CA125 Assay Research Articles

Clinical value of serum tumor markers in assessing the efficacy of neoadjuvant chemotherapy in advanced ovarian cancer: single-center prospective clinical study.

This study aimed to assess the clinical importance of various biomarkers, including NLR, CEA, CA199, CA125, CA153, and HE4, through dynamic testing to evaluate the effectiveness of neoadjuvant chemotherapy (NACT) for individuals facing advanced ovarian cancer. This provides valuable information for tailoring treatment plans to individual patients, thereby leading to a more personalized and effective management of individuals facing ovarian cancer. The levels of NLR, CA125, CA199, CEA, CA153, and HE4 were detected before chemotherapy and after 3 courses of chemotherapy. Patients were categorized into ineffective and effective groups according to the effectiveness of NACT. To evaluate the factors influencing NACT's effectiveness in individuals facing advanced ovarian cancer, receiver operating characteristic (ROC) curves, predictive modeling, and multifactorial regression analysis were employed. In the effective group, the patients' age, maximum tumor diameter, and CEA and HE4 levels of the patients were significantly higher compared to those in the ineffective group (P <.05). Additionally, the difference in HE4 levels before and after treatment between the effective and ineffective groups was statistically significant (P<.05). Multifactorial analysis showed that age and maximum tumor diameter were independent risk factors impacting the effectiveness of NACT in individuals facing advanced ovarian cancer (P<.05). The ROC curve for predicting the effectiveness of NACT in individuals facing advanced ovarian cancer showed a sensitivity of 93.3% for NLR and a specificity of 92.3% for CA199. HE4 emerged as the most reliable predictor, demonstrating a specificity of 84.6% and a sensitivity of 75.3%. The area under the curve of the combined CA125 and HE4 assays for predicting the ineffectiveness of NACT in individuals facing advanced ovarian cancer was 0.825, showcasing a specificity of 74.2% and a sensitivity of 84.6%. The predictive capacity for the effectiveness of NACT in individuals facing advanced ovarian cancer is notably high when considering the sensitivity of NLR and the specificity of CA199. Additionally, the combination of CA125 and HE4 assays can obtain a better predictive effect, which can accurately select patients suitable for NACT, determine the appropriate timing of the interval debulking surgery (IDS) surgery, and achieve a satisfactory tumor reduction effect.

Abstract B051: Genome-wide association studies of 26,187 women without ovarian cancer identifies 12 genetic loci of blood CA125

Abstract Background: CA125 is elevated in women with ovarian cancer and is the single best ovarian cancer screening biomarker candidate to date, although two randomized screening trials showed no clinically significant difference in ovarian cancer mortality. Consideration of genetic variants that influence blood CA125 levels in healthy women could improve its performance as an ovarian cancer screening biomarker. Furthermore, while studies have suggested CA125 is associated with ovarian carcinogenesis and progression, its biological role remains unclear. Thus, we aimed to identify genetic variants of CA125 in women without ovarian cancer. Methods: We conducted a genome-wide association analysis to identify common genetic variants associated with CA125 using data on 26,187 women without ovarian cancer, leveraging existing blood CA125 data and genetic data from Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), European Prospective Investigation into Cancer and Nutrition (EPIC), Nurses’ Health Studies (NHS/NHSII), and New England Case Control Study (NEC). All genotype data were inputted using TOPMed. For blood CA125 measurement, PLCO, NHS/NHSII, and NEC used the CA125II assay and EPIC used the MSD assay. We used multivariable linear regression models adjusting for age, study, and population ancestry (top 4 principal components). Analyses were conducted separately by CA125 assay, genotyping platforms, and menopausal status at blood draw. Because epidemiological predictors of CA125 differ by menopausal status, we conducted analyses stratified by menopausal status. When we meta-analyzed these results, there were no significant heterogeneity by menopausal status in majority of the genome-wide significant SNPs. Therefore, we performed a fixed-effects meta-analysis to combine summary statistics across all the results. Results: We identified 12 independent loci associated with CA125 at a genome-wide significance level (p&amp;lt;5 × 10−8), of which one SNP (rs73005869) had been previously linked with CA125 and is located in the MUC16 gene. In our meta-analysis, 7 SNPs were associated with lower and 5 were associated with higher levels of CA125. We discovered SNPs on chromosome 16 in the TET2 gene that were significantly associated with increased CA125 levels. We also discovered SNPs in MSLN, a gene reported to be overexpressed in ovarian tumors that contributes to metastasis in the peritoneal microenvironment, were associated with lower CA125 levels. SNPs in the HIC1 gene on chromosome 17, a tumor suppressor gene whose aberrant methylation has been observed in ovarian tumors, was associated with lower CA125 levels. Conclusion: We identified 12 independent loci associated with blood CA125 levels in women without ovarian cancer, providing novel biological insights on the role of CA125. Accounting for these genetic factors that influence blood CA125 levels could improve the performance of CA125 as ovarian cancer screening biomarker in average risk women, substantially improving survival through earlier detection of this deadly disease. Citation Format: Naoko Sasamoto, Jihye Kim, Constance Turman, Shelley S. Tworoger, Rudolf Kaaks, Renée T. Fortner, Daniel W. Cramer, Kathryn L. Terry, Nicolas Wentzensen, Peter Kraft. Genome-wide association studies of 26,187 women without ovarian cancer identifies 12 genetic loci of blood CA125 [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B051.

