Multivariate Index Assay Research Articles

Comparison of the Diagnostic Performances of CA125 and Multiple Marker Combinations for Early Diagnosis of Ovarian Cancer

Studies have proven the diagnostic efficiency of multiple markers for ovarian cancer diagnosis with in vitro diagnostic multivariate index assays. We compared the diagnostic performance of multiple marker combinations and carbohydrate antigen (CA) 125 alone, a widely utilized tumor marker, for early ovarian cancer detection. Overall, 257 serum samples from Korean women, including 204 patients with benign tumors and 53 patients with ovarian cancer, were analyzed. We used 22 serum markers showing specific reaction to ovarian cancer was the concentration value obtained from xMAP™ bead-based technology (Luminex Corp.). To identify markers that combined well with CA125, a multivariate model that comprised combinations of 2–3 marker, including CA125, was created, and the best marker combinations were selected by assessing area under the receiver-operating curves (AUCs). The AUC values of CA125 alone, CA125+M2, and CA125+M2+M4 were 69.96%, 76.63%, and 81.28%, respectively. It was confirmed that multiple marker combinations including CA125 showed better diagnostic performance than CA125 alone for early-stage ovarian cancer diagnosis.

Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer

OBJECTIVE: We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. STUDY DESIGN: Patients were recruited in 2 related prospective, multiinstitutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. RESULTS: A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primarystage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies,MIAcombinedwithclinicalassessmenthadsignificantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6e98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2e77.4), CA 125-II (62.8%; 95% CI, 52.2e72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8e84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8e96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4e76.4) for clinical assessment alone,35.7%(95%CI,20.7e54.2)forCA125-II,and78.6%(95%CI, 60.5e89.8) for modified ACOG guidelines.Early-stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9e99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8e82.2) for clinical assessment alone,75.9%(95%CI,63.5e85.0)forCA125-II,and75.9%(95%CI, 63.5e85.0) for modified ACOG guidelines. CONCLUSION: MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125-II, and modified ACOG guidelines with consistent performance across menopausal status.

Impact of a multivariate index assay on referral patterns for surgical management of an adnexal mass

Objectives: To determine the potential impact on referral patterns of using a Multivariate Index Assay (MIA), CA125-II, modified-American College of Obstetricians and Gynecologists (ACOG) referral guidelines, and clinical assessment among patients undergoing surgery for an adnexal mass and initially evaluated by a non-gynecologic oncologist (GO).

Clinical performance of a multivariate index assay for detecting early-stage ovarian cancer

We sought to analyze the effectiveness of a multivariate index assay (MIA) in identifying early-stage ovarian malignancy compared to clinical assessment, CA 125-II, and modified American Congress of Obstetricians and Gynecologists (ACOG) guidelines among women undergoing surgery for an adnexal mass. Patients were recruited in 2 related prospective, multi-institutional trials involving 44 sites. All women had preoperative imaging and biomarker analysis. Preoperative biomarker values, physician assessment of ovarian cancer risk, and modified ACOG guideline risk stratification were correlated with surgical pathology. A total of 1016 patients were evaluable for MIA, CA 125-II, and clinical assessment. Overall, 86 patients (8.5%) had primary-stage I/II primary ovarian malignancy, with 70.9% having stage I disease and 29.1% having stage II disease. For all early-stage ovarian malignancies, MIA combined with clinical assessment had significantly higher sensitivity (95.3%; 95% confidence interval [CI], 88.6-98.2) compared to clinical assessment alone (68.6%; 95% CI, 58.2-77.4), CA 125-II (62.8%; 95% CI, 52.2-72.3), and modified ACOG guidelines (76.7%; 95% CI, 66.8-84.4) (P < .0001). Among the 515 premenopausal patients, the sensitivity for early-stage ovarian cancer was 89.3% (95% CI, 72.8-96.3) for MIA combined with clinical assessment, 60.7% (95% CI, 42.4-76.4) for clinical assessment alone, 35.7% (95% CI, 20.7-54.2) for CA 125-II, and 78.6% (95% CI, 60.5-89.8) for modified ACOG guidelines. Early-stage ovarian cancer in postmenopausal patients was correctly detected in 98.3% (95% CI, 90.9-99.7) of cases by MIA combined with clinical assessment, compared to 72.4% (95% CI, 59.8-82.2) for clinical assessment alone, 75.9% (95% CI, 63.5-85.0) for CA 125-II, and 75.9% (95% CI, 63.5-85.0) for modified ACOG guidelines. MIA combined with clinical assessment demonstrated higher sensitivity for early-stage ovarian malignancy compared to clinical assessment alone, CA 125-II, and modified ACOG guidelines with consistent performance across menopausal status.

