogenase (ALDH) enzyme, which have diverse expression across samples. A more reliable indication of TICs may include the expression of embryonic transcription factors that support long-term self-renewal, multipotency, and quiescence. We hypothesize that SOX2, OCT4, and NANOG will be enriched in ovarian TICs and may indicate TICs with high relapse potential. We evaluated a panel of eight ovarian cancer cell lines grown in standard 2-D culture or in spheroid-enriching 3-D culture, and correlated expression with growth characteristics, TIC marker expression, and chemotherapy resistance. RNA-sequencing showed that cell cycle regulation pathways involving SOX2 were elevated in 3-D conditions. HGSOC lines had longer doubling-times, greater chemoresistance, and significantly increased expression of SOX2, OCT4, and NANOG in 3-D conditions. CD117+ or ALDH+/CD133+ cells had increased SOX2, OCT4, and NANOG expression. Limiting dilution in in vivo experiments implicated SOX2, but not OCT4 or NANOG, with early tumor-initiation. An analysis of patient data suggested a stronger role for SOX2, relative to OCT4 or NANOG, for tumor relapse potential. Overall, our findings suggest that SOX2 may be a more consistent indicator of ovarian TICs that contribute to tumor repopulation following chemotherapy. Future studies evaluating SOX2 in TIC biology will increase our understanding of the mechanisms that drive ovarian cancer relapse.

MiR-4478 sensitizes ovarian cancer cells to irradiation by inhibiting Fus and attenuating autophagy

Ovarian cancer (OC) is a type of cancer with high prevalence and shocking mortality in women around the world. Radioresistance is a major reason for OC relapse. Mounting studies have shown the significant function of dysregulated microRNAs (miRNAs) in cancer progression and the cellular response to irradiation. The present study inquired about the function and mechanism of microRNA (miR)-4478 in regulating radiosensitivity of OC cells. Results showed that miR-4478 was downregulated in OC, and a low miR-4478 level indicated a disappointing prognosis for OC patients. Besides, in OC cells exposed to irradiation, the expression of miR-4478 decreased over time. Functionally, the upregulation of miR-4478 retarded OC cell proliferation and sensitized OC cells to irradiation. Mechanistically, miR-4478 targeted and inhibited fused in sarcoma (Fus). Additionally, Fus was upregulated in OC and its expression further elevated in OC cells under irradiation. Furthermore, miR-4478 targeted Fus to inhibit autophagy, therefore sensitizing OC cells to irradiation. Collectively, our study uncovered miR-4478 as a novel radiosensitizer by targeting Fus in OC cells, which may shed a new light on developing targets for treating patients with OC, particularly those with radioresistance.

18F-FDG PET/CT in ovarian cancer recurrence: Clinical impact, correlation with ceCT and CA-125, and prognostic value

AimTo evaluate 18F-FDG-PET/CT for suspected ovarian cancer relapse with negative/inconclusive conventional imaging, or restaging potentially resectable ovarian cancer relapse. Material and methodsThirty-six cases and 140 locations were studied. PET/CT, ceCT and serum CA-125 was conducted in all cases. Nineteen cases were requested for restaging, 17 for suspected relapse.We compared ceCT and PET/CT, assessed by histopathology or radiological follow-up, calculating sensitivity (S) and positive predictive value (PPV) by cases and lesions.We evaluated the correlation between size, number, uptake of the lesions and CA-125. We conducted survival analysis, using ROC curves to calculate the optimal cut-off of SUVmax for survival prediction.We checked whether PET/CT modify the therapeutic attitude vs. conventional imaging. ResultsPET/CT and ceCT were concordant in 12 cases: 11 positives (30 lesions), all confirmed. There was 1 FN.In the 24 non-concordant, PET/CT was positive in 19 (97 lesions); ceCT in 21 (59 lesions); 54% of the lesions were concordant.Overall, PET/CT detected 127 lesions, with S=97% and PPV=100%. ceCT detected 89 lesions, with S=61% and PPV=90%.No significant correlation was found between CA-125 and the other parameters. PET/CT detected 10 positive cases, with normal CA-125.PET/CT modified therapeutic management in 15 cases.Significant differences were found in survival with SUVmax=11.8 ConclusionsPET/CT plays an important role in ovarian cancer relapse, with sensitivity and PPV higher than ceCT, modified therapeutic management in up to 42% of cases, and could be a valuable tool for predicting survival.

