Effect of Screening on Ovarian Cancer Mortality

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recently reported a reduction in the average overall mortality among ovarian cancer patients screened with an annual sequential, multimodal strategy that tracked biomarker CA125 over time, where increasing serum CA125 levels prompted ultrasound. However, multiple cases were documented wherein serum CA125 levels were rising, but ultrasound screens were normal, thus delaying surgical intervention. A significant factor which could contribute to false negatives is that many aggressive ovarian cancers are believed to arise from epithelial cells on the fimbriae of the fallopian tubes, which are not readily imaged. Moreover, because only a fraction of metastatic tumors may reach a sonographically-detectable size before they metastasize, annual screening with ultrasound may fail to detect a large fraction of early-stage ovarian cancers. The ability to detect ovarian carcinomas before they metastasize is critical and future efforts towards improving screening should focus on identifying unique features specific to aggressive, early-stage tumors, as well as improving imaging sensitivity to allow for detection of tubal lesions. Implementation of a three-stage multimodal screening strategy in which a third modality is employed in cases where the first-line blood-based assay is positive and the second-line ultrasound exam is negative may also prove fruitful in detecting early-stage cases missed by ultrasound.

Ovarian cancer typically presents late and has a poor prognosis. Ovarian screening aims to reduce mortality from the disease by detecting and treating women at an earlier, presymptomatic stage. The paper by Menon et al.1 published in BJOG more than a decade ago, set the stage for a multimodal approach to ovarian cancer screening, whereby a combination of CA125 levels and ultrasound scan findings could identify women at risk of the disease. Subsequent studies have not only informed the current management of women with suspected ovarian cancer but will also determine whether ovarian cancer screening can save lives. This commentary documents the ovarian screening story so far from inception to current day as we await the results from UKCTOCS, the largest ovarian cancer screening trial conducted to date. Ovarian cancer is known as the ‘silent killer’ because it only becomes symptomatic in its late stages. Compared with other common cancers, women diagnosed with ovarian cancer have a relatively poor prognosis. The overall 5-year survival rate of 42.9% masks vast differences in prognosis for those women presenting with Stage I disease compared with those with Stage IV disease.2 Since the late 1980s there has been a steady improvement in 5-year survival in the relatively small group of women who present with Stage I disease from 80% in 1987–91 to 92% in 2005–08.3 Changes in survival for the much larger proportion of women who present with Stage III and IV disease have been more modest. The 5-year survival rate for those with stage IV disease, however, stands unchanged at around 5%.3 These dismal survival rates for most women with ovarian cancer have stimulated enormous research effort aimed at identifying and treating women with early-stage disease. The hypothesis is that ovarian cancer screening may pick up early, asymptomatic disease in apparently healthy women that is then more amenable to surgical cure than disease that presents with symptoms. A major challenge when screening an asymptomatic population is that the proportion of true positives is extremely low given that the age-standardised incidence of ovarian cancer is only 16 per 100 000.4 Furthermore, the consequence of a positive screen is referral for laparoscopy/laparotomy with its incumbent risks. Hence, it has been suggested to ensure an acceptable false-positive rate any test needs to achieve a specificity of over 99.6%.5 This equates to nine women being offered further investigation or treatment for every woman diagnosed with an ovarian malignancy. This degree of specificity has not been achieved by any individual marker alone. To overcome this obstacle a number of strategies incorporating multiple markers have been proposed since the 1980s. The CA125 antigen was discovered in the early 1980s as part of an effort to develop a monoclonal antibody that could be used for immunotherapy of ovarian cancer.6 In this regard CA125 appeared to be relatively specific to epithelial ovarian cancers, being expressed in up to 80% of these cancers. Furthermore, it was found in the serum of women with ovarian cancer, although it can also be raised in a number of other cancers as well as some benign conditions. Although targeting CA125 has not proved to be therapeutically successful,7, 8 it was to prove a much more useful diagnostic/predictive biomarker. Its promise as a marker of early disease was shown in studies led by Zurawski in the 1980s. Serum CA125 levels were rarely elevated in healthy postmenopausal women9 but in up to 20% of cases, raised CA125 could be seen at least 2 years before ovarian cancer diagnosis.10 Alone, a raised CA125 has a high specificity but the likelihood of a woman having an occult cancer with a raised CA125 (Positive Predictive Value; PPV) remains low. PPV and sensitivity are determined in large part by the cut-offs used. Early