Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Prediction of lymphatic dissemination in endometrioid endometrial cancer: Comparison of three risk-stratification models in a single-institution cohort.

OBJECTIVES: To compare the performance characteristics of 3 risk-stratification models, referred to as Mayo, Helsinki and Milwaukee models, in predicting lymphatic dissemination in endometrial cancer. METHODS: A total of 1052 patients with stage I-III endometrioid endometrial cancer were included in the study. The areas under curve were compared with the receiver operating characteristic curve area comparison test. Chi-square and Fisher exact test were used for comparing categorical variables. The Kaplan-Meier method and multivariable Cox regression models were used for survival analyses. The median follow-up time was 55months (range 1-108). RESULTS: Areas under curve were 0.781, 0.830 and 0.829 for the Mayo, Helsinki (P=0.285 vs. Mayo) and Milwaukee (P=0.292 vs. Mayo) models, respectively, in predicting lymphatic dissemination. The rates of false negatives and false positives were similar for all models. The lymphadenectomy rate decreased in the order of Mayo model (71.5%)>Helsinki model (62.4%)>Milwaukee model (48.8%). In patients with stage I cancer, disease specific survival was better for those who satisfied low-risk criteria according to any of the models. In patients with stage II-III cancer, this difference in survival was significant only for the Milwaukee model. Both lymphatic dissemination and high-risk tumor features as per the risk models were independent predictors of survival. CONCLUSIONS: The studied models had a similar accuracy in predicting lymphatic dissemination in endometrial cancer. Lymphadenectomy rate was lowest for the Milwaukee model. Survival analyses suggest that variables included in the models predict patient outcome independently of tumor stage.

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells.

OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. RESULTS: Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.

Prediction of Site-Specific Tumor Relapses in Patients With Stage I-II Endometrioid Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate the association of predictors of an advanced disease and/or poor outcome with the occurrence of tumor relapses in different anatomical sites in patients with stage I-II endometrioid endometrial cancer. METHODS: A total of 929 patients were included in the study. The median follow-up time was 57 months (range, 1-108 months). The studied variables were: poor tumor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, lymphovascular space invasion, cervical stromal invasion, positive peritoneal cytology, old age (>77 years), obesity (body mass index ≥30 kg/m), and diabetes. RESULTS: A relapse was diagnosed in 98 patients (10.5%) (vaginal in 15, pelvic in 27, intra-abdominal beyond the pelvis in 27, extra-abdominal in 29). None of the variables were associated with an altered risk of vaginal or pelvic relapses in univariate analyses. Poor differentiation, myometrial invasion 50% or greater, tumor size 3 cm or greater, and positive peritoneal cytology were associated with an increased risk of intra-abdominal relapses beyond the pelvis (odds ratios [ORs] between 2.2 and 9.6). With the exception of obesity and diabetes, all variables were associated with an increased risk of extra-abdominal relapses (ORs between 2.3 and 13). Tumor size 3 cm or greater (OR, 3.1) and positive peritoneal cytology (OR, 16) predicted intra-abdominal relapses beyond the pelvis in multivariate analysis, whereas poor differentiation (OR, 2.9), myometrial invasion 50% or greater (OR, 4.0), and positive peritoneal cytology (OR, 27) predicted extra-abdominal relapses. Compared with vaginal relapses, intra-abdominal relapses beyond the pelvis and extra-abdominal relapses were associated with a worse disease-specific survival. Survival of patients with a pelvic relapse did not differ from that of patients with a vaginal relapse. CONCLUSIONS: Risk variables of endometrial cancer are differently associated with relapses in different locations. Our findings may promote studies that explore the most efficient adjuvant therapy in high-risk early-stage endometrioid endometrial cancer.

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.

Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors.