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

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

Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-sensitive recurrent ovarian cancer

Objective: The CLIO trial (NCT02822157) evaluated Olaparib single-agent therapy versus standard-of-care chemotherapy in platinum-sensitive recurrent epithelial ovarian cancer (relapse ≥6 months after platinum-based chemotherapy) (PSOC).

Interim results of the non-interventional C-PATROL study: Real-world treatment data from patients who switched from olaparib capsules to tablets

Objective: Olaparib (50-mg hard capsules) has been approved in the European Union since December 2014 as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. Subsequently, film-coated tablets (100/150 mg) were approved in the European Union in May 2018, but regardless of BRCA status. So far, no real-world olaparib treatment data from patients who switched from olaparib hard capsules to film-coated tablets (switcher) are available.

Primary site disease and recurrence location in ovarian cancer patients undergoing primary debulking surgery vs. interval debulking surgery

IntroductionThe natural history and patterns of ovarian cancer (OC) relapse are still unclear. Recurrent disease can be peritoneal, parenchymal, or nodal. This study aims to analyze the location and pattern of OC recurrence according to the primary site of disease and to the type of surgical approach used. Material and methodsAll OC patients underwent primary debulking surgery (PDS) or interval debulking surgery (IDS), with 2014 FIGO stage III-IV, and with platinum-sensitive recurrence were included in the study. Primary disease location and site of recurrences were divided into peritoneal, parenchymal, and nodal, according to the presence of peritoneal carcinomatosis, parenchymal metastasis, and nodal involvement, respectively. ResultsA total of 355 patients were initially considered; of them, 295 met the inclusion criteria. Two hundred thirty-three patients obtained no macroscopic residual tumor at the end of primary surgical treatment. Primary parenchymal disease relapsed in 84.6% cases at a parenchymal site (p < 0.001), 97.2% of peritoneal diseases relapsed on the peritoneum (p < 0.001), and 100% of nodal diseases had a nodal recurrence (p < 0.001). Stratifying by the surgical approach all these correlations have been confirmed both in the PDS (p < 0.001) and IDS (p < 0.001) groups. ConclusionOur study shows that the site of relapse in cases of platinum-sensitive OC recurrence is closely related to the primary location of the disease, regardless of the type of initial treatment. Therefore, more attention during followup should be paid to areas where the initial tumor was present.

DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment

BackgroundWith the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously...

814MO Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC)

814MO Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC)

Laparoscopic splenectomy for first single-site relapse of ovarian cancer

: Ovarian cancer is an highly aggressive disease and, despite complete surgical cytoreduction and adjuvant chemotherapy, women with this diagnosis usually develop recurrent disease. Platinum-sensitive recurrence can be treated either with secondary cytoreductive surgery (SCS) plus platinum-based chemotherapy or with chemotherapy alone. Patients with isolated splenic metastasis, are relatively rare and could benefit from a minimally invasive approach without compromising survival. In this setting, the advantages of laparoscopy in terms of reduced morbidity, faster recovery, and better cosmetic outcomes are positively reflected on the patient “recurrence experience”, lightening its burden with a potential positive impact on their quality of life. We present the case of a 53-year-old woman with isolated parenchymal splenic recurrence of high-grade serous ovarian cancer that was treated with laparoscopic splenectomy, using an “anterior approach”. Perioperative outcomes of the reported case were superimposable to the open technique, with an estimated blood loss of 50 mL and an operative time of 150 minutes. At 25 months of follow-up, the patient showed no evidence of disease. This study aims to show a step-by-step approach to laparoscopic splenectomy during SCS. In conclusion we showed that, in the hands of an experienced surgeon and through a meticulous surgical technique, laparoscopic splenectomy for recurrent ovarian cancer is feasible and safe.

