Screening Method For Ovarian Cancer Research Articles

Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

39P Longitudinal increases in albumin-adjusted serum calcium predict ovarian cancer

39P Longitudinal increases in albumin-adjusted serum calcium predict ovarian cancer

Engineering a G-quadruplex-based logic gate platform for sensitive assay of dual biomarkers of ovarian cancer

As most single tumor markers have low sensitivity or specificity, the joint detection of multiple tumor biomarkers is helpful to improve the positive rate and specificity of early diagnosis. To establish a sensitive, specific, and rapid screening method for ovarian cancer, two enzyme-free logic gates were developed to realize the joint detection of carbohydrate antigen 125 (CA125) and carcinoembryonic antigen (CEA). G-quadruplex with peroxidase activity was used as a chromogenic catalyst in this colorimetric diagnosis. For NOR gate, in the absence of CEA and CA125, template DNA (Tem-DNA), CEA aptamer with half of the G-quadruplex sequence (CEA-apt), and CA125 aptamer with the other half of the G-quadruplex sequence (CA125-apt) form a double-stranded DNA equipped with one G-quadruplex structure which can strongly combine with hemin to obtain the peroxidase-like activity; here, the output of this NOR gate is set as 1, which could exclude the risk of ovarian cancer. For AND gate, CEA-apt and CA125-apt are separated from magnetic beads in the co-existence of the dual biomarkers. After adding Tem-DNA, the G-quadruplex structure constructs with hemin to exhibit the output as 1, presenting a high risk of ovarian cancer. Under the optimized condition, this novel assay can not only show a sharp color difference between physiological state and pathological state, but also be employed for the quantitative analysis of every single biomarker. The linear detection range and detection limit for CEA are 5–500 ng mL−1 and 0.88 ng mL−1, while they are for CA125 are 35–500 U mL−1 and 0.91 U mL−1, respectively. Moreover, the established approach was successfully applied in detecting CA125 and CEA in human serum samples, which provides great promise in the fields of clinical examination and disease diagnosis.

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers.

A novel proteomic-based screening method for ovarian cancer using cervicovaginal fluids: A window into the abdomen

ObjectiveOur objective is to develop a site-specific proteomic-based screening test for ovarian cancer(OC) using the mucus of the cervix and vagina and evaluate a potential means for home testing. MethodsCervicovaginal fluid samples were obtained from ovarian cancer and normal control patients for LC-mass spectrometry(MS) proteomic evaluation. Statistical modeling determined the protein panel with the highest penetrance across ovarian cancer samples. A subcohort of patients consented to provide self-collected vaginal samples at home with questionnaire on feasibility. Cohen's kappa methodology was utilized to determine agreement between physician-collected and patient-collected samples. ResultsA total of 83 consecutive patient samples were collected prospectively (33 ovarian cancer & 50 controls). Thirty patients consented for self-collection. Using LC-MS, 30 peptides demonstrated independent statistical significance for detecting ovarian cancer. Using statistical modeling, the protein panel that determined the best predictor for detecting OC formed a “fingerprint” consisting of 5 proteins: serine proteinase inhibitor A1; periplakin; profilin1; apolipoprotein A1; and thymosin beta4-like protein. These peptides demonstrated a significant increase probability of detecting ovarian cancer with the ROC curve having an AUC of 0.86 (p = 0.00001). Physician-collected and patient-collected specimens demonstrated moderate agreement with kappa average of 0.6 with upper bound of 0.75. ConclusionsUsing novel site-specific collection methods, we identified an OC “fingerprint” with adequate sensitivity and specificity to warrant further evaluation in a larger cohort. Agreement of physician-collected and patient-collected samples were encouraging and could improve access to screening with a home self-collection if this screening test is validated in future studies.

