Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Breast cancer incidence in BRCA mutation carriers with ovarian cancer: A longitudal observational study.

OBJECTIVES: We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS: Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS: The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION: The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Prognostic significance of pretreatment thrombocytosis in endometrial cancer: an Israeli Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer prognosis is related to stage, histology, myometrial invasion, and lymphovascular space invasion. Several studies have examined the association between pretreatment thrombocytosis and patient outcomes with contrasting results regarding prognosis. Our aim was to evaluate the association of pretreatment platelet count with outcomes in endometrial cancer patients. METHODS: This is an Israeli Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer, who underwent surgery between January 2002 and December 2014. Patients were grouped as low risk (endometrioid G1-G2 and villoglandular) and high risk (endometrioid G3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma). Those with stage I disease were compared with stages II-IV. Disease stages were reviewed and updated to reflect International Federation of Gynecology and Obstetrics (FIGO) 2009 staging. All patients underwent pelvic washings for cytology and total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Pelvic lymph node assessment was performed in patients with tumors of moderate-high risk histology or deep myometrial invasion. Para-aortic sampling was performed at the surgeon's discretion. Patients were categorized by pretreatment platelet count into two groups: ≤400×109/L and >400×109/L (defined as thrombocytosis). Clinical and pathological features were compared using Student t-test, χ2 or Fisher's exact test. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations. RESULTS: Of the 1482 patients included, most had stage I disease (961; 74.8%) and most had endometrioid histology (927; 64.1%). A total of 1392 patients (94%) had pretreatment platelet counts ≤400×109/L and 90 (6%) had pretreatment thrombocytosis. Patients with thrombocytosis had a significantly higher rate of high-grade malignancy, advanced stage, lymphovascular space invasion, low uterine segment involvement, and lymph node metastases. They also had shorter 5 year disease-free survival (65% vs 80%, p=0.003), disease-specific survival (63% vs 83%, p<0.05) and overall survival (59% vs 77%, p<0.05). On multivariate analysis, an elevated pretreatment thrombocyte count remained a significant independent predictor for disease-specific survival and overall survival. CONCLUSIONS: Pretreatment thrombocytosis is an independent prognostic factor for decreased disease-specific survival and overall survival among patients with endometrial cancer, and can serve as a predictor of poor outcome.

Age is an independent predictor of outcome in endometrial cancer patients: An Israeli Gynecology Oncology Group cohort study.

INTRODUCTION: Advanced age is considered an adverse factor in endometrial cancers but may be a surrogate for other conditions that impact outcomes. The study objective was to assess the association of age with endometrial cancer features, treatment and prognosis. MATERIAL AND METHODS: In this multicenter cohort study, consecutive women with endometrial cancer treated at 10 Israeli institutions between 2000 and 2014 were accrued in an assimilated database. Postmenopausal women were stratified into age groups with a cut-off of 80. Clinical, pathological and treatment data were compared using t test or Mann-Whitney test for continuous variables, and Chi-square Test or Fisher's Exact test for categorical variables. Main outcome measures included disease recurrence and disease-specific and overall survival; these were plotted using the Kaplan-Meier method and compared using the log-rank test. The association between age and recurrence and survival, adjusted for other clinical and pathological factors, was assessed using multivariable Cox regression modeling. RESULTS: A total of 1764 postmenopausal women with endometrial cancer were identified. Adverse pathological features were more prevalent in older women, including high-risk histologies (35% vs 27%, P = .025), deep myoinvasion (44% vs 29%, P = .001) and lymphovascular involvement (22% vs 15%, P = .024). Surgical staging was performed less frequently among older women (33% vs 56%; P < .001). Chemotherapy was less often prescribed, even for non-endometrioid histologies (72% vs 45%; P < .001). On multivariable analysis, age remained a significant predictor for recurrence (HR = 1.75, P = .007), death of disease (HR = 1.89, P = .003) and death (HR = 2.4, P < .001). CONCLUSIONS: Older age in women with endometrial cancer is associated with more adverse disease features, limited surgery and adjuvant treatment, and worse outcomes. On multivariable analysis, age remains an independent prognosticator in this population.

