Symptom-related care and diagnoses before ovarian cancer detection: Patterns and differences by cancer stage.

e18195 Background: Ovarian cancer (OC) has a very poor clinical prognosis, with an average 5-year survival rate of < 50%. Symptoms indicating OC are often nonspecific and overlap with gastrointestinal (GI) diagnosis (eg, gastroesophageal reflux disease [GERD], diverticulosis, irritable bowel syndrome [IBS]). Thus, OC diagnosis can be difficult, with most cases diagnosed at an advanced stage. This study examined whether women with a prior GI diagnosis are more likely to undergo neoadjuvant chemotherapy (CT) as their initial OC treatment modality compared to those without a prior GI diagnosis who may be likely candidates for primary debulking surgery (PDS). Methods: This retrospective study identified patients with newly diagnosed OC in the United States from January 2014–July 2018 using MarketScan Commercial and Medicare Supplemental Databases. Analysis was limited to women with commercial or Medicare coverage for ≥12 months before and ≥1 month after the index date (defined as the earliest date of an OC diagnosis or surgery) who underwent CT or PDS. Patients with GI symptoms were identified by diagnosis codes from claims in the year before the OC index date. Logistic regression analysis was used to test the hypothesis that women with a prior GI diagnosis are diagnosed with more advanced OC as signaled by their initial OC treatment (CT vs PDS) compared to women without a prior GI diagnosis. Results: Of the 5865 patients with OC identified, 23% had a diagnosis of ≥1 of the following GI disorders before their OC diagnosis: IBS, inflammatory bowel disease, diverticulosis, and GERD. Of these patients, 40% and 60% had GI disorders that occurred 6–12 months before and < 6 months before their OC diagnosis, respectively. Women with a GI diagnosis were more likely to undergo CT versus PDS as their first OC treatment (odds ratio [OR], 1.37; P < 0.0001), even when controlled for age, region, insurance plan type, and index year (OR, 1.23; P = 0.0021). Conclusions: In this administrative claims database, nearly one-quarter of women with OC had a prior GI diagnosis within the past year and were at greater odds of being diagnosed with more advanced disease requiring CT prior to surgical intervention.

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

“You’ve got to know when to hold ‘em, know when to fold ‘em”: ovarian cancer risk reduction in patients with endometriosis

BackgroundThe serum tumor markers has been widely used in ovarian cancer diagnosis. BRCA1/2 germline mutations are the most common predisposing factors for ovarian cancer development. This study aimed to comprehensively investigate serum tumor markers and BRCA1/2 germline mutations and analyze their associations with ovarian cancer.MethodsLevels of 11 serum tumor markers were examined in ovarian cancer patients and controls with benign gynecologic diseases. By integrating multiplex PCR and next‐generation sequencing technologies, BRCA1/2 germline mutations were analyzed and confirmed by Sanger sequencing. The discriminative models with serum tumor markers and BRCA1/2 mutation status were constructed for ovarian cancer detection and patient stratification.ResultsAmong 11 markers, six of them were significantly elevated and only beta‐human chorionic gonadotropin (β‐HCG) was significantly reduced in ovarian cancer patients. A total of 54 (23.3%) ovarian cancer patients were found to harbor BRCA1/2 deleterious mutations, and BRCA1/2 mutations were significantly associated with Hereditary Breast and Ovarian Cancer‐related tumors and family history of cancer. Carbohydrate antigen 125 showed a good performance in ovarian cancer detection as a single marker (AUC = 0.799), while a panel of eight markers showed a good performance in BRCA1 mutation detection with an AUC value of 0.974. In addition, a panel of five serum tumor markers combined with BRCA1/2 mutation status showed a good performance in lymph node metastasis prediction (AUC = 0.843).ConclusionsWe found the association between BRCA1/2 germline mutation status and serum tumor marker levels, and identified discriminative models that combined serum tumor markers with BRCA1/2 mutation status for ovarian cancer detection and patient stratification.