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract LB047: Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract Objectives: Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers. Methods: Lavage of the uterine cavity was performed in 35 consecutive patients undergoing surgery with preoperative concern for an ovarian malignancy. Duplex sequencing, an ultra-accurate error-correction sequencing approach, was used to deeply sequence extracted DNA from lavage samples (average duplex depth ~2500x) with a panel of candidate ovarian cancer driver genes including TP53, ARID1A, PTEN, PPP2R1A, CDKN2A, KRAS (whole genes), CTNNB1, PIK3CA, and BRAF (hotspots only). Tumor DNA was sequenced to identify driver mutations and compare with mutations found in the lavages. The overall mutation frequency in lavage DNA was calculated by dividing identified non-polymorphism mutant alleles by the total number of nucleotides sequenced in coding regions. Results: In total, lavage samples were collected from fourteen women with benign disease, thirteen with high grade serous carcinoma (HGSC), three with clear cell carcinoma, three with endometrioid carcinoma, one with granulosa cell carcinoma and one with carcinosarcoma. Thirteen women had stage I or II disease (including five with stage I or II high grade serous). Processed lavage samples yielded a median DNA of 596.5 ng. Tumor sequencing is ongoing, but of seven fully sequenced lavage/tumor pairs, the tumor-specific mutation was identified in four lavage samples: TP53 mutations found in two HGSC (stage IIb and stage III), an ARID1A mutation from a stage Ic3 clear cell carcinoma, and a PIK3CA mutation from a stage Ia endometrioid carcinoma. The tumor-specific mutation was not identified in lavage samples from two patients with endometrioid and one with clear cell carcinoma. Of 21 lavage samples that have presently undergone duplex sequencing, a total of 596 additional somatic mutations were identified in the nine genes. Lavages from patients with HGSC tended to have increased average mutation frequency of TP53 compared to patients with benign disease (TP53 2.2x10-6 vs 9.2x10-7, p=0.09). Conclusion: Sequencing at high depth and using an expanded gene panel allows for the identification of tumor mutations in uterine lavage samples, including some early stage and non-serous ovarian cancers, as well as identifying significant somatic mutational background. Larger studies are needed to confirm the clinical utility of this method, which may have potential to improve the early detection of ovarian cancer. Citation Format: Talayeh Ghezelayagh, Jeanne Fredrickson, Enna Manhardt, Marc R. Radke, Brendan Kohrn, Heidi J. Gray, Renata R. Urban, Kathryn P. Pennington, John B. Liao, Kemi M. Doll, Elise J. Simons, Jennifer K. Burzawa, Barbara A. Goff, Paul Speiser, Elizabeth M. Swisher, Rosa Ana Risques, Barbara M. Norquist. Uterine lavage for the detection of ovarian cancer using an expanded gene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB047.

Analysis of Multimerin 1 (MMRN1) expression in ovarian cancer.

Ovarian cancer, the most lethal gynecological cancer, is the fifth most common cause of cancer-related deaths in women. A cost-effective and non-invasive early screening method for ovarian cancer is required to reduce the high mortality rate. Saliva is a clinically informative unique fluid, which is useful for novel approaches to prognosis, clinical diagnosis, and monitoring for non-invasive detection of disease. Multimerin1 (MMRN1) is a di-sulfide linked homo-polymeric glycoprotein from EMILIN family. Altered expression of MMRN1 has been reported in hepatocellular carcinoma, cervical cancer, and ovarian cancer. But, its role in epithelial ovarian cancer (EOC) is not clear and well documented. In this study, expression of Multimerin 1 was validated in saliva and tissues of EOC patients and age-matched controls by western blotting, ELISA, RT-PCR, and immunohistochemistry. Significant over expression of MMRN1 was observed by western blot and ELISA in saliva samples of EOC patients. The average concentration of MMRN1 in the saliva of healthy controls was 28.7pg/ml (SE ± 1.76), 42.53pg/ml (SE ± 4.06) in low grade and 52.91pg/ml (SE ± 4.24) with p < 0.01 in high-grade EOC. Upregulated cytoplasmic expression of MMRN1 was observed in EOC tissue by immunohistochemistry. Our results suggest that MMRN1 expression is associated with EOC progression and MMRN1 may be potential biomarker candidates for early-stage EOC detection however further experiments are required in a large cohort to establish this proposition. Also, saliva can be explored as a novel medium for ovarian cancer diagnosis.