studies by Klug et al. had determined that if a cut-off of 35 U/ml was used, then 82% of women with cancer, 6% of women with benign disease and 1% of normal women would have a raised CA125. Increasing the cut-off to 65 U/ml saw the percentage of ovarian cancer patients with a positive CA125 fall to 73% but those with benign disease and normal disease drop to 2% and 1%, respectively. To ensure that no women with benign disease would be included would necessitate the reference value to be set at 220 U/ml, which would mean that nearly 40% of women with ovarian cancers would be missed. Clearly serum CA125 measurement as a sole test was unlikely to offer the assurance of a low false-positive and false-negative rate needed to roll-out population screening. The 1950s saw the development of medical ultrasound and with it the ability to characterise gynaecological masses. Fittingly it was one of the first uses demonstrated by the seminal work of Ian Donald, Professor of Midwifery and a pioneer of diagnostic ultrasound.11 However, it would not be until the 1970s that this diagnostic tool was perceived to be a viable method for early detection in its own right, rather than a simple adjunct to the clinical examination of the symptomatic woman. Advances in ultrasound technology meant that by the mid-1970s lesions of 1 cm in diameter, which would normally be undetectable clinically, could be defined by ultrasound.12 Furthermore, various criteria to distinguish benign from malignant lesions with accuracies ranging from 70 to 90% were proposed.13-15 In 1982, Campbell et al.16 suggested that because ultrasound was able to define ovarian size accurately, ovarian volume could be a useful discriminator for potential ovarian disease in postmenopausal women. This strategy was studied in a large-scale prospective study of 5479 women followed over 8 years.17 Campbell et al. were able to identify 100% of the women that developed primary ovarian cancer within this time frame. The specificity of this procedure was 97.1% with a PPV of 1.5%, i.e. odds of a positive screen result representing a primary cancer of 1 in 67. Although Campbell et al. were able to demonstrate the utility of transabdominal ultrasound to identify women with asymptomatic ovarian masses, the inability to satisfactorily distinguish those with benign from malignant lesions underlies the high false-positive rates. The first approach proposed to reduce false positives was that only women with increasing ovarian volumes at a second scan, who had previously demonstrated either ovarian volumes >96th centile or abnormal morphology, e.g. cystic areas, should be offered surgery.18 Under this strategy, the PPV rose to 2.0%. The second approach came with the advent of transvaginal and Doppler ultrasound. Transvaginal ultrasound provided a higher resolution and so had the ability to detect abnormal morphology in smaller ovaries, while Doppler ultrasound provided the ability to visualise areas of neovascularisation more common in malignant lesions. Small studies showed promising results for the detection of women with ovarian pathology and the distinction of benign from malignant disease using transvaginal ultrasonography.19 The University of Kentucky Ovarian Cancer Screening Project was the first large-scale prospective trial to investigate whether transvaginal ultrasound assessment of ovarian volume could be used in ovarian cancer screening in pre- and postmenopausal women. In total, 90 women (1.4%) with persistent abnormalities were offered surgery to remove the affected ovary; six of whom were discovered to have a primary ovarian cancer. Overall, this strategy resulted in a sensitivity of 85.7%, specificity of 98.7% and 14 false positives for every woman with screen-detected ovarian cancer. Forgoing the possibility that the removal of benign ovarian masses with the potential for malignant transformation may lead to a resultant late fall in mortality from ovarian cancer, there remained a need for strategies to reduce the proportion of false positives. Jacobs et al.5 were the first to describe a multimodal approach for ovarian cancer screening in 1988. In their initial study, 1010 healthy postmenopausal women were offered serum CA125 measurement and a clinical pelvic examination. If either the clinical or biochemical assessment was abnormal women were offered a transabdominal ultrasound scan to assess ovarian volume. When CA125 measurements were considered individually, specificity was 97%, but when ultrasonography was added as a secondary test, specificity increased to 99.8%. This two-stage strategy was validated by a larger prevalence study in which 22 000 women were screened. With this approach equally high specificity and PPVs were achieved for a sensitivity of 79% at 1 year of follow up when a cut-off of 30 U/ml was used.20 The same cohort was then randomised to annual incidence screening or no further screening and followed up over 8 years. Initially, women recruited to this study in the late 1980s were offered transabdominal ultrasonography on entry. Subsequently, as evidence of the superiority of the transvaginal route in terms of image resolution with high acceptability among patients became available, follow-up scans were offered transvaginally. In contrast to the Kentucky Ovarian Cancer Screening Project, only postmenopausal women who had