High-grade Epithelial Ovarian Cancer Research Articles

Evaluation of a RAD51 functional assay in advanced ovarian cancer, a GINECO/GINEGEPS study.

5513 Background: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation ( BRCAmut)or high genomic instability, is currently used to identify patients (pts) with epithelial ovarian cancer (EOC) most likely to benefit from PARP inhibitors. While these genomic tests are useful, they are imperfect: some BRCAm EOC demonstrate primary PARPi resistance and some HR-proficient benefit. Another approach to evaluate HRD is to measure the capacity of tumor cells to recruit nuclear RAD51 foci during S/G2 phase in the presence of double strand DNA damage using multiplexed immunofluorescence (IF) for RAD51, geminin (GMN) and yH2AX. We aimed to describe for the 1st time HRD using this RAD51 functional assay in EOC and correlate RAD51 status to platinum response and BRCAmut. Methods: Tumor samples and clinical data were collected prospectively from pts in the randomized CHIVA trial of neoadjuvant platinum chemotherapy +/- nintedanib. IF for RAD51, GMN, and DAPI was performed on a 3uM slide from FFPE blocks, where feasible, yH2AX was positively scored on a consecutive slide. Tumors were considered RAD51-deficient if < 10% of gem+ tumor cells (TC) had > 5 RAD51+ foci. BRCAmut were identified by NGS. Results: 155 baseline chemotherapy naïve EOC samples were available. All were advanced stage (IIIC/IV), 75% were G3, 7% G2, 2% G1, and 16% grade UK. A contributive RAD51 result was obtained for 90% (139/155) of samples. Contributive NGS results were available for 130 samples. Overall, yH2AX scores were high (median % TC+: 86%, IQR: 56%-100%) confirming the presence of significant basal DNA damage in high grade EOC. Only 8 samples were yH2AX-low, including two of the three G1 tumors. In contrast, 55% (76/155) of samples were considered RAD51-deficient (score < 10%). With regard to outcome, pts with RAD51-deficient tumors had significantly higher overall response rates to neoadjuvant platinum (68% vs 37%, p = 0.04) and significantly longer median progression-free survival (HR 0.50, IC95% 0.25-0.98, p = 0.02). Considering BRCA status, 15% of tumors harbored a deleterious BRCAmut and 67% of these were RAD51-deficient. Importantly among BRCAmut EOC, the RAD51-proficient tumors had significantly poorer response to neoadjuvant chemotherapy (RR = 17% vs 75%, p = 0.02). Conclusions: We evaluated a novel functional assay of HR functionality in advanced EOC. The assay requires minimal tissue and yields contributive results in 90% of cases. Overall, EOC demonstrate high levels of basal DNA damage, yet 55% fail to recruit RAD51 foci during S/G2 cell cycle phase. These RAD51-deficient EOC have improved outcome after neoadjuvant platinum. Conversely, the RAD51 assay also identified a small subset of RAD51-high BRCAmut tumors with poor platinum response. Whether this RAD51 functional assay may also predict PARP inhibitor benefit is currently being investigated.

Genetic and clinical characterization of multigene hereditary breast and ovarian cancer (HBOC) panels in Málaga (Spain).

