UK Collaborative Trial Of Ovarian Cancer Screening Research Articles

Bayesian and deep-learning models applied to the early detection of ovarian cancer using multiple longitudinal biomarkers.

Ovarian cancer is the most lethal of all gynecological cancers. Cancer Antigen 125 (CA125) is the best-performing ovarian cancer biomarker which however is still not effective as a screening test in the general population. Recent literature reports additional biomarkers with the potential to improve on CA125 for early detection when using longitudinal multimarker models. Our data comprised 180 controls and 44 cases with serum samples sourced from the multimodal arm of UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Our models were based on Bayesian change-point detection and recurrent neural networks. We obtained a significantly higher performance for CA125-HE4 model using both methodologies (AUC 0.971, sensitivity 96.7% and AUC 0.987, sensitivity 96.7%) with respect to CA125 (AUC 0.949, sensitivity 90.8% and AUC 0.953, sensitivity 92.1%) for Bayesian change-point model (BCP) and recurrent neural networks (RNN) approaches, respectively. One year before diagnosis, the CA125-HE4 model also ranked as the best, whereas at 2 years before diagnosis no multimarker model outperformed CA125. Our study identified and tested different combination of biomarkers using longitudinal multivariable models that outperformed CA125 alone. We showed the potential of multivariable models and candidate biomarkers to increase the detection rate of ovarian cancer.

Ovarian cancer symptoms in pre-clinical invasive epithelial ovarian cancer – An exploratory analysis nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

ObjectiveUKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. MethodsIn UKCTOCS, 202638 postmenopausal women, aged 50–74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. Results1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. ConclusionsOur findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.

Association of hysterectomy and invasive epithelial ovarian and tubal cancer: a cohort study within UKCTOCS.

To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. Prospective cohort study. Thirteen NHS Trusts in England, Wales and Northern Ireland. A total of 202 506 postmenopausal women recruited between 2001 and 2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. Hysterectomy with conservation of one or both adnexa was reported in 41 912 (20.7%; 41 912/202 506) women. Median follow up was 11.1 years (interquartile range 9.96-12.04), totalling >2.17 million woman-years. Among women who had undergone hysterectomy, 0.55% (231/41 912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160 594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (hazard ratio 0.98, 95% CI 0.85-1.13, P = 0.765). This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. These data are important both for clinical counselling and for refining risk prediction models. Hysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer.

In postmenopausal women, multimodal or US screening for ovarian cancer did not reduce ovarian cancer mortality.

Menon U, Gentry-Maharaj A, Burnell M, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021;397:2182-93. 33991479.

Ovarian Cancer Population Screening and Mortality After Long-Term Follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A Randomised Controlled Trial

(Abstracted from Lancet 2021;397:2182–2193) Ovarian cancer is most commonly diagnosed at an advanced stage (3 or 4) and remains the deadliest gynecologic malignancy. When diagnosed at stage 1, a survival rate of greater than 90% has been demonstrated, compared with a 5-year survival rate of 27% and 13% for stage 3 and stage 4 disease, respectively.

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

SummaryBackgroundOvarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS.MethodsIn this randomised controlled trial, postmenopausal women aged 50–74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032.FindingsBetween April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1–17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (−41·8 to –2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (−21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group.InterpretationThe reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended.FundingNational Institute for Health Research, Cancer Research UK, and The Eve Appeal.