[THE PROLIFERATIVE EFFECT OF DENDRITIC CELLS IN OVARIAN CANCER AND THE RELATIONSHIP WITH THE IGF SIGNALING PATHWAY].

INTRODUCTION: Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies. Preclinical studies reported a significant anti-proliferative activity of IGF1 receptor (IGF1R) inhibitors in ovarian malignancies, however, clinical studies have shown variable response rates. Recent data indicate that immunotherapy could hold promise in improving EOC treatment. Dendritic cells (DCs) which are antigen presenting cells evoke a positive immune response. Moreover, a recent study shows that IGF treatment can inhibit DC maturation. AIMS: To investigate the involvement of IGF1R signaling in DCs and the effect of combined DCs and IGF1R inhibitor treatment on EOC cells growth. METHODS: HL-60 leukemic cells were differentiated to DCs and ligand induced phosphorylated IGF1R levels were measured by Western blotting. Next, inhibition of IGF1R in DCs was applied and the effect of this inhibition on EOC cell lines ES2 and SKOV3 was examined using the migration assay method. RESULTS: The differentiation of HL-60 into DCs was associated with decreased levels of both IGF1R phosphorylation and total IGF1R protein. In addition, in-vitro growth assays (scratch assay) demonstrated an increased growth of both ES2 and SKOV3 cells into the scratch zone when co-cultured with DCs which were not pre-treated with IGF1R inhibitor as compared to treated DCs. CONCLUSIONS: Preliminary data suggest that DC differentiation is associated with IGF1R signaling downregulation. Moreover, inhibition of IGF1R signaling in DCs might decrease EOC growth.

Oncogenic fusion proteins adopt the insulin-like growth factor signaling pathway.

The insulin-like growth factor-1 receptor (IGF1R) has been identified as a potent anti-apoptotic, pro-survival tyrosine kinase-containing receptor. Overexpression of the IGF1R gene constitutes a typical feature of most human cancers. Consistent with these biological roles, cells expressing high levels of IGF1R are expected not to die, a quintessential feature of cancer cells. Tumor specific chromosomal translocations that disrupt the architecture of transcription factors are a common theme in carcinogenesis. Increasing evidence gathered over the past fifteen years demonstrate that this type of genomic rearrangements is common not only among pediatric and hematological malignancies, as classically thought, but may also provide a molecular and cytogenetic foundation for an ever-increasing portion of adult epithelial tumors. In this review article we provide evidence that the mechanism of action of oncogenic fusion proteins associated with both pediatric and adult malignancies involves transactivation of the IGF1R gene, with ensuing increases in IGF1R levels and ligand-mediated receptor phosphorylation. Disrupted transcription factors adopt the IGF1R signaling pathway and elicit their oncogenic activities via activation of this critical regulatory network. Combined targeting of oncogenic fusion proteins along with the IGF1R may constitute a promising therapeutic approach.

Postoperative radiation rates in stage IIA1 cervical cancer: Is surgical treatment justified? An Israeli Gynecologic Oncology Group Study.

OBJECTIVES: Data on the outcome of stage IIA1 cervical cancer is limited, as these tumors comprise a small percentage of early tumors. NCCN guidelines suggest consideration of surgical management for small tumors with vaginal involvement. Our objective was to evaluate the risk of adjuvant radiotherapy in stage IIA1 cervical cancer and its associated features, in order to improve selection of patients for surgical management. METHODS: A retrospective cohort study comparing surgically treated cervical cancer patients with stage IB1 and stage IIA1 disease. Women treated between 2000 and 2015 in ten Israeli medical centers were included. Patient and disease features were compared between stages. The relative risk (Fisher's exact test) of receiving post-operative radiation was calculated and compared for each risk factor. A general linear model (GLM) was used for multivariable analysis. RESULTS: 199 patients were included, of whom 21 had stage IIA1 disease. Most features were comparable for stage IB1 and stage IIA1 disease, although patients with vaginal involvement were more likely to have close surgical margins (23.8% vs 8.5%, p = 0.03). Patients with stage IIA1 disease were more likely to receive radiation after surgery (76% vs. 46%, RR = 1.65 (1.24-2.2), p = 0.011). Vaginal involvement as well as depth of stromal invasion, LVSI and lymph node metastases were independent predictors of radiation on multivariable general linear modeling. CONCLUSIONS: Cervical cancer patients with vaginal involvement are highly more likely to require postoperative radiation. We recommend careful evaluation of these patients before surgical management is offered.