e22530 Background: Next Generation Sequencing (NGS) technologies have transformed hereditary breast and ovarian cancer (HBOC) testing process. Several multigene panels (MP) include from 10 to 100 candidate cancer susceptibility genes, but there is a debate about what genes should and should not be tested because of lack of actionability. Few studies have been reported about MP in Europe or Spanish cancer families and no studies in Andalusian population (southern Spain). Methods: We investigated a panel of 17 known genes of high/moderate-risk for HBOC in 938 clinically suspicious HBOC Andalusian families (SEOM 2015 criteria), tested from 2017 to 2019. Multigene panel including BRCA,1 BRCA2, CHEK2, PALB2, BRIP1, ATM, MLH1, MSH2, MSH6, PMS2, CDH1, NF1, PTEN, p53, STK11, RAD51C and RAD51D was performed. Results: We identified 130 patients who carried a high- or moderate-risk pathogenic variants: 61 in BRCA2 (47%), 30 in BRCA 1 (23%), 10 in CHEK2 (8%), 7 in ATM (5%), 7 in PALB2 (5%), 4 in RAD51 (3%), 4 in BRIP1 (3%), 4 in MSH6 (3%), 2 in MLH1 (1,5%) and 1 in MSH2. We detected 220 patients carry variants of uncertain significance (VUS), with a total of 248 VUS (some patients carried more than one VUS): 46 (19%) in ATM, 38 (15%) in BRCA 2, 28 (11%) in MSH6, 19 (8%) in PMS2, 17 (7%) in BRIP1, 16 (6%) in NF1, 14 (6%) in MSH2 and 12 (5%) in CDH1 and PALB2. The most frequent criteria in the entire cohort was “High-grade epithelial non-mucinous ovarian cancer”, reported in 243 cases (26%)”, whereas “Breast cancer (BC) diagnostic under 35” was the most frequent criteria between positives (48 cases (40%)). One case carried two pathogenic variants: BRCA2 and MUTYH. Conclusions: This is the first study reporting the mutational profile of MP gene testing in Andalusia. 70% of mutations were due to BRCA1 and 2 followed by far by CHEK2, ATM and PALB2. We also identified a large amount of VUS in BRCA2, ATM and MSH6. MP improve the diagnostic in andalusian HBOC patients.

LIO-1: Lucitanib + nivolumab in patients with advanced solid tumors—Updated phase 1b results and initial experience in phase 2 ovarian cancer cohort.

5538 Background: The phase (Ph) 1b part of LIO-1 (NCT04042116; ENGOT-GYN3/AGO/LIO) assessed the oral antiangiogenic, multikinase inhibitor lucitanib + immune checkpoint inhibitor nivolumab, confirming the recommended Ph2 dose (RP2D) of lucitanib as 6 mg QD + nivolumab (480 mg IV every 28 days). To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is being explored in a Ph2 part, across 4 recurrent gynecologic malignancies (endometrial, cervical, ovarian, and ovarian/endometrial clear-cell cancers) using a Simon 2-stage design. We present updated Ph1b data and describe initial experience for the first 24 patients (pts) enrolled in the Ph2 ovarian cancer (OC) cohort. Methods: In Ph1b, pts with advanced, metastatic solid tumors received lucitanib at 6, 8, and 10 mg QD + nivolumab (in a 4+3 dose escalation). In the Ph2 OC cohort, pts with recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer (excluding clear-cell histology) with ≥2 prior chemotherapy regimens (including ≥1 platinum doublet) received the combination at RP2D; lucitanib dose was escalated from 6 mg to 8 mg and then to 10 mg QD for pts who met safety-based titration criteria. Visit cutoff was Feb 1, 2021. Results: In the Ph1b part (N = 17), median treatment duration was 109 days (range 14–505+). There has been 1 confirmed complete response (CR; anal cancer) and 1 confirmed partial response (PR; cervical cancer) per RECIST v1.1 with durations of 7.1 and 12.8 months, respectively. Ten pts had stable disease (SD), 3 had progressive disease, and 2 were nonevaluable; 3 pts remain on treatment. Overall disease control rate (CR + PR + SD ≥16 wk) was 47.1%. One dose-limiting toxicity (DLT; grade [G] 3 proteinuria) was observed in a pt receiving lucitanib 6 mg, leading to lucitanib discontinuation; no DLTs were seen at 8 or 10 mg. G ≥3 treatment-emergent adverse events (TEAEs) reported in ≥2 pts included hypertension (HTN; n = 4), fatigue (n = 2), and proteinuria (n = 2). Of the first 24 pts enrolled in the Ph2 OC cohort, 13 (54%) remain on treatment (median duration 59 [2–167+] days). Most frequent any-grade TEAEs were HTN (n = 10), fatigue (n = 8), nausea (n = 7), and proteinuria (n = 6). The only G ≥3 TEAE experienced in ≥2 pts was HTN (n = 4); 1 pt discontinued due to G4 HTN/G2 angina pectoris and 1 pt to G2 colonic perforation. To date, 21 pts have completed ≥1 cycle; 11 met safety-based dose-titration criteria, 10 of whom escalated to the 8 mg lucitanib dose. Of these, 5 pts subsequently escalated to 10 mg. One pt required dose reduction from 6 mg to 4 mg lucitanib. Conclusions: Ph1b data suggest that lucitanib + nivolumab has promising signs of antitumor activity. A safety-based dose-titration strategy appears feasible with manageable toxicity, based on experience from the Ph2 OC cohort to date; efficacy data from this cohort will also be presented. Clinical trial information: NCT04042116.

