paywalled: Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.

Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.:


ABSTRACT:

More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI.

Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%.

The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results.

An In Vitro Diagnostic Multivariate Index Assay (IVDMIA) for Ovarian Cancer: Harvesting the Power of Multiple Biomarkers (OVA1)

An In Vitro Diagnostic Multivariate Index Assay (IVDMIA) for Ovarian Cancer: Harvesting the Power of Multiple Biomarkers

Dr. Zhang is the inventor of the OVA1 algorithm, and as such is entitled to royalty payments from the sale of OVA1® through a license agreement between Johns Hopkins University and Vermillion, Inc.

Main Points

• The advantages of an in vitro diagnostic multivariate index assay (IVDMIA) in comparison to a single biomarker assay are based on the premise that the single-valued index, with its aggregated information from complementary biomarkers, will outperform each of its component biomarkers used individually.
• The ability of multivariate models to capture complex patterns in high-dimensional data also means that non-disease-related artifacts that happen to confound the samples used to train the models will also be captured.
• The inclusion of biomarkers in an IVDMIA requires that they are complementary, and that they collectively outperform a single marker with respect to the test’s intended use.
• OVA1® (Vermillion, Inc., Austin, TX) combines results from five tests—CA-125 II, prealbumin, apolipoprotein A-1, β2-microglobulin, and transferrin—into a single-valued index between 0 and 10; a higher value corresponds to a higher risk of malignancy.
• The addition of OVA1 to clinical assessment brings significant improvement in sensitivity. This is, however, at the cost of a reduced specificity. During the construction of the OVA1 multivariate model and the choice of cutoff values, a conscious decision was made to emphasize the need for a high sensitivity. This decision took into consideration the need to mitigate the safety concern of OVA1 with respect to its predefined intended use. Because OVA1 is to be used prior to the decision to refer to a specialist, a high sensitivity minimizes the risk of false-negative results for patients who actually have malignant diseases.

press release: (OVA1) Vermillion Receives Notice of Allowance for Patent of Biomarker for Ovarian Cancer

Vermillion Receives Notice of Allowance for Patent of Biomarker for Ovarian Cancer


(press release) About OVA1
OVA1 is a blood test for pre-surgical assessment of ovarian tumors for malignancy, using a unique multi-biomarker approach. In a published clinical trial, OVA1 achieved 99% sensitivity in detecting epithelial ovarian cancers (EOC). This included 96% sensitivity for stage I EOC, the earliest and most curable EOC stage, compared with 57% for the conventional biomarker CA125.(1) In addition, OVA1 found 70% of malignancies missed by non-specialist pre-surgical assessment,(1) and it increased detection of malignancy over ACOG guidelines from 77% to 94%.(2) As the first protein-based, In Vitro Diagnostic Multi-Variate Index Assay (IVDMIA) cleared by the FDA, OVA1 also represents a new class of software-based diagnostics.

AMA Approves Vermillion MAAA Category 1 Code for OVA1; Will it Improve Reimbursement? GenomeWeb (Medicare)

"Medicare reimbursement has been a point of concern for the company. As previously covered in PGx Reporter sister publication ProteoMonitor, there have been reports that Medicare has been denying OVA1 claims at a rate of more than 80 percent (PM 12/23/2011)."

(OVA1) Vermillion Reports Preliminary Fourth Quarter and Full Year 2011 Results - business news

abstract: Risk of Malignancy in Sonographically Confirmed Ovarian Tumors

Abstract

Ovarian cancer is the leading cause of gynecologic cancer death in the United States. Once an ovarian tumor is identified, a pelvic ultrasound is recommended, including tumor volume and tumor structure. Unilocular and simple septate tumors are unlikely to be malignant and when asymptomatic, can be safely followed conservatively without surgery. Complex ovarian tumors are at an increased risk for malignancy and secondary testing is recommended. Secondary testing may include CA125, OVA1, the RMI, ROMA, or the ACOG referral guidelines. When secondary testing indicates that an ovarian tumor is at high risk for malignancy, referral to a gynecologic oncologist is recommended.

Vermillion plans to reduce headcount, expenses - financial news (OVA1)

Vermillion Inc. VRML -2.76% plans to reduce its headcount and other expenses and focus on strengthening sales of its ovarian cancer testing product (OVA1)  this year.

