The Cancer Biomarker Conundrum: Too Many False Discoveries

The boom in cancer [including ovarian] biomarker investments over the past 25 years has not translated into major clinical success. The reasons for biomarker failures include problems with study design and interpretation, as well as statistical deficiencies, according to an article published online August 12 in The Journal of the National Cancer Institute.

The boom in cancer [including ovarian] biomarker investments over the past 25 years has not translated into major clinical success. The reasons for biomarker failures include problems with study design and interpretation, as well as statistical deficiencies, according to an article published online August 12 in The Journal of the National Cancer Institute.

The National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” In the past decade, there have been numerous biomarker discoveries, but most initially promising biomarkers have not been validated for clinical use.

Eleftherios P. Diamandis, M.D., Ph.D., Head, Section of Clinical Biochemistry, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada

To understand why so-called biomarker “breakthroughs” have not made it to the clinic, Eleftherios P. Diamandis, M.D., Ph.D., professor of pathology and laboratory medicine at Mount Sinai Hospital in Toronto and associate scientist at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, reviewed some biomarkers initially hailed as breakthroughs and their subsequent failings.

Diamandis first describes the requirements for biomarkers to be approved for clinical use: A biomarker must be released into circulation in easily detectable amounts by a small asymptomatic tumor or its micro-environment; and it should preferably be specific for the tissue of origin. Also, if the biomarker is affected by a non-cancer disease, its utility for cancer detection may be compromised. For example, the prostate-specific antigen (PSA) biomarker, which is used to detect prostate cancer, is also elevated in benign prostatic hyperplasia.

Diamandis looks at seven biomarkers that have emerged in the past 25 years, all of which were considered promising when they were first described. These include nuclear magnetic resonance of serum for cancer diagnosis; lysophosphatidic acid for ovarian cancer; four– and six-parameter diagnostic panels for ovarian cancer; osteopontin for ovarian cancer; early prostate cancer antigen-2 (EPCA-2) for prostate cancer detection; proteomic profiling of serum by mass spectrometry for ovarian cancer diagnosis; and peptidomic patterns for cancer diagnosis. Problems ranged from inappropriate statistical analysis to biases in case patient and control subject selection. For example, the problems with EPCA-2 included reporting values that were beyond the detection limit of the assay and using inappropriate reagents to test EPCA-2, such as solid surfaces coated with undiluted serum.

Diamandis concludes that “problems with pre-analytical, analytical, and post-analytical study design could lead to the generation of data that could be highly misleading.”

Sources:

The Cancer Biomarker Conundrum: Too Many False Discoveries, Journal of the National Cancer Institute Advance Access,  published on August 12, 2010, DOI 10.1093/jnci/djq335.

Eleftherios P. Diamandis. Cancer Biomarkers: Can We Turn Recent Failures into Success? Commentary, Journal of the National Cancer Institute Advance Access published on August 12, 2010, DOI 10.1093/jnci/djq306.

BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells

Johns Hopkins medical researchers discovered through proteomic analysis that RELA and STAT5 are upregulated in carboplatin resistant ovarian cancer cells, according to a published study appearing in the June 18 edition of PLoS One. Moreover, the researchers also demonstrated that BMS-345541 (a NF-kappaB inhibitor) and dasatinib (a STAT5 inhibitor) could resensitize carboplatin-resistant, recurrent ovarian cancer cells.

Although most ovarian cancer patients are initially responsive to platinum-based chemotherapy, almost all develop recurrent chemoresistant tumors. For this reason, Johns Hopkins researchers set out to determine the scientific underpinnings of carboplatin drug resistance in ovarian cancer cells. The researchers compared the proteomes of paired primary and recurrent post-chemotherapy, high grade serous ovarian carcinomas from nine ovarian cancer patients.

As compared to the primary tumors, more than one-half of the recurrent tumors expressed higher levels of several proteins including:  CP, FN1, SYK, CD97, AIF1, WNK1, SERPINA3, APOD, URP2, STAT5B and RELA (NF-kappaB p65).  A short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn which can be used to silence gene expression through so-called “RNA interference.” Based on shRNA screening for the upregulated genes in in vitro carboplatin-resistant ovarian cancer cells, the researchers determined that simultaneous silencing of RELA and STAT5B was the most effective way to resensitize tumor cells for carboplatin treatment.