OBJECTIVE: Adult-type ovarian granulosa cell tumors (AGCTs) have an unpredictable tendency to relapse. In a carefully validated patient cohort, we evaluated the prognostic factors related to AGCT recurrence. METHODS: We identified all patients diagnosed with AGCT during 1956-2014 in Helsinki University Hospital, with a minimum follow-up of one year (n=240). After a histological review supplemented with FOXL2 (402C-G) mutation status analysis, we analyzed the clinical data for association with relapse. RESULTS: The final cohort included 164 (68%) molecularly defined AGCTs (MD-AGCTs). The majority of the women were postmenopausal (63%), and 92% of tumors were stage I. The median follow-up time was 15.5years. Fifty-two (32%) patients developed tumor recurrence, of whom 55% had successive recurrences. Multiple-site recurrences were common, and nearly half of the recurrences were asymptomatic. The median time to the first relapse was 7.4years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3years. Premenopausal status at initial diagnosis, FIGO stage Ic versus Ia, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGCT in a median time of 15.3years. CONCLUSION: Tumor rupture is the strongest predictive factor for recurrence, and these patients might benefit from a more aggressive initial treatment approach. AGCT requires active follow up for 10 to 15years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations.

Incidence of and risk factors for surgical site infections in women undergoing hysterectomy for endometrial carcinoma.

INTRODUCTION: The purpose of this study was to determine the incidence of, and risk factors for, surgical site infections in a contemporary cohort of women with endometrial carcinoma. MATERIAL AND METHODS: We retrospectively studied 1164 women treated for endometrial carcinoma by hysterectomy at a single institution in 2007-2013. In all, 912 women (78.4%) had minimally invasive hysterectomy. Data on surgical site infections were collected from medical records. Univariate and multivariate analyses were used to identify risk factors for incisional and organ/space infections. RESULTS: Ninety-four women (8.1%) were diagnosed with a surgical site infection. Twenty women (1.7%) had an incisional infection and 74 (6.4%) had an organ/space infection. The associations of 17 clinico-pathologic and surgical variables were tested by univariate analyses. Those variables that were identified as potential risk factors in univariate analyses (p < 0.15) were used in logistic regression models with incisional and organ/space infections as dependent variables. Obesity (body mass index ≥ 30 kg/m(2)), diabetes, and long operative time (>80th centile) were independently associated with a higher risk of incisional infection, whereas minimally invasive surgery was associated with a smaller risk. Smoking, conversion to laparotomy, and lymphadenectomy were associated with a higher risk of organ/space infection. CONCLUSIONS: Organ/space infections comprised the majority of surgical site infections. Risk factors for incisional and organ/space infections differed. Minimally invasive hysterectomy was associated with a smaller risk of incisional infections but not of organ/space infections.

The clinical utility of serum anti-Müllerian hormone in the follow-up of ovarian adult-type granulosa cell tumors--A comparative study with inhibin B.

Ovarian adult-type granulosa cell tumors (AGCTs) require prolonged follow-up, but evidence regarding the optimal follow-up marker is lacking. The objective of our study was to validate the clinical usefulness of serum anti-Müllerian hormone (AMH) and the current marker inhibin B as single and combined markers of AGCTs. We conducted a longitudinal, partially prospective cohort study of 123 premenopausal and postmenopausal AGCT patients with a median follow-up time of 10.5 years (range 0.3-50.0 years). Serum AMH and inhibin B levels were measured from 560 pretreatment and follow-up serum samples by using immunoenzymometric assays. We found that serum AMH and inhibin B levels were significantly elevated in patients with primary or recurrent AGCTs. The levels of both markers positively correlated to tumor size (p < 0.05). AMH and inhibin B performed similarly in receiving operator characteristic analyses; area under the curve (AUC) values were 0.92 [95% confidence interval (CI) 0.88-0.95] for AMH, and 0.94 (95% CI 0.90-0.96) for inhibin B. AMH was highly sensitive (92%) and specific (81%) in detecting a macroscopic AGCT. However, in AUC comparison analyses, the combination of the markers was superior to inhibin B alone. In conclusion, serum AMH is a sensitive and specific marker of AGCT, and either AMH or inhibin B can be monitored during follow-up. However, combining AMH and inhibin B in AGCT patient follow-up improves the detection of recurrent disease.