A Revised Molecular Model of Ovarian Cancer Biomarker CA125 (MUC16) Enabled by Long-read Sequencing.

Despite its crucial role in clinical management of ovarian cancer, the exact molecular sequence and structure of the biomarker, CA125, are not defined. Here, we combine long-read sequencing, mass spectrometry, and in silico modeling to provide the foundational dataset for a more complete characterization of the CA125 epitope.

Role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the detection of recurrence and peritoneal metastasis from ovarian cancer in correlation with cancer antigen-125 tumor marker levels

BackgroundThe chronic nature of ovarian cancer and disease recurrence has a considerable impact on the assessment of follow-up strategies and treatment planning for both oncologists and radiologists. It is imperative to conduct adequate follow-up in ovarian cancer to detect and treat recurrence as early as possible. Presently, surveillance of patients with this malignancy involves the combination of serial CA-125 assay and diverse imaging procedures, yet normal CA-125 levels cannot entirely rule out disease relapse. PET/CT provides whole-body functional imaging that does not necessities contrast injection, and allows for precise diagnosis and restaging of patients with suspected ovarian cancer recurrence, thereby strongly impacting disease management decisions. Our study aims to evaluate the value of FDG-PET/CT as a follow-up imaging tool in detecting and localizing recurrence of ovarian cancer, in conjunction with CA-125 tumor markers.ResultsIn our study, it was demonstrated that recurrent disease manifested in FDG-PET/CT in 24 cases, with 9 of those cases exhibiting CA-125 levels within the normal range. There were two instances of false negative results and one instance of false positive results in FDG-PET/CT. Additionally, three cases were found to be free of disease relapse in FDG-PET/CT and exhibited normal CA-125 levels throughout the follow-up period (true negative). The prevalence of disease recurrent sites was 12% for local recurrence, 60% for peritoneal metastasis, 64% for nodal deposits and 28% for distant metastatic disease. The accuracy of FDG-PET/CT was 88.8%, with a sensitivity of 91.3% and specificity of 75%. Furthermore, FDG-PET/CT showed a positive predictive value of 95.5% and a negative predictive value of 60.3%.ConclusionsPET/CT imaging provides a comprehensive and functional view of the entire body, which can accurately diagnose and restage cases with ovarian cancer recurrence. This approach plays a critical role in identifying peritoneal carcinomatosis and is considered a more dependable method than CA-125 tumor markers for detecting and monitoring ovarian cancer recurrence. Additionally, PET/CT imaging has the potential to decrease the number of second-look laparotomies and can thus significantly impact the management plan.

Screening for Ovarian Cancer in the General Population: State of Art and Perspectives of Clinical Research.