Is there a survival advantage in diagnosing endometrial cancer in asymptomatic postmenopausal patients? An Israeli Gynecology Oncology Group study.

BACKGROUND: Incidental ultrasonographic findings in asymptomatic postmenopausal women, such as thickened endometrium or polyps, often lead to invasive procedures and to the occasional diagnosis of endometrial cancer. Data supporting a survival advantage of endometrial cancer diagnosed prior to the onset of postmenopausal bleeding are lacking. OBJECTIVE: To compare the survival of asymptomatic and bleeding postmenopausal patients diagnosed with endometrial cancer. STUDY DESIGN: This was an Israeli Gynecology Oncology Group retrospective multicenter study of 1607 postmenopausal patients with endometrial cancer: 233 asymptomatic patients and 1374 presenting with postmenopausal bleeding. Clinical, pathological, and survival measures were compared. RESULTS: There was no significant difference between the asymptomatic and the postmenopausal bleeding groups in the proportion of patients in stage II-IV (23.5% vs 23.8%; P = .9) or in high-grade histology (41.0% vs 38.4%; P = .12). Among patients with stage-I tumors, asymptomatic patients had a greater proportion than postmenopausal bleeding patients of stage IA (82.1% vs 66.2%; P < .01) and a smaller proportion received adjuvant postoperative radiotherapy (30.5% vs 40.6%; P = .02). There was no difference between asymptomatic and postmenopausal bleeding patients in the 5-year recurrence-free survival (79.1% vs 79.4%; P = .85), disease-specific survival (83.2% vs 82.2%; P = .57), or overall survival (79.7% vs 76.8%; P = .37). CONCLUSION: Endometrial cancer diagnosed in asymptomatic postmenopausal women is not associated with higher survival rates. Operative hysteroscopy/curettage procedures in asymptomatic patients with ultrasonographically diagnosed endometrial polyps or thick endometrium are rarely indicated. It is reasonable to reserve these procedures for patients whose ultrasonographic findings demonstrate significant change over time.

High Efficacy and Low Toxicity of the Modified Docetaxel and Carboplatin Protocol in Patients with Recurrent Ovarian Cancer-A Phase 2 Cohort Study.

OBJECTIVE: Most patients with epithelial ovarian cancer will experience a recurrence; currently, there is no cure. In patients with platinum-sensitive disease (platinum-free interval >6 months), a combination similar to that used as frontline therapy (carboplatin and paclitaxel) is recommended. However, it is associated with a high incidence (20%) of neurotoxicity. This study evaluated the efficacy and toxicity of combination docetaxel/carboplatin therapy in patients with platinum-sensitive recurrent ovarian cancer. METHODS: Forty patients with recurrent, histologically proven ovarian, fallopian tube, or primary peritoneal cancer were enrolled in this phase 2 trial. The study protocol included combination therapy with docetaxel, 30 mg/m, on days 1 and 8, and carboplatin, area under the curve 5, on day 1, every 21 days. Twenty received the classical paclitaxel/carboplatin regimen (control group), and another 20 received the modified docetaxel/carboplatin protocol (study group). RESULTS: Median follow-up was 78 months for the study group and 62 months for the control group. The study group had a higher overall response rate compared to controls: 80% and 30%, respectively (P = 0.004; relative risk, 9.3; 95% confidence interval, 2.18-39.96). Complete response was achieved in 60% and 25%, respectively (P = 0.054). The study group patients showed a superior 2-year survival rate of 75% compared with the 35% of the controls (P = 0.011; relative risk, 5.57; 95% confidence interval, 1.47-21.56). Hematological and neurological toxicity rates did not differ between the groups (P = 0.451 and P = 0.605, respectively). CONCLUSIONS: Patients with recurrent ovarian cancer who received the modified docetaxel/carboplatin regimen had higher overall response and survival rates compared to those who had the paclitaxel/carboplatin regimen, with no difference in toxicity. Future larger studies should focus on strategies to compare this regimen to the current standard, with an emphasis on quality of life.