826P Comparative efficacy of first-line maintenance PARP inhibitors (PARPI) in advanced ovarian cancer (OC): A network meta-analysis

Most newly diagnosed women with advanced OC relapse within 3 years despite surgical resection and adjuvant platinum-based chemotherapy. Many studies explored the clinical benefit of PARPI and antiangiogenic agents (AA) as maintenance agents with varied results. This analysis was conducted to update and expand our current knowledge of the relative efficacy of first-line maintenance PARPI as they relate to one another, and as they compare to first-line AA in advanced OC. A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of advanced ovarian cancer; first-line maintenance treatment with Olaparib (O), Niraparib (NR), Veliparib (V), Bevacizumab (B), Pazopanib (P), Nintedanib (NN), and control (C); and phase III randomized studies reporting progression, death, and adverse (AE) events. A frequentists and Bayesian network meta-analyses were conducted using netmeta package and random-effects model. Seven studies comprising a total of 7,770 participants were included. The relative risk (RR) of death and progression was highest in C and B than in NN, P, V, NR, and O in decreasing order. RR of AE≥3 was highest in P than NR, O, NN, B, V, and C in decreasing order. PARPI significantly improved PFS in homologous-recombinant deficiency (HRD+), HRD-, BRCA mutation (BRCA+), BRCA-, BRCA2+, Stage 3, and Stage 4 subgroups. PARPI demonstrated an equivalent reduction in RR of death and progression in BRCA+ patients. In HRD+, O had the lowest RR followed by NR, V, and C in increasing order. However, in HRD-, V had the lowest RR followed by NR and then O which seemed to be equivalent to C. This network meta-analysis is the first to compare and rank first-line maintenance treatment therapies in advanced OC. It indicates that PARPI have better outcomes than AA. It also demonstrates that individual PARPI vary in frequency of AE≥3 as well as clinical efficacy across mutation subtypes.

Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance.

Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum-based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remains sparse. In the current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cell (CSC) maintenance. Depletion of KDM4C significantly reduced the CSC population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSC maintenance and underscore its importance as a potential therapeutic target.

Combined and expanded operations in patients with relapsed ovarian cancer and affected retroperitoneal lymph nodes

Objective: to analyze short-term and long-term outcomes of expanded surgeries in patients with recurrent ovarian cancer and to identify factors affecting their overall survival (OS) and progression-free survival (PFS). Materials and methods. This retrospective study included patients with recurrent ovarian cancer stage I–IV less than 80 years of age who was treated in the Department of Gynecologic Oncology, N. N. Blokhin National Medical Research Center of Oncology, between 2015 and 2017. Other inclusion criteria were as follows: time to relapse more than 12 months and no chemotherapy during the last 6 months or more. We analyzed the main perioperative parameters, OS, PFS, and prognostic factors affecting OS and PFS. Results. This study included 55 patients. Of them, 44 (80 %) women have undergone complete cytoreductive surgery, whereas 11 (20 %) women have undergone optimal cytoreductive surgery. The median duration of surgery was 210 minutes (range: 60–390 minutes), median blood loss was 400 mL (range: 30–4500 mL). Postoperative complications were observed in 23 (41.2 %) patients; 5 (9.1 %) patients developed grade IIIB complications. Median follow-up time was 30.3 months (range: 7.5–67.1 months). Three-year OS was 73.7 % and three-year PFS was 30.7 %. More than one line of chemotherapy before repeated cytoreductive surgery was found to be a negative factor affecting OS (hazard ratio 2.749; 95 % confidence interval 1.059–7.138; p = 0.038). The primary ECOG performance status had a significant impact on PFS (hazard ratio 0.543; 95 % confidence interval 0.347–0.851; p = 0.008). Conclusions. Poor ECOG status and more than one line of chemotherapy before repeated cytoreductive surgery for ovarian cancer relapse were demonstrated to have a negative impact on survival in this group of patients. However, in some patients, repeated cytoreductive surgeries ensured long-term remission.