Gastrointestinal symptoms and diagnosis preceding ovarian cancer diagnosis: Effects on treatment allocation and potential diagnostic delay

The aim of this study was to detect the expressions of serum micro-ribonucleic acid (miR)-26b and miR-21 in ovarian cancer patients, and to explore their associations with the diagnosis, clinicopathological parameters and prognosis of ovarian cancer. A total of 86 patients diagnosed with ovarian cancer in our hospital from January 2014 to January 2015 were enrolled in the observation group. Meanwhile, another 86 subjects receiving physical examination in our hospital during the same period were enrolled in the control group. The expressions of serum miR-26b and miR-21 in both groups were detected via Real Time fluorescence-quantitative Polymerase Chain Reaction (RT-qPCR). Receiver operating characteristic (ROC) curves were plotted. Later, the clinical diagnostic value of combined detection of miR-26b and miR-21 in ovarian cancer was analyzed. Moreover, the associations of serum miR-26b and miR-21 expressions with clinicopathological characteristics and prognosis of ovarian cancer patients were explored. The expression of serum miR-26b in ovarian cancer patients was significantly lower than that of healthy subjects, while miR-21 expression was markedly higher in ovarian cancer patients (p<0.05). The area under the ROC curve (AUC), the sensitivity and specificity of miR-26b detection, miR-21 detection and combined detection in the diagnosis of ovarian cancer were 0.753 vs. 0.826 vs. 0.916, 47.2 vs. 76.3 vs. 87.6 and 78.5 vs. 85.6 vs. 90.4, respectively. Therefore, it could be observed that both the sensitivity and specificity of combined detection were remarkably higher than those of single detection (p<0.05). In addition, the expressions of serum miR-26b and miR-21 were associated with clinical stage and lymph node metastasis of ovarian cancer patients, whereas it was not correlated with age and histological type. The 3-year survival rate of patients with high expression of serum miR-26b was significantly higher than that in those with low expression of serum miR-26b. However, the 3-year survival rate of patients with low expression of serum miR-21 was higher than that in those with high expression. MiR-21 is highly expressed, while miR-26b is lowly expressed in the serum of ovarian cancer patients. Both of them may be involved in the incidence and development of ovarian cancer. Furthermore, combined monitoring of serum miR-26b and miR-21 has a certain value in the clinical diagnosis and treatment of ovarian cancer.

Early detection of ovarian cancer has been a challenge to manage the high mortality rate caused by this deadly disease. The trends in mortality have been reduced by the scientific contributions from the corners across the globe, however accounting for the fifth leading cause of gynecological mortality. The complexities in the clinical presentation, origin of tumor, and gene expression profiles had added to much difficulty in understanding and diagnosis of the disease. Stage 1 diagnosis of ovarian cancer improves the 5-year survival rate to around 92%. Cancer antigen-125 (CA-125) is the gold standard tumor marker found at abnormally high levels in the blood of many women in ovarian cancer. However, many non-cancerous conditions exhibit high levels of CA-125 and several women have normal CA-125 level in the early stage of ovarian cancer, suggesting CA-125 biomarker is not specific enough for the screening of early stage ovarian cancer. In addition, several other biomarkers, including HE4 have been added in the diagnostic field for higher sensitivity and specificity in the diagnosis and progression of ovarian cancer. HE4 is a prospective single serum biomarker which has been approved by the FDA to monitor the disease progression in epithelial ovarian cancer. However, owing to low sensitivity and specificity, combination of a panel of biomarkers has been proposed in the diagnosis of the disease. Based on extensive biomarkers research findings, here we discuss current trends in diagnostic approaches and updated potential several panels of cancer biomarkers for early detection of ovarian cancer. It has been recently reported that CA125 in combinations with two or more biomarkers have outperformed single biomarker assays for early detection of the disease. Moreover, CA-125 with CA 19–9, EGFR, G-CSF, Eotaxin, IL-2R, cVCAM, MIF improved the sensitivity with 98.2 % and specificity of 98.7% in early stage detection of ovarian cancer. Overall, this review demonstrates a panel of biomarkers signature as the potential tool for prototype development in future and other advanced approaches for early diagnosis of ovarian cancer to avoid false-diagnosis and excessive cost.