In an attempt to recreate the same results achieved with gene silencing through therapeutic drug use, the researchers used BMS-345541 (a NF-kappaB inhibitor) and dasatinib (Sprycel®)(a STAT5 inhibitor)  to significantly enhance cell sensitivity to carboplatin. The researchers also discovered that expression of RELA and STAT5B enhanced Bcl-xL promoter activity; however, treatment with BMS-345541 and dasatinib decreased such activity.

Accordingly, the researchers concluded that proteomic analysis identified RELA and STAT5 as two major proteins associated with carboplatin resistance in recurrent ovarian cancer tumors. Furthermore, the study results reveal that NF-kappaB and STAT5 inhibitors could resensitize carboplatin-resistant, recurrent ovarian cancer cells, thereby suggesting that these inhibitor drugs can be used to benefit select ovarian cancer patients.

Source: Jinawath N, Vasoontara C, Jinawath A, et. al.  Oncoproteomic analysis reveals co-upregulation of RELA and STAT5 in carboplatin resistant ovarian carcinoma. PLoS One. 2010 Jun 18;5(6):e11198.

Identifying & Overcoming Taxane Drug Resistance

Proteomics study reveals a protein that, when suppressed, makes cancers more susceptible to chemotherapy involving taxane drugs.

Taxanes, a group of cancer drugs that includes paclitaxel (Taxol®) and docetaxel (Taxotere®), have become front-line therapy for a variety of metastatic cancers. But as with many chemotherapy agents, resistance can develop, a frequent problem in breast, ovarian, prostate and other cancers. Now, cancer researchers at Children’s Hospital Boston report a protein previously unknown to be involved in taxane resistance and could potentially be targeted with drugs, making a cancer more susceptible to chemotherapy.

The researchers believe that this protein, prohibitin1, could also serve as a biomarker, allowing doctors to predict a patient’s response to chemotherapy with a simple blood test. The study was published online by the Proceedings of the National Academy of Sciences in its online early edition during the week of January 25.

Bruce Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Vascular Biology Program, Department of General Surgery, Children's Hospital Boston

The study, led by Bruce Zetter, PhD, of Children’s Vascular Biology Program, used proteomics techniques to compare the proteins present in Taxol-susceptible versus Taxol-resistant human tumor cell lines. The researchers found that the resistant cell lines, but not the susceptible cell lines, had prohibitin1 on their surface. When they suppressed prohibitin1 with RNA interference techniques, the tumor cells became more susceptible to Taxol, both in cell culture and in live mice with implanted Taxol-resistant tumors.

Zetter’s lab is still investigating why having prohibitin1 on the cell surface makes a tumor cell resistant to taxanes. But in the meantime, he believes that not only could prohibitin1 be suppressed to overcome taxane resistance, but that it could also be exploited as a means of targeting chemotherapy selectively to resistant cancer cells.

“We are working to target various cancer drugs to taxane-resistant cells by attaching them to compounds that bind to prohibitin,” Zetter explains. One such compound is already known, and works well in animals to target other prohibitin-rich cells, but has yet to be tested in humans.

Suppressing prohibitin1 alone probably isn’t enough to make a cancer fully Taxol-susceptible, but could be combined with other strategies aimed at increasing taxane susceptibility, such as targeting another protein called GST Pi, the researchers say. Other mechanisms of resistance are known, but they so far haven’t been shown to present effective targets for therapy.

Zetter’s lab is also trying to develop prohibitin1 as a biomarker for taxane resistance that physicians could use in the clinic. Since it’s on the surface of the cell, Zetter believes prohibitin1 may circulate in the blood where it could easily be detected. His lab is in talks with several cancer centers to obtain serum samples from patients who did and didn’t respond to Taxol, so that prohibitin1 levels could be measured and compared.

Zetter notes that prohibitin1 could easily have been overlooked, and was found only because the team happened to look specifically at proteins in the cell membrane, rather than simply doing a whole-cell proteomic analysis.

“The interesting finding was that prohibitin was not just another over-expressed protein,” Zetter says. “It was up-regulated primarily on the cell surface. When we looked at the whole cell, the absolute amount of prohibitin wasn’t changed. Instead, prohibitin was moving from the inside of the cell to the cell surface. It had shifted from one location to another, and when it did, the tumor cells became resistant to taxanes. The fact that it moves to the cell surface also makes it easier to direct drugs to it.”

