Risk Of Ovarian Cancer Algorithm Research Articles

Normal Risk Ovarian Screening Study: 21-Year Update.

The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually. Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Executive Summary of the Ovarian Cancer Evidence Review Conference

ABSTRACT Ovarian cancer has the 17th highest incidence among all cancers in the United States; however, it is the deadliest gynecologic cancer and the fifth most common cause of cancer-related death in women in the United States. The Centers for Disease Control and Prevention funded the American College of Obstetricians and Gynecologists (ACOG) to create educational materials for clinicians on the early diagnosis and prevention of gynecologic cancers. This article is an evidence summary based on ACOG's extensive literature review on the early diagnosis and prevention of ovarian cancer. An expert panel was recruited from the Society for Academic Specialists in General Obstetrics and Gynecology and the Society of Gynecologic Oncology to review and summarize evidence from articles published between January 2000 and October 2021. Topics used to frame the literature review included the epidemiology of ovarian cancer, risk factors, prevention and risk reduction, screening strategies and early detection, health disparities, diagnosis and care coordination by primary care providers, and special considerations. The Ovarian Cancer Evidence Review Conference occurred in February 2022 where the expert panel and stakeholder professional and patient advocacy organizations discussed their findings and drafted summaries to develop educational materials. Review of the epidemiology revealed that in 2022 there were 19,880 new cases of ovarian cancer, 12,810 women died of ovarian cancer, 5-year survival is 49.7% and correlates strongly with stage at diagnosis, and fewer than 10% of women with stage 1 disease will have recurrence. Risk factors for ovarian cancer include older age, inactivity, nulliparity, early menarche, late menopause, postmenopausal hormone therapy, genetic mutations such as BRCA1 and BRCA2, and endometriosis. Risk-reducing bilateral salpingo-oophorectomy reduces incidence of ovarian cancer by 80% in BRCA1 and BRCA2 carriers (95% confidence interval, 0.12–0.39) and is recommended by ACOG for women at increased risk of ovarian cancer. Contraception, physical activity, and lactation may help reduce the risk of ovarian cancer. The most common methods studied for screening include transvaginal ultrasonography, bimanual palpation, and measuring tumor marker CA-125. The Risk of Ovarian Cancer Algorithm uses CA-125 and transvaginal ultrasound to estimate the risk of ovarian cancer based on age and change in CA-125; however, it is still being studied, and no established screening method exists for asymptomatic women. Several organizations including ACOG support identifying women at high risk and subsequent genetic counseling. Symptoms of ovarian cancer are nonspecific and include abdominal distention and pain, and while workup should include ultrasonography and CA-125 measurement, no high-quality studies have compared imaging, biomarkers, risk algorithms, or multimodal risk assessment tools for the primary evaluation of patients with high-risk symptoms. Regarding disparities, Black women consistently had worse outcomes compared with their White counterparts, and little evidence regarding other racial and ethnic groups or gender minorities was identified. Finally, care coordination is critical, and ACOG recommends a low bar for referral to a gynecologic oncologist for patients with suspicion of ovarian cancer, which has been shown to increase survival and offer other advantages. This evidence review identifies many research gaps and opportunities for ovarian cancer and provides a high-level educational summary of current best practices in the risk stratification, diagnosis, and prevention of ovarian cancer.

The Normal Risk Ovarian Screening Study (NROSS): Twenty-one year update.