an abnormal CA125 were offered an ultrasound. In this preselected group of women, ultrasonographical assessment led to a much higher PPV of 21.3% and 23.75%, respectively, when ovarian volume and morphology were considered separately.1 Furthermore, there appeared to be minimal loss in sensitivity or specificity with this approach (sensitivity 89.5% and 100%; specificity 93.75% and 93.95% when considering ovarian volume and morphology, respectively). This was a breakthrough as it demonstrated that the target of nine healthy women being investigated or treated for every woman with cancer identified by screening was not only attainable but could be improved upon. This landmark finding stimulated a new wave of research to refine the detection of early ovarian cancers by screening. While early detection is fundamental, it is only relevant if it can translate into lives saved. Further analysis showed that screening identified proportionately more early-stage ovarian cancer (31.3% versus 10%), although the difference between the two groups was not statistically significant (P = 0.171).21 Nevertheless, the histological grade was lower and length of survival following randomisation was longer for women with ovarian cancer in the screened group (P = 0.02 and P = 0.01, respectively). Despite large numbers, the study was underpowered to detect a difference in mortality among screened and unscreened women, setting the scene for a still larger trial to answer this crucial question. Until 1998 there had been 25 prospective studies of ovarian cancer screening but no comparison with an unscreened population.22 Both ultrasound-based and multimodal screening strategies appeared to be able to identify asymptomatic women with ovarian cancer at early stages, but the clinical significance of this in terms of survival and mortality remained unknown. Furthermore ultrasound-based techniques appeared to offer higher sensitivity although at the cost of lower specificity, than multimodal screening. Notably, most of the women who received diagnostic surgery as a result, were found to have a benign gynaecological condition. Again the clinical impact of surgery in these circumstances is unclear. To answer this question UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening), the largest randomised control trial to date of an ovarian cancer screening strategy, involving over 200 000 women followed over 7 years was established. This study primarily aimed to ascertain whether screening, be it by a multimodal or imaging-only approach, could have an impact on ovarian cancer mortality. The trial would also assess the physical and psychological impact of screening, volunteer compliance and cost-effectiveness to inform decisions about the use of a national screening programme. As a result of further analysis of data from the pilot study, the multimodal arm had a new weapon in its armamentarium: the Risk of Ovarian Cancer algorithm (ROCA).23 This algorithm stratifies patients according to their CA125 trajectory rather than using a single threshold of 30 U/ml and is recalculated with every successive CA125 result. It was designed to improve sensitivity for the detection of early-stage cancers where earlier intervention could offer the most survival benefit and where CA125 is >30 U/ml in only 57% of cases, compared with 84% of late-stage cancers.24 Using the ROCA, a woman with a low baseline CA125 that suddenly rose would be identified as at risk of ovarian cancer, even if the absolute level remained modest, while a woman with a static but high CA125 would be deemed low risk. Retrospective testing of the algorithm on a Swedish cohort demonstrated high levels of sensitivity and specificity, which were subsequently verified by a prospective cohort of over 16 000 women between 1995 and 2000.25-27 More recently, ROCA was employed by Lu et al.28 in a large single-arm prospective study, which like UKCTOCS triaged women deemed high risk by ROCA to transvaginal ultrasound. Encouragingly, this protocol resulted in <1% of women being referred for surgery, giving it a specificity of 99.9% (95% confidence interval 99.7–100%) and a PPV of 40% (95% confidence interval of 12.2–78%).28 This equates to just over two women requiring surgery for every woman diagnosed with cancer. The pilot study published in BJOG,1 although primarily aimed at providing the platform for general population screening for postmenopausal women in whom 90% of ovarian cancer occurs, also provided the basis for studies in a second group of women with a family history of ovarian cancer. Some women are diagnosed with gene faults that increase their risk of ovarian and also breast cancer, notably defects in the BRCA1 and BRCA2 genes, but others have unidentified gene faults and/or are labelled as ‘at risk’ by virtue of their strong family history. Given the poor prognosis of ovarian cancer presenting symptomatically, women at high risk of ovarian cancer are currently offered risk-reducing prophylactic salpingo-oophorectomy (RRSO) to prevent incident ovarian cancers and reduce their risk of premenopausal breast cancer. When performed in young women, such surgery inevitably results in infertility and premature menopause and so screening may facilitate women safely delaying surgery until after their natural menopause. The United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) recruited 