Impact of age, comorbidity, and treatment characteristics on survival in older women with advanced high grade epithelial ovarian cancer

ObjectivesOlder women have a worse prognosis with advanced epithelial ovarian cancer (EOC) and comorbidities likely contribute to poor outcomes. We sought to identify comorbid conditions and treatment-related factors in older women. MethodsA retrospective chart review identified 351 patients who underwent cytoreductive surgery (CRS). 100/351 (28.5%) were ≥ 70 years old. Demographic and clinicopathologic information was collected. Crude progression-free (PFS) and overall survival (OS) estimates were calculated using Kaplan-Meier method. Cox proportional hazards regression model was used to estimate hazard ratios and adjustments for confounders. ResultsStudy subjects ≥70 years old had significantly: higher Cumulative Illness Rating Scale-Geriatric (CIRS-G) score (5.9 vs 4.3; p = 0.0001), less completion of adjuvant chemotherapy (24% vs 15.1%; p = 0.049), less intraperitoneal (IP) therapy (18.2% vs 35.5%; p = 0.002), less clinical trial participation (16% vs 26.3%; p = 0.040), decreased platinum sensitivity (60% vs 73.7%; p = 0.012) and lacked BRCA mutations (0% vs 12%; p = 0.0006). They were less likely to have optimal CRS (75% vs 86.9%; p = 0.007) with same surgical complexity (p = 0.89). Patients ≥70 had significantly worse PFS and OS. In a multivariate analysis, better OS was associated with younger age (<70 years old), any IP therapy, completion of adjuvant chemotherapy, and platinum sensitivity. ConclusionThe older cohort had worse CIRS-G scores (5.9 vs 4.3; p = 0.0001), but no strong associations between comorbidities and treatment characteristics, but less optimal CRS rates (75% vs 86.9%; p = 0.007) with similar surgical complexity and less platinum sensitivity. Our results show comorbid conditions in older patients with advanced EOC may have less impact than tumor biology.

Ovarian Cancer Treatments Strategy: Focus on PARP Inhibitors and Immune Check Point Inhibitors.

Simple SummaryOvarian cancer treatment is the deadliest of gynecological cancers but the introduction of target therapies in its therapeutic algorithm has significantly improved outcomes. The aim of this article was to provide a review of completed and ongoing clinical trials involving the use of PARP inhibitors and/or immune checkpoint inhibitors for the treatment of ovarian cancer in front line and relapse settings. We confirmed the role of bevacizumab and PARP inhibitors which have transformed OC into a chronic disease while almost all trials involving immunotherapy were disappointing. Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.

A Prospective Study on Metronomic Scheduling of Non-chemotherapeutic Drugs in Advanced Epithelial Ovarian Cancers.

The online version contains supplementary material available at 10.1007/s13193-020-01261-w.

Analysis of Multimerin 1 (MMRN1) expression in ovarian cancer.

Ovarian cancer, the most lethal gynecological cancer, is the fifth most common cause of cancer-related deaths in women. A cost-effective and non-invasive early screening method for ovarian cancer is required to reduce the high mortality rate. Saliva is a clinically informative unique fluid, which is useful for novel approaches to prognosis, clinical diagnosis, and monitoring for non-invasive detection of disease. Multimerin1 (MMRN1) is a di-sulfide linked homo-polymeric glycoprotein from EMILIN family. Altered expression of MMRN1 has been reported in hepatocellular carcinoma, cervical cancer, and ovarian cancer. But, its role in epithelial ovarian cancer (EOC) is not clear and well documented. In this study, expression of Multimerin 1 was validated in saliva and tissues of EOC patients and age-matched controls by western blotting, ELISA, RT-PCR, and immunohistochemistry. Significant over expression of MMRN1 was observed by western blot and ELISA in saliva samples of EOC patients. The average concentration of MMRN1 in the saliva of healthy controls was 28.7pg/ml (SE ± 1.76), 42.53pg/ml (SE ± 4.06) in low grade and 52.91pg/ml (SE ± 4.24) with p < 0.01 in high-grade EOC. Upregulated cytoplasmic expression of MMRN1 was observed in EOC tissue by immunohistochemistry. Our results suggest that MMRN1 expression is associated with EOC progression and MMRN1 may be potential biomarker candidates for early-stage EOC detection however further experiments are required in a large cohort to establish this proposition. Also, saliva can be explored as a novel medium for ovarian cancer diagnosis.

