Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis.

BACKGROUND: Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. METHODS: We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. RESULTS: IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00-1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07-1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. CONCLUSIONS: Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. IMPACT: Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Efficacy and Safety of the Anti-PD-L1 mAb Socazolimab for Recurrent or Metastatic Cervical Cancer: a Phase I Dose-Escalation and Expansion Study.

PURPOSE: This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti-programmed death ligand 1 (PD-L1) mAb socazolimab in patients diagnosed with recurrent or metastatic cervical cancer. PATIENTS AND METHODS: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5 mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). RESULTS: 104 patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5 mg/kg treatment group. Ninety-two patients (5 mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1-positive tumor expression (combined positive score ≥1). ORR was 15.4% [95% confidence interval (CI), 8.7%-24.5%]. Median PFS was 4.44 months (95% CI, 2.37-5.75 months), and the median OS was 14.72 months (95% CI, 9.59-NE months). ORR of PD-L1-positive patients was 16.7%, and the ORR of PD-L1-negative patients was 17.9%. No treatment-related deaths occurred. CONCLUSIONS: Our study demonstrates that socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti-PD-1/PD-L1 mAbs.

WDR5 drives the development of cervical squamous cell carcinoma by inducing epithelial-mesenchymal transition and cancer-associated fibroblasts formation.

BACKGROUND: WD repeat domain 5 (WDR5) has been indicated to be involved in tumor progression, however, its role in cervical cancer (CC) has not been investigated yet. METHODS: A total of 350 pairs of CC tissues and para-carcinoma tissues (PCT) were collected. Primary human cervical epithelial cells (hCECs) and cancer-associated fibroblasts (CAFs) were isolated from cervical cancer tissues. MM102 was used to block the interaction between WDR5 and mixed lineage leukemia protein-1 (MLL1), and it was used in vivo to investigate its therapeutic value. RESULTS: WDR5 was up-regulated in cervical squamous cell carcinoma (CSCC) tissues compared to that in PCT. C-X-C motif chemokine ligand 8 (CXCL8) was indicated to be the target gene of WDR5. Highly expressed CXCL8 promoted epithelial-mesenchymal transition (EMT) to form CAFs, and enhanced the cytokine secretions in CAFs to promote CSCC progression. CXCL8 expression was regulated by the interaction between WDR5 and MLL1, and blocking the interaction between these two proteins using MM102 significantly suppressed tumor growth in mice models. CONCLUSIONS: WDR5 plays a key role in CSCC progression by inducing CXCL8 expression and promoting the transformation of CAFs from epithelial cells.

Germline BRCA variants, lifestyle and ovarian cancer survival.

OBJECTIVE: Women with ovarian cancer who have a pathogenic germline variant in BRCA1 or BRCA2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA-wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. METHODS: We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20-3.27) than non-carriers (HR 1.18; 95% CI 0.96-1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28-2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90-1.29) for non-carriers. CONCLUSIONS: Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers.

A Multi-Institutional Retrospective Analysis of Oncologic Outcomes for Patients With Locally Advanced Cervical Cancer Undergoing Platinum-Based Adjuvant Chemotherapy After Concurrent Chemoradiotherapy.

OBJECTIVE: To evaluated the oncologic outcomes associated with platinum-based adjuvant chemotherapy following concurrent chemoradiotherapy (CCRT) in the management of patients with locally advanced cervical cancer (LACC). METHODS: A total of 695 patients with FIGO stage IB2, IIA2, IIB-IVA LACC treated at 6 medical facilities were enrolled and divided into 2 groups: 478 were assigned to CCRT alone (CCRT group) and 217 to adjuvant chemotherapy after CCRT (CCRT-ACT group). The treatment outcomes were retrospectively compared and reported after the propensity score matching (PSM) analysis. RESULTS: With a median follow-up of 56.4 months, no statistically significant differences were found in overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and distance metastasis-free survival (DMFS) between 2 groups. In CCRT-ACT group, patients with lymph nodes involvement or squamous cell carcinoma (SCC) had significantly longer DMFS, but no significant benefit in survival outcomes were observed with more than 2 cycles of adjuvant chemotherapy. Moreover, patients with a high level of CA125 (>20.5U/mL) or SCC-Ag (>22.8µg/L) had a relatively better DFS or PFS, and grade 3-4 acute hematological toxicity, late urinary and lower gastrointestinal complications and diarrhea symptom were more frequent in CCRT-ACT group. CONCLUSIONS: Adjuvant chemotherapy after CCRT has a potential role in further improving disease control for LACC patients with lymph nodal-metastasis or SCC with a high level of CA125 or SCC-Ag. Due to increased treatment-related complications and diarrhea symptom affecting the quality of life, post-CCRT adjuvant chemotherapy with excessive cycles was not be considered as the most appropriate choice in general.

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

DGUOK-AS1 promotes cell proliferation in cervical cancer via acting as a ceRNA of miR-653-5p.