5522 Background: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in post-menopausal women at conventional hereditary risk where significantly rising CA125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 women-years in a single arm study ( NCT00539162 ). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was normal ( &lt; 1:2000), women returned in a year. If risk was elevated ( &gt; 1:500), TVS was undertaken immediately and if risk was intermediate, CA125 was repeated in 3 months, risk recalculated, and the participant re-triaged. An average of 2% of participants were referred to TVS annually. Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and 2 borderline tumors with 12 in early stage (I-II). In addition, 7 endometrial cancers were detected with 6 in early stage. Thus, the positive predictive value (PPV) of the NROSS trial was 50% (17/34) for detecting ovarian cancer and 74% (25/34) for any cancer, far exceeding the minimum acceptable study endpoint of 10% PPV. As 4 ovarian cancers and 2 borderline tumors were diagnosed within a year of each participant’s last normal risk, the sensitivity for detecting ovarian and borderline cancer was 74% (17/23) and 70% of ROCA-detected cases (12/17) were in stage I-II. NROSS screening reduced incidence of late stage (III-IV) disease by 34% compared to the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) control arm and by 30% compared to US SEER values. Results of our NROSS trial contrast dramatically with those of the recently reported UKCTOCS that showed only a modest 14% early-stage shift, underlying a lack of reduction in mortality. Across multiple randomized trials of mammography, those trials that demonstrated at least a 20% late-stage incidence reduction had a significant mortality reduction, whereas those with less of a stage shift did not. Conclusions: An elevated ROCA, characterized by a significantly rising CA125, prompted referral of 2% of participants to TVS each year and required only 2 operations to detect each case of ovarian cancer, indicating that CA125 used in this way is adequately specific for effective screening. While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV and marked stage shift support further development of this strategy. Clinical trial information: NCT00539162 .

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2

BackgroundOur study aimed to establish ‘real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).MethodsOur study recruited 875...

Advances in biomarker discovery and radiological techniques for early detection of ovarian cancer

Aim: This review investigates recent advances in biomarker discovery and radiological techniques for the early detection of ovarian cancer, emphasizing the significance of early diagnosis in improving patient outcomes. Methods: A comprehensive literature review was conducted, focusing on various biomarkers, including CA125, HE4, and emerging candidates such as circulating tumor DNA and microRNA, alongside radiological imaging techniques such as ultrasound and MRI. The sensitivity and specificity of these biomarkers and imaging modalities were analyzed through clinical studies and trials. Results: Current biomarkers like CA125 and HE4 demonstrate varied sensitivities and specificities, with CA125 having low sensitivity in early stages but higher specificity. Radiological techniques provide crucial complementary information, enhancing diagnostic accuracy. Novel approaches, such as the Risk of Ovarian Cancer Algorithm (ROCA) and multivariate index assays like OVA1 and ROMA, show promise in enhancing diagnostic accuracy. Additionally, potential biomarkers, including glycoforms of CA125, autoantibodies, and methylation changes, have emerged as significant candidates for further research. Conclusion: While significant progress has been made in biomarker and radiological technique development for ovarian cancer, challenges persist in achieving the ideal sensitivity and specificity for early detection.

Development of a longitudinal two-biomarker algorithm for early detection of ovarian cancer in women with BRCA mutations

ObjectiveTo develop a longitudinal algorithm combining two biomarkers, CA125 and HE4, for early detection of ovarian cancer in women with BRCA mutations. MethodsWomen with BRCA mutations and intact ovaries were invited to participate in a novel ovarian cancer early detection prospective study. The Risk of Ovarian Cancer Algorithm (ROCA) identifying significant increases above each woman's baseline in serum CA125 and HE4 was performed every four months; abnormal risks triggered a subsequent ultrasound. The study first used a risk algorithm for only CA125, a second algorithm was developed for HE4 and finally a risk algorithm combining the two biomarkers was implemented. The ROCA strategy was compared to Standard of Care (SOC) surveillance strategy. ResultsA total of 149 women enrolled in the ROCA arm while 43 women enrolled in the SOC arm. Abnormal scores were found in 24% of ROCA CA125 tests, 16% if ROCA CA125 or the novel ROCA HE4 were used independently and reduced to 8% using the new two-marker ROCA, significantly lower than the 15% of abnormal tests seen in the SOC arm (p = 0.042). The average false positive rate among women without ovarian cancer for two-marker ROCA for referral to ultrasound was 6.6% (specificity 93.4%), and for the two-marker ROCA plus ultrasound for referral to surgical consultation was 1.7% (specificity 98.3%). ConclusionA newly developed two-marker ROCA administered every 4 months had lower call-back rates than SOC surveillance. Having established high specificity, the two-marker ROCA score deserves further evaluation for sensitivity in a larger trial.