Children’s Hospital Boston has pending and issued international patents on this technology.  Nish Patel, PhD, was the study’s first author. The study was funded by a grant from the National Institutes of Health.

About Children’s Hospital Boston

Founded in 1869 as a 20-bed hospital for children, Children’s Hospital Boston today is one of the nation’s leading pediatric medical centers, the primary pediatric teaching hospital of Harvard Medical School, and the largest provider of health care to Massachusetts children. In addition to 396 pediatric and adolescent inpatient beds and more than 100 outpatient programs, Children’s houses the world’s largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children’s research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.

Sources:

What’s Feeding Cancer Cells? — Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use.

“Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature. …”

“February 15, 2009- Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature.

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

‘While we were looking for how Myc promotes cancer growth, it was unexpected to find that Myc can increase use of glutamine by cancer cells,’ says Chi V. Dang, M.D., Ph.D., the Johns Hopkins Family Professor of Oncology at Johns Hopkins. ‘This surprising discovery only came about after scientists from several disciplines came together across Hopkins to collaborate — it was a real team effort.’

In their search to learn how Myc promotes cancer, the researchers teamed up with protein experts, and using human cancer cells with Myc turned on or off, they looked for proteins in the cell’s powerhouse — the mitochondria — that appeared to respond to Myc. They found eight proteins that were distinctly turned up in response to Myc.

At the top of the list of mitochondrial proteins that respond to Myc was glutaminase, or GLS, which, according to Dang, is the first enzyme that processes glutamine and feeds chemical reactions that make cellular energy. So the team then asked if removing GLS could stop or slow cancer cell growth. Compared to cancer cells with GLS, those lacking GLS grew much slower, which led the team to conclude that yes, GLS does affect cell growth stimulated by Myc.

The researchers then wanted to figure out how Myc enhances GLS protein expression. Because Myc can control and turn on genes, the team guessed that Myc might directly turn on the GLS gene, but they found that wasn’t the case. ‘So then we thought, maybe there’s an intermediary, maybe Myc controls something that in turn controls GLS,’ says Ping Gao, Ph.D., a research associate in hematology at Johns Hopkins.

They then built on previous work done with the McKusick-Nathans Institute of Genetic Medicine at Hopkins where they discovered that Myc turns down some microRNAs, small bits of RNA that can bind to and inhibit RNAs, which contain instructions for making proteins. The team looked more carefully at the GLS RNA and found that it could be bound and regulated by two microRNAs, called miR23a and miR23b, pointing to the microRNAs as the intermediary that links Myc to GLS expression.

‘Next we want to study GLS in mice to see if removing it can slow or stop cancer growth,’ says Gao. ‘If we know how cancer cells differ from normal cells in how they make energy and use nutrients, we can identify new pathways to target for designing drugs with fewer side effects.’

This study was funded by the National Institutes of Health, the National Cancer Institute, the Rita Allen Foundation, the Leukemia and Lymphoma Society and the Sol Goldman Center for Pancreatic Cancer Research.

Authors on the paper are Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi V. Dang, of Johns Hopkins; and Kayoko Kita and Takfumi Ochi of Teikyo University in Japan.

On the Web:
http://www.hopkinsmedicine.org/hematology/faculty_staff/dang.html
http://www.proteomics.jhu.edu/index.php
http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/mendell.html
http://www.nature.com/nature/index.html

– JHM –

Media Contacts: Audrey Huang; 410-614-5105; audrey@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu

______________________

Quoted SourceWhat’s Feeding Cancer Cells? – Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use, Press Release, Johns Hopkins Medicine, February 15, 2009.

Primary Citationc-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism; Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang et. al., Letter, Nature advance online publication 15 February 2009.

Lost In Translation? FDA Believes That LabCorp’s Ovarian Cancer Early Detection Test (OvaSure) Lacks Adequate Clinical Validation

The U.S. Food and Drug Administration (FDA) sent a letter to the Laboratory Corporation of America (LabCorp) on August 7, 2008, stating that it believes the Yale ovarian cancer early detection test (marketed by LabCorp under the name OvaSure™) ” … has not received adequate clinical validation, and may harm the public health.” In that letter, the FDA invites LabCorp to discuss all validation studies that support the marketing of the OvaSure™ test.