Frequency and prediction of deep uterine involvement in advanced high-grade epithelial ovarian cancer: is uterine preservation an option?

IntroductionHysterectomy is traditionally part of the surgical treatment for advanced high-grade epithelial ovarian carcinomas, although the incidence of uterine involvement has not been fully investigated. Some young patients with advanced...

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

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...

Phase II Trial on the Feasibility of Single-Dose Intraoperative Intraperitoneal Carboplatin in Advanced Epithelial Ovarian Cancer Following Optimal Cytoreductive Surgery.

To evaluate the feasibility administering single-dose intraoperative intraperitoneal carboplatin (IP) in advanced epithelial ovarian cancer (EOC) after optimal primary or interval debulking surgery. A phase II non-randomized prospective study conducted at a regional cancer institute from January 2015 to December 2019. The advanced high-grade epithelial ovarian cancer FIGO stage IIIB-IVA was included. A total of 86 consented patients with optimal primary and interval cytoreductive surgeries received single-dose intraoperative IP carboplatin. The immediate (< 6h), early (6-48h), and late (48h-21days) perioperative complications were recorded and analyzed. The severity of adverse events was graded on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). A total of 86 patients received single-dose intra-operative IP carboplatin during the study period. The 12 (14%) patients underwent primary debulking surgery and 74(86%) interval debulking surgery (IDS). The 13 (15.1%) patients underwent laparoscopic/robotic IDS. All the patients tolerated the intraperitoneal carboplatin well with no or minimal adverse events. Three cases (3.5%) needed resuturing for the burst abdomen, three cases (3.5%) had paralytic ileus for 3-4days, one case (1.2%) underwent re-explorative laparotomy for hemorrhage, and one case (1.2%) mortality due to due late sepsis. The 84 (97.7%) of 86 cases received scheduled IV chemotherapy on time. Single-dose intraoperative IP carboplatin is a feasible procedure with no or minimal manageable morbidity. The procedure is user friendly combining the prognostic benefits of IP chemotherapy with assurance of earliest timely administration of chemotherapy in advanced EOC. Our study is a hypothesis generating for the future clinical trials comparing single-dose NIPEC versus HIPEC in advanced EOC.

Expression and significance of PD-1 and PD-L1 in the specimens of epithelial ovarian cancer

Objective: To examine the expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) in epithelial ovarian cancer (EOC) tissues, and investigate the correlation among their expression, clinicopathological features and prognosis. Methods: The specimens of 180 patients with EOC treated in the First Affiliated Hospital of Dalian Medical University from October 2002 to December 2013 were confirmed by pathological examination. The pathological tissue specimens of subtypes ，included 120 cases of serous carcinoma, 30 cases of mucinous carcinoma, 20 cases of endometrioid carcinoma, and 20 cases of clear cell carcinoma. The normal paracancerous tissues of 50 cases randomly selected from the 180 patients as control group. Immunohistochemical SP method was used to detect the expressions of both PD-1 and PD-L1 in epithelial ovarian cancer tissues, and the relationships among their expressions,the clinicopathological parameters and prognosis were respectively analyzed. Results: （1） PD-1 was expressed in lymphocytes infiltrated in EOC tissues, and PD-L1 was expressed in the cell membranes of cancer tissues. In all EOC cases, 33 cases (18.3%, 33/180) of both PD-1 and PD-L1 were highly expressed, and only 1 (2.0%, 1/50) of control group showed high expression. There was statistically significant difference between two groups (P<0.01). (2) Among the four subtypes tissue specimens of EOC, the high expression rate of PD-1 was 25.0% (30/120) for serous carcinoma, 3/15 for endometrioid carcinoma, 0 (0/30) for mucinous carcinoma, and 0 (0/15) for clear cell carcinoma. The high expression rate of PD-L1 was 23.3% (28/120) for serous carcinoma, 3.3% (1/30) for mucinous carcinoma, 2/15 for endometrioid carcinoma, and 2/15 for clear cell carcinoma. Both PD-1 and PD-L1 expressions in the four sub-types of tissue specimens were significantly different (P<0.05). The high expression rate of both PD-1 and PD-L1 was 9.2% (8/87) in the early stage and 26.9% (25/93) in the late stage. There was a statistically significant difference between the two groups (P<0.01). Similarly, the expression of both PD-1 and PD-L1 were significantly higher in the cases of high-grade EOC （type Ⅱ） than those of low-grade （type Ⅰ） and in the cases of EOC distributed bilaterally than that distributed unilaterally, and there were statistically significant differences (P<0.05). (3) The Kaplan-Meier survival analysis showed that the survival time were respectively 35 and 36 months in the cases with high expressions of both PD-1 and PD-L1, and the survival time were the same as 61 months in the cases with low expression of both PD-1 and PD-L1, and the comparison was statistically significant (P<0.05). Conclusions: The expression levels of PD-1 and PD-L1 in EOC tissues are higher than those in adjacent tissues, especially in serous carcinomas. The expression of both PD-1 and PD-L1 is higher in specimens of the patients with advanced stages. The results showed that the high expression of both PD-1 and PD-L1 is an indicator of poor prognosis of patients suffering from EOC.