Objective: To look for the association of raised CA 125/ CEA ratio and positive ascitic fluid cytology with the diagnosis of epithelial ovarian cancer in patients with an adnexal mass. Study Design: Comparative Cross-sectional study. Setting: Department of Oncology and Gynecology, Sheikh Zayed Hospital Rahimyarkhan. Period: September 2021 to February 2022. Material &amp; Methods: A total of three hundred patients presenting with adnexal mass were recruited for the study. All patients underwent detailed evaluation, including CA 125 levels, CEA levels and ascitic fluid cytology. After complete staging workup, they underwent surgery and histopathological analysis of adnexal mass. A consultant histopathologist made the diagnosis of ovarian cancer. Association of various factors, including raised CA 125/ CEA ratio and positive ascitic fluid cytology with the diagnosis of ovarian cancer, was established. Results: Out of 350 patients of adnexal mass included in analysis, 273 (88%) were diagnosed with ovarian carcinoma, while 77 (22%) were not diagnosed with ovarian cancer after the surgery and had a diagnosis other than ovarian cancer. 179 (51.2%) patients were post-menopausal whereas 171 (48.8%) were pre-menopausal. It was revealed that raised CA-125/CEA ratio and positive ascitic fluid cytology had a statistically significant association with the diagnosis of ovarian carcinoma on histopathology (p-value&lt;0.001). Conclusion: Most patients who presented with adnexal mass were diagnosed with ovarian carcinoma in our study. Raised CA 125/ CEA ratio and positive ascitic fluid cytology at baseline predicted a histopathological diagnosis of ovarian cancer in our study participants.

IntroductionMutations in Breast Cancer Susceptibility Genes (BRCA) are associated with an increased risk of both breast and ovarian cancer. In previous studies, about 20% of ovarian cancer patients reported a...

Ovarian cancer ranks seventh worldwide and is the third most common type of cancer diagnosed in women in India. Numerous studies have demonstrated that the number of people affected by ovarian cancer is expected to rise significantly in the future. Proactive measures for early cancer detection are essential to prevent death and recurrence. This paper attempts to review the various deep learning (DL) models in ovarian cancer diagnosis, including detecting risk factors, analyzing genomic data sets, predicting disease progression, recurrence, and mortality rates, and identifying correlations and patterns. The patient's electronic health records contain effective analytics on imaging and other types of data that may open the door to more accurate or early identification of ovarian cancer. The taxonomy of the several ways that DL aids in the diagnosis, early detection, and treatment of ovarian cancer will be compiled in this review article. As per the reviews, more research studies have examined the Convolutional Neural Networks (CNNs) approach for the Early Detection and Diagnosis of Ovarian Cancer. This is because CNNs are a popular and potent architecture for image classification tasks because of their capacity to learn spatial and hierarchical features from images effectively. The review article seeks to give future research topics and assess the state-of-the-art application of DL algorithms for ovarian cancer diagnosis.

Simple SummaryOvarian cancer has the highest lethality among gynecological tumors. Therefore, it is essential to find reliable biomarkers to improve early detection. This is the first report describing ADAM17 detection in serum and ascites fluid of ovarian cancer patients. A high ADAM17 concentration in serum at primary diagnosis is associated with early FIGO stages and predicts complete resection of the tumor mass. In addition, ADAM17 and CA-125 complement each other, especially in the diagnosis of early stages. In summary, ADAM17 appears to be a promising screening marker for detecting early-stage ovarian cancer.Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it is highly expressed in many solid tumors, including ovarian and breast cancer. The aim of this work is to evaluate the relevance of ADAM17 as a potential diagnostic blood-based biomarker in ovarian cancer. Ovarian cancer cell lines IGROV-1 and A2780, as well as primary patient-derived tumor cells obtained from tumor tissue and ascitic fluid, were cultured to analyze ADAM17 abundance in the culture supernatant. In a translational approach, a cohort of 117 well-characterized ovarian cancer patients was assembled and ADAM17 levels in serum and corresponding ascitic fluid were determined at primary diagnosis. ADAM17 was quantified by enzyme-linked immunosorbent assay (ELISA). In the present study, ADAM17 was detected in the culture supernatant of ovarian cancer cell lines and primary cells. In addition, ADAM17 was found in serum and ascites of ovarian cancer patients. ADAM17 level was significantly increased in ovarian cancer patients compared to an age-matched control group (p < 0.0001). Importantly early FIGO I/II stages, which would not have been detected by CA-125, were associated with higher ADAM17 concentrations (p = 0.007). This is the first study proposing ADAM17 as a serum tumor marker in the setting of a gynecological tumor disease. Usage of ADAM17 in combination with CA-125 and other markers could help detect early stages of ovarian cancer.