The U.S. Food and Drug Administration (FDA) sent a letter to the Laboratory Corporation of America (LabCorp) on August 7, 2008, stating that it believes the Yale ovarian cancer early detection test (marketed by LabCorp under the name OvaSure™) “… has not received adequate clinical validation, and may harm the public health.” In the letter, the FDA invites LabCorp to discuss all validation studies that support the marketing of the OvaSure™ test. The August 7 FDA letter appears to reflect a previously announced, yet controversial, change in FDA policy. Libby’s H*O*P*E*™ reported previously on the development of the Yale ovarian cancer early detection test [March 14, 2008], and LabCorp’s subsequent market release of that test under the name OvaSure™ [June 23, 2008].

On August 19, 2008, the Oncology STAT™ news service reported that the August 7 FDA letter was posted on the website of the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) on August 15, but was removed from the site a few days later. On August 22, 2008, we identified the “cached” copy of the August 7 FDA letter on the OIVD website. The August 7 FDA letter is provided below in its entirety.

The August 7 FDA letter was issued by OIVD and informs LabCorp that “[i]t appears that you are marketing the Ovasure™ Test with performance characteristics (specifically, 95.3% sensitivity and 99.4% specificity) that are identical to those reported in a research study published by Visintin, I. et al., in the February 15 edition of Clinical Cancer Research (Visintin, I. et al., Clin Cancer Res. 2008 Feb 15;14(4):1065-72.).” The OIVD Director, Steven Gutman, M.D., M.B.A., states that the Visintin, I. et. al ” … research was carried out, and performance derived, on two populations that are strongly clinically biased for being healthy and normal, and for having already experienced ovarian cancer.” Based upon this rationale, the OIVD concludes that it does not believe “… the scientific community would consider the reported study sufficient to establish performance characteristics of a test in high risk women who might have ovarian cancer, i.e., in a clinical setting, as claimed in your intended use and promotional materials.”

Historical FDA Policy Regarding Laboratory-Developed (“Home Brew”) Tests

Based upon historical FDA policy, LapCorp would not be required to obtain FDA premarket or postmarket approval for the OvaSure™ test because the early detection test would be categorized as a “laboratory-developed test” (also referred to as a “home brew” test) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). In general, the CLIA establishes quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test is performed.

Prior to 2006, the FDA did not exercise its authority to regulate home brew tests, which are developed by a laboratory for in-house use as a test service. The reasons are likely twofold. First, the FDA believed that the regulatory oversight exercised by the Centers for Medicare & Medicaid Services (CMS) with respect to the laboratories (under CMS jurisdiction pursuant to CLIA), ensured that such laboratories were competent to properly manufacture and use home brew tests without additional FDA intervention. Second, the FDA possessed regulatory authority to review the primary ingredients or components in the home-brew tests (known as “analyte specific reagents” (ASRs)), and did not believe that further test regulation was necessary.

Announcement of FDA Policy Change For Select In Vitro Diagnostic Assays

In 2006, and again in 2007, the FDA issued draft guidance (entitled, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays) in which, for the first time, the agency exercised its authority to regulate select in vitro diagnostic multivariate index assays (“IVDMIAs”) that are developed and manufactured by clinical laboratories for their own use (i.e., laboratory-developed tests/home brew tests). An IVDMIA is a diagnostic laboratory assay or test that utilizes mathematical formulae to interpret genetic and protein data required for the generation of information used to make critical diagnosis and treatment decisions for patients. IVDMIAs, for FDA regulatory purposes, are classified as medical devices under the Federal Food, Drug & Cosmetic Act (FDCA), and therefore, can be subject to premarket and postmarket regulation. IVDMIAs developed and manufactured by commercial, non-laboratory-based companies are currently regulated by the FDA. The majority of IVDMIAs, however, are developed and manufactured by laboratories for their own use as home brew tests.

Under the FDA draft guidance, home brew IVDMIAs would in many cases require 510(k) pre-market clearance or Pre-Market Approval (PMA). In addition, these same IVDMIAs would have to comply with “device” post-market manufacturing and reporting requirements. The August 7 FDA letter does not state that a 510(k) pre-market clearance or Pre-Market Approval is required; rather OIVD invites LabCorp to discuss any “validation strategies” undertaken beyond the research results reported by Visintin, I. et. al. LabCorp is not the only company affected by the FDA policy change. The FDA also used its change in regulatory policy to prevent Correlogic Systems, Inc. from marketing its ovarian cancer early detection test, known as OvaCheck®, without prior FDA approval. Arguably, the FDA is placing the OvaSure™ and OvaCheck® ovarian cancer early detection tests on equal regulatory footing.