Sonographic appearance of uterine lymphoma: case report and review of the literature.

Uterine lymphoma is rare and tends to be misdiagnosed due to lack of specific radiologic features. Few reports have been published on the sonographic characteristics of uterine lymphoma. We present a case report of uterine lymphoma manifested by a fast growing uterus and describe the sonographic findings.

Integration of PET/CT into the preoperative evaluation of patients with early cervical cancer does not decrease the proportion of patients with positive lymph nodes found after surgery.

PURPOSE: The aim of this study was to evaluate whether preoperative positron emission tomography/computed tomography (PET/CT) in patients with early-stage cervical carcinoma reduced the proportion of patients with metastatic lymph nodes identified after surgery. PATIENTS AND METHODS: This is a multicenter case-control study of 599 patients with early cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy at 1 of 10 gynecological oncology units in Israel. The patients were divided into 2 groups according to whether or not they underwent a preoperative PET/CT. The primary outcome was the proportion of patients with nodal involvement. The 2 groups were compared with regard to the clinical and histological variables. RESULTS: Of the 599 patients who underwent surgery, 180 (36%) had preoperative PET/CT study. There were no significant differences between the PET/CT and control groups with regard to clinical and histological risk factors. The proportion of patients with involved nodes was similar in the control and PET/CT groups (20.8% vs 19%; P = 0.73) as well as the proportion of patients receiving adjuvant radiotherapy/chemoradiation (58.3% vs 55.1%; P = 0.55). CONCLUSIONS: Preoperative PET/CT in patients with early cervical cancer does not reduce proportion of patients with metastatic nodal involvement and the employment of multimodality treatment. Prospective clinical trials comparing management based on PET/CT findings are warranted.

The MISOPRED score: Development and validation of a clinical scoring system to predict the effectiveness of Misoprostol treatment for early pregnancy loss.

BACKGROUND: Misoprostol treatment for early pregnancy loss has varied success demonstrated in previous studies. Incorporating predictors in a single clinical scoring system would be highly beneficial in clinical practice. OBJECTIVE: To develop and evaluate the accuracy of a scoring system to predict misoprostol treatment outcomes for managing early pregnancy loss. STUDY DESIGN: Retrospective cohort and validation study. METHODS: Patients discharged from the gynecologic emergency department from 2013 to 2016, diagnosed with early pregnancy loss, who were treated with 800 mcg misoprostol, administrated vaginally were included. All were sonographically reevaluated within 48-72 hours. Patients in whom the gestational sac was not expelled or with endometrial lining >30 mm were offered a repeat dose and returned for reevaluation after seven days. A successful response was defined as complete expulsion. Clinical data were reviewed to identify predictors for successful responses. The scoring system was then retrospectively evaluated on a second cohort to evaluate its accuracy. Multivariate logistic regression was performed to identify factors most predictive of treatment response. RESULTS: The development cohort included 126 patients. Six factors were found to be most predictive of misoprostol treatment effectiveness: nulliparity, prior complete spontaneous abortion, gestational age, vaginal bleeding, abdominal pain, and mean sac diameter, yielding a score of 0-8 (the MISOPRED score), where 8 represents the highest-likelihood of success. The score was validated retrospectively with 119 participants. Successful response in the group with the lowest likelihood score (score 0-3) was 9%, compared with 82% in the highest likelihood score group (score 7-8). Using the MISOPRED score, approximately 15% of patients previously planned to receive misoprostol treatment can be referred for surgical management. CONCLUSIONS: MISOPRED score can be utilized as an adjunct tool for clinical decision-making in cases of Early pregnancy loss. To our knowledge, this is the first scoring system suggested to predict the success rate in these cases.

