Exploration of Preliminary Objective Triage by Menopause Score and CA 125 Result Prior to Accelerating Fast-Track Booking for Suspected Ovarian Cancer-A Role for the Pathway Navigator?

The 28-days-to-diagnosis pathway is the current expected standard of care for women with symptoms of ovarian cancer in the UK. However, the anticipated conversion rate of symptoms to cancer is only 3%, and use of the pathway is increasing. A rapid triage at the moment of receipt of the referral might allow resources to be allocated more appropriately. In secondary care, multidisciplinary teams (MDTs) use the risk of malignancy index (RMI) score, (multiply menopausal status pre = 1 or post = 3 × ultrasound score = 0 - 3 × the CA 125 level), using a score of >200, to triage urgency and management in possible ovarian cancer cases. The most powerful determinant of the RMI score variables is CA 125 level, an objective number. Could a simple modification of the RMI score retain a high sensitivity for cancer whilst improving specificity and, consequently, decrease the morbidity of false-positive classification? To test this hypothesis, a retrospective evaluation of an ovarian two-week-wait telephone clinic of one consultant gynaecological oncologist was undertaken. Enquiry re menopause status was scored as one for pre- and three for postmenopausal or uncertain. CA 125 levels of >67 u/mL for premenopausal and >23 u/mL for postmenopausal women were used to precipitate urgent cross-sectional imaging requests and MDT opinions. These CA 125 cut thresholds were calculated using an assumption that the RMI imaging score, regardless of whether the result was available, could be three. We contemplate that women who did not exceed a provisional RMI score of >200 might be informed they are extremely unlikely to have cancer, removed from the malignancy tracker and appropriate follow-up arranged. One hundred and forty consecutive cases were analysed; 43% were deemed premenopausal and 57% postmenopausal. Twenty of the women had cancer, eighteen (90%) of whom had an RMI > 200. One hundred and twenty were benign, and only twenty-three (19%) classified as urgent cases in need of accelerated referral to imaging. In contrast, CA 125 > 35 u/mL, whilst retaining the sensitivity of 90%, misclassified 36 (30%) of the benign cases. It is possible that a telephone triage via a questionnaire determining menopausal status and the CA 125 result could offer a sensitivity for cancer of 90% and urgent expert review of under 20% of benign cases. This rapid initial telephone assessment could be presented by a trained pathway navigator, physician associate or nurse specialist. Substantial savings in NHS cancer services resources, anxieties all around and reduced patient morbidity may occur as a result.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study.

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development.

BACKGROUND: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. METHODS AND FINDINGS: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. CONCLUSIONS: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

GALR1 methylation in vaginal swabs is highly accurate in identifying women with endometrial cancer.

Endometrial cancer has become the most common gynecological cancer in developed countries. Postmenopausal bleeding is indicative of the disease in only 1 of 10 women with this symptom. A noninvasive tool to identify women with cancer would be highly desirable. We analyzed more than 27,000 CpGs in normal endometrial tissue (n = 23) and endometrial cancers (n = 64) and found that DNA methylation of GALR1 is among the most frequent epigenetic alterations in this cancer. We then developed a real-time polymerase chain reaction-based GALR1 methylation test and applied this test to vaginal swabs from 79 women who presented with postmenopausal bleeding. The receiver operating characteristics area under the curve, describing sensitivity and specificity to correctly identify the 41 women with both premalignant and malignant endometrial changes, was 0.93 (95% confidence interval, 0.87-0.97; P < 0.0001).GALR1 DNA methylation is one of the most common molecular alterations in endometrial cancer, and the presence of GALR1 methylation in vaginal swabs from women with postmenopausal bleeding indicates the presence of endometrial malignancy with a sensitivity of 92.7% and a specificity of 78.9%.

Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule.

PURPOSE: To establish the performance characteristics of annual transvaginal ultrasound and serum CA125 screening for women at high risk of ovarian/fallopian tube cancer (OC/FTC) and to investigate the impact of delayed screening interval and surgical intervention. PATIENTS AND METHODS: Between May 6, 2002, and January 5, 2008, 3,563 women at an estimated ≥ 10% lifetime risk of OC/FTC were recruited and screened by 37 centers in the United Kingdom. Participants were observed prospectively by centers, questionnaire, and national cancer registries. RESULTS: Sensitivity for detection of incident OC/FTC at 1 year after last annual screen was 81.3% (95% CI, 54.3% to 96.0%) if occult cancers were classified as false negatives and 87.5% (95% CI, 61.7% to 98.5%) if they were classified as true positives. Positive and negative predictive values of incident screening were 25.5% (95% CI, 14.3 to 40.0) and 99.9% (95% CI, 99.8 to 100) respectively. Four (30.8%) of 13 incident screen-detected OC/FTCs were stage I or II. Compared with women screened in the year before diagnosis, those not screened in the year before diagnosis were more likely to have ≥ stage IIIc disease (85.7% v 26.1%; P = .009). Screening interval was delayed by a median of 88 days before detection of incident OC/FTC. Median interval from detection screen to surgical intervention was 79 days in prevalent and incident OC/FTC. CONCLUSION: These results in the high-risk population highlight the need for strict adherence to screening schedule. Screening more frequently than annually with prompt surgical intervention seems to offer a better chance of early-stage detection.