Abstract CT124: First-in-human study of SC-004, an antibody-drug conjugate targeting CLDN6/9, in patients with epithelial ovarian cancers

Abstract Background: More than 90% of ovarian cancers are epithelial ovarian cancers (EOC), and approximately 70% of EOCs are serous histology. Despite advancements with the development of PARP inhibitors and incorporation of bevacizumab, a clear unmet need remains for patients (pts) with recurrent EOC which is no longer considered appropriate for platinum-based chemotherapy (platinum-resistant). Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and there are limited options for pts who progress after first and/or second line chemotherapy. Claudins (CLDNs) are four-pass transmembrane proteins with key roles in tight junction formation and function, regulation of paracellular transport, and maintenance of cell polarity. CLDN6 and CLDN9 are expressed on neoplastic cells in a proportion of high-grade EOC and high-grade serous EC with minimal expression in normal tissues. SC-004 is an antibody-drug conjugate (ADC), consisting of an antibody targeting CLDN6/9 linked to a pyrrolobenzodiazepine (PBD) dimer DNA cross-linking agent. In this open-label, phase 1 clinical trial, the safety, tolerability and maximum tolerated dose (MTD) of SC-004 were assessed in pts with platinum-resistant/refractory EOC and EC (NCT03138408). Methods: Enrolled pts were adults with platinum-refractory or resistant high-grade serous EOC or EC, who had previously received at least 1 platinum-based chemotherapeutic regimen. SC-004 was administered intravenously at 0.005-0.3 mg/kg every 3 weeks (0.3 mg/kg was administered every 4 weeks). Treatment emergent adverse events (TEAEs) were defined as any adverse event (AE) that worsened from the first dose of SC-004 through 90 days following discontinuation of treatment. Membranous CLDN6 expression was assessed by immunohistochemistry retrospectively. Results: A total of 24 pts were enrolled (11 with ovarian and 13 with EC). Pts received SC-004 for a median of 2.5 cycles (range:1-25). The most common TEAEs (&amp;gt;20% of pts, N=24) were fatigue (38%), peripheral edema (33%), vomiting (33%), pleural effusion (25%), urinary tract infection (25%), rash maculo-papular (25%), anemia (21%), abdominal pain (21%), diarrhea (21%), and decreased appetite (21%). Twenty-one pts (88%) had at least 1 AE possibly related to SC-004. Eight pts (33%) had at least 1 grade 3 or higher AE with a possibility of being related to SC-004, the most common being pericardial effusion in 2 pts (8%). Eight pts (33%) had at least 1 SAE, including pericardial effusion, pleural effusion, renal failure, respiratory failure, abdominal pain, and failure to thrive, each occurring in 2 pts (8%) each. Eight pts (33%) had at least 1 AE leading to SC-004 dose interruption. Three pts (13%) had a fatal AE considered unrelated to SC-004. Thirteen pts (54%) died during the trial, mainly due to disease progression. The MTD was 0.2 mg/kg Q3W. Among 19 evaluable pts, best overall response of stable disease occurred in 14 pts (73%), partial response in 1 pt (5%), and progressive disease in 4 pts (21%). 4/19 pts (21%) with evaluable tissue had at least 50% of tumor cells with membranous CLDN6 expression, and one of these pts had the only partial response. Conclusion: SC-004 demonstrated low tolerability with a side effect profile similar to other PBD-conjugated ADCs, along with insufficient evidence of activity to support continued investigation. Citation Format: Erika Hamilton, Gini F. Fleming, Premal H. Thaker, Vivek Subbiah, Chris Chen, Abraham Fong, Daniel Brickman, Kathleen Moore. First-in-human study of SC-004, an antibody-drug conjugate targeting CLDN6/9, in patients with epithelial ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT124.