Performance Characteristics of the Ultrasound Strategy during Incidence Screening in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Simple SummaryThe United Kingdom Collaborative Trial of Ovarian Cancer Screening was undertaken to assess whether screening postmenopausal women from the general population might result in detection of ovarian/tubal cancers at an earlier stage and thus save lives. One of the screening strategies tested was a yearly transvaginal ultrasound scan of the ovaries (USS). Following the initial screen, 44,799 of the 50,639 women in the USS group went on to have a further 280,534 annual scans during April 2002–December 2011. Abnormalities leading to surgery were detected in 960 women of whom 113 (80 invasive epithelial) had ovarian/tubal cancer. Ovarian/tubal cancer was missed in 52 (50 invasive epithelial) women. Of the screen-detected cancers, 37.5% and missed cancers 6% were early stage(I/II). The number (detection rate 61.5%; 80/130) and advanced stage of the missed invasive cancers suggests that a yearly ultrasound scan may not be suitable for screening average risk women for ovarian cancer.Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95% CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95% CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95% CI: 60.8–75.5), 99.7% (95% CI: 99.7–99.7), and 11.8% (95% CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95% CI: 52.6–69.9); 99.7% (95% CI: 99.7–99.7) and 8.3% (95% CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000.

When Less is Not More: Population-level Perspective on Adnexal Cyst Surveillance for Post-Menopausal Women.

Ovarian simple cysts are found with high frequency in older women, and at least a third eventually regress in a year. Multiple large studies, including the sample from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial, have found no direct association with ovarian cancer incidence, corroborating earlier, smaller studies [ 1 Hartge P. Hayes R. Reding D. et al. Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors: preliminary data from the prostate, lung, colon, and ovarian cancer screening trial. Am J Obstet Gynecol. 2000; 183: 1232-1237 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 2 Menon U. Gentry-Maharaj A. Hallett R. et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009; 10: 327-340 Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar ]. The current practice of safely following, rather than resecting, asymptomatic ovarian cystic lesions accompanied a rejection of an older, simple biologic model of ovarian cystic lesions as cancer precursors or markers of subsequent cancer onset in either ovary. Instead, it is now widely accepted that aggressive or high-grade ovarian neoplasms arise via a solid tumor pathway from serous tubal intraepithelial carcinoma [ 3 Erickson B.K. Conner M.G. Landen Jr., C.N. The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol. 2013; 209: 409-414 Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar ]. In this decision-analytic modeling study by Pandharipande et al, the question of managing ovarian cystic lesions in postmenopausal women is revisited within the practical and highly informative context of overall health status and wide-ranging life expectancy [ 4 Seguin C.L. Lietz A.P. Wright J.D. et al. Surveillance in older women with incidental ovarian cysts: Maximal projected benefits by age and comorbidity level. J Am Coll Radiol. 2020; 18: 10-18 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar ]. Surveillance in Older Women With Incidental Ovarian Cysts: Maximal Projected Benefits by Age and Comorbidity LevelJournal of the American College of RadiologyVol. 18Issue 1PreviewThe aim of this study was to estimate effects on life expectancy (LE) of imaging-based ovarian surveillance after detection of incidental postmenopausal ovarian cysts, under different assumptions of patient age, comorbidity level, and cancer risk and detection. Full-Text PDF

Ovarian cancer symptoms, routes to diagnosis and survival – Population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

ObjectiveThere are widespread efforts to increase symptom awareness of ‘pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency’ in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the ‘no screen’ (control) UKCTOCS arm. MethodsOf 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. ResultsWomen presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p < 0.0001) had significantly worse survival than those who did not. Each additional presenting symptom decreased survival (HR1·20, 95%CI1·12–1·28, p < 0.0001). In multivariable analysis, in addition to advanced stage, increasing residual disease and inadequate primary treatment, abdominal pain and loss of appetite/feeling full were significantly associated with increased mortality. ConclusionsThe ovarian cancer symptom indices identify postmenopausal women with a poorer prognosis. This study however cannot exclude the possibility of better outcomes in those who are aware and act on their symptoms.

Sexual functioning in 4,418 postmenopausal women participating in UKCTOCS: a qualitative free-text analysis.