Ever-Increasing Sophistication of Genetic and Proteomic Assay Technology

The emergence and increased use of IVDMIAs using novel technology (e.g., proteomics) as an integral part of patient diagnosis and treatment, and their direct advertisement to consumers, may have influenced the FDA to conclude more recently that the current level of oversight with respect to genetic and proteomic testing by laboratories was inadequate. Assuming the FDA position is correct, inadequate federal oversight could lead to significant issues related to the quality and validity of IVDMIAs.

LabCorp Amendment of OvaSure™ “Use” Information

LabCorp recently amended its intended use and promotional materials to provide that the OvaSure™ test cannot be used by a woman who has had both ovaries removed (i.e., a woman who previously had a bilateral oophorectomy). Specifically, LabCorp intends that the OvaSure™ test be used to identify a woman who is at “high-risk” for ovarian cancer; however, an ovarian cancer survivor who is currently in remission, cannot use the OvaSure™ test to screen for a recurrence of the disease if her ovaries were removed as part of her first-line treatment after the initial ovarian cancer diagnosis. CLICK HERE to view Libby’s H*O*P*E* post (with updates) dated June 23, 2008, regarding the OvaSure™ test use and limitation information as amended.

Letter to the President and Chief Executive Officer of LabCorp

August 7, 2008
Via FedEx

David P. King
President and Chief Executive Officer
Laboratory Corporation of America
430 South Spring Street
Burlington, North Carolina 27215

Dear Mr. King:

It has come to our attention that you are currently marketing the OvaSure™ Yale Ovarian Cancer Test, also advertised as the OvaSure™ For Women at High-Risk for Ovarian Cancer, and OvaSure™ For Women at High-Risk for Ovarian Cancer, (Serial Monitor), (collectively referred to hereafter as the OvaSure™ Test) which is intended to be used as a tool to identify high-risk women who might have ovarian carcinoma. It appears that you are marketing the OvaSure™ Test with performance characteristics (specifically, 95.3% sensitivity and 99.4% specificity) that are identical to those reported in a research study published by Visintin, I., et al., in the February 15 edition of Clinical Cancer Research (Visintin, I. et al., Clin Cancer Res. 2008 Feb 15;14(4):1065-72.). We note that this research was carried out, and performance derived, on two populations that are strongly clinically biased for being healthy and normal, and for having already experienced ovarian cancer. Based on the available information, we do not believe the scientific community would consider the reported study sufficient to establish performance characteristics of a test in high risk women who might have ovarian cancer, i.e., in a clinical setting, as claimed in your intended use and promotional materials.

Based on our review of your promotional materials and the research publication cited above, we believe you are offering a high risk test that has not received adequate clinical validation, and may harm the public health. We would like to discuss with you your offer of this test, and any validation strategies you have undertaken beyond those reported in the publication cited above.

We look forward to discussing this with you, and are committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance.

Sincerely yours,

/S/

Steven I. Gutman, M.D., M.B.A.
Office Director
Office of In Vitro Diagnostic Device Evaluation and Safety
Center for Devices and Radiological Health

Comments:

  • The corporate and governmental intrigue surrounding the FDA regulatory issues with respect to the OvaSure™ and OvaCheck® ovarian cancer early detection tests would make for a thrilling Hollywood screenplay, except for the catastrophic fact that approximately 15,000 U.S. women die annually from ovarian cancer due to the lack of a reliable early detection test. Because of the latter, approximately 80 percent of women are not diagnosed until they are in advance stages of the disease.
  • The FDA’s current – and still evolving – policy signals a strong possibility that previously unregulated diagnostics could require FDA approval or clearance prior to marketing as well as being subject to other medical device requirements under the FDCA.
  • It is critical for the FDA to take whatever action is necessary to protect U.S. public health. It is also essential that ovarian cancer survivors, clinicians and all affected corporate entities receive clear, consistent regulatory guidance and prompt action from the FDA with respect to this potential life-saving matter.

Sources:

Updates:

  • September 9, 2008: The FDA recently reposted on its website, a copy of the August 7th letter to the President and Chief Executive Officer of LabCorp regarding OvaSure™. To view a copy of the letter, CLICK HERE.