Screening for ovarian cancer in the general population is a challenging issue. The aim of this review was to analyze both the studies based on serum CA125 assay and ultrasound (US) and the novel perspectives of clinical and biological research on this issue. The trials on the combination of serum CA125 and vaginal/pelvic US as well as the investigations on microRNA (miRNA)s, circulating tumor DNA and tumor protein 53 (TP53) variants in DNA purified from Pap smears have been critically analyzed. Two large randomized trials failed to detect a reduction in ovarian cancer-related deaths in women who underwent serum CA125- and US-based screening compared to those who had no screening. The United Kingdom Collaborative Trial of Ovarian Cancer Screening reported a 39.2% higher incidence of stage I-II and 10.2% lower incidence of stage III-IV disease in women who underwent annual multimodal screening with serum CA125 and vaginal US compared to women who had no screening, but this stage shifting did not translate into a survival benefit. A longitudinal, multiple biomarker algorithm-based strategy might improve ovarian cancer detection compared with serial CA125 alone. The use of serum tumor-associated autoantibodies, circulating tumor DNA and microRNA is still investigational. The identification of TP53 clonal variants in DNA purified from Pap smears can detect early steps of serous ovarian carcinogenesis. The availability of sensitive next-generation sequencing-based approaches for TP53 assessment in PAP smears may allow the reliability of this genetic marker for early detection of ovarian cancer to be verified.

Diagnostic potential of nanoparticle aided assays for MUC16 and MUC1 glycovariants in ovarian cancer.

Our study reports the discovery and evaluation of nanoparticle aided sensitive assays for glycovariants of MUC16 and MUC1 in a unique collection of paired ovarian cyst fluids and serum samples obtained at or prior to surgery for ovarian carcinoma suspicion. Selected glycovariants and the immunoassays for CA125, CA15‐3 and HE4 were compared and validated in 347 cyst fluid and serum samples. Whereas CA125 and CA15‐3 performed poorly in cyst fluid to separate carcinoma and controls, four glycovariants including MUC16MGL, MUC16STn, MUC1STn and MUC1Tn provided highly improved separations. In serum, the two STn glycovariants outperformed conventional CA125, CA15‐3 and HE4 assays in all subcategories analyzed with main benefits obtained at high specificities and at postmenopausal and early‐stage disease. Serum MUC16STn performed best at high specificity (90%‐99%), but sensitivity was also improved by the other glycovariants and CA15‐3. The highly improved specificity, excellent analytical sensitivity and robustness of the nanoparticle assisted glycovariant assays carry great promise for improved identification and early detection of ovarian carcinoma in routine differential diagnostics.

CA125 and Ovarian Cancer: A Comprehensive Review.

Simple SummaryCA125 has been the most promising biomarker for screening ovarian cancer; however, it still does not have an acceptable accuracy in population-based screening for ovarian cancer. In this review article, we have discussed the role of CA125 in diagnosis, evaluating response to treatment and prognosis of ovarian cancer and provided some suggestions in improving the clinical utility of this biomarker in the early diagnosis of aggressive ovarian cancers. These include using CA125 to screen individuals with symptoms who seek medical care rather than screening the general population, increasing the cutoff point for the CA125 level in the plasma and performing the test at point-of-care rather than laboratory testing. By these strategies, we would detect more aggressive ovarian cancer patients in stages that the tumour can be completely removed by surgery, which is the most important factor in redusing recurrence rate and improving the survival of the patients with ovarian cancer.Ovarian cancer is the second most lethal gynecological malignancy. The tumour biomarker CA125 has been used as the primary ovarian cancer marker for the past four decades. The focus on diagnosing ovarian cancer in stages I and II using CA125 as a diagnostic biomarker has not improved patients’ survival. Therefore, screening average-risk asymptomatic women with CA125 is not recommended by any professional society. The dualistic model of ovarian cancer carcinogenesis suggests that type II tumours are responsible for the majority of ovarian cancer mortality. However, type II tumours are rarely diagnosed in stages I and II. The recent shift of focus to the diagnosis of low volume type II ovarian cancer in its early stages of evolution provides a new and valuable target for screening. Type II ovarian cancers are usually diagnosed in advanced stages and have significantly higher CA125 levels than type I tumours. The detection of low volume type II carcinomas in stage IIIa/b is associated with a higher likelihood for optimal cytoreduction, the most robust prognostic indicator for ovarian cancer patients. The diagnosis of type II ovarian cancer in the early substages of stage III with CA125 may be possible using a higher cutoff point rather than the traditionally used 35 U/mL through the use of point-of-care CA125 assays in primary care facilities. Rapid point-of-care testing also has the potential for effective longitudinal screening and quick monitoring of ovarian cancer patients during and after treatment. This review covers the role of CA125 in the diagnosis and management of ovarian cancer and explores novel and more effective screening strategies with CA125.