Impact of a multivariate index assay on referral patterns for surgical management of an adnexal mass

To determine the impact on referral patterns of using a Multivariate Index Assay, CA125, modified-American College of Obstetricians and Gynecologists referral guidelines, and clinical assessment among patients undergoing surgery for an adnexal mass after initial evaluation by nongynecologic oncologists. Overall, 770 patients were enrolled by nongynecologic oncologists from 2 related, multiinstitutional, prospective trials and analyzed retrospectively. All patients had preoperative imaging and biomarker analysis. The subset of patients enrolled by nongynecologic oncologists was analyzed to determine the projected referral patterns and sensitivity for malignancy based on multivariate index assay (MIA), CA125, modified-American College of Obstetricians and Gynecologists (ACOG) guidelines, and clinical assessment compared with actual practice. The prevalence of malignancy was 21.3% (n = 164). In clinical practice, 462/770 patients (60.0%) were referred to a gynecologic oncologist for surgery. Triage based on CA125 predicted referral of 157/770 patients (20.4%) with sensitivity of 68.3% (95% confidence interval [CI], 60.8-74.9). Triage based on modified-ACOG guidelines would have resulted in referral of 256/770 patients (33.2%) with a sensitivity of 79.3% (95% CI, 72.4-84.8). Clinical assessment predicted referral of 184/763 patients (24.1%) with a sensitivity of 73.2% (95% CI, 65.9-79.4). Risk stratification using multivariate index assay would have resulted in referral of 429/770 (55.7%) patients, with sensitivity of 90.2% (95% CI, 84.7-93.9). MIA demonstrated statistically significant higher sensitivity (P < .0001) and lower specificity (P < .0001) for detecting malignancy compared with clinical assessment, CA125, and modified-ACOG guidelines. In this study population, use of MIA as a risk stratification test was associated with referral patterns by nongynecologic oncologists comparable to actual clinical practice and higher sensitivity for malignancy than other adnexal mass triage algorithms.

Ovarian Malignancy Risk Stratification of the Adnexal Mass Using a Multivariate Index Assay

Abstract Objective To validate the effectiveness of a multivariate index assay in identifying ovarian malignancy compared to clinical assessment and CA125-II, among women undergoing surgery for an adnexal mass after enrollment by non-gynecologic oncology providers. Methods A prospective, multi-institutional trial enrolled female patients scheduled to undergo surgery for an adnexal mass from 27 non-gynecologic oncology practices. Pre-operative serum samples and physician assessment of ovarian cancer risk were correlated with final surgical pathology. Results A total of 494 subjects were evaluable for multivariate index assay, CA125-II, and clinical impression. Overall, 92 patients (18.6%) had a pelvic malignancy. Primary ovarian cancer was diagnosed in 65 patients (13.2%), with 43.1% having FIGO stage I disease. For all ovarian malignancies, the sensitivity of the multivariate index assay was 95.7% (95%CI=89.3–98.3) when combined with clinical impression. The multivariate index assay correctly predicted ovarian malignancy in 91.4% (95%CI=77.6–97.0) of cases of early-stage disease, compared to 65.7% (95%CI=49.2–79.2) for CA125-II. The multivariate index assay correctly identified 83.3% malignancies missed by clinical impression and 70.8% cases missed by CA125-II. Multivariate index assay was superior in predicting the absence of an ovarian malignancy, with a negative predictive value of 98.1% (95%CI=95.2–99.2). Both clinical impression and CA125-II were more accurate at identifying benign disease. The multivariate index assay correctly predicted benign pathology in 204 patients (50.7%, 95%CI=45.9–55.6) when combined with clinical impression. Conclusion The multivariate index assay demonstrated higher sensitivity and negative predictive value for ovarian malignancy compared to clinical impression and CA125-II in an intended-use population of non-gynecologic oncology practices.