New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere.

INTRODUCTION: Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results. AREAS COVERED: This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies. EXPERT OPINION: EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.

Endometrial cancer (EC) is the only female cancer that is increasing among women. While the usual treatments work best when the disease is caught early, new advances in genetic studies have greatly improved the management of the disease. Four sub-types of EC have been identified. They are called: POLE-mutated, MMR-deficient, p53-abnormal, and no specific molecular profile. Treatments for EC can now be tailored more accurately to achieve better results. This review gives an overview of the most new and important evidence in the scientific literature about the molecular analysis of EC and how it can be used to help tailor the best treatments and surgeries for women with EC.

IGF1R inhibition and PD-1 blockade improve anti-tumor immune response in epithelial ovarian cancer.

Introduction: The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in epithelial ovarian cancer (EOC) and is considered a promising therapeutic target. EOC is an immunosuppressive disease, although there are limited data about the involvement of the IGF1R system in the anti-tumor immune response in the EOC microenvironment. Methods: In the current study, we hypothesized that IGF 1 receptor (IGF1R) involvement in the maturation of dendritic cells (DC) with the co-inhibition of IGF1R and PD-1 would affect the EOC microenvironment. Results: We found that DC pretreated with IGF1R inhibitor resulted in fewer EOC cells. Moreover, in vivo experiments conducted with an EOC mouse model, with anti-PD-1/IGF1R combined, resulted in lower tumor weight compared to individual treatments. Additionally, anti-PD-1/IGF1R treatment increased DC by 34% compared with AEW-541 and 40% with anti-PD-1. The combined treatment increased CD8+ T-cell levels compared to AEW-541 alone. RNA-seq data analysis indicated that anti-PD-1/IGF1R led to a more potent immune response, as reflected by altered gene expression levels related to anti-tumor immune response, compared with either treatment alone. Discussion: These findings provide novel evidence that IGF1R axis inhibition combined with PD-1 blockade may be an effective therapeutic strategy for selected EOC patient populations.

Assessment of oncological safety and utility of hysteroscopy in high grade endometrial cancers: Results from an Israel gynecologic oncology group study.

OBJECTIVE: To compare survival measures of women with Stage I high-grade endometrial cancer who underwent either hysteroscopy or a non-hysteroscopic procedure as a diagnostic procedure. STUDY DESIGN: 298 patients with stage I high grade endometrial cancer who underwent surgery between 2002 and 2014. Patients were divided into two groups: hysteroscopy and non-hysteroscopy (curettage or office endometrial biopsy). Clinical, pathological, and survival measures were compared between the groups. High grade histology included endometroid grade -3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma. RESULTS: There were 71 patients in the hysteroscopy group and 227 patients in the non-hysteroscopy group. The median follow-up was 52 months (range 12-120 months). There were no differences between the groups in the 5-year recurrence-free survival (73.9 % vs. 79.7 %; p = 0.65), disease-specific survival (79.3 % vs. 83.6 %; p = 0.87), and overall survival (65.7 % vs. 80.3 %; p = 0.35). CONCLUSION: Hysteroscopic diagnosis in women with early-stage and high-grade endometrial cancer does not adversely affect the survival outcomes.

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial.

PURPOSE: To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS: The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS: Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION: Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Weekly topotecan for recurrent ovarian, fallopian tube and primary peritoneal carcinoma: tolerability and efficacy study--the Israeli experience.