The prevalence of occult ovarian cancer in the series of 155 consequently operated high risk asymptomatic patients – Slovenian population based study

BackgroundWe assessed the prevalence, localization, type and outcome of occult cancer at risk-reducing salpingo-oophorectomy or salpingectomy (RRSO) in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women.Patients and methodsA retrospective analysis of all consecutive gynaecologic preventive surgeries from January 2009 to December 2015 was performed. Participants underwent genetic counselling and BRCA1/2 testing before the procedure. Data on clinical parameters, adjuvant treatment and follow-up were collected and analysed.ResultsOne hundred and fifty-five RRSO were performed in 110 BRCA1, 35 BRCA2 carriers of pathogenic or likely pathogenic variants and 10 high-risk BRCA1/2 negative women, at the mean age of 48.3 years. Nine occult cancers (9/155, 5.8%) were identified; eight in BRCA1 positive women and one in high-risk BRCA1/2 negative woman. We identified four non-invasive serous intraepithelial tubal carcinomas (3 in BRCA1 carriers and 1 in a high-risk BRCA1/2 negative woman) and five invasive tubo-ovarian high grade serous cancers (all detected in BRCA1 carriers). Only one out of nine patients (11.1%) with occult cancer had a slightly elevated CA-125 value preoperatively.ConclusionsA 5.8% prevalence of occult invasive and noninvasive tubo-ovarian serous cancer after RRSO was found in high risk asymptomatic and screen negative women. We conclude that RRSO should be performed in BRCA1/2 carriers and in high-risk BRCA1/2 negative women. Age of preventive gynaecologic surgery should be carefully planned, taking into account the completion of childbearing age and type of mutation. The results favour the tubal hypothesis of tubal origin of high grade serous ovarian and peritoneal cancer. Cytology result of peritoneal cavity washing was important for the decision making process in determining treatment. Cytology examination should be performed in all cases of RRSO. CA-125 assay did not prove to be an effective screening tool for early cancer detection in our patients.

CuO–ZnO heterojunction derived from Cu2+-doped ZIF-8: A new photoelectric material for ultrasensitive PEC immunoassay of CA125 with near-zero background noise

By direct calcination of Cu2+-doped ZIF-8 in oxygen atmosphere, a new photoelectric material, CuO–ZnO heterojunction, was prepared. The morphology and structure were investigated in detail by several methods, such as scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption method and X-ray diffraction. Under visible light irradiation, CuO–ZnO heterojunction exhibits excellent PEC behavior in aqueous media with the presence of ascorbic acid (AA) and dissolved oxygen at −0.3 V. Taking the CA125-antibody functionalized CuO–ZnO heterojunction (CuO–ZnO-Ab2) as a signal source, a novel photoelectrochemical (PEC) immunosensing platform was developed for ultrasensitive assay of CA125. Because of the target-induced introduction of photoelectric material to the sensing platform, the proposed PEC immunosensor has excellent performance for CA125 assay: near-zero background noise, wide linear response range (1 × 10−5 U/mL to 100 U/mL) and low detection limit (3.16 × 10−6 U/mL). The developed CuO–ZnO heterojunction and the related PEC sensing platform may have promising applications in ultrasensitive and highly accurate monitoring of various proteins in bioanalysis and disease diagnosis.

Ethnic disparity in clinical performance between multivariate index assay and CA125 in detection of ovarian malignancy.

Aim: Based on evidence that African-American (AA) women have lower CA125 values than Caucasian (C) women, we investigated this to see if this disparity would have an impact on ovarian cancer detection using CA125 and multivariate index assay (MIA). Materials & methods: Serum from two prospective trials of 1029 (274 malignancies [250 C/24AA]) were analyzed for CA125 and MIA results. Clinical performance was calculated. Results: Sensitivity of MIA in Caucasian women was 93.2%, 74.4% for CA125 at the ACOG approved cut-off level of 200 U/ml cutoff, and 80.4% using the 2007, Dearking 67 U/ml cutoff. In AA American women, MIA sensitivity was 79.2%, 33.3% for CA125 at the ACOG approved cut-off levels and 62.5% at the 2007, Dearking 67 U/ml cutoff. Conclusion: Our results support that CA125 in AA women with adnexal masses has lower sensitivity than MIA no matter what the cutoff value is. Implementation of MIA in evaluation of adnexal masses should increase sensitivity of detection of malignancy compared with CA125, particularly in AA women.

Theranostic Nanostructures for Ovarian Cancer.