Investigation of human cationic antimicrobial protein-18 (hCAP-18), lactoferrin and CD163 as potential biomarkers for ovarian cancer

BackgroundEpithelial ovarian cancer is one of the leading causes of gynaecological cancer morbidity and mortality in women. Early stage ovarian cancer is usually asymptomatic, therefore, is often first diagnosed when it is widely disseminated. Currently available diagnostics lack the requisite sensitivity and specificity to be implemented as community-based screening tests. The identification of additional biomarkers may improve the diagnostic efficiency of multivariate index assays. The aims of this study were to characterise and compare the ovarian tissue immunohistochemical localisation and plasma concentrations of three putative ovarian cancer biomarkers: human cationic antimicrobial protein-18 (hCAP-18); lactoferrin; and CD163 in normal healthy women and women with ovarian cancer.MethodsIn this case–control cohort study, ovarian tissue and blood samples were obtained from 164 women (73 controls, including 28 women with benign pelvic masses; 91 cancer, including 21 women with borderline tumours). Localisation of each antigen within the ovary was assessed by immunohistochemistry and serum concentrations determined by ELISA assays.ResultsImmunoreactive (ir) hCAP-18 and lactoferrin were identified in epithelial cells, while CD163 was predominately localised in stromal cells. Tissue ir CD163 increased significantly (P<0.05) with disease grade. Median plasma concentrations of soluble (s)CD163 were significantly greater in the cases (3220 ng/ml) than in controls (2488 ng/ml) (P< 0.01). Median plasma concentrations of hCAP-18 and lactoferrin were not significantly different between cases and controls. The classification efficiency of each biomarker (as determined by the area under the receiver operator characteristic curve; AUC) was: 0.67± 0.04; 0.62 ± 0.08 and 0.51 ± 0.07 for sCD163, hCAP-18 and lactoferrin, respectively. When the 3 biomarkers were modelled using stochastic gradient boosted logistic regression, the AUC increased to 0.95 ± 0.03.ConclusionsThe data obtained in this study establishes the localisation and concentrations of CD163, hCAP-18, and lactoferrin in ovarian tumours and peripheral blood. Individually, the 3 biomarkers display only modest diagnostic efficiency as assessed by AUC. When combined in a multivariate index assay, however, diagnostic efficiency increases significantly. As such, the utility of the biomarker panel, as an aid in the diagnosis of cancer in symptomatic women, is worthy of further investigation in a larger phase 2 biomarker trial.

Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay

ObjectiveTo validate the effectiveness of a multivariate index assay in identifying ovarian malignancy compared to clinical assessment and CA125-II, among women undergoing surgery for an adnexal mass after enrollment by non-gynecologic oncology providers. MethodsA prospective, multi-institutional trial enrolled female patients scheduled to undergo surgery for an adnexal mass from 27 non-gynecologic oncology practices. Pre-operative serum samples and physician assessment of ovarian cancer risk were correlated with final surgical pathology. ResultsA total of 494 subjects were evaluable for multivariate index assay, CA125-II, and clinical impression. Overall, 92 patients (18.6%) had a pelvic malignancy. Primary ovarian cancer was diagnosed in 65 patients (13.2%), with 43.1% having FIGO stage I disease. For all ovarian malignancies, the sensitivity of the multivariate index assay was 95.7% (95%CI=89.3–98.3) when combined with clinical impression. The multivariate index assay correctly predicted ovarian malignancy in 91.4% (95%CI=77.6–97.0) of cases of early-stage disease, compared to 65.7% (95%CI=49.2–79.2) for CA125-II. The multivariate index assay correctly identified 83.3% malignancies missed by clinical impression and 70.8% cases missed by CA125-II. Multivariate index assay was superior in predicting the absence of an ovarian malignancy, with a negative predictive value of 98.1% (95%CI=95.2–99.2). Both clinical impression and CA125-II were more accurate at identifying benign disease. The multivariate index assay correctly predicted benign pathology in 204 patients (50.7%, 95%CI=45.9–55.6) when combined with clinical impression. ConclusionThe multivariate index assay demonstrated higher sensitivity and negative predictive value for ovarian malignancy compared to clinical impression and CA125-II in an intended-use population of non-gynecologic oncology practices.