Vermillion Files FDA Pre-Market Application for OVA1 Ovarian Tumor Triage Test

” …The OVA1 [Ovarian Tumor Triage Test] test will help assess the risk of malignancy in the hundreds of thousands of women who require surgery for ovarian tumors each year. ‘This information can be used to identify those who might benefit from referral to a gynecologic oncologist,’ said Fred Ueland, M.D., principal investigator of the study and Associate Professor of Gynecologic Oncology at the University of Kentucky. While most tumors are benign, numerous studies have shown that women with ovarian cancer have better overall outcomes when their surgery is performed by a gynecologic oncologist.”

FREMONT, Calif., June 25 /PRNewswire-FirstCall/ — Vermillion, Inc. (Nasdaq: VRML), a molecular diagnostics company, today announced that it has submitted a 510(k) pre-market notification application to the U.S. Food & Drug Administration (FDA) requesting regulatory clearance of its Ovarian Tumor Triage Test known as OVA1™.

As announced previously, the OVA1 prospective clinical trial met its primary endpoints, indicating that the test is capable of stratifying women with pelvic masses into high- and low-risk categories to help determine whether the patient should be referred to a specialist prior to surgery. The clinical trial was one of the largest ovarian cancer studies ever conducted and assessed more than 550 women with a confirmed adnexal mass at 27 clinical sites in the United States. Additionally, the trial was the culmination of more than eight independent studies in more than 2,500 women.

The OVA1 test will help assess the risk of malignancy in the hundreds of thousands of women who require surgery for ovarian tumors each year. ‘This information can be used to identify those who might benefit from referral to a gynecologic oncologist,’ said Fred Ueland, M.D., principal investigator of the study and Associate Professor of Gynecologic Oncology at the University of Kentucky. While most tumors are benign, numerous studies have shown that women with ovarian cancer have better overall outcomes when their surgery is performed by a gynecologic oncologist.

This is an important milestone for Vermillion and a significant step toward the commercialization of OVA1™. ‘We are pleased with the results of the trial and look forward to discussing the significance of our data and our commercialization strategy in an upcoming investor roundtable, planned for July,’ said Gail Page, President and CEO of Vermillion. ‘We also look forward to receiving regulatory clearance from the FDA and making OVA1 available to the hundreds of thousands of women who could benefit considerably from the test.’

Vermillion will host a roundtable teleconference to address the need for OVA1 on Tuesday, July 15. Fred Ueland, M.D., principal investigator of the OVA1 clinical study, will serve as the keynote speaker. Conference call details, including dial-in information and timing, are forthcoming.

About Vermillion’s Ovarian Cancer Diagnostic Program

In addition to developing a diagnostic test designed to distinguish between benign and malignant pelvic masses, Vermillion has a broad program of ovarian cancer diagnostic tests in development. Studies are underway to validate diagnostic tests developed to detect early-stage ovarian cancer, predict prognosis and recurrence, and identify women considered at high-risk for the disease.

Vermillion’s comprehensive diagnostic development program is being conducted with several leading collaborators at The Johns Hopkins School of Medicine, The University of Texas M.D. Anderson Cancer Center, Rigshospitalet (Copenhagen), and the University of Kentucky.

The Company’s OVA1 test is part of a strategic alliance with Quest Diagnostics to jointly develop and commercialize diagnostic tests.

About Vermillion

Vermillion, Inc. is dedicated to the discovery, development and commercialization of novel high-value diagnostic tests that help physicians diagnose, treat and improve outcomes for patients. Vermillion, along with its prestigious scientific collaborators, has diagnostic programs in oncology, hematology, cardiology and women’s health. Vermillion is based in Fremont, California. Additional information about Vermillion can be found on the Web at http://www.vermillion.com.”

[Quoted Source: Vermillion Files 510(k) Application With U.S. Food & Drug Administration for OVA1 Ovarian Tumor Triage Test – Significant Milestone Achieved Based on Compelling Clinical Studies, Vermillion, Inc. Press Release, June 25, 2008.]

Additional Information:  To learn more about molecular diagnostics and proteomics, see Understanding Cancer Series: Molecular Diagnostics, National Cancer Institute, September 1, 2006.

LabCorp Announces Availability of Ovarian Cancer Blood Test To Assess The Presence of Early Stage Ovarian Cancer

“Laboratory Corporation of America® Holdings is now offering OvaSure™, an Ovarian Cancer Screening test to assess the presence of early stage ovarian cancer in high-risk women. In a recent study of high risk and average risk subjects, this blood test, using six biomarkers and research conducted at Yale University School of Medicine, was shown to discriminate between disease-free women and ovarian cancer patients (stage I-IV) with high specificity (99.4%) and sensitivity (95.3%). Additional studies performed at Yale University School of Medicine demonstrate comparable findings.”