Do Women Present to the Emergency Department (ED) with Symptoms Prior to Diagnosis of Ovarian Cancer? A Secondary Analysis of a Retrospective Study of Symptoms Experienced Prior to Diagnosis of Ovarian Cancer

The US healthcare system does not support a standard screening method for ovarian cancer, a disease where over 60% of cases are found at a late stage. The primary purpose of this study is to determine whether certain symptoms are evident prior to the diagnosis of ovarian cancer and is there are an opportunity to evaluate these symptoms in an ED setting.

Are symptoms distinguishable in ovarian cancer? A nested case control study of insurance claims.

6063 Background: Over 60% of ovarian cancer cases are diagnosed with Stage III and IV disease. The US healthcare system does not support a standard screening method for ovarian cancer. Our goal was to determine whether certain symptoms based on ICD-9 categories are distinguishable among women diagnosed with ovarian cancer and women without ovarian cancer. Methods: Women diagnosed with ovarian cancer were randomly matched 1:1 to women without cancer to support a nested case-control analysis of health insurance claims between 2008 through 2013 from a commercial payer. The following eligibility criteria were applied: 1) 24 years of age or older; 2) continuously enrolled in healthcare plan for a minimum period of 6 months; 3) experienced more than 1 symptom over the observation period; and 4) an observation period of a minimum of 6 months. Symptoms were based on 47 ICD-9 diagnosis codes and categorized specific to pain, abdominal and pelvic, digestive, and bladder. The analysis was based on 1,578 women (789 cases; 789 controls). Results: Overall, 90% (n = 1,421) of the women experienced abdominal and pelvic symptoms, and 92% (n = 725) of the women with ovarian cancer visited their physician for this complaint 6-70 months prior to diagnosis, OR 1.66 (CI 1.14 to 2.41; p = .008). Pain was reported as a complaint by cases at nearly 60% (n = 464) and controls at 48% (n = 376); OR 1.75 (CI 1.39 to 2.19; p &lt; .001). Symptoms for bladder and digestive combined represented 68% of complaints for both cases (n = 507) and controls (n = 555), p = .024 and p = .298, respectively. Of the 1,578 women, 77% (cases = 621; controls = 595) experienced more than one category of symptoms. Both cases (n = 206) and controls (n = 153) complained of abdomen and pelvic symptoms along with pain; OR 1.54 (CI 1.19 to 1.99; p = .001). A second combination included abdomen and pelvic symptoms with pain and digestive symptoms in 14% of women (cases n = 99; controls n = 67); OR 1.58 (CI 1.13 to 2.22; p = .008). Sixty percent (n = 473) of women with ovarian cancer experienced the majority of associated pre-diagnosed symptoms analyzed for the study. Conclusions: Certain recurring symptoms associated with abdomen and pelvic as well as pain appear to indicate an association with ovarian cancer, signifying that symptom awareness remains relevant to this disease that is diagnosed at a late stage and currently does not have routine screening methods to support early detection.

Reducing Ovarian Cancer Mortality Through Early Detection: Approaches Using Circulating Biomarkers.

More than two-thirds of all women diagnosed with epithelial ovarian cancer (EOC) will die from the disease (>14,000 deaths annually), a fact that has not changed considerably in the last three decades. Although the 5-year survival rates for most other solid tumors have improved steadily, ovarian cancer remains an exception, making it the deadliest of all gynecologic cancers and five times deadlier than breast cancer. When diagnosed early, treatment is more effective, with a 5-year survival rate of up to 90%. Unfortunately, most cases are not detected until after the cancer has spread, resulting in a dismal 5-year survival rate of less than 30%. Current screening methods for ovarian cancer typically use a combination of a pelvic examination, transvaginal ultrasonography, and serum cancer antigen 125 (CA125), but these have made minimal impact on improving mortality. Thus, there is a compelling unmet need to develop new molecular tools that can be used to diagnose early-stage EOC and/or assist in the clinical management of the disease after a diagnosis, given that more than 220,000 women are living with ovarian cancer in the United States and are at risk of recurrence. Here, we discuss the state of advancing liquid-based approaches for improving the early detection of ovarian cancer.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.