Bevacizumab in maintenance therapy for ovarian cancer patients

Ovarian cancer is one of the most common cancers in women. Growth and extension of the tumor are associated with active neoangiogenesis regulated by vascular endothelial growth factor (VEGF). Bevacizumab decreases VEGF activity and inhibits the tumor growth.Purpose of the study. The aim of the study was to evaluate results of bevacizumab in maintenance therapy for ovarian cancer.Materials and methods. 26 patients with ovarian cancer received maintenance therapy with drop infusions of bevacizumab 15 mg/kg once a day for 21 days in 2014–2019 after completing chemotherapy for relapses.Results. Bevacizumab mainterned partial response or stabilization in 76.9% of patients. The adverse events were mainly of grades 1–2 (in 88.5% of all adverse events) and could be managed by an appropriate medical correction. Hemorrhagic complications caused the cancellation of bevacizumab in one patient.Conclusions. Bevacizumab in maintenance therapy after completing chemotherapy for ovarian cancer relapses (both platinum-sensitive and platinum-resistant) significantly improves the treatment results. The toxicity profile of bevacizumab in maintenance treatment is acceptable.

Value of pre-existent bacterial colonization in patients with advanced/relapsed ovarian neoplasms undergoing cytoreductive surgery: a multicenter observational study (BONSAI)

ObjectiveAs an increasing number of patients with advanced/relapsed ovarian cancer need extensive cytoreductive procedures, there is an increasing number of complex cases collected in accredited tertiary cancer centers. With nosocomial...

THE VALUE OF CYTOREDUCTIVE SURGERY FOR ISOLATED LYMPH NODE RECURRENCE OF OVARIAN CANCER

The purpose of the study was to undertake a systematic literature review regarding the role of cytoreductive surgery in treatment of recurrent ovarian cancer, as well as to summarize available data on various current studies and estimate indications for secondary cytoreduction in recurrent ovarian cancer with isolated lymph node involvement.Material and Methods. The search for relevant sources was carried out in PubMed, Gynecol Oncol, Medline, NCCN, Elibrary systems; publications were included from January 2006 up to March 2019. Of the 87 studies found, 26 were used to write a systematic review.Results. Ovarian cancer (OC) remains the leading cause of death from gynecological cancer. The initial treatment for IC-IV stages of OC includes surgical cytoreduction followed by platinum-containing chemotherapy. The best outcomes are observed in patients, in whom complete cytoreduction has been achieved. Despite this fact, most patients develop relapses and the 5-year survival rate is about 30 %. The frequency of lymph node involvement in patients with recurrent OC is not reliably known; isolated lymph node recurrence is reported to occur in 5–32 % of patients. To date, the problem regarding the extent of lymph node dissection in treatment of OC recurrence is still unsolved. In our paper we review the available data concerning the role of secondary cytoreductive surgery for isolated lymph node recurrence of ovarian cancer.Conclusion. Isolated lymph node recurrence of ovarian cancer may indicate a more favorable prognosis and has a less aggressive pattern of OC relapse. The role of secondary cytoreduction in this context is not fully understood, but this category of patients may be one of the most suitable for surgical treatment of ovarian cancer recurrence.

Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model.

Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.