Ovarian cancer (OC) has emerged as one of the leading causes of death in women due to the lack of early-stage diagnosis resulting in impairment and delay in treatment of malignancy, which raises the morality rate. Existing diagnostic (pelvic examination, CA125, and enzyme-linked immunosorbent assay) or therapeutic modalities (radiotherapy, abdominal pelvic radiation therapy, and chemotherapy) are insufficient to decrease the 5-year survival rate. Nanoparticles (NPs) have been extensively explored as probes for imaging or therapy of cancer. As an extension of this, probes have been designed to possess both imaging and therapeutic modality in a single molecule and this has emerged as the science of nanotheranostics. This review presents the existing diagnostic and therapeutic strategies in use for OC and discusses their loopholes that limit the prognosis of OC. The review presents a general description of important properties of nanostructures and the type of nanostructures that have been used as imaging/therapeutic probe in cancer. The state-of-the-art nanotheranostics probe for targeting OC is presented. Systematic and complete studies that can correlate the findings of researchers from different global areas are lacking. The current status of nanostructures in various phases of clinical trials and those approved by U.S. Food and Drug Administration (FDA) has been presented. No specific targeted theranostic probe for OC has yet been approved by the FDA. Here, the underlying reasons and the challenges faced for nanotheranostics of OC are discussed, along with its future prospects.

Abstract IA15: Early detection of ovarian cancer: An update

Abstract IA15: Early detection of ovarian cancer: An update

Diagnostic Accuracy of Risk of Ovarian Malignancy Algorithm (ROMA) in Post-Menopausal Patients with Ovarian Mass.

To determine the diagnostic accuracy of ROMA in postmenopausal women with history of ovarian mass. Observational study. Dr. Ziauddin University Hospital, Karachi, from May 2014 to June 2015. Two hundred and sixty postmenopausal women of 40-65 years of age with ovarian masses, planned for surgery, were included in the study. Their samples were obtained preoperatively and analysed on Abbot Architect i1000 SR immunoassay analyser for quantitative estimation of tumor markers, i.e. HE4 and CA125. By combination of these two tumor markers, ROMA scores were calculated and studied after histopathological verification of masses. Total number of patients were 260, out of which 122 (46.9%) were diagnosed as having ovarian cancer, while 138 (53.0%) were diagnosed as benign condition. Median ROMA score levels in patients with malignant masses were 95.58 (IQR=44.4) as compared to 20.6 (IQR=14) in benign masses. ROMA had sensitivity 92.6% (CI=86.47-96.04), specificity 78.3% (CI=70.09-83.82), positive predictive value 79% (CI=70.87-84.29), negative predictive value 92.3% (CI=86.02-95.9) and positive likelihood ratio 4.26, while negative likelihood ratio 0.1. Diagnostic accuracy of ROMA was 85%, based on ROC curve analysis. ROMA had the highest sensitivity in detecting ovarian carcinoma. ROMA is a very useful diagnostic tool for the preoperative stratification of patients with ovarian masses showing 85% diagnostic accuracy. However, there is need of more studies with homogenous laboratory procedures for HE4 and CA125 assays as well as patients, selection criteria, so we can draw firm conclusion about utility of ROMA in clinical setups.

Interassay Comparison of the Tumor Markers CA125, CA15.3, and CA27.29.

Cancer antigens 125, 27.29, and 15-3 (CA125, CA27.29, and CA15-3) are markers of ovarian and breast cancer. Comparing tumor marker results across methods is challenging because of the lack of harmonization. Documenting comparability of results is important. Siemens Advia Centaur CA125 and CA27.29 assays were compared to their corresponding Beckman Coulter DxI CA125 and CA15-3 assays. The interassay bias was determined and the manufacturer-recommended reference intervals were evaluated. The DxI CA125 assay demonstrated an overall positive 29% bias relative to the Centaur CA125 assay. The DxI CA15-3 assay demonstrated an overall negative 65% bias relative to the Centaur CA27.29 assay. For patients with multiple comparisons during the study period, the trend of results over time was similar across both sets of assays. Implementing the manufacturer-recommended reference interval for the DxI CA125 assay increased the abnormal flagging rate by 4.5%. In contrast, implementing the manufacturer-recommended reference interval for the DxI CA15-3 assay decreased the abnormal flagging rate by 13.0%. The overall trends for the majority of patients were similar. Therefore, despite the overall biases, transitioning tumor marker assays should not affect clinical interpretation of results.