OVA1 Improves Ovarian Cancer Detection Over CA 125 Blood Test and Clinical Assessment - press release - 2nd study

Second study in Obstetrics & Gynecology showcases OVA1's role in evaluating women with an ovarian mass

 "In the manuscript "Effectiveness of a Multivariate Index Assay in the Preoperative Assessment of Ovarian Tumors," physician assessment and the use of OVA1 correctly identified 70% of malignancies missed by physician assessment among gynecologists and other non-gynecologic oncologists, and 95% of malignancies missed by physician assessment among gynecologic oncologists. OVA1 also detected 76% of malignancies that would have been missed by CA 125 using ACOG-recommended guidelines......"

press release- (OVA1 test) Vermillion to Host Conference Call to Present Company Update and Review Financial Results May 10th, 2011

financial news: Healthcare Stock on Watch; Vermillion (OVA1) climbs on Poster Presentation | Beacon Equity: Penny Stocks, Stock Alerts

Healthcare Stock on Watch; Vermillion climbs on Poster Presentation

Posted by g.zalesak on Mar 08, 2011

Vermillion Inc. (NASDAQ: VRML) shares are up nearly 2.5% to $4.99 mid-day on word of the company’s poster presentation of its preliminary results from its collaboration with John Hopkins University School of Medicine to identify biomarkers that improve the identification of malignant ovarian tumors.
The poster evaluated more than 20 candidate biomarkers for their ability to complement the company’s CA125 in distinguishing benign ovarian tumors from malignant ones.

(OVA1) Vermillion Attends 42nd Annual Meeting of the SGO March 7, 2011 /PRNewswire/ --

Note: see press release for more details "OVA1 improves the sensitivity of the ACOG referral guidelines for an ovarian mass" "OVA1 Has High Sensitivity in Identifying Ovarian Malignancy Compared to Preoperative Assessment and CA125"

(OVA1 ovarian cancer blood test) Vermillion Inks New Agreement with Quest Diagnostics - GLG News

In research - Georgia Tech Team Claims 100 Percent Accuracy for Metabolomic Ovarian Cancer Test in Initial Trial ProteoMonitor GenomeWeb

........"In ovarian cancer, the single protein that's commonly used [as a biomarker], CA-125, is not a very accurate test," he said. "The reason for that is that all cancers are variable. So if you're relying on a single biomarker, it's very unlikely that that single biomarker will be 100 percent accurate or even 99 or 95 percent accurate."
"Even going from one to five [biomarkers] increases accuracy tremendously. In our case we're using at the minimum 2,000 to 3,000 features. That should in theory give us an even higher degree of accuracy," he said.
By comparison, most protein-based tests that are commercially available or under development use a handful of markers. Vermillion's OVA1, for example, analyzes five protein markers, including CA-125. The HealthLinx OvPlex test also uses five proteins, including CA-125, and the company is currently evaluating two additional markers to add to the test (PM 6/18/2010)....cont'd

Vermillion's OVA1 2010 Sales Target Is Looking Like a Moon Shot. How Will it Hit It? GenomeWeb (financial)

The test, approved last September, costs $650 and is reimbursed at $540 by Medicare, according to the company. (assuming U.S. dollars)

OVA1 - Vermillion Announces Relocation of Corporate Offices to Austin, Texas - MarketWatch

Vermillion Announces Relisting on NASDAQ - re: OVA1 ovarian diagnositic test (financial news)

For Vermillion, a Likely Off-Label Play for OVA1 as OVA2 Gains R&D Traction GenomeWeb

Note: financial news

Arrayit Corporation Reports Strong Surge in Customer Demand for the Company's Leading Edge Life Sciences Microarray Instruments - financial news

Note: in prior new/press releases the Arrayit testing is still seeking FDA (U.S.) approval, this is not the same test as OVA1 which is the test for determining suspicion of ovarian cancer malignancy (search blog for further information on both)

"Arrayit microarrays and instruments offer richer content and greater sensitivity than competing platforms, and these attributes have allowed us to discover the world's only definitive pre-symptomatic biomarkers for ovarian cancer and Parkinson's Disease, as well as a new pharmaceutically important pathway in human biology that will be the subject of future announcements."

Arrayit Signs on Docro to Help Ovarian Cancer Diagnostic Gain FDA Clearance GenomeWeb

Vermillion's OVA1 became the first protein-based in vitro diagnostic multivariate index assay to receive FDA clearance [See PM 09/17/09] and earlier this month it and Quest Diagnostics began marketing OVA1.

In addition, Correlogic is in discussions with the FDA about its OvaCheck test,

and

Healthlinx, which launched its test called OvPlex in the UK in February, has said that it may launch the test in the US next year, if it receives regulatory approval.

This week, Arrayit said that OvaDx will be the market's first "comprehensive diagnostic for ovarian cancer" and will be targeted to all women over the age of 35.

Medical News: SGO: Test Aids Preop Decisions About Ovarian Masses - in Meeting Coverage, SGO - OVA1

"...However, the test's low specificity raised some concern, as verbalized by an invited discussant of the study." MedPage Today Action Points * Explain to patients that in this study, use of a laboratory test improved the presurgical evaluation of ovarian tumors compared with physician clinical assessment alone. * Note that the test is for preoperative assessment of ovarian tumors and is not a screening or diagnostic test. * Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.