Advanced Severity Detection in Histopathological Ovarian Cancer: Rank-Based Leaf Wind Optimization and Alpha Piecewise Linear Fuzzy Techniques.

The role of ultrasound evaluation in the detection of early-stage epithelial ovarian cancer

Commentary on 'Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening'.

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

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.

Combining the biomarkers macrophage inhibitory factor, osteopontin and prolactin with CA-125 improves early detection of ovarian cancer

Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

Differential Methylation Profile of Ovarian Cancer in Tissues and Plasma

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Introduction: Ovarian cancer is the leading cause of death from gynecological related cancers worldwide. Most patients are diagnosed at late stages due to asymptomatic disease and lack of effective screening modalities. Additionally, in women with an ovarian mass the diagnosis of ovarian cancer can be challenging with many women having surgery only to discover a benign pathology. Liquid biopsies, including analyses of cell-free DNA (cfDNA) fragmentomes in the circulation, have shown promise for the early detection of cancer and may provide a useful avenue for detection of ovarian cancer. Methods: To evaluate cfDNA fragmentomes for detecting ovarian cancer, we assessed plasma from 507 women, including 128 with ovarian cancers comprising high grade serous, endometrioid, mucinous and clear cell subtypes, 48 with benign masses, and 223 without cancer, as well as a validation cohort of 108 women with (n=14) and without (n=94) ovarian cancers from a separate institution. We obtained cfDNA from each individual and performed low-coverage (1-2x) whole genome sequencing. The cfDNA fragmentome data were analyzed with our DELFI (DNA evaluation of fragments for early interception) approach optimized for high specificity. We used a cross-validated machine learning model, and the fixed DELFI model was evaluated in the external validation cohort. Results: Individuals with ovarian cancer had significantly higher DELFI scores than those without cancer (mean 0.59 vs 0.18, respectively, p < 0.0001) resulting in an AUC of 0.85 (95% CI = 0.80-0.90). DELFI was successful in identifying high-grade serous ovarian cancer across all stages, with sensitivities of 56%, 60%, 58% and 100% for stages I - IV, respectively, at 99% specificity. We further applied DELFI to evaluate women with ovarian masses in a prospective observational cohort (NL58253.031.16). Women with benign masses had DELFI scores lower than those with ovarian cancer (mean 0.23 vs 0.59, p< .0001) and were distinguished with an overall AUC of 0.80 (95% CI = 0.73-0.86). In the external validation cohort, women with cancer were distinguished from women without cancer with an AUC of 0.88 (95% CI = 0.72 - 1.0). At the DELFI score threshold with 99% specificity in the cross-validated cohort, the external validation cohort had specificity of 97% with an overall sensitivity of 79%. The cfDNA fragmentome profiles reflected chromosomal, chromatin, transcription factor binding site, and disease-specific pathway changes known to be altered in ovarian cancer. We are extending these efforts to over 1000 individuals with and without ovarian cancer and the integrated results will be presented. Conclusion: Overall, we demonstrate the utility of cfDNA fragmentomes for noninvasive detection of ovarian cancer. These results may provide a feasible approach for ovarian cancer screening and management of patients with ovarian masses. Citation Format: Akshaya V. Annapragada, Jamie E. Medina, Pien Lof, Dimitrios Mathios, Zachariah H. Foda, Michaël Noë, Sarah Short, Adrianna Bartolomucci, Daniel C. Bruhm, Euihye Jung, Jenna Canzoniero, Noushin Niknafs, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van de Broek, Stephen B. Baylin, Michael F. Press, Dennis Slamon, Gottfried Konecny, Susan Domchek, Ronny Drapkin, Jillian Phallen, Robert B. Scharpf, Christianne Lok, Victor E. Velculescu. Early detection of ovarian cancer using cell-free DNA fragmentomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 773.

The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125?

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.

The discovery of novel early detection biomarkers of disease could offer one of the best approaches to decrease the morbidity and mortality of ovarian and other cancers. We report on the use of a single-chain variable fragment antibody library for screening ovarian serum to find novel biomarkers for the detection of cancer. We alternately panned the library with ovarian cancer and disease-free control sera to make a sublibrary of antibodies that bind proteins differentially expressed in cancer. This sublibrary was printed on antibody microarrays that were incubated with labeled serum from multiple sets of cancer patients and controls. The antibodies that performed best at discriminating disease status were selected, and their cognate antigens were identified using a functional protein microarray. Overexpression of some of these antigens was observed in cancer serum, tumor proximal fluid, and cancer tissue via dot blot and immunohistochemical staining. Thus, our use of recombinant antibody microarrays for unbiased discovery found targets for ovarian cancer detection in multiple sample sets, supporting their further study for disease diagnosis.

The objective of this review is to summarize recent research advances in the detection and prevention of ovarian cancer and discuss the experts’ opinions of future directions. The 12th Biennial...

Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present.

Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present.