The Prognostic Value of PARP Expression in High-Grade Epithelial Ovarian Cancer

In an attempt to clarify the prognostic relevance of poly (ADP-ribose) polymerase (PARP) expression, we analysed the clinical data of 86 high-grade epithelial ovarian cancer (EOC) cases in which PARP immunohistochemistry results were available. Immunostaining to highlight PARP protein expression was performed using a Leica Bond MAX Immunostainer (Leica Microsystems, Wetzlar, Germany). We applied a rabbit polyclonal anti-PARP antibody (ab6079 330, Abcam, Cambridge, UK) for the specific reaction. The intensity and distribution of immunostaining were assessed by light microscopy (Leica DM2500 microscope, DFC 420 camera, and Leica Application Suite V3 software; Leica) and evaluated with a four-grade (0–3+) system. The median progression-free survival (PFS) was generated for each semiquantitative group of PARP expression among chemotherapy-naive cases at the time of PARP immunohistochemistry. Eighty-six cases were chemotherapy-naive at the time of PARP immunohistochemistry, and 41 cases showed no PARP expression. Forty-five cases showed intermediate or high PARP expression. The median PFS among patients in the PARP-negative group was 16 months (interquartile range; IQR 10.7–35.9 months), and the median PFS of patients in the PARP-positive group was 12 months (IQR 6.1–21.8 months). The difference was significant according to the log-rank test (p = 0.01). The median overall survival (OS) of patients in the PARP-negative group was 65 months (IQR 43.6–110.8 months), and the median OS of patients in the PARP-positive group was 52 months (IQR 36.9–66.7 months). The difference was significant according to the log-rank test (p = 0.028). Multiple comparisons confirmed that PARP expression results in a significant difference in PFS and OS achieved by first-line Taxol-carboplatin chemotherapy. The lack of PARP expression assessed by immunohistochemistry may predict improved PFS in ovarian cancer patients after adjuvant platinum-based chemotherapy.

Serum lncRNA LOXL1-AS1 is a diagnostic and prognostic marker for epithelial ovarian cancer.

BackgroundThe present study aimed to examine the levels of circulating LOXL1‐AS1 in epithelial ovarian cancer (EOC) patients and to analyze its diagnostic and prognostic value.MethodsThe levels of LOXL1‐AS1 in 185 EOC patients and 43 healthy volunteers were evaluated by a quantitative reverse transcriptase‐polymerase chain reaction. The potential of LOXL1‐AS1 as a biomarker for EOC diagnosis was determined by receiver‐operating characteristic (ROC) curve assays. The associations between clinicopathological parameters and LOXL1‐AS1 expression were analyzed using a chi‐squared test. The influence of LOXL1‐AS1 on overall survival was analyzed by the use of Kaplan–Meier. A Cox proportional hazards assays were conducted for the determination of the prognostic value of LOXL1‐AS1.ResultsThe expression of LOXL1‐AS1 was dramatically higher in EOC patients compared to healthy controls (p < 0.01). LOXL1‐AS1 yielded an area under the ROC curve of 0.843 with 65.3% sensitivity and 68.2% specificity in discriminating high‐grade EOC from healthy controls. It was also shown that LOXL1‐AS1 expression was associated with advanced FIGO stage (p = 0.004) and positively distant metastasis (p = 0.013). Kaplan–Meier assays revealed that patients with high LOXL1‐AS1 expression had a shorter overall survival than those with low expression (p = 0.0006). By performing multivariate assays, LOXL1‐AS1 was confirmed to be an independent prognostic factor for predicting the prognosis of EOC patients.ConclusionsWe provide evidence indicating that LOXL1‐AS1 expression is correlated with a poor clinical outcome in EOC patients and may act as an independent prognostic indicator, as well as a new diagnostic biomarker.