Ovarian Cancer Classification using Bayesian Logistic Regression

Cancer is one of the most common cause of death. One of the diseases that can be threaten women all over the world is ovarian cancer. Ovarian cancer is the eighth type of cancer that most women suffer from. Estimated that around 225.000 new cases are detected every year and around 140.000 people die each year from ovarian cancer. Based on WHO data, published in 2014, in Indonesia 7,6% of all cancer deaths are caused by ovarian cancer. So far there is no effective screening method for ovarian cancer. Current screening applications for high-risk women are still very controversial. There are many classification techniques has been applied for ovarian cancer prediction, for example deep learning, neuro fuzzy, neural network, and so many more. In this paper, we propose Bayesian logistic regression for ovarian cancer classification. We use data of patients suffer from ovarian cancer from RS Al-Islam Bandung to demonstrate the method. The accuracy expectation in this paper around 70%.

Are symptoms of ovarian cancer evident: A retrospective analysis of claims data to determine prior symptoms to diagnosis.

5565 Background: There are no standard of care screening methods for ovarian cancer. Over sixty percent (60%) of ovarian cancer cases are found at Stage III and IV, which ultimately impacts a woman’s survival rate. The purpose of this study is to determine if specific symptoms are evident prior to diagnosis of ovarian cancer. Methods: A retrospective analysis of health insurance claims between 2008 through 2013 from a commercial payer was performed based on the following eligibility criteria: 1) women diagnosed with ovarian cancer, 2) at the time of diagnosis, 24 years of age or older, 3) enrolled in healthcare plan for a period of 24 months or more prior to diagnosis, and 4) resident in the state of Texas. Symptoms were identified based on ICD-9 diagnosis codes and categorized specific to pain, abdominal and pelvis, digestive, and bladder and were evaluated at minimum of six months prior to diagnosis. ICD9 codes are used for this analysis as the data is limited to years before the change to ICD10. Results: Baseline data of 3,641 women diagnosed with ovarian cancer were identified and were associated with 927,528 claims specific to the symptoms. The age of women diagnosed with cancer ranged between 24 and 88 (mean=52; SD: 0.1833). Nearly 70% of women were treated for one or more symptoms prior to diagnosis. The symptoms women experienced the most were associated with abdomen and pelvis at 60%. Pain, digestive, and bladder ranged between 20% and 30%. Conclusions: This research is intended to further explore whether symptoms are evident in women diagnosed with this disease, and if so, how long and how frequent did the symptoms occur prior to diagnosis. Additionally, a review of combination of symptoms is explored. This research is intended to provide a better understanding of the disease as well as support that women may need to be referred to an oncologist earlier for further evaluation should reoccurring symptoms present.

Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2−16), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

Salpingectomy and Ovarian Cancer Prevention

Ovarian cancer is a major health concern for women. Women are often diagnosed late in the course of the disease, making the mortality rate high. Currently, screening methods for ovarian cancer are limited and, therefore, prevention methods remain an area of focus for researchers. Recent research has examined the salpingectomy and tubal ligation/sterilization as a prevention method for ovarian cancer. This column takes a second look at two recent research studies that examine salpingectomy and tubal ligation/sterilization as a method of ovarian cancer risk reduction.