A new strategy for calculating the risk of ovarian malignancy algorithm (ROMA).

Reliable quantitative measurements of HE4 and CA125 levels are required to calculate the risk of ovarian malignancy algorithm (ROMA) value. We suggest a new reporting strategy for interpreting ROMA values based on analytical measurement range (AMR) and qualified-intervals of the HE4 and CA125 results. HE4 and CA125 assays from Abbott and Roche were used. The AMRs and the qualified-intervals were as follows: Architect HE4 assay, 20-1500 and 17.2-2637.8 pmol/L; Architect CA125 II assay, 1-1000 and 3.9-14,163.0 U/mL; Elecsys HE4 assay, 15-1500 and 28.8-3847 pmol/L; Elecsys CA125 II assay, 0.6-5000 and 6.5-5000 U/mL. These values were used to simulate the ROMA values. Reporting algorithm for the ROMA value could be classified into three categories. (1) If quantitative HE4 and CA125 levels are reliable, the numerical ROMA value can be reported. (2) If HE4 value is <20 and <28.8 for Abbott and Roche in premenopausal woman, the ROMA value should be reported as "low risk" regardless of the CA125 result. In postmenopausal woman, however, it should be reported as "low risk" (CA125<203.0 and <165.8 for Abbott and Roche) or "undetermined" (vice-versa value). (3) If CA125 value is <3.9 and <6.5 for Abbott and Roche, it should be reported as "low risk" (premenopausal HE4<51.5 and <62.2, postmenopausal HE4<323.0 and <281.5 for Abbott and Roche) or "undetermined" (vice-versa value). New reporting strategy will provide more informative reporting of ROMA values in clinical practice.

The adnexal mass: Benign or malignant? Evaluation of risk of malignancy index

Background: Screening programme for ovarian malignancy is an international public demand. Ojective: To validate a risk of malignancy index (RMI) incorporating serum CA125, abdominal ultrasound findings and menopausal status for preoperative diagnosis of ovarian malignancy among patient with adnexal mass.Methods: This prospective observa­tional study was conducted on 57 patients having adnexal mass admitted consecutively for surgical exploration in BSMMU from January 2000 to March 2001. S. CA125 assay &amp; abdominal ultrasonography was done within 10 days preoperatively. Ultrasound score (0, 1 &amp; 3) using 5 sonographic features &amp; menopausal score (1 &amp; 3) were calculated. RMI was detected by the formula "RMI = Ultrasound score - Menopausal score - S. CA125 level" Definitive diagnosis was based on histopathological examination.See PDF for the rest of the abstract.

Abstract AS13: Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer

Abstract Background: CA125 is elevated in 80% of ovarian cancer cases and has proven utility in assessing response to therapy and prognosis. Unfortunately, CA125 is elevated in a variety of benign conditions and only in 50% of early stage ovarian cancers, resulting in a sensitivity and specificity unacceptable for population-based screening. Therefore, understanding factors that influence CA125 at presentation could provide important insights for interpreting CA125 values. Methods: Using pre-treatment CA125 and detailed epidemiologic data from 12 studies participating in the Ovarian Cancer Association Consortium (OCAC), we evaluated factors previously reported to influence CA125 levels, including age, race, oral contraceptive use, parity, tubal ligation, endometriosis, body mass index (BMI), personal history of breast cancer, or a family history of breast or ovarian cancer. We used linear regression to estimate the association between each variable and CA125 probit scores, which we used to standardize values between studies. Secondary analyses included adjustment for histologic subtype. We also estimated the associations within each study using log-transformed CA125 as the outcome and estimated summary measures using random effects meta-analyses. Results: Of the 4417 cases included in the analysis, 2918 (66%) were serous, 227 (5%) were mucinous, 484 (11%) were endometrioid, and 258 (6%) were clear cell carcinomas. Median CA125 values varied between studies with a high of 831 U/mL and a low of 271 U/mL. We observed no association between race, oral contraceptive use, tubal ligation, endometriosis, prior breast cancer, and family history of breast cancer and pre-treatment CA125. However, we observed increased pre-treatment CA125 levels with older age (&amp;gt;70 vs. &amp;lt; 50, p=0.03), parity (p=0.01), number of children (p=0.02), obesity (BMI&amp;gt;30 vs. 21-25, p=0.03), and family history of ovarian cancer (p=0.05). Results were similar but attenuated when we calculated summary estimates of the association using meta-analysis of study specific estimates of the association with log-transformed CA125 rather than probit scores. Age and BMI remained predictive of pre-treatment CA125 values after adjustment for histologic subtype. Our data are limited by between site variability in CA125 assays; therefore, validation of these findings is needed with adjustment for type of assay used or in a study population in which all cases had pre-treatment CA125 values measured with the same assay. Conclusions: Despite these limitations, results from this analysis of over 4000 ovarian cancer cases suggest that age and body size may influence pre-treatment CA125 values. Citation Format: KL Terry, A Babic, BY Karlan, MT Goodman, D Lambrechts, F Heitz, K Matsuo, I McNeish, T Pejovic, S Kruger Kjaer, PM Webb, E Hogdall, EL Goode, DW Cramer, for the Ovarian Cancer Association Consortium. Epidemiologic predictors of pre-treatment CA125 in women with ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS13.