Management of complex pelvic masses using a multivariate index assay: A decision analysis

ObjectiveTo develop a cost-minimization analysis of a multivariate index assay (MIA) used for women with complex pelvic masses. MethodsA decision analysis model was used to evaluate 81,000 hypothetical patients with a complex pelvic mass requiring surgery. Three strategies were evaluated: (1) referral to a gynecologic oncologist (GO) based on clinical assessment including physical exam, ultrasonography, and CA125 (CLINICAL); (2) utilization of a multivariate index assay (MIA); or (3) referral of all patients to a GO (REFER ALL). Various reoperation rates were evaluated with sensitivity analyses. Actual payer costs were compared between each strategy. ResultsThe CLINICAL strategy cost $933.9million (M) and resulted in 72% of patients receiving appropriate initial surgical staging. The REFER ALL strategy cost $939.7M and all patients were appropriately staged. The MIA strategy cost $976.7M and resulted in 91% of patients having appropriate initial staging. Using conservative reoperation rates (10–20%), 461 patients required reoperation using CLINICAL strategy compared to 142 patients in MIA strategy. Using aggressive reoperation rates (40–50%), 1715 patients required reoperation using CLINICAL strategy resulting in an incremental cost of $15.2M compared to 529 patients at $4.7M in MIA strategy. The increased costs associated with an aggressive reoperation rate resulted in the REFER ALL strategy being the least expensive alternative, with the highest rates of appropriate initial surgery. ConclusionsUtilizing an MIA resulted in more ovarian cancer patients receiving appropriate initial surgery, but at increased costs. Referring all patients with complex masses avoids the most reoperations at reduced cost compared to using an MIA.

Performance of a multianalyte test as an aid for the diagnosis of ovarian cancer in symptomatic women.

BackgroundConcomitant with the development of in vitro diagnostic multivariate index assays (IVDMIAs) to improve the diagnostic efficiency of ovarian cancer detection is the need to identify appropriate biostatistical approaches to assess improvements in risk predication. In this study, we assessed the utility of three different approaches for comparing diagnostic efficiency of an ovarian cancer multivariate assay in a retrospective case - control phase 2 biomarker trial. The control cohort included both disease-free women and women with benign gynecological conditions to more accurately reflect the target population of symptomatic women.MethodsThe study cohort comprised plasma samples from 244 healthy controls, 223 women with benign gynecological conditions, 53 borderline ovarian cancer cases and 222 women with malignant epithelial ovarian cancer. A multivariate classification model was developed that incorporated plasma concentrations of CA125, C-reactive protein (CRP), serum amyloid-A (SAA), interleukin-6 (IL6) and interleukin-8 (IL8) that were measured using in vitro diagnostics assays on medical device approved clinical analysers. The posterior probability values derived from the implemented algorithm were used for comparisons of the diagnostic performance between the multianalyte panel and CA125 using multiple methods; area under the curve (AUC) of the receiver operating characteristics curve, integrated discrimination improvement (IDI) and net reclassification improvement (NRI).ResultsEach of the biomarkers displayed significantly elevated plasma concentrations in malignant ovarian cancer patients compared with either benign or control subjects. For the discrimination of borderline and malignant ovarian cancer from control and benign subjects, the multivariate classification model showed a significantly greater AUC than that for CA125 alone (88.4% versus 84.3%, respectively, p < 0.001). At a posterior probability threshold of 0.5, the IVDMIA delivered a specificity of 92.3% and a sensitivity of 76.4%. When set at a specificity of 95%, the multimarker diagnostic delivered a sensitivity of 69.5% compared with 62.5% for CA125. Enhanced diagnostic performance of the IVDMIA over the use of CA125 alone was confirmed statistically by alternative comparisons using IDI and NRI.ConclusionsThis study confirms in an independent sample set that a blood-based multianalyte assay has significant advantages over CA125 for distinguishing symptomatic women with borderline and malignant ovarian cancer from controls or those with benign disease.

Using a Multivariate Index Assay to Assess Malignancy in a Pelvic Mass

A multivariate index assay recently was developed to assist physicians in the assessment of the risk of ovarian cancer in women with pelvic masses undergoing operative intervention. Its aim is to improve the identification of patients with ovarian malignancy so that these patients can be appropriately referred to a subspecialist with ovarian cancer-management expertise, thereby affording the opportunity for improved outcome. This commentary questions the need to obtain a multivariate index assay test in all women with pelvic masses who are scheduled for operative intervention. Common-sense guidelines for more judicious use of this new triage test in the evaluation of these patients also are provided.

