[Show abstract][Hide abstract] ABSTRACT: Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality.
Participants resident in England who had completed both baseline (Wave 1) and follow up (Wave 2) questionnaires were included. Follow-up was through the Health and Social Care Information Centre with deaths censored on 31st December 2012. IMD, education and a range of covariates were explored. Cox regression models adjusted for all covariates were used. Sensitivity analysis using imputation was performed (1) including those with missing data and (2) on the entire cohort who had completed the baseline questionnaire.
Of the 54,539 women resident in England who completed both Wave 1 and Wave 2 questionnaires, 4,510 had missing data. The remaining 50,029 women were included in the primary analysis. Area-level IMD was positively associated with all-cause mortality for the most deprived group compared to the least deprived (HR=1.42, CI=1.14-1.78) after adjusting for all potential confounders. Sensitivity analyses showed similar results with stronger associations in the entire cohort (HR=1.90, CI=1.68-2.16). The less educated an individual, the higher the mortality risk (test for trend p=<0.001). However, the crude effect on mortality of having no formal education compared to college/university education disappeared when adjusted for IMD rank (HR=1.08, CI=0.93-1.26).
Women living in more deprived areas continue to have higher mortality even in this less deprived cohort and after adjustment for a range of potential confounders.
This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978.
BMC Public Health 12/2015; 15(1). DOI:10.1186/s12889-015-1609-5 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To define risk thresholds for cost-effectiveness of risk-reducing salpingo-oophorectomy(RRSO) for ovarian cancer(OC) prevention in low/intermediate risk postmenopausal women.
A decision-analytic model compares lifetime costs-&-effects of offering 'RRSO' with 'no RRSO' to postmenopausal women ≥50years for different lifetime OC-risk thresholds: 2%, 4%, 5%, 6%, 8% and 10%. Well established data from the literature are used to estimate total costs, effects in terms of Quality-Adjusted-Life-Years(QALYs), cancer incidence, incremental cost-effectiveness ratio(ICER) and impact. Costs are reported at 2012 prices; costs/outcomes discounted at 3.5%. Deterministic/Probabilistic sensitivity analysis(PSA) evaluate model uncertainty.
RRSO does not save QALYs and is not cost-effective at the 2% general population lifetime OC-risk. At 4% OC-risk RRSO saves QALYs but is not cost-effective. At risk thresholds ≥5%, RRSO saves more life-years and QALYs and is highly cost-effective. The ICERs for OC-risk levels 5%, 6%, 8% and 10% are £15,247, £9958, £4584, and £1864 respectively. The gain in life-years from RRSO equates to 29.2, 40.1, 62.1 and 80.3days at risk thresholds of 5%, 6%, 8% and 10% respectively. The results are not sensitive to treatment costs of RRSO/OC/cardiovascular events but are sensitive to utility-scores for RRSO. On PSA, 67%, 80%, 84%, 91% and 94% of simulations at risk thresholds of 4%, 5%, 6%, 8% and 10% respectively are cost-effective for RRSO.
RRSO is highly cost-effective in postmenopausal women aged >50 with ≥5% lifetime OC-risk and increases life-expectancy by >29.2days. The results could have significant clinical implications given the improvements in risk prediction and falling costs of genotyping.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here we evaluated associations between common genetic variants (single nucleotide polymorphisms (SNPs) and indels) in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15,397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r(2) with rs17507066=0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1 x10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72x10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r(2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 x 10(-8)). These data suggest that common variants at 22q11.2 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
[Show abstract][Hide abstract] ABSTRACT: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
[Show abstract][Hide abstract] ABSTRACT: To compare the differences in mammogram completion rates over time between Chinese American women with and without a history of mammogram screening.
Secondary analysis of a randomized, controlled intervention study.
Metropolitan areas of Portland, Oregon.
300 foreign-born Chinese immigrant women aged 40 years or older. Of these, 83 women (28%) had never had a mammogram.
Participants who had not been screened with a mammogram within the past 12 months were randomized into either an education group or a control (brochure) group. All participants completed a baseline survey, which was administered again at 3, 6, and 12 months.
Mammography history, breast cancer knowledge, perceived risks, susceptibility, benefits, and common and cultural barriers.
Women who had never been screened were less likely to have insurance, a regular healthcare provider, or to have been instructed to have a mammogram. Postintervention in the education group, mammogram completion was not significantly different between those with or without a history of screening (p = 0.52). In the control brochure group, significantly more women with a history of screening had a mammogram (p = 0.03).