Background18F-fluorodeoxyglucose (FDG) PET/CT is a noninvasive imaging tool that has been used successfully for the diagnosis, staging, restaging, therapy monitoring, and prognostic prediction of ovarian cancer. For ovarian cancer surveillance, rising CA-125 levels raise the suspicion of recurrence despite its reported low specificity; being elevated in other benign and inflammatory conditions, and thus, confirmation is required. This work aimed to evaluate the role of 18F-FDG PET/CT in suspected ovarian cancer recurrence in patients presenting with elevated CA-125 levels.ResultsFifty female patients with suspected ovarian cancer recurrence owing to elevated CA-125 levels were included in this study. Recurrence was confirmed in 46/50 cases whether by histopathological confirmation or by serial follow-up imaging and clinical follow-up. Positive PET/CT findings were reported in 45/50 cases with 2 false-negative cases and 1 false-positive case. PET/CT examination was found to be superior to contrast-enhanced CT in the detection of peritoneal metastatic nodules and metastatic lymph nodes. According to this study, the estimated sensitivity, specificity, and overall diagnostic accuracy of PET/CT in the detection of recurrent ovarian cancer were 95.6%, 75%, and 94%, respectively.ConclusionsIn ovarian cancer surveillance, 18F-FDG PET/CT was found to be a sensitive and accurate noninvasive imaging tool that can be used in the detection of recurrent ovarian cancer in patients with elevated CA-125 levels, thus interfering with the management plan. The advantage of whole-body imaging in PET/CT allows for the detection and precise localization of recurrent or metastatic foci in abdominal and extra-abdominal sites as well.

Earlier studies regarding the risk of colorectal cancer (CRC) in women with a prior diagnosis of gynecologic malignancies have revealed conflicting results. We sought to further clarify this association. A retrospective cohort study was performed using the General Practice Research Database of the United Kingdom. Patients with a prior diagnosis of ovarian, uterine, or cervical cancers were compared with control patients without a prior gynecologic malignancy. The primary outcome was a diagnosis of CRC. Poisson regression analysis was used to assess the effects of potential confounders. The study included 1995 ovarian, 1348 uterine, and 1101 cervical cancer patients and 7980, 5392, and 4404 matched control patients, respectively. The adjusted incidence rate ratio (IRR) of CRC among ovarian cancer patients was 2.90 [95% confidence intervals (CI) 1.45-5.82]. Five of 10 cases of CRC in ovarian cancer patients were diagnosed within 6 months of the cancer diagnosis with an adjusted IRR of 8.0 (95% CI 1.9-33.6). Excluding the initial 6 months of follow-up after the diagnosis of ovarian cancer, the adjusted IRR was 1.6 (95% CI 0.76-5.03). The adjusted IRR of CRC in patients with a prior diagnosis of uterine and cervical cancer was 0.79 (95% CI 0.24-2.61) and 1.50 (95% CI 0.43-5.21), respectively. Women with a prior diagnosis of ovarian cancer are at an increased risk of CRC. The risk of CRC was not increased among patients with a prior history of uterine and cervical cancer.

Evidence indicates that type 2 diabetes may stimulate the initiation and progression of several types of cancer. Metformin, a drug most commonly used to treat type 2 diabetes, may inhibit cancer cell growth and reduce the risk of cancer. However, evidence of the antitumor effects of metformin on ovarian cancer is still limited.In this study, we retrospectively examined the effects of metformin on ovarian cancer patients with diabetes at our institution.We identified 568 consecutive patients who were newly diagnosed with ovarian cancer and treated between January 2011 and March 2014. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to IV epithelial ovarian, fallopian, or peritoneal cancer were included. Patients with type 1 diabetes, incomplete records (including medication records) and any other cancer before their ovarian cancer diagnosis, as well as those diagnosed with diabetes more than 6 months after their ovarian cancer diagnosis, were excluded. Out of 568 patients, 48 (8.5%) patients with type 2 diabetes continuously used metformin, 34 (5.9%) patients with type 2 diabetes did not take metformin, 22 (3.9%) patients with type 2 diabetes discontinued metformin, and 464 (81.7%) ovarian cancer patients were nondiabetic controls. Longer progression-free survival (PFS) and overall survival (OS) were observed in ovarian cancer patients with diabetes who were taking metformin than in diabetic patients not taking metformin, diabetic patients who discontinued metformin, and nondiabetic ovarian cancer patients (P = .001). After adjusting for possible confounders, metformin use was associated with a lower risk for disease relapse [hazard ratio (HR) = 0.34; 95% confidence interval (CI): 0.27–0.67; P < .01] and disease-related death (HR = 0.29; 95% CI: 0.13–0.58, P = .03) among ovarian cancer patients with diabetes.Metformin use may decrease the risk for disease recurrence and death in patients with ovarian cancer, but the drug treatment must be continuous.