3563 women with a 10% or greater lifetime risk of ovarian cancer between 2002 and 2008 to determine whether screening could be a viable alternative to RRSO. Reports from the first phase of the UKFOCSS study suggest that a negative screen can reliably reassure women (99.9% probability) that they will not develop ovarian cancer in the subsequent year. Screening was able to detect incident disease with a sensitivity of >80% and may reduce the proportion of stage IIIc disease.29 Phase II of the study drew on the successes of the UKCTOCS by stratifying patients according to ROCA using a computerised system, which would prompt investigators to repeat blood tests in women with intermediate risk and organise scans/referrals in women who were high risk. Additionally, screening intervals were reduced to 4 months to reduce false negatives.29 These amendments to the study design resulted in no interval cancers in this phase with no significant increase in the proportion of women referred.30 PPV in this phase was 13%. All women diagnosed with ovarian cancer as a result of screening went on to have optimal cytoreduction at surgery and survival was increased by 43 months.30 However, until such time as the efficacy of screening in this context has been fully evaluated, RRSO will remain the recommended intervention in women with a genetic predisposition to ovarian cancer. This research1 has also benefitted women with suspected ovarian cancer. The search for screening strategies which could be translated from women with clinically apparent cysts to those with occult disease fortuitously led to the development of the ‘Risk of Malignancy’ Index (RMI).31 This simple algorithm combines three factors that are independently predictive for an increased risk of ovarian cancer; menopausal status (scored 1or 3), serum CA125 and ultrasound features of the cyst (scored 0, 1 or 3). The product of these three criteria results in a score that can be used to provide a quantitative and reproducible assessment of likelihood that a symptomatic patient does indeed have an ovarian malignancy. Cut-offs can be useful tools for clinical decision making, e.g. referral to tertiary gynaecological oncology centres for surgery. To put this into context an RMI of 200 equates to a likelihood ratio of 42.1 of malignant disease and a likelihood ratio of 0.22 of benign disease; a 280-fold difference.32 Although the effect of the use of the RMI on the prognosis of a woman diagnosed with ovarian cancer has not been formally assessed, many studies have demonstrated the survival benefit of being treated by a specialist gynaecological oncologist.33 Where resources are limited, adjusting cut-offs can ensure only those at highest risk will be referred to tertiary centres. RMI remains the most widely used and evidenced stratification tool34 and in the UK, National Institute for Health and Care Excellence (NICE) guidance suggests the use of this tool to assess all women presenting to primary and secondary care with suspected ovarian cancer. The beauty of the RMI is its simplicity, which has helped it to stand the test of time. Accurate ultrasound assessment of an adnexal mass is fundamental to the success of the RMI. Substituting the subjective assessment by a skilled sonographer35-37 with a score defined by the presence or absence of certain key features facilitates reproducibility. However, the diagnostic test accuracy of the RMI appears lower in external validation studies than the original publications.38, 39 The International Ovarian Tumour Analysis (IOTA) collaboration was formed to encourage the development of better indices by standardising ultrasound reporting across research groups and prospectively collecting a database of features observed in cancerous and benign cysts from which new models could be developed and validated. Initial reports suggest that IOTA models (including simple rules and LR2) demonstrate better sensitivity for the detection of ovarian cancer with a lower false-positive rate than the RMI.38, 40 The challenge is to demonstrate the translation of highly sophisticated ultrasound protocols into ‘real-life’ clinical practice in different centres around the world.41 Women's symptoms have also gained attention as the search for strategies to reduce mortality from ovarian cancer through early detection has gathered pace. To this end, Goff et al.42 developed a symptom index using questionnaire data from women with and without ovarian cancer who were participating in a screening study. Over two-thirds of women had symptoms between 3 and 36 months before diagnosis. Using the Goff index the sensitivity for ovarian disease is 66.7% for a specificity of 90%, which has been validated in a number of external studies.43-45 This has formed the basis of the recommendation in the UK by NICE that symptomatic women are identified as at risk of ovarian cancer and offered further assessment. Much of the criticism surrounding general population screening for ovarian cancer is that low PPV would lead to the overtreatment of large numbers of women. A recent study has demonstrated that the prevalence of ovarian cancer among symptomatic women is ten times higher than that seen in asymptomatic women.46 Furthermore, when offered assessment with CA125 and transvaginal ultrasound at presentation, symptomatic women had lower