Cervical cancer (CC) holds the second highest incidence and is the fourth dominating cause of cancer-induced death in women. It has been widely accepted that long noncoding RNAs (lncRNAs) are implicated in pathological and physiological activities of CC. However, the research of lncRNAs is still in the initial stage. The biological function of lncRNA deoxyguanosine kinase antisense RNA 1 (DGUOK-AS1) in human cancers has not been reported yet. We found that DGUOK-AS1 was aberrantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues through TCGA database. Real-time quantitative polymerase chain reaction (RT-qPCR) also verified the high expression of DGUOK-AS1 in CC cell lines. Loss-of-function assays indicated that DGUOK-AS1 silence repressed CC cell growth. In addition, dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments validated the binding relation between miR-653-5p and DGUOK-AS1 or EMSY. Results of the rescue assays elucidated that EMSY overexpression or miR-653-5p downregulation reversed the suppressive function of DGUOK-AS1 knockdown on cell growth and DNA repair in CC. To sum up, this research highlighted that DGUOK-AS1 could promote CC cell proliferation via serving as a ceRNA of miR-653-5p to release EMSY, which might inspire us to discover novel strategies for CC treatment. SIGNIFICANCE OF THE STUDY: DGUOK-AS1 knockdown hinders proliferation of CC cells. DGUOK-AS1 sequesters miR-653-5p to elevate EMSY in CC. EMSY is required for DGUOK-AS1 to induce cell proliferation and repress DNA damage in CC.

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

BACKGROUND: There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. METHODS: We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. RESULTS: The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). CONCLUSION: This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies.

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.

Significant Efficacy of Additional Concurrent Chemotherapy with Radiotherapy for Postoperative Cervical Cancer with Risk Factors: a Systematic Review and Meta-analysis.

BACKGROUND: Whether concurrent chemotherapy treatment is superior to radiotherapy alone as an adjuvant regimen for postoperative cervical carcinoma with risk factors remains controversial. MATERIALS AND METHODS: A literature search strategy was used to examine Pubmed, Embase, the Cochrane Library, the China National Knowledge Internet Web, the Chinese Biomedical Database and the Wanfang Database. Article reference lists and scientific meeting abstracts were also screened. Controlled trials comparing concurrent chemoradiotherapy versus radiotherapy alone in postoperative cervical cancer were included. The methodological quality of non-randomized controlled trials was evaluated using the Newcastle-Ottawa Scale. Randomized controlled studies were evaluated with the Cochrane handbook. A meta-analysis was performed with RevMan 5.3. RESULTS: A total of 1,073 patients from 11 clinical trials were analysed, with 582 patients in the concurrent chemoradiotherapy group and 491 patients in the radiotherapy group. Hazard ratios (HR) of 0.47 (95% CI 0.31-0.72) and 0.50 (95% CI 0.35-0.72) were observed for overall survival and progression-free survival, indicating a benefit from the additional use of concurrent chemotherapy. Subgroup analyses demonstrated that cervical cancer with high risk factors significantly benefitted from concurrent chemotherapy when examining overall survival (HR 0.44, 95% CI 0.28-0.67) and progression-free survival (HR 0.48, 95% CI 0.33-0.70), but patients with intermediate risk factors showed no benefit from concurrent chemotherapy in overall survival (HR 1.72, 95% CI 0.28-10.41) and progression-free survival (HR 1.09, 95% CI 0.19-6.14). No significant differences were observed for grade 3-4 anaemia (risk ratio (RR) 3.87, 95% CI 0.69-21.84), grade 3-4 thrombocytopenia (RR 3.04, 95% CI 0.88- 10.58), grade 3-4 vomiting or nausea (RR 1.71, 95% CI 0.27-10.96), or grade 3-4 diarrhoea (RR 1.40, 95% CI 0.69-2.83). Significant differences were observed for grade 3-4 neutropenia in favour of the radiotherapy group (RR 7.23, 95% CI 3.94-13.26). CONCLUSIONS: Concurrent chemoradiotherapy improves survival in postoperative cervical cancer cases with high risk factors but not in those with intermediate risk factors.

Effects of estradiol on VEGF and bFGF by Akt in endometrial cancer cells are mediated through the NF-κB pathway.

Endometrial carcinogenesis may be related to the long-term effects of estradiol with no antagonism. However, how estradiol regulates cell proliferation is unknown. In the present study, through investigating the molecular events involved in estradiol induced angiogenics factors VEGF and bFGF, we found that estradiol induced endometrial cancer cell division, proliferation, migratory and invasive capacity in vitro and upregulated mRNA expression and protein synthesis of VEGF and bFGF. The estradiol-dependent induction of the expression of VEGF and bFGF was blocked by ER inhibitor, AKT inhibitor and NF-κB inhibitor (PDTC) in estrogen receptor positive Ishikawa cells and blocked by AKT inhibitor, NF-κB inhibitor (PDTC) in estrogen receptor negative HEC-1A cells. Moreover, estradiol activation of AKT was also blocked by AKT antagonist. NF-κB activation was restricted by estradiol concentration and time. Estradiol leading to VEGF and bFGF induction was also confirmed by the development of xenograft tumors in vivo. Taken together, our data suggest that estradiol induces the production of angiogenic factors via a mechanism involving AKT-mediated NF-κB activation partly in non-genomic manner without the estrogen receptor.

Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.

BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. METHODS: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. RESULTS: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)). CONCLUSIONS: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. IMPACT: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.

The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies.

PURPOSE: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS: Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.

PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations.

Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

BACKGROUND: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). METHODS: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). RESULTS: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). CONCLUSIONS: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. IMPACT: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.