OBJECTIVES: The purpose of this study was to assess the clinical activity and toxicity of weekly topotecan in a large cohort of epithelial ovarian (EOC), primary peritoneal (PPC), and tubal cancer patients. METHODS: Records of patients with recurrent EOC, PPC, and tubal cancer who were treated with weekly topotecan (4.0 mg/m on days 1, 8, and 15 on a 28-day cycle) after failure of more than 1 prior regimen were retrospectively reviewed in 8 centers in Israel. RESULTS: Two hundred four patients were evaluated for efficacy and toxicity. Median age was 62 years (range, 27-89 years); 121 (59.3%) were platinum sensitive. Patients were exposed to a median of 2 previous lines (range, 1-9), and 48.5% received only 1 prior chemotherapy regimen. Median follow-up was 15.5 months (range, 2.5-112 months). Overall response rate was 26.5%, of which 11 patients (5.4%) had complete response, and 43 patients (21.1%) had partial response. Clinical benefit rate (complete response + partial response + stable disease) was 65.7%. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.5-4.5 months). There was no significant difference between platinum-sensitive and platinum-resistant patients regarding response rate or progression-free survival. Median overall survival from disease diagnosis was 45.0 months (95% CI, 40.04-49.6 months) and 16.0 months (95% CI, 12.3-19.7 months) from initiation of topotecan therapy. Overall survival was significantly different between patients with platinum-sensitive and platinum-resistant disease (19.9 vs. 10.8 months, respectively, P = 0.003; 95% CI, 8.1-16.3 months). Multivariate analysis showed that only platinum sensitivity and topotecan line were associated with overall survival. Weekly topotecan was well tolerated-with only 16.7% of patients experiencing grade 3 to 4 hematologic toxicities. There were no other grade 4 toxicities, and only 6.9% grade 3 toxicities. CONCLUSIONS: In this large cohort of recurrent EOC, PPC, and tubal cancer, weekly topotecan was well tolerated with good clinical benefit rate, comparable to previous studies.

Preoperative clinical and radiological features of metastatic ovarian tumors.

PURPOSE: To investigate the clinical characteristics and pre-operative imaging features of non-genital metastatic ovarian tumors. METHODS: A retrospective case series study that compared 18 patients with histologically confirmed non-genital metastatic ovarian tumors (the study group) with 25 patients who were diagnosed with a primary ovarian cancer (control group). RESULTS: The most common primary disease was breast cancer (n = 10; 55 %), followed by colon cancer, gastric cancer, lymphoma, and unknown primary malignancy. The diagnosis of the previous primary neoplasm preceded the ovarian tumor diagnosis by 1-20 years (mean 7 years). No differences were found in the presenting signs and symptoms between the two groups. Statistically significant differences were noted between the two groups in the composition of the adnexal mass on sonography (p < 0.0005) and the CA-125 levels (p = 0.007). The presence of a complex adnexal mass with papillary projections and CA-125 >170 U/ml predicted primary ovarian cancer in 95.7 % of patients. Pre-operative CT scan revealed a greater tendency toward omental involvement and ascites in the control group (p = 0.058). The median risk of malignancy index (RMI) 2 score was significantly higher in the control group compared to the study group (8,000 and 1,120 respectively, p = 0.001). Using a RMI 2 cut-off level of 3,800 for diagnosing primary ovarian cancer versus metastatic ovarian cancer, the sensitivity was 70 %, with a positive predictive value of 87.5 %. CONCLUSION: Pre-operative sonography findings, CA-125 levels and RMI 2 scores can be highly accurate in differentiating between primary and metastatic ovarian tumors.

IGF-1 and BRCA1 signalling pathways in familial cancer.

The insulin-like growth factor (IGF) system has a direct effect on cellular proliferation and survival, and interacts with genetic and environmental factors implicated in causing cancer. Experimental, clinical, and epidemiological evidence show that the IGF signalling pathways are important mediators in the biochemical and molecular chain of events that lead from a phenotypically normal cell to one harbouring neoplastic traits. BRCA1 and BRCA2 have an important role in the development of hereditary and sporadic breast and ovarian cancer. Recent evidence suggests that risk of cancer conferred by BRCA mutations can be modified by genetic and environmental factors, including ambient concentrations of IGF-1 and polymorphisms in IGF system components. This Review addresses interactions between the IGF and BRCA1 signalling pathways, and emphasises the convergence of IGF-1-mediated cell survival, proliferative pathways, and BRCA1-mediated tumour protective pathways. Understanding the complex interactions between these signalling pathways might improve our understanding of basic molecular oncology processes and help to identify new molecular targets, predictive biomarkers, and approaches for optimising cancer therapies.