A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA-MONO comparison of rucaparib versus placebo. METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment.

BACKGROUND: Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment. METHODS: Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq analysis was utilized to identify genes and the associated genetic pathways that were differentially regulated in artesunate resistant organoid models compared to organoids that were sensitive to artesunate. RESULTS: Artesunate treatment reduces cell viability in 2D and 3D ovarian cancer cell models. Clinically relevant concentrations of artesunate induce G1 arrest, but do not induce DNA damage. Pathways related to cell cycle progression, specifically G1/S transition, are upregulated in ovarian organoid models that are innately more resistant to artesunate compared to more sensitive models. Depending on the sequence of administration, the addition of artesunate to carboplatin and paclitaxel improves their effectiveness. CONCLUSIONS: Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer.

CD151-α3ß1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling.

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3ß1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3ß1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of ß-catenin and Axin-2 as well as resistance to the inhibition in ß-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3ß1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.

Computed tomography adnexal mass score to estimate risk for ovarian cancer.

OBJECTIVE: We wish to develop a CT scan-based scoring system which estimates the probability of adnexal mass malignancy. METHODS: Patients (324) undergoing adnexal mass surgery were recruited into the study from June 1, 2002, to January 1, 2009. All study patients had a preoperative CT scan and serum CA-125 test. CT scan abnormalities included any solid tumor components, ascites, and pelvic or abdominal lymphadenopathy and omental caking. RESULTS: There were 225 (70%) benign and 99 (30%) malignant ovarian masses. Using logistic regression with the area under the curve of the receiver operating curve of 82%, the cancer probability was determined by the equation. e(-3.6372+0.0306*(A)+0.001*(C)+1.551*(D)+1.7377*(E)+2.76*(F)) / 1+e(-3.6372+0.0306*(A)+0.001*(B)+0.876*(C)+1.551*(D)+1.7377*(E)+2.76*(F)) where A = age, B = CA-125, C = solid adnexal mass is 1 and cystic is 0, D = ascites is 1, E = omental caking is 1 and absence is 0, F = node size ≥1 cm is 1 and <1 cm is 0 value. The natural logarithm e is a constant [2.718281828]. For example, for a woman of age 60, CA-125 = 50 U/mL, with solid adnexal mass, ascites, omental caking, and lymphadenopathy, the probability is 0.994. Hence, this woman has a 99.4% probability of having cancer. CONCLUSION: The computed tomography adnexal mass score combines CT scan findings, CA-125, and patient age into an equation to predict the malignant probability of an adnexal mass.

Ten-year relative survival for epithelial ovarian cancer.

OBJECTIVE: Most patients with epithelial ovarian cancer who are alive at 5 years have active disease. Thus, 10-year survival rather than 5-year survival may be a more appropriate endpoint. Relative survival adjusts for the general survival of the United States population for that race, sex, age, and date at which the diagnosis was coded. Our objective was to estimate relative survival in epithelial ovarian cancer over the course of 10 years. METHODS: Using the Surveillance, Epidemiology and End Results 1995-2007 database, epithelial ovarian cancer cases were identified. Using the actuarial life table method, relative survival over the course of 10 years was calculated, stratified by stage, classification of residence, surgery as the first course of treatment, race, and age. RESULTS: There were 40,692 patients who met inclusion criteria. The overall relative survival was 65%, 44%, and 36% at 2, 5, and 10 years, respectively. The slope of decline in relative survival was reduced for years 5-10 as compared with years 1-5 after diagnosis. Relative survival at 5 years was 89%, 70%, 36%, and 17%, and at 10 years relative survival was 84%, 59%, 23%, and 8% for stages I, II III, and IV, respectively. At all stages, patients with nonsurgical primary treatment and those with advanced age had reduced relative survival. CONCLUSIONS: The 10-year relative survival for stage III is higher than expected. This information provides the physician and the patient with more accurate prognostic information.

Risk of malignancy in sonographically confirmed septated cystic ovarian tumors.