The development and evaluation of a nationwide training program for oncology health professionals in the provision of genetic testing for ovarian cancer patients

BackgroundBRCA1/2 mutation status has increasing relevance for ovarian cancer treatments, making traditional coordination of genetic testing by genetic services unsustainable. Consequently alternative models of genetic testing have been developed to improve testing at the initial diagnosis for all eligible women. MethodsA training module to enable mainstreamed genetic testing by oncology healthcare professionals was developed by genetic health professionals. Oncology healthcare professionals completed questionnaires before and 12 months post-training to assess perceived skills, competence and barriers to their coordinating genetic testing for women with high-grade non-mucinous epithelial ovarian cancer. Genetic health professionals were surveyed 12 months post-training to assess perceived barriers to implementation of mainstreaming. Results185 oncology healthcare professionals were trained in 42 workshops at 35 Australasian hospitals. Of the 273 tests ordered by oncology healthcare professionals post-training, 241 (93.1%) met national testing guidelines. The number of tests ordered by genetic health professionals reduced significantly (z = 45.0, p = 0.008). Oncology healthcare professionals' perceived barriers to mainstreamed testing decreased from baseline to follow-up (t = 2.39, p = 0.023), particularly perceived skills, knowledge and attitudes. However, only 58% reported either ‘always’ or ‘nearly always’ having ordered BRCA testing for eligible patients at 12 months, suggesting oncology healthcare professionals' perceived barriers were not systematically addressed through training. ConclusionsOncology healthcare professionals have demonstrated a willingness to be involved in the provision of genetic testing in a mainstreaming model. If oncology services are to hold responsibility for coordinating genetic testing, their readiness will require understanding of barriers not addressed by training alone to inform future intervention design.

Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancer undergoing cytoreductive surgery.

e18046 Background: Although advances in chemotherapy, cytoreductive surgery, and maintenance therapy (SOC) improved PFS for high grade epithelial ovarian cancer, &gt; 20% of patients relapse during the first 6 months and 60% relapse after 6 months. Submicron particles (~800 nm) of paclitaxel (SPP) contain 1-2 billion molecules of pure drug that release tumoricidal levels of paclitaxel over many weeks. In a previous trial, percutaneous instillations of SPP in nonsurgical patients with intraperitoneal cancer were associated with reduced systemic and local toxicity as compared to standard chemotherapy regimens. (Williamson et al Cancer Chemo Pharm (2015) 75:1075). Methods: This study compared two dose-levels of IP SPP instilled in 200 ml of saline post-cytoreductive surgery. Eligible patients with primary (n = 6) or recurrent (n = 4) epithelial ovarian cancer who underwent complete cytoreductive surgery were enrolled to receive a single instillation of IP SPP followed by standard IV carboplatin and paclitaxel. Endpoints were PFS and evaluation of treatment-emergent adverse events. Clinical response was determined by CT scans and serum CA-125 measurements. Results: Of the 24 subjects screened, 10 were enrolled and received treatment: seven patients received 100 mg/m2 and three received 200 mg/m2. For analysis purposes, 7 out of 10 subjects were evaluable (1 withdrew, 1 died unrelated to study drug during IV treatment and 1 was unevaluable). Upon completion of planned chemotherapy post-SPP instillation, the PFS at 6 months was 66% (4/6) and at 12-months 66% (4/6) using RECIST 1.1. One subject had a complete response at the end of IV treatment, but died (unrelated to study treatment) before PFS evaluation. There was one case of incision dehiscence and one case of vaginal cuff leakage after surgery. Conclusions: This pilot study supports further evaluation of IP SPP to treat peritoneal carcinomas. Clinical trial information: NCT03029585.

MIRASOL (GOG 3045/ENGOT OV-55): A randomized, open-label, phase III study of mirvetuximab soravtansine versus investigator’s choice of chemotherapy in advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate-alpha (FRα) expression.