Clinical outcomes and patterns of severe late toxicity in the era of chemo-radiation for cervical cancer.

BACKGROUND: We present a comprehensive analysis of both therapy-induced severe late toxicity and outcome in a cohort of cervical cancer patients following radiation who were treated according to current guidelines and discuss the methodologic problems of systematically reporting these cases. We introduce a revised concept of reporting treatment failure. PATIENTS AND METHODS: The records of 128 cervical cancer patients who received radiation from 2003 to 2008 were reviewed. RESULTS: Thirteen patients (10.2%) developed severe late toxicity. The combination of heavy smoking and cardiovascular diseases was found to be a significant contributing factor (HR 6.55, 95% CI 0.99-43.49, p = 0.048). Thirty patients (23.4%) experienced treatment failure. Of these, 12 (9.4%) were defined to have persistent disease, and 18 (14.0%) developed recurrent disease. Patients with recurrent disease had significantly better survival time (p < 0.001). Compared with the persistence subgroup, they had significantly more often multiple sites of relapse (66.7 vs. 8.3%, p = 0.002) and the sites were more often diagnosed outside the pelvis (70.7 vs. 7.7%, p < 0.001). Early disease stages (OR 4.46, 95% CI 1.87-10.63, p < 0.001) and severe late toxicity (p = 0.037) were found to be significant factors for an improved disease-free survival. CONCLUSIONS: A comprehensive depiction of both late therapy-related toxicity and treatment failure requires precise clinical descriptions and analyses of the clinical courses. Our new concept to differentiate treatment failure following radiotherapy in cervical cancer into persistent and recurrent disease permits a clear differentiation between distinct subgroups of patients with regard to prognosis and clinical presentation and will lead to a more precise description of these cases in the future.

Total vaginal necrosis: a representative example of underreporting severe late toxic reaction after concomitant chemoradiation for cervical cancer.

INTRODUCTION: There is paucity of information regarding a late toxic reaction after chemoradiation for locally advanced cervical cancer. We discuss this problem with special consideration to total vaginal necrosis (TVN), an underreported severe late complication of chemoradiation. METHODS: The records of 98 cervical cancer patients who received chemoradiation at the Department of Oncology of the University College London Hospital between January 2004 and May 2008 were reviewed. RESULTS: Eight women (8.2%) developed a severe late toxic reaction. From these, 3 patients (3.1% of the entire cohort and 37.5% of the patients with a severe late toxic reaction), who were 44 to 60 years old, developed a TVN 6 to 18 months after completion of chemoradiation. In all the TVN cases, surgical debridement was necessary to alleviate the symptoms. This was followed by an extensive period (up to 24 months) of consolidation. Heavy smoking (P = 0.022) was found to be a significant contributing factor for TVN. CONCLUSIONS: Total vaginal necrosis is an underreported but serious late complication after chemoradiation and leads to considerable chronic morbidity. Radiologic examinations and biopsies are required to exclude recurrent disease. Microvascular damage from radiation combined with heavy cigarette smoking is likely to be pivotal etiologic factors in the development of TVN. For radiotherapy-induced late toxic effects to step out of the gray area of oncologic literature, the clinical pictures should be reported in a more detailed manner. It might be a promising approach to work out a toxicity scale that combines the existing objectifiable grading systems with subjective quality-of-life assessments.

DNA methylation analysis in liquid-based cytology for cervical cancer screening.

Cervical cancer is the second most common type of cancer in women worldwide. Preinvasive disease can be detected by cervical cytology. All currently available cytology technologies rely on the visual analysis of exfoliated cells from the uterine cervix. Improvement of conventional cytological screening has been proposed by the introduction of molecular-based markers applied to liquid-based cytology (LBC), the suspension of cells collected from the cervix. DNA methylation changes occur very early in carcinogenesis and identification of appropriate DNA methylation markers in such samples should be able to distinguish high-grade squamous intraepithelial lesions (HSIL) from nonspecific cytology changes and the normal cervix. To address this potential, we have undertaken a proof-of-principle study of methylation status of LBC samples from HSIL cytology cases compared against matched normal controls. Using quantitative methylation-specific PCR on 28 genes, we found SOX1, HOXA11 and CADM1 to significantly discriminate between the groups analyzed (p<0.01). Area under the receiver operating characteristic (ROC) curve (AUC) demonstrated that methylation of SOX1, HOXA11 and CADM1 could discriminate between HSIL cases and controls with high sensitivity and specificity (AUC 0.910, 0.844 and 0.760, respectively). The results were further validated in an independent set. This proof-of-principle study is the first to validate the results in an independent case/control set and presents HOXA11, a gene that is important for cervical development, as a potentially useful DNA marker in LBC samples. Further assessment of these preliminary estimates will need to be performed in a larger cohort to confirm clinical utility.