Risk-stratification of endometrial carcinomas revisited: a combined preoperative and intraoperative scoring system for a reliable prediction of an advanced disease.

OBJECTIVE: The aim of this study is to develop a risk-scoring system for predicting lymph node and distant metastasis in endometrial carcinoma. METHODS: A total of 1166 patients, treated at a single institution between 1-2007 and 12-2013, were included in the study. The association of stage IIIC-IV disease with demographic factors (age, body mass index), biochemical factors (complete blood count, serum CA125), preoperative histology and tumor size was examined in unadjusted analyses. Logistic regression analysis was used for the identification of variables that independently predict an advanced disease. RESULTS: Thrombocytosis, serum CA125>35 U/mL, preoperative high-risk histology (nonendometrioid or grade 3 endometrioid carcinoma) and tumor size≥3 cm were independently associated with an advanced disease. These predictors were internally validated by a bootstrapping method with statistical significance. A risk-scoring system with an area under the receiver operating characteristic curve of 0.852 (95% confidence interval, 0.821-0.883) was developed. Total risk score points ranged from 0 to 8 for individual patients. With a cut-off of 1 point, stratifying 66.3% of patients to surgical staging, the model predicted stage IIIC-IV carcinomas with a sensitivity of 100%, specificity of 38.0%, positive predictive value of 17.1%, and negative predictive value of 100%. With the same cut-off, the corresponding values were 100%, 34.7%, 16.5% and 100% in predicting stage IIIC carcinomas in a subgroup that underwent lymphadenectomy and had a stage I-IIIC disease. CONCLUSIONS: This risk-scoring system is highly sensitive in predicting an advanced stage endometrial carcinoma at a cut-off of risk score points that is associated with an acceptable lymphadenectomy rate.

Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Magnetic resonance imaging in the assessment of high-risk features of endometrial carcinoma: a meta-analysis.

OBJECTIVE: The aim of this study was to review the available literature on the reliability of contemporary magnetic resonance imaging (MRI) techniques in the assessment of high-risk features of endometrial carcinoma, that is, deep myometrial invasion, cervical stromal involvement, and lymph node metastasis. METHODS: The PubMed and Scopus databases were searched for studies published before March 2014. Studies on plain MRI were excluded. RESULTS: Fifty-two eligible studies were identified. For the assessment of deep (≥ 50%) myometrial invasion (50 studies, 3720 patients), the pooled sensitivity, specificity, positive predictive value, and negative predictive value were 80.7%, 88.5%, 77.6%, and 89.5%, respectively, by random-effects analysis. For predicting cervical stromal involvement (12 studies, 1153 patients), the pooled values were 57.0%, 94.8%, 68.7%, and 90.5%, respectively. For lymph node metastasis on a per-patient basis (10 studies, 862 patients), they were 43.5%, 95.9%, 66.3%, and 92.2%, respectively. In a meta-regression analysis, dynamic imaging was associated with a higher sensitivity in detecting deep myometrial invasion, as compared with contrast-enhanced imaging (P = 0.021). The improvement by diffusion-weighted imaging was of a borderline significance (P = 0.057). Significant small-study effects were found for the sensitivity of MRI in detecting deep myometrial invasion (P < 0.0001) and cervical stromal involvement (P = 0.049). CONCLUSIONS: Considering the poor-to-moderate sensitivity of MRI in detecting high-risk features of endometrial carcinoma, patients with negative findings on MRI may not safely forgo surgical staging unless the findings are confirmed by a backup method. The high specificities allow the targeting of staging procedures by MRI alone in patients with positive findings. Compared with contrast-enhanced imaging, dynamic and diffusion-weighted imaging may be more reliable in the radiological staging of endometrial carcinoma.

Clinical characteristics and survival of patients with an adult-type ovarian granulosa cell tumor: a 56-year single-center experience.