tumour burdens, which were then more amenable to complete surgical resection, though unfortunately not earlier stage disease than those presenting to gynaecological oncologists by traditional routes. It is suggested that detecting women with lower tumour burdens may account for the increased survival of women diagnosed with stage 3 disease in the first randomised control trials of ovarian cancer screening.47 Data from UKCTOCS showed that the risk of a woman with an adnexal mass developing ovarian cancer within 3 years is 1 in 22.48 Therefore screening asymptomatic women for ovarian cancer will no doubt increase the numbers of women with incidental findings. On the one hand this has offered an unprecedented opportunity to conduct a number of nested cohort studies to assess the natural history of the conditions readily detectable by ultrasonography. But on the other hand, incidental findings cause and will resources in terms of and/or surgery. The of cancers which would not have clinically is a in The incidental finding of cancer is Although has been widely as a risk for cancer in women with postmenopausal the significance of a in the asymptomatic and so its potential use as a screening tool for cancer, is from UKCTOCS suggest that the cut-off for the detection of women with asymptomatic cancer or needs to be in the of as to the used cut-off of in symptomatic But even with an of the risk of cancer in an asymptomatic woman remains low at just Further studies will be needed to the value of early detection of cancer, the acceptability of screening and In the of the roll-out of an ovarian cancer screening that pelvic the need for such studies will more saw a to the cause of ovarian cancer screening. The and Ovarian Cancer Screening which randomised women to ovarian cancer screening, that there was no overall mortality benefit for annual with CA125 and transvaginal ultrasound rate confidence interval Furthermore there was no difference in survival or stage at between the screened and unscreened Additionally, this intervention resulted in more women to from to potential ovarian cancer. in study design between and UKCTOCS provide the that screening may offer for women with ovarian cancer. of the protocol that the study used a single cut-off CA125 level rather than the ROCA to identify women at had clinical in to with positive and follow up for many years after the screening were which time they to Initial data from UKCTOCS have been with of the ovarian cancers identified being as providing evidence for a in screened have suggested that these strategies identify and I cancers which may have clinically apparent within a II cancers representing up to of ovarian cancers diagnosed in symptomatic women, over two-thirds of the ovarian cancers identified by ultrasonography in UKCTOCS were or I screening appears to be more specific for II cancers but screening have had a number of interval cancers all of which were II cancers. These findings are in with the current that ovarian cancers may in the rather than from ovarian the women diagnosed with II cancers, had no adnexal pathology and were diagnosed at an It has been suggested that differences in the that CA125 was used to determine screen in the two trials for the of sensitivity of the trial to detect early Although of the algorithm to the data to any data from the Risk Ovarian Screening Study where women from the general population were using the ROCA followed by transvaginal ultrasound scan if they as high showed specificity and high PPV for the detection of ovarian It is that the UKCTOCS trial will answer whether CA125 as a test will be to translate to in ovarian cancer mortality. If UKCTOCS does not demonstrate survival or mortality benefit from general population ovarian cancer screening, it is to that any randomised trials will be to this given the to such a study The of any benefit from ovarian cancer screening in may be by poor sensitivity of screening to detect true early disease. disease suggests that cancers 90% of the of opportunity where intervention may prognosis at and may have been present for between 8 and years before detectable by current CA125 current screening strategies may detect disease at a that is late to disease The prospective of serum in asymptomatic women may result in the of more relevant of early disease than have been suggested by the comparison of from women with clinically detectable cancers with studies aimed at identifying an from the serum of women who subsequently developed ovarian cancer in UKCTOCS are The years have seen a in the of ovarian cancer, its natural history and the of mortality. Despite in and there has been in the prognosis for women with disease. with the ability of ovarian cancer screening strategies to the of disease to earlier stages, which may translate to better clinical and reduced mortality. screening and ultrasound-based have been shown to be and specific for detecting ovarian cancer but whether these in will provide lead time to the of the disease remains to be success will on the of the multiple and to ensure that research will for better that can be translated into clinical It is that and to the and on the by the high compliance rates seen in the screening studies to work mortality from ovarian cancer. have no to and this was to this is a and is an at the Institute of Cancer University of