Sexual well-being can contribute significantly to the overall quality of women's lives. This qualitative study aimed to examine sexual activity, functioning, and satisfaction in a large sample of postmenopausal women from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) METHODS:: Thematic analysis was used to evaluate the free-text data of the Fallowfield Sexual Activity Questionnaire (FSAQ) completed by UKCTOCS participants at baseline before annual screening. A total of 24,305 women completed the baseline FSAQ and 4,525 (19%) provided free-text data, with 4,418 comments eligible for analysis. Median age was 64 years; 65% had a partner and 22.5% were sexually active. Four interrelated themes were derived: partner availability, physical and sexual health, mental well-being, and interpersonal relationships. Primary reason for absence of sexual activity was lack of a partner, mainly due to widowhood (n = 1,000). Women discussed how partner's medical condition (27%) or sexual dysfunction (13.5%), their own physical health (18%) or menopause-related symptoms (12.5%), and prescribed medication (7%) affected sexual activity. Impact of low libido in self (16%) or partner (7%), relationship problems (10.5%) or logistics (6%), and perceptions of ageing (9%) were also mentioned. Few (3%) referred to positive sexual experiences or had sought medical help for sexual problems (6%). This qualitative analysis explored postmenopausal women's perspective on their sexual functioning. Having an intimate partner and good physical health are key factors for continuation of sexual activity and satisfaction. Further sexual education for healthcare professionals is needed to raise awareness about sexuality and sexual difficulties in later life. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A426.

Colorectal cancer ascertainment through cancer registries, hospital episode statistics, and self-reporting compared to confirmation by clinician: A cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundElectronic health records are frequently used for cancer epidemiology. We report on their quality for ascertaining colorectal cancer (CRC) in UK women. MethodsPopulation-based, retrospective cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Postmenopausal women aged 50–74 who were diagnosed with CRC during 2001–11 following randomisation to the UKCTOCS were identified and their diagnosis confirmed with their treating clinician. The sensitivity and positive predictive value (PPV) of cancer and death registries, hospital episode statistics, and self-reporting were calculated by pairwise comparisons to the treating clinician’s confirmation, while specificity and negative predictive value were estimated relative to expected cases. ResultsNotification of CRC events were received for 1,085 women as of 24 May 2011. Responses were received from 61% (660/1,085) of clinicians contacted. Nineteen women were excluded (18 no diagnosis date, one diagnosed after cut-off). Of the 641 eligible, 514 had CRC, 24 had a benign polyp, and 103 had neither diagnosis. The sensitivity of cancer registrations at one- and six-years post-diagnosis was 92 (95% CI 90–94) and 99% (97–100), respectively, with a PPV of 95% (95% CI 92/93–97). The sensitivity & PPV of cancer registrations (at one-year post-diagnosis) & hospital episode statistics combined were 98 (96–99) and 92% (89–94), respectively. ConclusionsCancer and death registrations in the UK are a reliable resource for CRC ascertainment in women. Hospital episode statistics can supplement delays in cancer registration. Self-reporting seems less reliable.

A quantitative performance study of two automatic methods for the diagnosis of ovarian cancer.

We present a quantitative study of the performance of two automatic methods for the early detection of ovarian cancer that can exploit longitudinal measurements of multiple biomarkers. The study is carried out for a subset of the data collected in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). We use statistical analysis techniques, such as the area under the Receiver Operating Characteristic (ROC) curve, for evaluating the performance of two techniques that aim at the classification of subjects as either healthy or suffering from the disease using time-series of multiple biomarkers as inputs. The first method relies on a Bayesian hierarchical model that establishes connections within a set of clinically interpretable parameters. The second technique is a purely discriminative method that employs a recurrent neural network (RNN) for the binary classification of the inputs. For the available dataset, the performance of the two detection schemes is similar (the area under ROC curve is 0.98 for the combination of three biomarkers) and the Bayesian approach has the advantage that its outputs (parameters estimates and their uncertainty) can be further analysed by a clinical expert.

Ovarian Cancer Screening With the Risk Of Ovarian Cancer Algorithm (ROCA): Good, Bad, or Just Expensive?