Practitioners must be aware of differential effects of education on mammography cancer screening based on women's history of screening.
Print material may not be as effective with women who have never been screened with a mammogram. Targeted approaches based on such understanding has the potential to decrease the breast cancer screening disparity among Chinese immigrant women.
Oncology Nursing Forum 09/2015; 42(5):470-478. DOI:10.1188/15.ONF.470-478 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify priority areas of research for the Oncology Nursing Society (ONS) Research Agenda for 2014-2018, consistent with ONS's mission to promote excellence in oncology nursing and quality cancer care.
Review of the literature, 2013 ONS Research Priorities Survey, National Institute of Nursing Research, and the National Cancer Institute research foci.
Multimethod consensus-building approach by content leaders and content experts of the ONS Research Agenda Project Team.
The 2014-2018 Research Agenda Project Team identified eight high-priority research areas.
The Research Agenda is a synthesis of the state of the science in cancer and identifies gaps and directions for the conduct and dissemination of research. Oncology nurses can use the agenda to inform clinical practice, develop research proposals, inform policy makers, support interdisciplinary research efforts, and promote scientist and clinician collaborations in targeted patient-centered research.
Oncology Nursing Forum 09/2015; 42(5):450-65. DOI:10.1188/15.ONF.450-465 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10-8), rs711830 at 2q31.1 (P = 7.5 × 10-12) and rs688187 at 19q13.2 (P = 6.8 × 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
[Show abstract][Hide abstract] ABSTRACT: The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) aims to establish the efficacy of 2 different ovarian cancer screening schedules. The psychosocial substudy examines the psychological factors associated with the screening program.
Women aged 50 to 75 years from 16 UK gynecologic centers randomized to annual multimodal screening or ultrasound screening (US) groups were followed up for 7 years. Psychosocial data from women who withdrew from the study after a repeat screen were examined.
Sixteen percent (3499/21,733) of women requiring a repeat screening test in addition to annual screen withdrew from the study: 12.9% (1560/12,073) from the multimodal group and 20.1% (1939/9660) from the US group. An estimated relative risk of withdrawal is 1.46 (95% confidence interval, 1.36-1.56; P ≤ 0.001) for the US arm. High anxiety trait and increased psychological morbidity significantly influenced withdrawal, even when age, screening center, and group were taken into account (P < 0.001). The risk of withdrawal decreased significantly the longer a woman stayed in UKCTOCS, irrespective of the number of screens and intensity in the preceding year.
Withdrawal rate was greater in women undergoing US screening and in those who had repeats earlier in UKCTOCS. Having a high predisposition to anxiety, high current state anxiety, and above threshold general psychological morbidity all increased the withdrawal rate.
International Journal of Gynecological Cancer 07/2015; DOI:10.1097/IGC.0000000000000507 · 1.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Risk-reducing-salpingectomy and Delayed-Oophorectomy (RRSDO) is being proposed as a two-staged approach in place of RRSO to reduce the risks associated with premature menopause in high-risk women. We report on the acceptability/attitude of UK health professionals towards RRSDO. An anonymised web-based survey was sent to UK Cancer Genetics Group (CGG) and British Gynaecological Cancer Society (BGCS) members to assess attitudes towards RRSDO. Baseline characteristics were described using descriptive statistics. A Chi square test was used to compare categorical, Kendal-tau-b test for ordinal and Mann-Whitney test for continuous variables between two groups. 173/708 (24.4 %) of invitees responded. 71 % respondents (CGG = 57 %/BGCS = 83 %, p = 0.005) agreed with the tubal hypothesis for OC, 55 % (CGG = 42 %/BGCS = 66 %, p = 0.003) had heard of RRSDO and 48 % (CGG = 46 %/BGCS = 50 %) felt evidence was not currently strong enough for introduction into clinical practice. However, 60 % respondents' (CGG = 48 %/BGCS = 71 %, p = 0.009) favoured offering RRSDO to high-risk women declining RRSO, 77 % only supported RRSDO within a clinical trial (CGG = 78 %/BGCS = 76 %) and 81 % (CGG = 76 %/BGCS = 86 %) advocated a UK-wide registry. Vasomotor symptoms (72 %), impact on sexual function (63 %), osteoporosis (59 %), hormonal-therapy (55 %) and subfertility (48 %) related to premature menopause influenced their choice of RRSDO. Potential barriers to offering the two-stage procedure included lack of data on precise level of benefit (83 %), increased surgical morbidity (79 %), loss of breast cancer risk reduction associated with oophorectomy (68 %), need for long-term follow-up (61 %) and a proportion not undergoing DO (66 %). There were variations in perception between BGCS/CGG members which are probably attributable to differences in clinical focus/expertise between these two groups. Despite concerns, there is reasonable support amongst UK clinicians to offering RRSDO to premenopausal high-risk women wishing to avoid RRSO, within a prospective clinical trial.