Patient acceptability and compliance for ovarian cancer surveillance: Comparing strategies among women with BRCA mutations

Objective: To compare test acceptability and compliance of two surveillance strategies in a high-risk group of women who were all BRCA mutation carriers over a 23-month follow-up period, (1) a new surveillance strategy based on assessment of serum CA-125 and HE4 every 4 months using a Risk of Ovarian Cancer Algorithm (ROCA) and (2) standard of care (SOC) surveillance with a CA-125 blood test and a pelvic ultrasound examination every 6 months were conducted.

Statistical approaches using longitudinal biomarkers for disease early detection: A comparison of methodologies.

Early detection of clinical outcomes such as cancer may be predicted using longitudinal biomarker measurements. Tracking longitudinal biomarkers as a way to identify early disease onset may help to reduce mortality from diseases like ovarian cancer that are more treatable if detected early. Two disease risk prediction frameworks, the shared random effects model (SREM) and the pattern mixture model (PMM) could be used to assess longitudinal biomarkers on disease early detection. In this article, we studied the discrimination and calibration performances of SREM and PMM on disease early detection through an application to ovarian cancer, where early detection using the risk of ovarian cancer algorithm (ROCA) has been evaluated. Comparisons of the above three approaches were performed via analyses of the ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Discrimination was evaluated by the time-dependent receiver operating characteristic curve and its area, while calibration was assessed using calibration plot and the ratio of observed to expected number of diseased subjects. The out-of-sample performances were calculated via using leave-one-out cross-validation, aiming to minimize potential model overfitting. A careful analysis of using the biomarker cancer antigen 125 for ovarian cancer early detection showed significantly improved discrimination performance of PMM as compared with SREM and ROCA, nevertheless all approaches were generally well calibrated. Robustness of all approaches was further investigated in extensive simulation studies. The improved performance of PMM relative to ROCA is in part due to the fact that the biomarker measurements were taken at a yearly interval, which is not frequent enough to reliably estimate the changepoint or the slope after changepoint in cases under ROCA.

Feasibility, patient compliance and acceptability of ovarian cancer surveillance using two serum biomarkers and Risk of Ovarian Cancer Algorithm compared to standard ultrasound and CA 125 among women with BRCA mutations

ObjectiveWe assessed the feasibility, patient acceptability of and compliance of a new surveillance strategy for ovarian cancer surveillance in women with BRCA mutations, based on assessments of serum CA125 and HE4 every 4 months (Risk of Ovarian Cancer Algorithm (ROCA) arm), compared to Standard of Care (SOC) surveillance with CA125 blood tests and pelvic ultrasounds every 6 months. MethodsWomen were recruited 6/13/16–9/11/17 from an integrated health care system in California for this non-randomized prospective cohort study. Women were invited to participate in a novel serum biomarker surveillance strategy using ROCA or they could opt to be in the standard of care control arm with ultrasound and CA 125 every 6 months. Outcomes assessed included compliance, self-reported distress using the Impact of Event Scale (IES) and cancer anxiety using the Cancer Worry Scale. ResultsThere were 159 women in the ROCA arm and 43 in the SOC arm. Overall, compliance was higher in the ROCA arm (83.2%) than in SOC (51.9%), p < 0.0001. Based on the IES, ROCA arm women reported less feelings about intrusion and avoidance at 12 months compared to baseline; the difference approached significance for intrusion (7.6% vs 4.1% severe, p = 0.057) and was statistically significant for avoidance (20.8% vs 9.9% severe, p = 0.034). ConclusionsThis pilot demonstrated that compliance was high with blood tests performed every four months for ovarian cancer surveillance. Moreover, ROCA women had lower stress scores over time than SOC women. Given the lack of clinical utility and poor compliance shown with traditional ultrasound and CA125 tests, further investigation is warranted of longitudinal biomarker surveillance for early detection of ovarian cancer.

Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses

BackgroundTransvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4.ObjectiveThe objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses.Study DesignThis was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared.ResultsOf 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers.ConclusionOur population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women.

Complementary Longitudinal Serum Biomarkers to CA125 for Early Detection of Ovarian Cancer.