Abstract Objectives To measure the effectiveness of ovarian cancer screening using the Risk of Ovarian Cancer Algorithm (ROCA). Methods A Markov model was constructed based on the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This model was used to predict the outcome of ovarian cancer screening with ROCA. Results The model predicted the ovarian cancer mortality from age 50 to age 85 to be 0.954% with a decrease in life expectancy of 0.178years (yrs) per person. Using data from the UKCTOCS the model predicted a similar reduction in mortality (11% vs. 10%), and similar curves for ovarian cancer mortality. Screening at age 50 for 20yrs reduced ovarian cancer mortality from 0.953% to 0.898%, an absolute decrease of 6%, yielding an increase in life expectancy of 0.0101yrs, preventing 55 deaths per 100,000 screened at a cost of $585,946 per life-yr. Screening for 30yrs reduced mortality from 0.954% to 0.872%, an absolute decrease of 9%, preventing 82 deaths at a cost of $763,970 per life-yr. Conclusion The ROCA test can improve the detection of early ovarian cancer but is not practical for screening in an average-risk population. We predict the ROCA test will reduce overall ovarian cancer mortality by 6% to 9% but at a substantial cost. For ROCA to be practical, the cost would need to be reduced ten-fold and would have only a marginal impact on mortality from ovarian cancer. This model supports the FDA's criticism of the ROCA test. Ovarian cancer screening may reduce mortality from ovarian cancer but is not cost effective.

Sonographers' self-reported visualization of normal postmenopausal ovaries on transvaginal ultrasound is not reliable: results of expert review of archived images from UKCTOCS.

ABSTRACTObjectiveIn the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), self‐reported visualization rate (VR) of the ovaries by the sonographer on annual transvaginal sonographic (TVS) examinations was a key quality control (QC) metric. The objective of this study was to assess self‐reported VR using expert review of a random sample of archived images of TVS examinations from UKCTOCS, and then to develop software for measuring VR automatically.MethodsA single expert reviewed images archived from 1000 TVS examinations selected randomly from 68 931 TVS scans performed in UKCTOCS between 2008 and 2011 with ovaries reported as ‘seen and normal’. Software was developed to identify the exact images used by the sonographer to measure the ovaries. This was achieved by measuring caliper dimensions in the image and matching them to those recorded by the sonographer. A logistic regression classifier to determine visualization was trained and validated using ovarian dimensions and visualization data reported by the expert.ResultsThe expert reviewer confirmed visualization of both ovaries (VR‐Both) in 50.2% (502/1000) of the examinations. The software identified the measurement image in 534 exams, which were split 2:1:1 providing training, validation and test data. Classifier mean accuracy on validation data was 70.9% (95% CI, 70.0–71.8%). Analysis of test data (133 exams) provided a sensitivity of 90.5% (95% CI, 80.9–95.8%) and specificity of 47.5% (95% CI, 34.5–60.8%) in detecting expert confirmed visualization of both ovaries.ConclusionsOur results suggest that, in a significant proportion of TVS annual screens, the sonographers may have mistaken other structures for normal ovaries. It is uncertain whether or not this affected the sensitivity and stage at detection of ovarian cancer in the ultrasound arm of UKCTOCS, but we conclude that QC metrics based on self‐reported visualization of normal ovaries are unreliable. The classifier shows some potential for addressing this problem, though further research is needed. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Ovarian cancer screening with the Risk of Ovarian Cancer Algorithm (ROCA): Good, bad, or just expensive?

