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Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

ObjectiveTo evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer.MethodsPatients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3-6 and as maintenance monotherapy in cycles 7-34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival.ResultsAn interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual.ConclusionsThe addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.

Data from colon, breast and prostate cancers suggest that aspirin users have reduced mortality. While the direct mechanism remains uncertain, aspirin can suppress the COX-dependent and independent pathways involved in tumor progression. We hypothesized that aspirin users with clear cell ovarian cancer would have improved survival outcomes. We performed a retrospective review of patients with clear cell ovarian cancer diagnosed between 1995 and 2010, and followed outcomes through 2016. Patients underwent primary cytoreductive surgery followed by platinum-based chemotherapy. Aspirin use was defined by medication documentation in two records more than six months apart. Statistical tests included Fisher's exact, Kaplan-Meier and Cox regression analyses. Seventy-seven patients met inclusion criteria. Fifty-four patients (70%) had stage I-II disease. Thirteen patients (17%) used aspirin. Aspirin users had a statistically longer disease-free survival compared to non-users (HR 0.13, p = .018). While median disease-free survival was not reached for either group, 1 of 13 (8%) aspirin users recurred at 24 months, compared to 18 of 64 (28%) non-users. Aspirin users demonstrated longer overall survival (HR 0.13, p = .015). Median survival was not reached for aspirin users, compared to 166 months for non-users. Aspirin use retained significance (HR 0.13, p = .044) after controlling for age, stage and cytoreductive status. In this small cohort of women with clear cell ovarian cancer, aspirin use correlated with improved disease-free and overall survival, and retained independent significance as a positive prognostic factor. Further research is warranted to confirm these findings before considering aspirin as a therapeutic intervention.

ObjectiveOvarian clear cell carcinoma (OCCC) and high grade serous ovarian cancer (HGSOC) are associated with the highest risk of VTE among patients with epithelial ovarian cancer (EOC). Tissue factor (TF) is a transmembrane glycoprotein which can trigger thrombosis. We sought to evaluate if there is an association between VTE and tumor expression of tissue factor (TF), plasma TF, and microvesicle TF (MV TF) activity in this high-risk population.MethodsWe performed a case-control study of OCCC and HGSOC patients with and without VTE. 105 patients who underwent surgery at a tertiary care center between January 1995 and October 2013 were included. Plasma TF was measured with an enzyme-linked immunosorbent assay. A TF-dependent Factor Xa generation assay was used to measure MV TF activity. Immunohistochemical (IHC) analysis was performed to evaluate tumor expression of TF.Results35 women with OCCC or HGSOC diagnosed with VTE within 9months of surgery were included in the case group. Those with VTE had a worse OS, p

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

ObjectiveTo report the frequency and features of occult carcinomas and the incidence of subsequent cancers following risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers.Methods257 consecutive women with germline BRCA mutations who underwent RRSO between January 1, 2000 and December 31, 2014 were identified in an Institutional Review Board approved study. All patients were asymptomatic with normal physical exams, CA 125 values, and imaging studies preoperatively, and had at least 12months of follow-up post-RRSO. All patients had comprehensive adnexal sectioning performed. Patient demographics and clinico-pathologic characteristics were extracted from medical and pathology records.ResultsThe cohort included 148 BRCA1, 98 BRCA2, 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 mutation carriers. Occult carcinoma was seen in 14/257 (5.4%) of patients: 9 serous tubal intraepithelial carcinomas (STIC), 3 tubal cancers, 1 ovarian cancer, and 1 endometrial cancer. Three patients (1.2%) with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and 2 of 9 patients (22%) with STIC subsequently developed pelvic serous carcinoma. 110 women (43%) were diagnosed with breast cancer prior to RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer following RRSO. Median follow-up of the cohort was 63months.ConclusionIn this cohort, 5.4% of asymptomatic BRCA mutation carriers had occult carcinomas at RRSO, 86% of which were tubal in origin. The risk of subsequent PPSC for women with benign adnexa at RRSO is low; however, the risk of pelvic serous carcinoma among women with STIC is significantly higher.

ObjectiveHigh-grade vaginal intraepithelial neoplasia (VAIN) II-III has a variable clinical course. Due to the rarity of VAIN, existing data on the efficacy of treatment, risk of recurrence and progression to carcinoma is limited. Our objective was to evaluate predictors of recurrent disease and describe the risk of progression to carcinoma.MethodsUnder an IRB-approved protocol 42 patients with biopsy-proven VAIN II-III from 1995 to 2015 were retrospectively identified. Demographics, treatment, and clinical course were abstracted from medical records. Patients were followed with semi-annual colposcopy and biopsies at physician discretion. Standard statistical analyses were applied.ResultsMedian patient age was 58years old (range 20-81). Median follow-up time was 45months (range 9-195). Management included excision (31%), laser ablation (33%), topical agents (19%), and observation (10%), with the following rates of recurrence: 38%, 43%, 75%, and 50% (p=0.26). 20 patients (48%) had recurrent or persistent disease during treatment follow-up. No specific primary treatment was significantly more effective in preventing recurrence. Recurrence of VAIN II-III occurred at a median of 17.4months (7-78months) from time of initial diagnosis. Five (12%) patients developed invasive cancer of the lower genital tract. Median time to cancer diagnosis was 64months (30 to 101months).ConclusionsPatients with VAIN II-III are at high risk of recurrence and progression, suggesting the need for ongoing evaluation with cytology and comprehensive colposcopy by a skilled specialist. There were no clear risk factors or histopathologic criteria which predicted recurrence or progression to cancer.

Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-β-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-β signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.

ObjectiveThis study describes the patterns of end of life (EOL) discussions and their impact on the use of aggressive measures in women with terminal gynecologic malignancies at a single institution.MethodsAn IRB-approved retrospective chart review identified 136 patients who died of gynecologic cancer between 2010 and 2012 with at least one interaction with their oncologists in the last 6 months of life. Aggressive measures were defined as chemotherapy within the last 14 days of life, emergency department (ED) visits, hospital and intensive care unit (ICU) admissions within the last 30 days of life, and inpatient deaths. The frequency and timing of EOL conversations were recorded. Utilization of hospice care was also described.ResultsIn the last 30 days of life, 54 (40%) patients were evaluated in the ED, 67 (49%) were admitted into hospital, and 16 (12%) were admitted to the ICU. Thirteen patients (10%) had chemotherapy in the last 14 days of life. Ninety-seven (71%) patients had a documented EOL conversation, eighteen (19%) as outpatients, and 79 (81%) as inpatients. Thirty (22%) patients died in the hospital. At the time of death, 55 (40%) patients were enrolled in outpatient hospice care. The mean amount of time in hospice was 28 days.ConclusionsEnd of life care discussions rarely occurred in the outpatient setting or >30 days before death. Inpatient encounters led to discussions about hospice and code status. Evaluation in the ED frequently resulted in escalation of care. Earlier EOL care discussions resulted in less aggressive measures.

The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane-based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current 'one size fits all' approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of argininosuccinate synthetase previously observed in ovarian cancers, these tumours have been considered unlikely candidates for arginine depletion therapy. However, argininosuccinate synthetase levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of argininosuccinate synthetase at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high-grade and low-grade serous ovarian carcinomas express high levels of argininosuccinate synthetase, which tend to further increase in recurrent tumours. In contrast to the serous subtype, non-serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable argininosuccinate synthetase expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with pegylated arginine deiminase was inversely correlated with argininosuccinate synthetase expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non-serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with pegylated arginine deiminase.

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

ObjectivesA growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease.MethodsUnder an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan-Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 10(9)/L and optimal resection at SCS as microscopic residual disease.ResultsThirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p=0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p=0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p=0.025) after controlling for age at SCS (p=0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66).ConclusionsElevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology.

ObjectiveThere are few studies analyzing surveillance for Type II endometrial cancer recurrence. Our objective was to determine the types of post treatment surveillance tests performed in our institution and the efficacy of these tests in detecting recurrence in type II endometrial cancer patients.MethodsOne hundred and thirty six cases of type II endometrial cancers at Cedars-Sinai Medical Center from January of 2000 to August of 2011 were identified and 106 patients met inclusion criteria. Medical charts were reviewed for surveillance methods and number of follow up visits. For patients who underwent a recurrence of disease, the surveillance method utilized for detection was documented.ResultsForty-seven of the 106 (44%) patients developed recurrence with a mean progression free interval of 11 months. All patients had a history and physical at each surveillance visit, 78% had Pap testing, 57% had CA-125 levels drawn, 59% had CT (computed tomography) scans done, 6% had PET (positron emission tomography) scans done for surveillance. In our cohort, recurrence was detected by symptoms in 16, by CA-125 in 11, by physical exam in 7, by CT scan in 12, and by PET scan in one patient. No patients had recurrence detected by vaginal cytology.ConclusionsAlthough performed in the majority of patients, Pap testing did not detect any recurrences within this cohort. History and physical exam detected the most recurrences. These findings suggest that educating patients about relevant symptoms and performing thorough follow-up exams may be the most important aspects of detecting type II endometrial cancer recurrence.