Early detection of ovarian cancer has the potential to impact mortality. A multimodal screening strategy where rising CA125 values over time, analyzed with the risk of ovarian cancer algorithm (ROCA), triggers transvaginal sonography and possible surgery has high sensitivity and specificity, but still fails to detect the 20% of early-stage cases that do not express CA125. Use of multiple biomarkers could detect cases missed by CA125. We have studied the sensitivity and lead time of a multi-marker panel (CA125, HE4, MMP-7, and CA 72-4) compared with CA125 alone. We used PRoBE design principles to select preclinical longitudinal specimens from 75 women (50 screen-positive, 25 screen-negative) who developed invasive epithelial ovarian cancer (3-5 serial specimens each) and 547 corresponding healthy controls (1-10 serial specimens each) from the ovarian cancer screening trial, UKCTOCS, in a blinded fashion. We measured the multi-marker concentrations in ultra-low serum volumes (16 μL) utilizing multiplexed bead-based immunoassays with low detection limits, high inter- and intra-assay precision, negligible cross-reactivity, and good correlation with standard immunoassays. While, at least one of the complementary biomarkers rose with CA125 in 44% (22/50) of screen-positive cases, there was no advantage in lead time over CA125. Therefore, we developed single-marker longitudinal algorithms (ROCA-like) to determine the presence of a change point to distinguish between the cases and controls. Using these algorithms, at 98% specificity, HE4 and CA72-4 identified 16% (4/25) of screen-negative cases, while MMP-7 identified none. Taken together, HE4 and CA72-4 show promise as complementary biomarkers to CA125 for longitudinal screening.

Ovarian cancer: screening and future directions.

Ovarian cancer carries a lifetime risk of approximately 2% for women and is the leading cause of death from any gynecologic malignancy. Currently, no screening program for ovarian cancer exists for the general population in the UK. This review focuses on the evidence surrounding the efficacy of current markers and discusses future improvements in screening for this disease. One-off cancer antigen 125 (CA125) measurements for detecting ovarian cancer have been well researched. However, studies have highlighted low positive predictive values (5%) and high false positive rates leading to patient anxiety and unnecessary invasive follow-up. Commonly, in the UK, CA125 is combined with transvaginal ultrasound, but there is little evidence that this approach can decrease mortality from ovarian cancer. Recently the Risk of Ovarian Cancer Algorithm, involving a combination of serial CA125 measurements and age, has been shown to detect more early stage cancers. Nevertheless, these measures are not robust in decreasing mortality from ovarian cancer and are costly to implement. Newer markers, such as human epididymis protein 4, have shown greater specificity. Its combination with CA125 and menopausal status in the Risk of Ovarian Malignancy Algorithm can predict the risk of malignancy but provides no additional benefit as a screening tool. Advanced techniques are emerging, including ultrasound molecular imaging techniques using microbubbles targeted to kinase domain receptors, and fallopian tube cytology. To reduce mortality from ovarian cancer, detection of pre-invasive lesions is imperative as ovarian cancer may develop in the fallopian tube and spread to the peritoneal cavity before being detected systemically. It seems that screening tools for ovarian cancer are currently not worthwhile for implementation into a national program. An emphasis on reducing false positives rates, associated anxiety and subsequent overdiagnosis is needed.

PMD80 - IS SCREENING FOR OVARIAN CANCER EFFECTIVE AND COST EFFECTIVE IN AUSTRIA? A MODEL-BASED ECONOMIC EVALUATION

Ovarian cancer is the seventh most common cancer in females and associated with major health and economic burden for women and the society. We aimed to evaluate the impact of different early-detection strategies for ovarian cancer on long-term clinical and health-economic consequences for the Austrian health care context. A decision-analytic Markov cohort simulation model was developed and calibrated to predict the natural history of ovarian carcinogenesis. We assessed (1) annual multimodal screening (MMS), (2) annual ultrasound screening (USS), and (3) no screening in a cohort of asymptomatic postmenopausal women during their lifetime. We used Austrian epidemiological cancer data from the Tyrolean Cancer Registry, international literature data for utilities and direct medical costs. Costs were transformed into 2017 Euros via GDP-PPP and CPI. Outcomes included the reduction in cancer mortality, (quality-adjusted) life expectancy, and the discounted incremental cost-effectiveness ratio (ICER in Euro/life-years gained (LYG), or quality-adjusted life-years (QALY)). We adopted the healthcare payer perspective and 3% annual discount rate was applied for costs and effects. A willingness-to-pay threshold of 50,000 Euro/LYG for cost effectiveness was applied. Extensive deterministic sensitivity analyses were performed. In the base-case analysis, MMS can be considered a cost-effective strategy with an ICER of 36,600 Euro/LYG. A total of 33% reduction in ovarian cancer associated mortality was achieved by MMS compared to no screening. USS resulted in higher total costs and eight times more false positive cases compared to MMS. The discounted ICERs of MMS exceeded 50,000 Euro/LYG with annual discount rates > 5%, test costs > 75 Euro or when quality of life was considered (ICUR of 62,300 Euro/QALY). Our analyses suggest that annual multimodal screening based on the Risk of Ovarian Cancer Algorithm (ROCA) in postmenopausal asymptomatic women in Austria compared to no screening is likely to be considered cost effective.

Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population.

Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the "Risk of Ovarian Cancer Algorithm" (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4-91.9] and PEB (88.5%; 95% CI, 80.6-93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6-80.8).Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726-33. ©2018 AACR.

Algorithms Used in Ovarian Cancer Detection: A Minireview on Current and Future Applications

Ovarian cancer is the 5th most common cause of cancer death among women in the US. Currently, there is no screening algorithm for asymptomatic women that has been shown to lower mortality rates. Screening is currently not recommended and has been shown to increase harm. Epithelial ovarian cancer (EOC) detection is reviewed, with a focus on high-grade serous, clear-cell, and endometrioid histotypes. A review of current literature surrounding tools used in detection of ovarian cancer will be presented. CA 125, HE4, risk of ovarian cancer algorithm (ROCA), risk of malignancy algorithm (ROMA), risk of malignancy (RMI), OVA1, and future potential biomarkers are reviewed. Screening and early identification of EOC is currently managed as a single disease entity. However, recent evidence has shown ovarian cancer varies with relation to cellular origin, pathogenesis, molecular alterations, and prognosis, depending on histotype. There is a clear need for future studies identifying histotype-specific preclinical tumor markers to aid in detection and improvement of survival rates.

Serum Biomarker Based Algorithms in Diagnosis of Ovarian Cancer: A Review.

Epithelial ovarian cancer accounts for more than 90% of ovarian tumours and continues as a leading cause of death from gynaecological malignancies. It is often difficult to differentiate a benign ovarian mass from malignant ones. Invasive histopathological biopsy is used as the gold standard diagnostic tool to diagnose cancer in patients with ovarian mass. A wide spectrum of Biomarkers were tried in various studies to develop a non invasive diagnostic tool, out of which HE4 and CA 125 remain the only clinically useful biomarker. Consequently various Biomarker based algorithms i.e. Risk of Malignancy Index, risk of ovarian cancer algorithm, OVA1, risk of malignancy algorithm were generated that have been developed to assess the risk of a mass being malignant. These algorithms help in timely triage of patients. Recently in 2016 FDA cleared Ova1 test (OVERA) with CA 125-II, HE4, apolipoprotein A-1, FSH, and transferring (Sensitivity 91% and Specificity 69%) as a referral or Triage test in patients presenting with ovarian mass. Combination of protein and circulating Micro RNA analysis in blood, could provide a comprehensive screening and diagnostic panel, in management of patients presenting with ovarian mass in one clinical setting.

Abstract IA15: Early detection of ovarian cancer: An update

Abstract IA15: Early detection of ovarian cancer: An update

Abstract LB-176: HE4 antigen-autoantibody complexes complement CA125 for detecting early stage ovarian cancer and can be elevated with CA125 in preclinical ovarian cancer