Quality process in genomic pathology

The fundamental basis of quality control was pioneered by Shewhart in the 1920s, and developed by Demming during the 1940 s. Although these principles were developed in manufacturing, many pathology laboratories have recognised their importance. Whether in manufacturing or in pathology the basic principles remain the same: identify the sources of variation in the finished product, define measures of product quality at each stage in processing, routinely record those quality measures, and develop statistical decision rules to identify when a process is out of control—that is when it is delivering an unacceptable proportion of low quality results. The more complex an assay, the greater need there is for formal quality control processes. Few assays are as complex as those implemented using modern genomic platforms. Yet these assays produce vast quantities of data, which make comprehensive monitoring and the development of appropriate decision rules challenging. We consider a case study involving a multivariate index assay based on gene expression. Raw gene expression data were produced by a pathology laboratory as a technical service to the diagnostics company. The diagnostic company then provided interpretation, through computation of the multivariate index assay. The diagnostic company's quality processes revealed a substantial deterioration of the quality of raw results, and the service laboratory was found to have inadequate controls in place. We provide details of the appropriate quality metrics and decision rules, but the identity of both the diagnostics company and service laboratory are withheld.

Abstract C6: Composite profiling of angiogenic factors using Bio-Plex Pro™ Human Cancer Biomarker Panel-I.

Abstract Angiogenesis is a feature of over 50 different disease states. These include cancer, rheumatoid arthritis, cardiovascular diseases, diabetes and psoriasis. Methods developed to study these diseases are important tool to establish a model for testing potential therapeutics. These methods include both in vivo and in vitro assays. In vivo angiogenesis assays are considered to be the most informative because of the complex nature of vascular responses to test reagents and responses that no in vitro model can achieve. However in vivo assays can be expensive, laborious and require extensive training to perform. In contrast, in vitro assays can be carried out expeditiously, less costly and easier to interpret. Often, these in vitro assays provide maximum benefit when developed as a multivariate index assay where the data of multiple assays function to yield a composite result to interpret experimental studies. Using the Luminex xMAP technology, we have developed a multiplex Bio-Plex Pro™ Human Cancer Biomarker Panel I that employs a magnetic bead-based workflow to measure angiogenesis biomarkers in diverse matrices including serum, plasma, cell culture supernatant and many other sample types. In combination with the Bio-Plex® suspension array and the Bio-Plex Pro™ wash station, the multiplexing feature makes it possible to quantify the level of multiple angiogenesis targets in a single well of a 96-well microplate in just 3 hours, using as little as 12.5 μL of serum or plasma. The panel of 16 markers includes sEGFR, FGF basic, Follistatin, G-CSF, sHER2/neu, HGF, sIL-6Ra, Osteopontin, Leptin, PDGF-BB, PECAM-1, Prolactin, SCF, sTie-2, sVEGFR-1 and sVEGFR-2. These markers were selected because of their direct relevance to the pathogenesis of tumor-associated angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C6.

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

University of Kentucky Markey Cancer Center, Lexington, Kentucky Financial Disclosure: Dr. Ueland was the principal investigator for the OVA1 trial and has received honoraria as a speaker for Vermillion Inc. The other author did not report any potential conflicts of interest.

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

Performance of the American College of Obstetricians and Gynecologists' Ovarian Tumor Referral Guidelines With a Multivariate Index Assay

University of Kentucky Markey Cancer Center, Lexington, Kentucky Financial Disclosure: Dr. Ueland was the principal investigator for the OVA1 trial and has received honoraria as a speaker for Vermillion Inc. The other author did not report any potential conflicts of interest.

Are Multiplex Assays Approvable?