P0563THE SHORT AND LONG-TERM EFFECTS OF HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY ON RENAL FUNCTION IN PLATINUM-SENSITIVE RECURRENT OVARIAN CANCER

Abstract Background and Aims Cytoreductive surgery (CRS) with platinum based Hyperthermic Intraperitoneal Chemotherapy (HIPEC) represents a valid therapeutic approach in the treatment of ovarian cancer patients with peritoneal spread (vanDriel NEJM). Nevertheless, cisplatin nephrotoxicity represents one limitation to the diffusion of HIPEC in clinical practice. To date, few studies evaluated the nephrotoxicity of hyperthermic intraperitoneal cisplatin and the risk of acute kidney injury (AKI) in patients treated with HIPEC. The aim of our study is to evaluate short- and long-term changes in serum creatinine (SCr) levels in a cohort of patients with a first relapse of platinum-sensitive ovarian cancer, receiving CRS plus or minus HIPEC. Method We compared a cohort of patients with a first relapse of platinum-sensitive ovarian cancer, receiving CRS plus/minus HIPEC in a period from January 2013 to October 2018. The HIPEC technique required the perfusion of the abdominal cavity with a 4 L/m2 of a heated saline solution containing cisplatin 75 mg/m2. We assessed the estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, and SCr from the preoperative value, at 24, 48, 72 hours, 7 days and the last SCr value available on the electronic record, at least 3 months after the procedure. We analyzed the effect of HIPEC treatment on SCr values over time and we used logistic regression models to investigate the effect of HIPEC treatment on clinical outcomes. No patient in the HIPEC group had kidney protective treatment with thiosulphate. Results Our analyses included complete data of 110 patients treated in our Institution from January 2013 to October 2018. The two groups had significant differences in baseline SCr (p-value = 0.002), with lower average values in the CRS+HIPEC group (mean 0.68, standard deviation [SD] 0.14 mg/dL) compared to the CRS group (mean 0.76, SD 0.13 mg/dL). The baseline eGFR was significantly higher in the CRS+HIPEC group (mean 95, SD 16 mL/min/1.73 m2) than in the CRS group (mean 88, SD 14 mL/min/1.73 m2) (p-value = 0.014) and three patients in each group had chronic kidney disease (CKD) before surgery. SCr values in the HIPEC group were significantly higher at post-operative day #7 (1.22 ± 1.10 mg/dL vs 0.69 ± 0.16 mg/dL; p-value &amp;lt;0.001) and the differences remained during follow-up at least three months after randomization (0.96 ± 0.55 vs 0.69 ± 0.19 mg/dL; p-value &amp;lt;0.001). Seventeen patients (31%) developed Acute Kidney Injury (AKI), according to the KDIGO Guidelines, in the first week after CRS+HIPEC versus seven patients (13%) after CRS alone. No patients who developed AKI post-HIPEC needed renal replacement treatment, although 5 (9%) had AKI stage III and 7 (13%) stage II. The CRS+HIPEC group had a significantly higher risk of developing AKI [OR: 3.48 (2.30-5.27)] compared with the CRS group (p-value &amp;lt;0.001). There were no statistically significant differences between the two groups with regard to risk of complications other than AKI. Conclusion To our knowledge, our study represents the first investigation on short- and long-term changes in SCr and on the risk of AKI in patients with a first relapse of platinum-sensitive ovarian cancer, treated with CRS and HIPEC. There is a strong correlation between the intraperitoneal cisplatin at elevated temperatures and the rise of SCr over the time. However, this event was no reversible and influenced following treatments in only eight women.

Olaparib treatment in patients (pts) with platinum-sensitive relapsed (PSR) ovarian cancer (OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Phase II LIGHT study.