On March 14, 2008, the H*O*P*E*™ weblog reported that a new blood test developed by the Yale University School of Medicine detected early stage ovarian cancer with 99% accuracy in Phase II clinical trial testing. To review the March 14 H*O*P*E*™ weblog post, click here. In 2006, Laboratory Corporation of America (Lab Corp) obtained licensing rights to the ovarian cancer early detection blood test, known as OvaSure™, from Yale. Today, Lab. Corp. announced in a press release that it is making the OvaSure™ blood test immediately available nationwide to women who are at high risk of developing ovarian cancer in the future. The relevant portion of the Lab Corp. press release dated June 23, 2007 is set forth below.

LabCorp Announces Availability of OvaSure™

Burlington, NC, June 23, 2008 – Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) is now offering OvaSure™, an Ovarian Cancer Screening test to assess the presence of early stage ovarian cancer in high-risk women. In a recent study of high risk and average risk subjects, this blood test, using six biomarkers and research conducted at Yale University School of Medicine, was shown to discriminate between disease-free women and ovarian cancer patients (stage I-IV) with high specificity (99.4%) and sensitivity (95.3%). Additional studies performed at Yale University School of Medicine demonstrate comparable findings.

‘LabCorp is pleased to offer for high-risk women the OvaSure test to enhance the potential of detecting and treating ovarian cancer in its early or localized stage when the likelihood of survival is greatest,’ said Myla P. Lai-Goldman, M.D., Executive Vice President, Chief Medical Officer of LabCorp. ‘OvaSure is a significant addition to LabCorp’s family of proteomic tests, and a major component of LabCorp’s strategy to bring the latest in diagnostic technology to women’s healthcare.’

It has been estimated that for the year 2008, 21,650 women will be newly diagnosed with ovarian cancer. It has been further estimated that 15,520 women will die from the disease in 2008. Despite being one-eighth as common as breast cancer, it is three times more lethal. If ovarian cancer is diagnosed and treated at the localized stage, the 5-year survival rate is 92%; unfortunately, only 19% of all cases are found at the localized stage. Most women have their ovarian cancer detected at the regional or distant stage when the 5-year survival rates are 71% and 30% respectively.

‘I am pleased that this test is available to help physicians detect and treat ovarian cancer in its earliest stages,’ said Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale and a member of Yale Cancer Center. ‘Our team is proud that our research may help play a role in higher survival rates for women with this disease.’”

[Quoted Source: LabCorp Announces Availability of OvaSure™ , Laboratory Corporation of America Press Release dated June 23, 2008.]

Comment**: Although additional Phase III clinical trial testing with a larger patient population is required, the OvaSure™ blood test may represent the “gold standard” for early stage ovarian cancer detection in the near future. The immediate availability of the OvaSure™ blood test for use by women who are at high risk for developing ovarian cancer could save lives by catching ovarian cancer in its earliest stages, thereby making treatment of the disease highly effective. To view the ABCNews.com news report regarding the Yale ovarian cancer screening blood test that aired on April 21, 2008, click here.

**As of August 21, 2008, the amended OvaSure™ test “use” information provides, among other things, that a woman who has had both ovaries removed (i.e., a bilateral oophorectomy) should not use the test. Accordingly, it appears that the OvaSure™ test cannot be used by a “high-risk” woman to screen for an ovarian cancer recurrence, if she had both ovaries removed as part of her first line treatment following initial diagnosis of the disease.

OvaSure™ Information: The OvaSure™ blood test is now available nationwide through LabCorp. If you want to review OvaSure™ blood test information on the LabCorp. website, click here (then click on the letter “O” located on the upper left side panel keyboard and scroll down until you find the three OvaSure™ blood test information entries). It is our understanding that the OvaSure™ test cost approximately (U.S.)$225 and test results are available within five business days.

OvaSure™ Use (updated 8/21/08): “The OvaSureTM assay may be used as a tool to identify high-risk women who might have ovarian carcinoma. OvaSureTM is not indicated for a patient who is currently undergoing chemotherapy, who has had both ovaries removed, who is pregnant, or who is lactating. About 10% of women with benign ovarian masses (including cysts) may have positive results by this test.”

