Ovarian cancer screening in the general population.

Despite significant improvements in therapy, ovarian cancer continues to be a leading cause of death amongst women with gynaecological malignancies. Advanced stage at diagnosis is thought to be a major contributor to mortality. Hence, there is considerable interest in early detection through screening. In the 1990s, Professor Jacobs pioneered the development of a multimodal ovarian cancer screening (OCS) strategy using serum CA125 as the first line screen and pelvic ultrasound as the second line test. This thesis summarises the next steps in the journey with refining of the screening algorithm, feasibility testing in a pilot randomised control trial (RCT) and finally setting up and recruiting 200,000 women into the largest ever RCT . The risk of ovarian cancer in postmenopausal women with elevated CA125 levels was established through a detailed analysis of 1219 pelvic scans from 741 women with raised CA125 levels in the completed trial of 22,000 women. Based on this, the multimodal 'Risk of Ovarian Cancer' (ROC) algorithm was refined and morphology instead of volume was used to interpret the ovarian scans. The refined ROC algorithm was then prospectively evaluated in a pilot RCT of 13,582 postmenopausal women. The trial established that screening using the ROC algorithm was feasible and could achieve high specificity and positive predictive value. The improved performance characteristics of the screening strategy and the experience accumulated in running and organising the pilot trial led to the design and successful implementation of a RCT - the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - to assess the impact of early detection on disease mortality. The trial commenced in 2001 with recruitment of 202,638 postmenopausal women by September 2005. The issues involved in setting up the trial, recruitment of 202,000 women and the baseline characteristics of this population are described

Opportunistic bilateral salpingectomy (OBS) for the prevention of ovarian cancer should be offered in the context of a clinical trial: FOR: There is lack of clarity on a number of key issues.

Increasing evidence and acceptance of the role of the tube in the etiopathogenesis of ovarian cancer has led to opportunistic bilateral salpingectomy (OBS) being considered as an ovarian cancer prevention strategy for premenopausal women (who have completed childbearing) undergoing tubal sterilisation/benign gynaecological surgery. Some clinicians or jurisdictions (e.g. British Columbia) have incorporated this into routine practice. Recent guidelines from the American College of Obstetrics & Gynaecology and the Society of Gynaecological Oncology recommend that OBS be considered for ovarian cancer prevention, but also highlight the need/importance for further trials to confirm the validity and benefit of this approach

Ovarian Cancer Screening: Current status and future directions

Ovarian cancer is the third most common gynaecological malignancy and the most lethal worldwide. Most patients are diagnosed with advanced disease which carries significant mortality. Improvements in treatment have only resulted in modest increases in survival. This has driven efforts to reduce mortality through screening. Multimodal ovarian cancer screening using a longitudinal CA125 algorithm has resulted in diagnosis at an earlier stage, both in average and high risk women in two large UK trials. However, no randomised controlled trial has demonstrated a definitive mortality benefit. Extended follow up is underway in the largest trial to date, UKCTOCS to explore the delayed reduction in mortality that was noted. Meanwhile, screening is not currently recommended in the general population Some countries offer surveillance of high risk women. Novel screening modalities and longitudinal biomarker algorithms offer potential improvements to future screening strategies as does the development of better risk stratification tools

Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer.

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer

Constraints on B and Higgs Physics in Minimal Low Energy Supersymmetric Models

We study the implications of minimal flavor violating low energy supersymmetry scenarios for the search of new physics in the B and Higgs sectors at the Tevatron collider and the LHC. We show that the already stringent Tevatron bound on the decay rate B_s -> mu+ mu- sets strong constraints on the possibility of generating large corrections to the mass difference Delta M_s of the B_s eigenstates. We also show that the B_s -> mu+ mu- bound together with the constraint on the branching ratio of the rare decay b -> s gamma has strong implications for the search of light, non-standard Higgs bosons at hadron colliders. In doing this, we demonstrate that the former expressions derived for the analysis of the double penguin contributions in the Kaon sector need to be corrected by additional terms for a realistic analysis of these effects. We also study a specific non-minimal flavor violating scenario, where there are flavor changing gluino-squark-quark interactions, governed by the CKM matrix elements, and show that the B and Higgs physics constraints are similar to the ones in the minimal flavor violating case. Finally we show that, in scenarios like electroweak baryogenesis which have light stops and charginos, there may be enhanced effects on the B and K mixing parameters, without any significant effect on the rate of B_s -> mu+ mu-.Comment: 40 pages, 14 figures; added references and note about recent measurement

Screening for gynecological cancers

An estimated 17% of all new cancers in women worldwide are due to cancers of the cervix, the ovary and the uterus. Together, these cancers account for 14.6% of all female cancer deaths. This is a significant societal and economic burden, which can be limited through cancer screening. In the developed world, marked reductions of 50-90% in disease rates have been observed as a result of cervical cancer screening. By contrast, in developing countries, where more than 85% of all new cases and deaths from this cancer are reported, significant challenges need to be overcome. Although cytology remains a key component of cervical screening, the newer molecular tests offer a more targeted, risk-attuned approach. The situation for the other two gynecological cancers is different. The case for ovarian cancer screening has yet to be made with the results of key screening trials in high-and low-risk populations still pending. Screening for endometrial cancer is traditionally not advocated as women become symptomatic during the earlier, treatable stages of disease. However, consideration of screening options for these two cancers is warranted since endometrial cancer rates are on the increase and in ovarian cancer, the high case:fatality ratio remains unchanged. © 2013 Expert Reviews Ltd

Screening and prevention of ovarian cancer.

Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

Ovarian and cervical cancer awareness: development of two validated measurement tools.

The aim of the study was to develop and validate measures of awareness of symptoms and risk factors for ovarian and cervical cancer (Ovarian and Cervical Cancer Awareness Measures)