ObjectivesTo determine the impact of venous thromboembolism (VTE) during primary treatment of ovarian clear cell carcinoma (OCCC) on survival.MethodsAfter Institutional Review Board approval, 74 cases of OCCC were retrieved from our pathology files. Clinical and pathological data were obtained by medical record and pathology review. Standard statistical analyses were performed.ResultsAmong 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary treatment and 7 (9%) at time of cancer recurrence. 56 (76%) patients never developed VTE. Patients with VTE during OCCC primary treatment had shorter progression-free survival (PFS) and overall survival (OS) than OCCC patients without VTE (median PFS 11 vs. 76 months, p=0.01, median OS 19 vs. 90 months, p=0.001). Patients with VTE during OCCC primary treatment had a 3.9-fold increase in risk of recurrence (p=0.007) and a 6.3-fold increase in risk of death (p

Abstract: Objectives. : MDM2 is an important negative regulator of the p53 tumor suppressor protein. A naturally occurring T/G single nucleotide polymorphism (SNP) in the MDM2 gene promoter, SNP309, causes an increase in MDM2 protein levels and impairment of p53 tumor suppressor activity. SNP309 occurs at a relatively high frequency in the general population and has been associated with accelerated tumorigenesis in hereditary Li-Fraumeni associated cancers as well as in sporadic soft tissue sarcomas. The objective of this study was to examine the association between SNP309 and sporadic endometrial cancer risk. Methods. : Genomic DNA was isolated from 73 patients with endometrial cancer and 79 healthy, female controls. The MDM2 gene promoter region was amplified by PCR and the SNP309 genotype determined by restriction enzyme digestion of the amplified DNA fragment. Unconditional logistic regression analysis was used to determine the relationship between genotypes and endometrial cancer risk and histopathologic features. Results. : The homozygous G/G genotype was found in 25% of endometrial cancer cases and 11% of controls. In an age-adjusted analysis of cases and controls, the G/G genotype increased the risk of endometrial cancer 2.76-fold (95% CI: 1.06, 7.20; p =0.03) compared to presence of a wild-type T allele (T/G and T/T genotypes). No association was found between the SNP309 G/G genotype and either endometrial cancer histology, grade, stage, or age at diagnosis. Conclusions. : The MDM2 SNP309 homozygous G/G genotype may be a genetic variant that influences sporadic endometrial cancer susceptibility. [Copyright &y& Elsevier]

Abstract: Objectives: We have shown that preoperative thrombocytosis (platelet counts >400×109/l) is an independent poor prognostic factor in epithelial ovarian cancers (EOC) and is associated with worse survival. In light of the similarities between uterine papillary serous carcinomas (UPSC) and EOC, we sought to determine the incidence of thrombocytosis in UPSC and examine associations with clinico-pathologic features and survival. Methods: 68 patients with UPSC were identified between 1996 and 2004 at 3 institutions. After IRB approval, records were retrospectively reviewed and data analyzed using Chi-squared and Cox proportional hazards model; survival was analyzed by the method of Kaplan and Meier. Results: 8/68 (12%) patients had thrombocytosis at primary diagnosis. Patients with thrombocytosis were found to have more advanced stage disease (p =0.002) and ascites >1 L (p <0.0001). Of the 21 patients with stage IV disease, those with normal preoperative platelet counts demonstrated a greater likelihood of optimal tumor resection to less than 1 cm residual disease (13/15 versus 1/6 in patients with thrombocytosis, p <0.002). Patients with thrombocytosis had a shorter disease-free interval (17 months versus median survival not yet reached, p =0.0067) and overall survival (24 versus 45 months, p =0.0026). On multivariate analysis, thrombocytosis retained significance as a poor prognostic indicator in patients after controlling for age and stage (p =0.04). Conclusions: Thrombocytosis may be a marker of aggressive tumor biology in UPSC. Platelet-secreted growth factors may promote aggressive cancer phenotype through contribution to metastasis, invasion, and primary tumor growth. [Copyright &y& Elsevier]

Abstract: Objectives: Cervical adenocarcinoma in situ (AIS) is a precursor of invasive disease that is increasing in incidence primarily among reproductive-age women of low parity. Conization is an alternative to hysterectomy that allows future pregnancy, but has an inherent risk of residual AIS. The purpose of this study was to determine the outcomes of patients treated by this fertility-sparing strategy over an extended period of surveillance. Methods: Women diagnosed with cervical AIS who underwent primary fertility-sparing surgery with either loop excision or cold knife conization between 1993 and 2001 were identified at three institutions. A retrospective medical record review was performed. Patients 40 years of age and older and those undergoing hysterectomy within 12 months of diagnosis were excluded. Results: A total of 101 women underwent cone biopsy and expectant management. The median age was 29 years. Fifty-seven percent were nulliparous and 23% primiparous. Cold knife conization was most commonly performed (69 vs. 32 procedures) and had a higher efficacy of achieving negative margins (72% vs. 47%; P =0.036). Thirty-five women had a total of 49 pregnancies during a mean follow-up of 51 months. Thirty-five gestations were delivered at term. There were two preterm births, eight spontaneous miscarriages, three elective terminations, and one ectopic pregnancy. Thirty-six patients had a repeat cone biopsy. Five ultimately underwent hysterectomy. No invasive cervical adenocarcinomas were observed during the study interval. Conclusion: Fertility-sparing surgery enables women with cervical AIS to achieve pregnancy with minimal risk of developing invasive disease during surveillance. [Copyright &y& Elsevier]