OBJECTIVE: To determine the risk of malignancy in septated cystic ovarian tumors. MATERIALS: 1319 (4.4%) of 29,829 women were identified by transvaginal sonography (TVS) as having a complex cystic ovarian tumor with septations without solid areas or papillary projections and were placed on long-term ultrasound surveillance for ovarian malignancy. RESULTS: These 1319 patients had a total of 2870 septated cystic ovarian tumors. 2288 tumors (79.7%) had a septal width <2 mm and 582 (20.3%) had a septal width >or=2 mm. 2286 tumors (79.6%) were <5 cm in diameter and 584 (20.4%) were>or=5 cm in diameter. 1114 septated cystic tumors (38.8%) resolved spontaneously (mean duration to resolution-12 months) and 1756 (61.2%) tumors persisted. 128 patients underwent surgical tumor removal within 3 months of ultrasound. Most common histopathology was: serous cystadenoma (75), mucinous cystadenoma (13), and endometrioma (10). One patient had an ovarian tumor of borderline malignancy (Stage IB). There were no cases of ovarian cancer. Patients were followed from 4 to 252 months (mean-77 months). One patient developed papillary morphology in the contralateral ovary 3.2 years after detection of a septated ovarian cyst and had epithelial ovarian cancer in that ovary and in the omentum (Stage IIIC disease). The remaining patients are all free of ovarian neoplasia after a total of 7642 follow-up years. CONCLUSIONS: Septated cystic ovarian tumors without solid areas or papillary projections have a low risk of malignancy and can be followed sonographically without surgery.

Predicting risk of malignancy in adnexal masses.

OBJECTIVE: To estimate the accuracy of preoperative ultrasonography, serum CA 125, and patient demographics as a means of predicting risk of malignancy in women with a ultrasonographically confirmed adnexal mass. METHODS: Tumor morphology derived from ultrasonographic images, tumor size, tumor bilaterality, serum CA 125, and patient demographics were evaluated preoperatively in 395 patients undergoing surgery from 2001 to 2008. Tumor morphology was classified as complex, solid, or cystic. Preoperative findings were compared with tumor histologic findings at the time of surgery. Multivariable classification and regression tree analysis were used to identify a group of patients at high risk of ovarian malignancy. RESULTS: One hundred eighteen patients had ovarian cancer, 13 patients had ovarian tumors of borderline malignancy, and 264 had benign ovarian tumors. Multivariable classification and regression tree analysis defined women at high risk of ovarian malignancy as those with an adnexal mass having complex or solid morphology and a serum CA 125 value greater than 35 units/mL. This definition had a positive predictive value of 84.7% and a negative predictive value of 92.4% and correctly identified 77.3% of patients with stage I and stage II ovarian cancer and 98.6% of patients with stage III and stage IV ovarian cancer. CONCLUSION: Patients with solid or complex ovarian tumors and an elevated serum CA 125 level (greater than 35 units/mL) are at high risk of ovarian malignancy. LEVEL OF EVIDENCE: II.

The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size.

OBJECTIVE: To compare pelvic examination under anesthesia to transvaginal sonography (TVS) as a method for ovarian detection and measurement. METHODS: Two hundred and eighty-nine ovaries from 151 women were evaluated. After induction of anesthesia, a complete pelvic examination and TVS were performed, and the ovaries were removed surgically. Ovarian dimensions generated sonographically and estimated on clinical examination were compared to those obtained from the measured surgical specimen. RESULTS: Forty-four percent of ovaries were palpable clinically whereas 85% were visualized sonographically (P < 0.001). Right ovaries were palpable more frequently than left ovaries (P < 0.01). Ovaries were detected clinically in 30% of women > or = 55 years of age versus 51% of women <55 years of age (P < 0.05), in 9% of women weighing > or = 200 lb versus 55% of women weighing <200 lb (P < 0.001), and in 12% of women with a uterine weight > or = 200 g versus 51% of women with a uterine weight <200 g (P < 0.001). TVS was significantly more accurate than clinical examination in detecting ovaries in women with these high risk characteristics. CONCLUSIONS: TVS is significantly more accurate than clinical examination in detecting ovaries and in defining their dimensions. Ovaries frequently are not palpable in women > or = 55 years of age, women who weigh > or = 200 lb, or women with an enlarged uterus (> 200 g). The addition of TVS to annual pelvic examination may be beneficial in women > or = 55 years of age who are overweight and therefore at high risk to develop ovarian cancer.