6013 Background: In Study 19 (NCT00753545), olaparib capsules demonstrated improvement in progression-free survival (PFS) vs placebo in the PSR OC maintenance setting, irrespective of BRCAm status (Ledermann et al. Lancet Oncol 2014). LIGHT is the first prospective study to evaluate olaparib tablet treatment in PSR OC pts by BRCAm and HRD status. Methods: This is an open-label, non-randomized study (NCT02983799) that assessed efficacy and safety of olaparib monotherapy (300 mg BID) in pts with PSR, high-grade serous/endometrioid epithelial OC and ≥1 prior line of platinum chemotherapy. Pts were assigned to one of four cohorts: germline (g) BRCAm; somatic (s) BRCAm; HRD+ve (non-BRCAm); HRD–ve; by Myriad BRACAnalysis CDx and myChoice tests. HRD+ve was a score ≥42. Primary endpoint was objective response rate (ORR). Secondary endpoints included: disease control rate (DCR) and investigator-assessed PFS (RECIST v1.1). Primary analysis was to be ~6 months (mo) after the last pt was enrolled. Results: Data cut off was 8/27/19. Of 271 pts treated (median of 31.7 weeks [2.1–96.0]), 270 had measurable disease at baseline and were included in efficacy analyses (Table). The most common treatment-emergent adverse events (AEs) were nausea (66%) and fatigue (62%).Serious AEs and Grade ≥3 AEs were experienced by 25% and 44% of pts, respectively. AEs leading to olaparib dose interruptions, reductions and discontinuations occurred in 33%, 24% and 4% of pts, respectively. Conclusions: Olaparib treatment demonstrated activity across all cohorts. As observed in the maintenance setting, similar efficacy was seen in the gBRCAm and sBRCAm cohorts. For non-BRCAm pts, longer median PFS and higher ORR were observed in the HRD+ve cohort. Olaparib treatment was well tolerated with no new safety signals identified and a safety profile consistent with that seen in the PSR and first-line settings. Clinical trial information: NCT02983799. [Table: see text]

Multipeptide vaccine to prevent epithelial ovarian cancer relapse by microenvironment immunomodulation.

e15268 Background: Typically cancer vaccines for relapse prevention in epithelial ovarian cancer (EOC) are administrated in distant anatomical sites away from the primary tumor location. Ideally for EOC relapse prevention vaccines we should explore different anatomical sites related with the original tumor location and nearby lymph nodes, in order to observe if the administration would have better clinical impact due to a potential access to the tumor microenvironment. Moreover most trials for EOC relapse prevention use one or few targets and is mainly unknown if they are relevant to promote EOC relapse. We treated EOC patients with a multi-peptide vaccine administered in lymph nodes (LN) and in the peritoneum area and were able to suppress cancer relapse with not significant adverse effects after eight years. Methods: We enrolled n = 25 EOC patients in our study and identified by systematic review and validated by siRNA six proteins involved in EOC relapse and fourteen peptides were predicted. Twelve peptides were immunogenic by Granzyme B ELISPOT, DTH and ELISA. Patients were immunized with the vaccine in axillary and inguinal LN subcutaneously every week for four weeks, every two-weeks four times and finally every month for a total of thirty-six months. Clinical and laboratory evaluations were performed every 2-months and at the end of the study. Results: 100% of the patients developed both antibodies against all the peptides by ELISA and CD8 specific cells. The peptides of the six proteins were able to induce T cell expansion in both peptides and purified protein (p = 0.0001) and (p = 0.05), respectively for Ape-1. The selected targets were all able to induce DTH and ELISA responses with statistical significance. Peptides predicted from Bcl-2, survivin, Ape-1, Sox2, EGFR and RCAS1/EBAG9 were able to increase and sustain the levels of Granzyme B ELISPOT. Bcl-2 A peptide (p = 0.001), Bcl-2 B (p = 0.005), Bcl-2 C (p.0002), survivin A (p = 0.001), Survivin C (0.05), Ape-1 A (0.0001), Ape-1 D (p = 0.001), Sox2 A (p = 0.003), Sox2 B (p = 0.0001), EGFR B (p = 0.0001) and EGFR D (p = 0.001). Conclusions: Treating EOC patients in remission in zones hardly explored previously in order to potentially improve the activation of antigen-specific Th1 and CD8 cells with specific peptides seems promising as a feasible and safe approach to prevent EOC relapse.