Abstract POSTER-THER-1441: Biomarker evaluation of phase 1 clinical trials of antibody-drug conjugates (ADCs) in platinum resistant ovarian cancer

Abstract Purpose: DNIB0600A and DMUC5754A are two ADCs that conjugate the anti-mitotic agent MMAE with anti-NaPi2b and anti-MUC16 monoclonal antibodies, respectively. Both ADCs have shown promising anti-tumor activity in patients with platinum resistant ovarian cancer. Here we report biomarker analysis in patient samples collected from these phase 1 studies. The main goal of this study is to evaluate tissue-based biomarkers that can predict response or resistance to these ADCs. We also explored the utility of serum protein biomarkers and circulating tumor cells (CTCs) as potential surrogates for monitoring treatment response to ADCs and disease progression. Methods: Biomarker analysis was done on 55 ovarian cancer patients treated with clinically relevant doses (1.8-3.2mg/kg) from DNIB0600A and DMUC5754A Phase 1 studies. Protein and mRNA expression levels of NaPi2b and MUC16 targets were assessed in archival tumor specimen by immunohistochemistry (IHC) and qRT-PCR respectively. Serum collected at baseline and post-treatment were analyzed by CA125 and HE4 ELISA assays as well as by the OLINK 96-plex PEA protein biomarker panel. CTCs at baseline and post-treatment were analyzed using the Veridex CellSearch System. Results: Target expression in tumor tissues for both NaPi2b and MUC16 measured by IHC and qRT-PCR are concordant. High NaPi2b or MUC16 expression (IHC 2+/3+) was identified in all responders by RECIST criteria (11 from DNIB0600A and 5 from DMUC5754A) for respective target, while no patient from either study with IHC 0 showed RECIST response. In patients treated with DNIB0600A, longitudinal changes in serum CA125 level correlated with RECIST response. Additionally, CTC was detected in 60% of patients at baseline in the DNIB0600A trial, and decreased CTC counts was observed after 1-2 cycles of treatment for two-third of patients. In patients treated with DMUC5754A, circulating CA125 (i.e. extra-cellular domain of MUC16 shed in circulation) is cleared after initial dosing; therefore other ovarian cancer biomarkers including HE4 were assessed. Baseline serum HE4 level correlates well with the tumor burden at pre-treatment in DMUC5754A trial, and showed excellent correlation with RECIST response post-treatment. Conclusions: Target expression in archival tumor tissues is predictive to clinical response to ADCs. CTC enumeration as well as serum HE4 could be used as potential surrogate biomarkers for monitoring treatment response in ovarian cancer. Further validation of these findings is required. Citation Format: Yulei Wang, Ron Firestein, Lisa Ryner, Walter Darbonne, Yinghui Guan, Shan Lu, YJ Choi, Yuanyuan Xiao, Paul Polakis, Becky Suttmann, Rupal Desai, Ling Fu, Ola Saad, Kirsten Achilles Poon, Mitch Denker, Vincent Leveque, Teiko Sumiyoshi, Mark Lackner, David Shames, Eric Humke, Daniel Mayslar. Biomarker evaluation of phase 1 clinical trials of antibody-drug conjugates (ADCs) in platinum resistant ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1441.