OBJECTIVE: The objective of this study was to evaluate clinical prognostic factors and survival of patients with ovarian granulosa cell tumors (GCTs) in a long-term follow-up study. METHODS: A total of 240 adult-type GCTs diagnosed in Helsinki University Central Hospital from 1956 to 2012 were histologically reevaluated. Data were analyzed for several clinical factors in relation to major developments in imaging, surgery, and chemotherapy: the old era (1956-1983) and the new era (1984-2012). Prognostic factors for survival were evaluated in the univariate and multivariate analyses. RESULTS: The original diagnosis was confirmed in 187 (77.9%) patients. The International Federation of Gynecology and Obstetrics stage I disease was present in 89.2%; stage II, in 7.0%; stage III, in 3.8%; and stage IV, in 0% of cases. The mean age at diagnosis (52.9 years) and the mean tumor size (10.8 cm) did not change significantly over time. The most common presenting symptom was abnormal bleeding, but 14% were asymptomatic. The mean follow-up period was 15.7 years. Recurrence rate was similar in both eras. The GCT-specific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% in the old era as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate analyses, old era, patient age older than 60 years, tumor size greater than 10 cm, advanced stage, residual tumor, and use of hormonal adjuvant treatment were associated with GCT-related deaths. Prior use of oral contraceptives and history of infertility improved survival rates. In the multivariate analysis, stage was the only independent prognostic factor for GCT-specific survival. CONCLUSIONS: An accurate histological diagnosis of GCT is essential. Stage IV disease is an extreme rarity. However, tumor stage overcomes other possible clinical prognostic factors for GCT-specific survival. Fertility-sparing surgery, the use of oral contraceptives, or hormonal replacement therapy seems not to be risk factors for survival.

Combined use of endometrial sample and magnetic resonance imaging in the preoperative risk-stratification of endometrial carcinomas.

OBJECTIVE: To compare two treatment strategies in women undergoing surgery for endometrial carcinoma. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. POPULATION: 1166 patients. Uterine biopsy/curettage was obtained in 1140 women, of whom 229 also had pelvic magnetic resonance imaging (MRI). METHODS: We compared two strategies: (i) routine pelvic lymphadenectomy and (ii) selective pelvic lymphadenectomy for women with high-risk carcinomas as determined from preoperative histology and MRI. High-risk carcinomas included grade 1-2 endometrioid carcinomas with ≥50% myometrial invasion, grade 3 endometrioid carcinomas, and nonendometrioid carcinomas. Others were considered low-risk carcinomas. MAIN OUTCOME MEASURES: Diagnostic indices, treatment algorithms. RESULTS: Of the women who underwent lymphadenectomy, positive pelvic nodes were found in 2.3% of low-risk carcinomas and 18.3% of high-risk carcinomas. The combination of preoperative histology and MRI detected high-risk carcinomas with a sensitivity of 85.7%, a specificity of 75.0%, a positive predictive value of 74.4%, and a negative predictive value of 86.1%. Area under curve was 0.804. In the routine lymphadenectomy algorithm, 54.1% of lymphadenectomies were performed for low-risk carcinomas. In the selective lymphadenectomy algorithm, 14.3% of women with high-risk carcinomas did not receive lymphadenectomy. Missed positive pelvic nodes were estimated to occur in 2.1% of patients in the selective strategy. Similarly, the estimated risk for isolated para-aortic metastasis was 2.1%, regardless of treatment strategy. CONCLUSIONS: The combination of preoperative histology and MRI is moderately sensitive and specific in detecting high-risk endometrial carcinomas. The clinical utility of the method is hampered by the relatively high proportion of high-risk cases that remain unrecognized preoperatively.

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

A phase 3 trial of bevacizumab in ovarian cancer.

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Prediction of para-aortic spread by gross pelvic lymph node findings in patients with endometrial carcinoma.