TPS6103 Background: Elevated FRα expression is a characteristic of several solid tumors, including epithelial ovarian cancer (EOC), thereby providing an attractive candidate for targeted therapeutic approaches. Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent that has shown consistent and meaningful single agent clinical activity, along with favorable tolerability, in patients with high FRα expressing tumors. Methods: MIRASOL is a randomized phase III study designed to evaluate the efficacy of mirvetuximab soravtansine compared with that of standard-of-care chemotherapy in adult patients with platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer. Confirmation of high FRα positivity by immunohistochemistry (high expression; ≥ 75% of cells with PS2+ staining intensity) and ≤ 3 prior lines of therapy are required for inclusion. MIRASOL is designed to randomize 430 patients, 1:1 to Arm 1 (intravenous mirvetuximab soravtansine at a dose of 6 mg/kg, calculated using adjusted ideal body weight, on Day 1 of a 21-day cycle) or Arm 2 (investigators’ choice chemotherapy: paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary efficacy endpoint is progression-free survival (PFS; by investigator) and secondary endpoints include objective response rate, quality of life, overall survival, and safety and tolerability. MIRASOL opened for enrollment in December 2019. Clinical trial information: NCT04209855.

Homologous recombination deficiency in epithelial ovarian cancer

SummarySince the introduction of poly-ADP-ribose polymerase (PARP) inhibitor therapy for epithelial ovarian cancer (EOC) patients, testing for aberrations of homologous recombination (HR) repair as a predictive biomarker of therapy response has become an area of particular clinical interest. As HR represents a crucial repair pathway of otherwise possibly lethal DNA double strand breaks, its deficiency triggers a phenotypic behavior of tumor cells resulting in the accumulation of genetic damage. PARP inhibitors target this emerging genomic instability by fostering DNA strand breaks. Whereas testing for mutations of the tumor-suppressor genes BRCA 1 and BRCA 2 as a pivotal part of the HR apparatus has entered clinical routine, approximately 30% more high-grade EOC patients harbor aberrations of the HR pathway other than BRCA mutations and may therefore respond to PARP inhibition therapy. In recent years, several double-blind, placebo-controlled trials investigating sizeable patient cohorts have reported positive results of PARP inhibitor therapy response in HR-positive patient subgroups. Therefore, introducing HR testing in both the primary and recurrent setting as a biomarker for PARP inhibitor response may expand the range of patients who may profit from this therapeutic option beyond BRCA-mutated tumors.

Impact of Provider Imaging Practices on Survival Outcomes in Advanced Ovarian Cancer.

This study sought to describe how high- versus low-frequency surveillance imaging practices among providers at Memorial Sloan Kettering Cancer Center (MSKCC) impact overall survival (OS) and time to recurrence of patients with advanced epithelial ovarian cancer in first remission. The study cohort included patients with stage II-IV high-grade epithelial ovarian cancer diagnosed in January 2001 through January 2017 who experienced recurrence after initial platinum-based chemotherapy. To determine usual imaging practices for providers at MSKCC, median frequency of CT or MRI of the abdomen/pelvis was calculated among patients with a long-term remission (defined as at least 1 year) treated by each provider. Cox proportional hazards models were used to examine differences in OS and time to recurrence among patients treated by providers with high versus low imaging frequency practices, with additional subgroup analysis among patients with elevated CA-125 levels >35 U/mL at diagnosis. Chi-square tests were used to examine differences in the proportion of patients who enrolled in clinical trials or underwent secondary cytoreductive surgery (SCS) by imaging frequency. A total of 543 patients were treated by providers with high imaging frequency (>1 scan every 12 months) and 141 were treated by providers with low imaging frequency (≤1 scan every 12 months). Time to recurrence was shorter among patients treated by providers with high versus low imaging frequency (18.0 vs 19.2 months; hazard ratio, 1.33; P=.003). Results were similar when restricted to patients with elevated CA-125 levels at diagnosis. There was no significant difference in OS, clinical trial enrollment, or SCS by imaging practice. Within the limitations of this retrospective analysis, patients with advanced ovarian cancer treated by high-frequency-imaging providers had earlier detection of recurrence. Future analyses in a larger population are warranted to elucidate the risks versus benefits of surveillance imaging.