Screening for Familial Ovarian Cancer: A Ray of Hope and a Light to Steer by

ImportanceOvarian cancer is relatively rare but the fifth-leading cause of cancer mortality among United States women.ObjectiveTo systematically review evidence on benefits and harms of ovarian cancer screening among average-risk women to inform the United States Preventive Services Task Force.Data SourcesMEDLINE, PubMed, Cochrane Collaboration Registry of Controlled Trials; studies published in English from January 1, 2003, through January 31, 2017; ongoing surveillance in targeted publications through November 22, 2017.Study SelectionRandomized clinical trials of ovarian cancer screening in average-risk women that reported mortality or quality-of-life outcomes. Interventions included transvaginal ultrasound, cancer antigen 125 (CA-125) testing, or their combination. Comparators were usual care or no screening.Data Extraction and SynthesisIndependent critical appraisal and data abstraction by 2 reviewers. Meta-analytic pooling of results was not conducted because of the small number of studies and heterogeneity of interventions.Main Outcomes and MeasuresOvarian cancer mortality, false-positive screening results and surgery, surgical complications, and psychological effects of screening.ResultsFour trials (N = 293 587) were included; of these, 3 (n = 293 038) assessed ovarian cancer mortality, and 1 (n = 549) reported only on psychological outcomes. Evaluated screening interventions included transvaginal ultrasound alone, transvaginal ultrasound plus CA-125 testing, and CA-125 testing alone. Test positivity for CA-125 was defined by a fixed serum level cutpoint or by a proprietary risk algorithm based on CA-125 level, change in CA-125 level over time, and age (risk of ovarian cancer algorithm [ROCA]). No trial found a significant difference in ovarian cancer mortality with screening. In the 2 large screening trials (PLCO and UKCTOCS, n = 271 103), there was not a statistically significant difference in complete intention-to-screen analyses of ovarian, fallopian, and peritoneal cancer cases associated with screening (PLCO: rate ratio, 1.18 [95% CI, 0.82-1.71]; UKCTOCS: hazard ratio [HR], 0.91 [95% CI, 0.76-1.09] for transvaginal ultrasound and HR, 0.89 [95% CI, 0.74-1.08] for CA-125 ROCA). Within these 2 trials, screening led to surgery for suspected ovarian cancer in 1% of women without cancer for CA-125 ROCA and in 3% for transvaginal ultrasound with or without CA-125 screening, with major complications occurring among 3% to 15% of surgery. Evidence on psychological harms was limited but nonsignificant except in the case of repeat follow-up scans and tests, which increased the risk of psychological morbidity in a subsample of UKCTOCS participants based on the General Health Questionnaire 12 (score ≥4) (odds ratio, 1.28 [95% CI, 1.18-1.39]).Conclusions and RelevanceIn randomized trials conducted among average-risk, asymptomatic women, ovarian cancer mortality did not significantly differ between screened women and those with no screening or in usual care. Screening harms included surgery (with major surgical complications) in women found to not have cancer. Further research is needed to identify effective approaches for reducing ovarian cancer incidence and mortality.

The effect on mortality of screening for lung cancer with modern chest radiographs is unknown. To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed. Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009. Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality. Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10). Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care. clinicaltrials.gov Identifier: NCT00002540.