OBJECTIVE: Isolated para-aortic lymph node metastases are rare in patients with endometrial carcinoma. We wanted to determine the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic space involvement in these patients. METHODS: We identified all women with surgically treated endometrial carcinoma at our institution between January 2008 and February 2013 (n = 854). One hundred seventeen patients received pelvic-aortic lymphadenectomy. Lymph nodes were considered grossly positive based on size and morphology. RESULTS: In patients who underwent comprehensive lymphadenectomy, grossly positive pelvic nodes predicted para-aortic metastasis with a sensitivity of 52.4% and specificity of 93.8%. The positive and negative likelihood ratios were 8.4 and 0.51, respectively. The predictive power of grossly positive pelvic nodes remained significant (odds ratio, 18; 95% confidence interval, 4.1-78; P < 0.0001) after correcting for deep myometrial invasion, poor tumor differentiation, and nonendometrioid histology as confounders. The whole sample of 854 patients was used for Bayesian calculations. The cutoff for a clinically useful test was set at the negative predictive value of 98.0%. The negative predictive value of the test (ie, grossly positive pelvic nodes at surgery in predicting the likelihood of para-aortic metastasis) was 99.7% for patients with superficial grade 1 to 2 endometrioid carcinomas and 98.0% for patients with deeply invasive grade 1 to 2 endometrioid carcinomas. For patients with grade 3 endometrioid and nonendometrioid carcinomas, the negative predictive values were 97.3% and 92.2%, respectively. For the whole study population, the value was 98.4%. CONCLUSIONS: When uterine factors are used for risk stratification of endometrial carcinomas, selective para-aortic lymphadenectomy, based on gross findings of pelvic nodes, is feasible for patients with grade 1 to 2 endometrioid carcinomas, regardless of the depth of myometrial invasion. Similarly, gross findings of pelvic nodes can be used to evaluate the need for para-aortic lymphadenectomy in the strategy of routine pelvic lymphadenectomy.

[Treatment of endometrial carcinoma]. / Kohdunrunkosyövän hoito.

The mainstay of the initial treatment for endometrial carcinoma is surgery with total hysterectomy and bilateral salpingo-oophorectomy. Pelvic-aortic lymphadenectomy may be appropriate for patients having tumors with a high risk for extrauterine spread. Most importantly, these include carcinomas with deep (≥ 50%) myometrial invasion, poor differentiation, or nonendometrioid histology, in which lymphadenectomy aids in prognostication and tailoring of adjuvant treatments. Vaginal cuff brachytherapy ensures vaginal control in stage I endometrioid carcinomas with high-risk features. For advanced carcinomas, chemotherapy is the adjuvant treatment of choice, combined with whole pelvic external beam radiotherapy in selected cases.

Prediction of lymph node and distant metastasis in patients with endometrial carcinoma: a new model based on demographics, biochemical factors, and tumor histology.

OBJECTIVE: To develop a model that might predict the probability of lymph node and distant metastasis (stages IIIC-IV) in endometrial carcinoma. METHODS: We studied 774 patients with endometrial carcinoma treated in a single institution. Demographic factors, biochemical factors and preoperative tumor characteristics, identified as potential risk factors for advanced carcinoma in unadjusted analyses, were used to create a logistic regression model with lymph node and distant metastasis as the dependent variable. Statistically significant odds ratios in the regression model were rounded to the nearest whole number. These rounded values were the estimated weights for each factor that were summed to generate a score that might predict the probability of stage IIIC-IV carcinoma. RESULTS: Biochemical factors and preoperative tumor characteristics predicted lymph node and distant metastasis in the regression model, whereas demographic factors were without effect. The score combining weighted risk factors was: (2 × leukocytosis)+(3 × thrombocytosis)+(7 × elevated CA125)+(4 × high-risk histology). The area under curve (AUC) for this total score was 0.823, with 71.6% sensitivity, 75.2% specificity, 25.9% positive predictive value, and 95.7% negative predictive value, using 6 as cut-point. After excluding stage IV carcinomas from the dataset, the AUC was 0.813 for the total score in predicting nodal involvement (P=0.82 vs. total score in predicting stage IIIC-IV carcinomas in the complete dataset). CONCLUSIONS: Based on the high negative predictive value, this prediction model could be applied for identifying patients who may not benefit from lymphadenectomy for endometrial carcinoma staging.