Abstract Early detection of ovarian cancer could significantly improve patient outcomes. Serial monitoring of CA125 with the Risk of Ovarian Cancer Algorithm (ROCA) can attain sufficient specificity for cost effective screening when combined with transvaginal sonography, but not all early stage disease can be detected with CA125 alone. Sensitivity could be improved by combining CA125 with other biomarkers. Different autoantibodies (AAb) have been evaluated including TP53 AAb, but antigen-autoantibody (Ag-Ab) complexes have received less attention. We have measured AAb reactive with the serum biomarker human epididymal protein 4 (HE4) and Ag-Ab complexes containing HE4 in sera from patients with epithelial ovarian cancer at the time of conventional diagnosis and from asymptomatic women with or without ovarian cancer enrolled in the Normal Risk Ovarian Cancer Screening Study (NROSS). We developed a Magplex-based immunoassay to measure autoantibodies against HE4 in human serum. Immune complexes were dissociated in pH3 buffer for 30 min, separated on a desalting spin column and assayed for HE4 AAb. When sera from patients with early stage (I-II) ovarian cancer (n=72) and from healthy women (n=213) in the NROSS trial were assayed for free HE4 autoantibody, 4 cases (5.6%) had autoantibodies against HE4 at 98% specificity using a cut-off of 80 ng/mL. HE4 Ag-Ab complexes were detected in sera from 29 of 72 ovarian cancer cases (40.3%) at early stage (I-II) at the time of conventional diagnosis using a cut-off of 730 ng/mL to achieve a specificity of 98.2%. Complementarity was observed between HE4 Ag-Ab complexes and CA125 levels in early stage cancer cases. Either HE4 Ag-Ab complexes or CA125 were detected in 58 of 72 sera (80.2%) in cancer cases. This result suggests that combining assays for HE4 Ag-Ab complexes and for CA125 might improve detection of early stage ovarian cancer. To determine whether HE4 Ag-Ab complexes could be detected at an earlier interval than CA125, we assayed preclinical serum samples from 16 ovarian cancer patients, 2 women with endometrial cancer and 5 with benign pelvic disease from the NROSS study. Elevated HE4 Ag-Ab complexes were detected in 5 of 16 ovarian cancer cases (31.2%) and exhibited a strong correlation with rising CA125. Free HE4 AAb was found in 2 cases immediately before diagnosis. Consequently, HE4 AAb and Ag-Ab complexes, in contrast to TP53 AAb, appear to arise at the time of CA125 elevation, but can still detect early stage disease, complement CA125 and deserve further evaluation for screening and early detection. Citation Format: Wei-Lei Yang, Zhen Lu, Karen H. Lu, Usha Menon, Makoto Kobayashi, Samir Hanash, Steven Skates, Robert C. Bast. HE4 antigen-autoantibody complexes complement CA125 for detecting early stage ovarian cancer and can be elevated with CA125 in preclinical ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-176.

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.

Ovarian Cancer Prevention and Screening.

There has been much progress in ovarian cancer screening and prevention in recent years. Improved tools that combine genetic and epidemiologic factors to predict an individual's ovarian cancer risk are set to become available for tailoring preventive and screening approaches. The increasing evidence on tubal origins of a proportion of ovarian cancer has paved the way to use of opportunistic bilateral salpingectomy at tubal ligation and hysterectomy in the general population. Clinical trials are in progress to estimate the long-term effects on endocrine function. In women at high risk, risk reducing salpingo-oophorectomy remains the standard of care with the current focus on management of resulting noncancer outcomes, especially sexual dysfunction in younger women. This has led to evaluation of early bilateral salpingectomy and delayed oophorectomy in this population. Meanwhile, modeling suggests that BRCA mutation carriers should consider using the oral contraceptive pill for chemoprevention. In the general population, the largest ovarian cancer screening trial to date, the UK Collaborative Trial of Ovarian Cancer Screening reported a stage shift with annual multimodal screening using the longitudinal CA 125 Risk of Ovarian Cancer Algorithm but not with annual transvaginal ultrasound screening. There was no definitive mortality reduction with either screening strategy compared with no screening. Further follow-up until December 2018 in now underway. Stage shift and higher rates of optimal cytoreduction were also reported during 3- to 4-monthly multimodal screening in the United Kingdom and U.S. high-risk screening trials. Although all agree that there is not yet evidence to support general population screening, recommendations for high-risk screening vary between countries. A key finding from the screening trials has been the better performance of longitudinal algorithms compared with a single cutoff for CA 125. A major focus of ovarian cancer biomarker discovery work has been tumor DNA markers in both plasma and novel specimens such as cervical cytology samples.