BioanalysisVol. 3, No. 16 EditorialAre multiplex assays approvable?Mya ThomaeMya ThomaeCEO, Myraqa, Inc., 3 Lagoon Drive, Suite 280, Redwood City, CA 94065, USA. Search for more papers by this authorEmail the corresponding author at mya@myraqa.comPublished Online:30 Aug 2011https://doi.org/10.4155/bio.11.174AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: clinical diagnosticsintended usemultiplex assayUS FDA-approvedUS FDA-clearedWebsites1 Class II special controls guidance document: instrumentation for clinical multiplex test systems – guidance for industry and FDA staff. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm077819.htmGoogle Scholar2 Draft guidance for industry, clinical laboratories, and FDA staff: in vitro diagnostic multivariate index assays. www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071455.pdfGoogle Scholar3 FDA shelves IVDMIA final guidelines in order to focus on overall LDT regulation. Genome Web. www.genomeweb.com/dxpgx/fda-shelves-ivdmia-final-guidelines-order-focus-overall-ldt-regulationGoogle Scholar4 Draft Guidance for Industry and FDA staff – commercially distributed in vitro diagnostic products labeled for research use only or investigational use only: frequently asked questions. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm253307.htmGoogle ScholarFiguresReferencesRelatedDetails Vol. 3, No. 16 Follow us on social media for the latest updates Metrics Downloaded 242 times History Published online 30 August 2011 Published in print August 2011 Information© Future Science LtdKeywordsclinical diagnosticsintended usemultiplex assayUS FDA-approvedUS FDA-clearedFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Aberrant glycosylation associated with enzymes as cancer biomarkers

BackgroundOne of the new roles for enzymes in personalized medicine builds on a rational approach to cancer biomarker discovery using enzyme-associated aberrant glycosylation. A hallmark of cancer, aberrant glycosylation is associated with differential expressions of enzymes such as glycosyltransferase and glycosidases. The aberrant expressions of the enzymes in turn cause cancer cells to produce glycoproteins with specific cancer-associated aberrations in glycan structures.ContentIn this review we provide examples of cancer biomarker discovery using aberrant glycosylation in three areas. First, changes in glycosylation machinery such as glycosyltransferases/glycosidases could be used as cancer biomarkers. Second, most of the clinically useful cancer biomarkers are glycoproteins. Discovery of specific cancer-associated aberrations in glycan structures of these existing biomarkers could improve their cancer specificity, such as the discovery of AFP-L3, fucosylated glycoforms of AFP. Third, cancer-associated aberrations in glycan structures provide a compelling rationale for discovering new biomarkers using glycomic and glycoproteomic technologies.SummaryAs a hallmark of cancer, aberrant glycosylation allows for the rational design of biomarker discovery efforts. But more important, we need to translate these biomarkers from discovery to clinical diagnostics using good strategies, such as the lessons learned from translating the biomarkers discovered using proteomic technologies to OVA 1, the first FDA-cleared In Vitro Diagnostic Multivariate Index Assay (IVDMIA). These lessons, providing important guidance in current efforts in biomarker discovery and translation, are applicable to the discovery of aberrant glycosylation associated with enzymes as cancer biomarkers as well.

Effectiveness of a Multivariate Index Assay in the Preoperative Assessment of Ovarian Tumors

To compare the effectiveness of physician assessment with a new multivariate index assay in identifying high-risk ovarian tumors. The multivariate index assay was evaluated in women scheduled for surgery for an ovarian tumor in a prospective, multi-institutional trial involving 27 primary- care and specialty sites throughout the United States. Preoperative serum was collected, and results for the multivariate index assay, physician assessment, and CA 125 were correlated with surgical pathology. Physician assessment was documented by each physician before surgery. CA 125 cutoffs were chosen in accordance with the referral guidelines of the American College of Obstetricians and Gynecologists. The study enrolled 590 women, with 524 evaluable for the multivariate index assay and CA 125, and 516 for physician assessment. Fifty-three percent were enrolled by nongynecologic oncologists. There were 161 malignancies and 363 benign ovarian tumors. Physician assessment plus the multivariate index assay correctly identified malignancies missed by physician assessment in 70% of nongynecologic oncologists, and 95% of gynecologic oncologists. The multivariate index assay also detected 76% of malignancies missed by CA 125. Physician assessment plus the multivariate index assay identified 86% of malignancies missed by CA 125, including all advanced cancers. The performance of the multivariate index assay was consistent in early- and late-stage cancers. The multivariate index assay demonstrated higher sensitivity and lower specificity compared with physician assessment and CA 125 in detecting ovarian malignancies.