Abstract 5299: Monitoring of ovarian cancer recurrence and progression via Lumipulse G CA125II assay

Abstract CA125 is useful for monitoring the course of ovarian cancer. The correlation between CA125 serum levels and the course of the disease was reported to be 87% (Kenemans, 1993). Persistently rising CA125 levels may be associated with malignant disease and poor response to therapy, whereas decreasing CA125 assay values may indicate a favorable response to therapy (Bast, 1984; Atack, 1986; Schilthuis, 1987; Crombach, 1985). This study was to evaluate the use of LUMIPULSE G CA125II assay with patient serum or plasma for the monitoring of the recurrence and progression of ovarian cancer. METHODS: LUMIPULSE G CA125II assay is a second-generation CA125 immunoassay using monoclonal antibody (MAb) OC125 as the solid phase antibody and the MAb M11 as the labeled antibody. In the assay, serum or plasma was added to and incubated with the MAb OC125-linked magnetic particles. The particles were then washed and rinsed to remove unbound materials. Alkaline phosphatase-labeled MAb M11 was added to and incubated with the CA125-bound particles. The particles were then washed and rinsed again to remove unbound materials. Substrate 3-(2′-spiroadamantane)-4-methoxy-4-(3”-phosphoryloxy) phenyl-1, 2-dioxetane disodium salt (AMPPD) solution was then added to and mixed with the particles. Luminescence signals were thus generated by the cleavage reaction of dephosphorylated AMPPD and converted into the amount of CA125 in the serum or plasma. RESULTS: In the monitoring study, changes in CA125 levels in serial serum samples collected in SST tubes from 61 patients with ovarian cancer were compared to changes in disease status, that is, progression or no progression. A total of 297 pairs of observations were undertaken with an average number of 5.9 observations per patient. A positive change in CA125 was defined as an increase in the value that was at least 20% greater than the previous value of the assay. 67% of the 52 patient samples with a positive change correlated with the disease progression of ovarian cancer while 75% of the 245 patient serial samples with no significant change in CA125 value correlated with no progression of ovarian cancer. The total concordance was 73%. A ROC curve for the diagnosis of progression of ovarian cancer from the ratio of successive CA125 readings showed an area under the ROC curve (AUC) of 0.727 with SE 0.047; this is highly statistically significantly better than the no-association AUC of 0.5. In addition, a reference range study of this assay showed that serum CA125 levels were ≤35.0 U/mL in 98% of the healthy female subjects (n = 240), 80% of females with pregnancy (n = 40), 91% of females with benign gynecological disease (n = 300), 92% of females with non-gynecological benign disease (n = 40), 80% of females with congestive heart failure (n = 40), and 85% of females with hypertension (n = 40), respectively. CONCLUSION: The LUMIPULSE G CA125II assay has demonstrated to be useful in monitoring the course of disease in patients with ovarian cancer. Citation Format: Rachel R. Radwan, Savitha S. Raju, Sara J. Gannon, John Le, Sharee D. Jones, Catherine Peacock, Katherine Falcone, Julianna T. Young, Zhong-Qian Li, Diana L. Dickson. Monitoring of ovarian cancer recurrence and progression via Lumipulse G CA125II assay. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5299. doi:10.1158/1538-7445.AM2015-5299

Detection of glyco-mucin profiles improves specificity of MUC16 and MUC1 biomarkers in ovarian serous tumours

The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum assays. Our aim was to refine ovarian cancer biomarkers by detection of aberrant glycoforms (Tn, STn, and T) of MUC16 and MUC1 in ovarian cancer tissue using Proximity Ligation Assays (PLA).We studied two series of serous ovarian tumours, a pilot series of 66 ovarian tumours (27 cystadenomas, 16 borderline tumours and 23 adenocarcinomas) from Centro Hospitalar S. João, Porto and a validation series of 89 ovarian tumours (17 cystadenomas, 25 borderline tumours and 47 adenocarcinomas) from the Portuguese Institute of Oncology Francisco Gentil, Lisbon.PLA reactions for MUC16/Tn, MUC16/STn, MUC1/Tn and MUC1/STn were negative in benign lesions but often positive in borderline and malignant lesions, in both series. An even better yield was obtained based on positivity for any of the four glyco-mucin profiles, further increasing sensitivity to 72% and 83% in the two series, respectively, with 100% specificity. The strategy is designated glyco-mucin profiling and provides strong support for development of PLA-based serum assays for early diagnosis.