Familial Cancer 07/2015; DOI:10.1007/s10689-015-9823-y · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.
In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.
The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).
These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
PLoS ONE 06/2015; 10(6):e0128106. DOI:10.1371/journal.pone.0128106 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe the quality assurance (QA) processes and their impact on visualisation of postmenopausal ovaries in the ultrasound arm of a multicentre ovarian cancer screening trial.
In UKCTOCS, 50,640 women aged 50-74 at recruitment were randomised to the ultrasound arm and underwent annual transvaginal scans. QA processes were developed during the course of the trial and included regular monitoring of Visualisation Rate (VR) of right ovary. Non-subjective factors previously identified as impacting on VR of right ovary were included in a generalised estimating equation(GEE) model for binary outcomes to enable comparison of observed versus adjusted VR between individual sonographers who had undertaken >1000scans on trial /centres. Analysis of annual VR of sonographers / centres was undertaken.
Between June 2001 and December 2010, across 13 centres, 48230 (of 50639) women attended for 270035 annual transvaginal scans. One or both ovaries were seen in 84.5% (228145/270035) of scans. The observed VR of the right ovary was 72.7% (196426/270035). For the 78 sonographers included in the model, the median difference between observed and adjusted VR was 2% (range 0-8%) and median change in rank was 3 (range 0-18). For the 13 centres, the median difference between observed versus adjusted VR was 0% (range 0-2%) with no change in ranking. The median adjusted VR for sonographers was 73% (IQR 65-82%) and for centres was 74.7% (IQR 67.1-79.0%). Despite increasing age of the cohort, there was a steady decrease in the number of sonographers with VR<60% (21.4% in 2002 to 2.1% in 2010)and a rise in those with VR >80% (14.3% in 2002 to 40.8 % in 2010). Median centre VR increased from 65.5% (range 55.7-81.0%) in 2001 to 80.3% (range74.5%-90.9%) in 2010.
A robust QA programme can improve visualisation of postmenopausal ovaries and is an essential component of ultrasound-based ovarian cancer screening trials. While VR should be adjusted for non-subjective factors that impact on ovarian visualisation, subjective factors are likely to be the largest contributors to VR differences.
This article is protected by copyright. All rights reserved.
Ultrasound in Obstetrics and Gynecology 06/2015; DOI:10.1002/uog.14929 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blood-borne biomarkers for early detection of colorectal cancer (CRC) could markedly increase screening uptake. The aim of this study was to evaluate serum carcinoembryonic antigen (CEA), CYFRA21-1 and CA125 for the early detection of CRC in an asymptomatic cohort.
This nested case-control study within UKCTOCS used 381 serial serum samples from 40 women subsequently diagnosed with CRC, 20 women subsequently diagnosed with benign disease and 40 matched non-cancer controls with three to four samples per subject taken annually up to 4 years before diagnosis. CEA, CYFRA21-1 and CA125 were measured using validated assays and performance of markers evaluated for different pre-diagnosis time groups.
CEA levels increased towards diagnosis in a third of all cases (half of late-stage cases), whereas longitudinal profiles were static in both benign and non-cancer controls. At a threshold of >5 ng ml(-1) the sensitivities for detecting CRC up to 1 and 4 years before clinical presentation were 25% and 13%, respectively, at 95% specificity. At a threshold of >2.5 ng ml(-1), sensitivities were 57.5% and 38.4%, respectively, with specificities of 81% and 83.5%. CYFRA21-1 and CA125 had no utility as screening markers and did not enhance CEA performance when used in combination. CEA gave average lead times of 17-24 months for test-positive cases.
CEA is elevated in a significant proportion of individuals with preclinical CRC, but would not be useful alone as a screening tool. This work sets a baseline from which to develop panels of biomarkers which combine CEA for improved early detection of CRC.British Journal of Cancer advance online publication, 2 June 2015; doi:10.1038/bjc.2015.202 www.bjcancer.com.
British Journal of Cancer 06/2015; 113(2). DOI:10.1038/bjc.2015.202 · 4.84 Impact Factor