Cord Blood Milking

Ovarian cancer is a major health concern for women. Women are often diagnosed late in the course of the disease, making the mortality rate high. Currently, screening methods for ovarian cancer are limited and, therefore, prevention methods remain an area of focus for researchers. Recent research has examined the salpingectomy and tubal ligation/sterilization as a prevention method for ovarian cancer. This column takes a second look at two recent research studies that examine salpingectomy and tubal ligation/sterilization as a method of ovarian cancer risk reduction.

New Resource for Applying Evidence to Practice

Ovarian cancer is a major health concern for women. Women are often diagnosed late in the course of the disease, making the mortality rate high. Currently, screening methods for ovarian cancer are limited and, therefore, prevention methods remain an area of focus for researchers. Recent research has examined the salpingectomy and tubal ligation/sterilization as a prevention method for ovarian cancer. This column takes a second look at two recent research studies that examine salpingectomy and tubal ligation/sterilization as a method of ovarian cancer risk reduction.

A novel proteomic-based screening method for ovarian cancer using cervi- covaginal fluids: A window into the abdomen

Objective: To develop a site-specific proteomic-based screening test for ovarian cancer using the mucus of the cervix and vagina. Although this location is counterintuitive, the sole purpose of the fallopian tube is to actively transport oocytes from the ovary to the endometrium. This active transport spills a protein-rich fluid that eventually drains down the uterus, through the cervix, and into the vagina. Coupled with this transport mechanism, emerging molecular data demonstrate that most ovarian cancers potentially originate within the fallopian tube itself.

Screening for Ovarian Cancer

Ovarian cancer remains the most deadly of the gynecologic cancers. It is difficult to diagnose until in advanced stages. An effective screening test may help to decrease mortality from ovarian cancer. Due to the low incidence of ovarian cancer in the general population, a good screening test must have high sensitivity and specificity to allow accurate detection without excessive false-positive results. Thus, effective screening for ovarian cancer has remained elusive. Studies evaluating screening methods for ovarian cancer are reviewed. Screening methods investigated include ultrasound, CA-125, and serum proteins. The use of CA-125 or ultrasound alone does not result in adequate sensitivity or specificity for routine screening. A combination of the two modalities improves sensitivity, specificity, and positive predictive value. Using a combination of serum proteins may also improve sensitivity, specificity, and positive predictive value, but such studies have yet to be validated. No effective screening methods for ovarian cancer that have been adequately validated are available. Routine screening for ovarian cancer in the general population is not currently recommended.

Ovarian cancer screening with annual transvaginal sonography

Ovarian cancer has the highest mortality rate of all gynecologic malignancies, and most women present with advanced-stage disease. The current investigation was performed to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. Annual TVS screening was performed on 25,327 women from 1987 to 2005. Asymptomatic women aged>or=50 years and women aged>or=25 years who had a family history of ovarian cancer were eligible for participation in this trial. Among 364 patients (1.4%) with a persisting ovarian tumor on TVS who underwent exploratory laparoscopy or laparotomy with tumor removal, 35 primary invasive ovarian cancers, 9 serous ovarian tumors of low malignant potential, and 7 cancers metastatic to the ovary were detected. Stage distribution was as follows: 28 patients had stage I disease, 8 patients had stage II disease, and 8 patients had stage III disease. Four patients died of disease, 2 patients died of other causes, and 38 patients were alive and well from 0.5 years to 15.8 years after diagnosis (mean, 5.3 years). Nine women developed ovarian cancer within 12 months of a negative screen (false-negative results), and 3 of these patients died of disease. TVS screening had a sensitivity of 85.0%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%. After 107,276 screening years, there have been 7 ovarian cancer deaths in the annually screened population and 3 ovarian cancer deaths among women who were noncompliant. Excluding patients with nonepithelial or borderline ovarian malignancies, the survival of patients with ovarian cancer in the annually screened population was 89.9%+/-10.1% at 2 years and 77.2%+/-22.8% at 5 years. TVS screening, when it was performed annually, was associated with a decrease in disease stage at detection and with case-specific ovarian cancer mortality, but it was not effective in detecting ovarian cancers in women who had normal ovarian volume.