OvaSure™ Limitations (updated 8/21/08) : “Pregnant women or women who are lactating should not be screened by the assay because it may lead to false-positive results. A Calculated Risk Index of 0.50 or greater indicates a positive reading, which is suggestive of ovarian cancer (possible presence of disease). In a clinical study (see Journal Abstract below) across all disease stages, the six-marker panel composed of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 demonstrated a sensitivity of 95.3% and a specificity of 99.4% in detecting disease. Greater than 99% sensitivity (119 of 120) was shown in late-stage disease (stage III and stage IV). In early stage disease (stage I and stage II), the assay demonstrated a sensitivity of 91.6%, providing a significant improvement over CA-125 alone (less than 60% of stage I and stage II combined) for ovarian cancer detection. All positive readings should be retested on a new sample drawn at least three weeks after the original sample was collected. Patients with positive results confirmed by retesting on a second sample should be followed by a women’s health specialist who may order additional evaluations, such as sensitive imaging. Components used in this test are labeled as research purposes only. The performance characteristics of this product have not been established by the assay manufacturer. Results should not be used as a diagnosis for ovarian cancer without confirmation of the diagnosis by another medically established diagnostic product or procedure.”

OvaSure™ Journal Abstracts and Full Text Studies:

Updates:

  • July 2, 2008: The Society of Gynecologic Oncologists (SGO) issued a statement regarding the Labcorp OvaSure™ test. The SGO statement, dated July 2, 2008, is quoted below in its entirety.

“July 2, 2008

Society of Gynecologic Oncologists
Statement Regarding OvaSureTM

The Society of Gynecologic Oncologists (SGO) recognizes the need for accurate early detection biomarkers for ovarian cancer. For this reason, SGO reviewed the literature regarding OvaSure, a serum-based diagnostic test for ovarian cancer.

After reviewing OvaSure’s materials, it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.

SGO is committed to actively following and contributing to this vitally important research. As physicians who care only for women with gynecologic cancers, our hope is that these cancers can either be prevented or detected early. Because no currently available test has been shown to reliably detect ovarian cancer in its earliest and most curable stages, we will await the results of further clinical validation of OvaSure with great interest.”

The SGO is a national medical specialty organization of physician-surgeons who are trained in the comprehensive management of women with malignancies of the reproductive tract. The purpose of the SGO is to improve the care of women with gynecologic cancers by encouraging research and disseminating knowledge to raise the standards of practice in the prevention and treatment of gynecologic malignancies, in cooperation with other organizations interested in women’s health care, oncology and related fields.

Quoted Update Source: Society of Gynecologic Oncologists Statement Regarding OvaSure™, Society of Gynecologic Oncologists, July 2, 2008 (Adobe Reader PDF document).

Other Update Sources: Fast Facts: Background on The Society of Gynecologic Oncologists, Society of Gynecologic Oncologists Press Kit, undated.

“AM Nick is a Fellow in the Department of Gynecologic Oncology, and AK Sood is the Bettyann Asche-Murray Distinguished Professor in the Department of Gynecologic Oncology and in the Department of Cancer Biology, both at the University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In order to overcome the significant mortality associated with ovarian cancer, a highly sensitive and specific screening test is urgently needed. CA125 is used to assess response to chemotherapy, detect recurrence, and distinguish malignant from benign disease; however, this marker is elevated in only 50-60% of stage I ovarian cancers, making it inadequate for early detection of malignancy. In this Practice Point, we discuss Visintin et al.‘s attempt to validate a novel multiplex assay that uses a panel of six serum biomarkers-leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA125 [medical abstract & full text of Visintin et. al. study provided above]. The study included 362 healthy controls and 156 patients with newly diagnosed ovarian cancer. The final model yielded 95.3% sensitivity, 99.4% specificity, a positive predictive value of 99.3% and a negative predictive value of 99.2%. These results indicate potential utility of this assay for early detection of ovarian cancer, although further validation is needed in a sample set representative of the general population.”

  • August 21, 2008: The Labcorp information with respect to the OvaSure™ test was recently modified. Despite that fact that the test was made available for “high-risk” women, it cannot be used by women who have had both ovaries removed. Consequently, it appears that a woman who had both ovaries removed (i.e., bilateral oophorectomy) after an initial diagnosis of ovarian cancer, cannot use the OvaSure™ test to screen for a potential recurrence of the disease in the future.