ObjectivesTo measure the effectiveness of ovarian cancer screening using the Risk of Ovarian Cancer Algorithm (ROCA). MethodsA Markov model was constructed based on the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This model was used to predict the outcome of ovarian cancer screening with ROCA. ResultsThe model predicted the ovarian cancer mortality from age 50 to age 85 to be 0.954% with a decrease in life expectancy of 0.178years (yrs) per person. Using data from the UKCTOCS the model predicted a similar reduction in mortality (11% vs. 10%), and similar curves for ovarian cancer mortality. Screening at age 50 for 20yrs reduced ovarian cancer mortality from 0.953% to 0.898%, an absolute decrease of 6%, yielding an increase in life expectancy of 0.0101yrs, preventing 55 deaths per 100,000 screened at a cost of $585,946 per life-yr. Screening for 30yrs reduced mortality from 0.954% to 0.872%, an absolute decrease of 9%, preventing 82 deaths at a cost of $763,970 per life-yr. ConclusionThe ROCA test can improve the detection of early ovarian cancer but is not practical for screening in an average-risk population. We predict the ROCA test will reduce overall ovarian cancer mortality by 6% to 9% but at a substantial cost. For ROCA to be practical, the cost would need to be reduced ten-fold and would have only a marginal impact on mortality from ovarian cancer. This model supports the FDA's criticism of the ROCA test.Ovarian cancer screening may reduce mortality from ovarian cancer but is not cost effective.

Methylation patterns in serum DNA for early identification of disseminated breast cancer

BackgroundMonitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA.MethodsWe used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints.ResultsA total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC.ConclusionsDetection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent.

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer.

Purpose: The TP53 tumor-suppressor gene is mutated in >95% of high-grade serous ovarian cancers. Detecting an autologous antibody response to TP53 that might improve early detection.Experimental Design: An immunoassay was developed to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and 944 age-matched healthy controls from the United States, Australia, and the United Kingdom. Serial preclinical samples from cases and controls were also assayed from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).Results: Using a cutoff value of 78 U/mL to achieve a specificity of 97.4%, TP53 autoantibody was elevated in 30% of 50 cases from MD Anderson, 21.3% of 108 cases from the Australian Ovarian Cancer Study, and 21% of 220 cases from the UKCTOCS. Among 164 cases with rising CA125 detected with the UKCTOCS risk of ovarian cancer algorithm (ROCA), 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months before CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Similar sensitivity was obtained using assays with specific mutant and wild-type TP53.Conclusions: TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 holds promise for earlier detection of invasive epithelial ovarian cancer. Clin Cancer Res; 23(19); 5912-22. ©2017 AACR.

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background:To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy.Methods:Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model.Results:Using a CA125–ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125–ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY.Conclusion:Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.

Cost-effectiveness of ovarian cancer screening: An analysis of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) from a U.S. health system perspective.

6608 Background: UKCTOCS is the largest randomized controlled trial to evaluate screening’s impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum CA125 interpreted with a risk algorithm; annual transvaginal ultrasound; or no screening (NS). There was a non-statistically significant 15% reduction in mortality over 11 years in MMS group. As most of the potential benefit of screening was seen after 7 years, follow-up is ongoing to determine if an observed stage shift translates into significant mortality reduction. The current study estimates the cost-effectiveness of an MMS screening program in the US. Methods: A modified Markov model was constructed using data from UKCTOCS to compare MMS to NS. Published estimates of the long term effect of MMS screening on ovarian cancer mortality were used to simulate mortality over 40 years from the start of screening. Base case costs included CA125, ultrasounds, clinical evaluations and false-positive surgeries, with an annual weighted cost of $35 in addition to an estimated risk algorithm cost of $100. The utility and costs of ovarian cancer treatment were incorporated into the model. Incremental cost-effectiveness ratios (ICERs) were calculated in 2016 U.S. dollars per quality-adjusted year of life saved (QALY). Additional sensitivity analyses were performed. Results: MMS is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than NS. Screening women from age 50 to 75 with MMS reduced mortality by 24% with an ICER of $98,062/QALY. If screening begins at age 60, MMS reduces mortality by 12%, with ICER below the willingness to pay threshold of $100,000/QALY only if the algorithm costs &lt; $50. In probabilistic sensitivity analyses, the probability that screening from age 50-75 at an algorithm cost of $100 was less than $100,000/QALY was 41%. Conclusions: Ovarian cancer screening is potentially cost-effective in the US depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.