5001 Background: Ovarian cancer is among the five leading causes of cancer death in women in the United States. Women diagnosed with early stage disease have significantly improved survival compared to women diagnosed with advanced ovarian cancer. However, the effect on mortality of screening for the early detection of ovarian cancer with CA-125 and transvaginal ultrasound (TVU) is unknown. We evaluated the effect on mortality of screening for ovarian cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: PLCO is a randomized controlled trial involving 10 screening centers across the U.S. that recruited 78,216 women aged 55-74 years. Women were randomized to receive either annual screening(intervention arm; 39,105 participants) or usual care (39,111 participants) between November 1993 and July 2001. Women in the intervention arm were offered annual CA-125 testing for6 years and TVU for 4 years. Participants and their health care providers received the screening test results and managed evaluation of abnormal results. All participants were followed for up to 13 years for cancer diagnoses and death. The primary outcome was ovarian cancer mortality. Secondary outcomes included ovarian cancer incidence and complications associated with screening exams and diagnostic procedures. Results: Ovarian cancer was diagnosed in 212 women in the intervention arm and 176 in the usual care arm, for a rate ratio of 1.21 (95% Confidence Interval (CI) 0.99 – 1.48). There were 118 deaths from ovarian cancer in the intervention arm and 100 in the usual care arm, for a mortality rate ratio of 1.18 (95% CI 0.91-1.54). Of 3,285 women undergoing surgery following a false positive exam, 166 encountered at least one serious complication. Deaths from all other causes (excluding ovarian, colorectal and lung cancer) were 2,924 and 2,914 in the intervention and usual care arms, respectively. Conclusions: Screening simultaneously with CA-125 and TVU did not reduce ovarian cancer mortality in women from the general population, and there was evidence of harm from diagnostic evaluation following a false positive screening test.

Extended mortality results for ovarian cancer screening in the PLCO trial with median 15 years follow-up

BACKGROUND: Cancer antigen 125 (CA125) is a membrane bound glycosylated mucin which has been reported to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening with CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 thereby improving its performance as an ovarian cancer screening biomarker. We developed and conducted internal and external validation of two prediction models (linear and dichotomous) of circulating CA125 among postmenopausal women using 28,842 controls without ovarian cancer in four large population-based studies. METHODS: We identified controls from three prospective cohort studies, including Prostate, Lung, Colorectal, and Ovarian (PLCO, n=26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n=861), and the Nurses' Health Studies (NHS, n=164) as well as one population-based case-control study, the New England Case Control Study (NEC, n=1,000). CA125 was measured using the CA125II assay in PLCO, NHS, and NEC. Meso Scale Discovery (MSD) platform was used to measure CA125 in EPIC. The MSD assay values were recalibrated to the CA125II scale based on 534 NEC controls with both measurements. CA125 levels were log-transformed to achieve normal distribution or dichotomized by the upper limit of normal (35 U/ml). The prediction models were developed and internally validated using postmenopausal controls in PLCO, and then were externally validated using postmenopausal controls in EPIC, NHS and NEC. The prediction models were developed using stepwise linear or logistic regression with &amp;lt;0.15 as significance level for entry and retention considering factors which have been previously reported to be associated CA125 in postmenopausal women as candidate predictors (age, race, body-mass index (BMI), smoking status and duration, age at menarche, oral contraceptive use, party, age at menopause, time since menopause, hormone replacement therapy (HRT) use and duration, family history of ovarian or breast cancer, previous history of cancer, previous history of benign ovarian cyst, history of endometriosis). We then evaluated the performance of the model in the independent validation datasets. RESULTS: The linear CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, parity, age at menopause, and duration of HRT use as predictors, explaining 5% of the variability of log-transformed CA125 levels. The correlation coefficient of the measured and predicted log-transformed CA125 was 0.18 in the PLCO testing dataset, and showed comparable correlations across the independent validation datasets (0.14-0.16). The dichotomous CA125 prediction model included age, race, BMI, duration of HRT use, and hysterectomy as predictors with an AUC of 0.63 in the PLCO testing dataset and 0.71 in NEC. CONCLUSION: We developed linear and dichotomous circulating CA125 prediction models in postmenopausal women that can form the foundation for creating personalized thresholds of CA125. However, other factors should be considered to increase the predictive capacity of the model. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Renée T. Fortner, Allison F. Vitonis, Hidemi Yamamoto, Raina N. Fichorova, Daniel W. Cramer, Rudolf Kaaks, Shelley S. Tworoger, Kathryn L. Terry. DEVELOPMENT AND VALIDATION OF CIRCULATING CA125 PREDICTION MODEL IN POSTMENOPAUSAL WOMEN WITHOUT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-013.

Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: Findings from the initial screen of a randomized trial

Biomarkers for diagnosis: looking for change.

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 16/46/01, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S0140-6736(21)00731-5 Summary Background Ovarian 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. Methods In 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. Findings Between 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. Interpretation The 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. Funding National Institute for Health Research, Cancer Research UK, and The Eve Appeal. Funding This publication was funded by the Health Technology Assessment programme as a part of award number 16/46/01. This article reports on one component of the research award Long term impact of screening on ovarian cancer mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/16/46/01] DOI https://doi.org/10.1016/S0140-6736(21)00731-5

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial

Many biomarkers have been evaluated as potential early detection markers for ovarian cancer. Better understanding of factors associated with inter-individual variation in circulating concentrations of these biomarkers is useful for optimizing their clinical utility for early detection. The study objective was to characterize the associations of sociodemographic-, lifestyle-, and health-related factors in relation to circulating ovarian biomarker concentrations in cancer-free women. The associations between the independent variables and concentrations of 20 biomarkers were examined in a cross-sectional study of 913 women without ovarian cancer who participated in the ovarian cancer screening arm of the Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial. Older age was significantly associated with trends in concentrations of ten biomarkers, eight that increased with age (human epididymis protein 4 [HE4], beta-2-microglobulin [B2M], epidermal growth factor receptor [EGFR], insulin-like growth factor binding protein 2 [IGFBPII], kallikrein-related peptidase [KLK6], mesothelin [MSLN], matrix metalloproteinase-3 [MMP3], and spondin 2 [SPON2]) and two that decreased with age (insulin-like growth factor 2 [IGFII] and inter-alpha-trypsin inhibitor heavy chain H4 [ITIH4]). Compared to women with no family history of breast or ovarian cancer, those with a positive family history had significantly higher concentrations of B2M, EGFR, and hepcidin and lower concentrations of cancer antigen 125 (CA125) and cancer antigen 72.4 (CA72.4). Post hoc case-control comparisons showed case-control heterogeneity concentrated in specific biomarkers; for example, case-control differences for cancer antigen 15.3 (CA15.3) were statistically significant for all 11 independent variables. Significant trends were observed between age and circulating concentrations of 10 of the 20 biomarkers studied. The strong, consistent findings with age support the need to consider age when assigning thresholds for biomarkers being evaluated for the early detection of ovarian cancer. Integrating data from cancer cases provides valuable context for assessing the generalizability of findings.

Recent advances in the biomarkers for epithelial ovarian cancer

Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial. Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction. Pathology tissue specimens were obtained for prostate cancer (n = 1,052), lung cancer (n = 434), colorectal cancer (n = 675) and adenoma (n = 658), ovarian cancer and borderline tumors (n = 212), breast cancer (n = 870), and bladder cancer (n = 204). The process of creating this resource was complex, involving multidisciplinary teams with expertise in pathology, epidemiology, information technology, project management, and specialized laboratories. Creating the PLCO tissue resource required a multistep process, including obtaining medical records and contacting pathology departments where pathology materials were stored after obtaining necessary patient consent and authorization. The potential to link tissue biomarkers to prospectively collected epidemiologic information, screening and clinical data, and matched blood or buccal samples offers valuable opportunities to study etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for early detection and prognosis. The methods and protocols developed for this effort, and the detailed description of this resource provided here, will be useful for those seeking to use PLCO pathology tissue specimens for their research and may also inform future tissue collection efforts in other settings. Cancer Epidemiol Biomarkers Prev; 25(12); 1635-42. ©2016 AACR.