Subject:
Analysis of Proteomic Patterns in Serum to Identify Cancer
Description:
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IMPORTANT NOTE:
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The analysis of proteomic patterns in serum for early detection of cancer has been proposed. Several of these proteomic tests are being studied, particularly in ovarian and prostate cancer.
Background
The genetic basis of cancer has been the focus of intense research; however, genetic mutations do not reflect the complicated interactions between individual cells, tissue, and organs. Proteins are the functional units of cells and represent the end product of the interactions among the underlying genes. Research interest has been increasing in the field of proteomics (referring to the protein product of the genome), in an effort to improve on screening and detection efforts for malignancies.
Serum protein biomarkers
Current diagnostic and follow-up serum biomarkers in clinical oncology (e.g., prostate-specific antigen [PSA, prostate cancer], CA-125 [ovarian cancer]) involve identifying and quantifying specific proteins, but limitations may include non-specificity and elevation in benign conditions.
Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States; most patients present with advanced disease, which has a 5-year survival rate from 15–45%. If the disease is diagnosed in Stage I, survival rates are 95%. Therefore, there is great interest in using a biomarker to detect ovarian cancer in its earliest stages, as current screening methods are inadequate.
Serum measurements of PSA are used as a screening method for detecting prostate cancer. Very low or very high serum PSA results are most reliable in determining cancer risk. However, values often fall within a range that is nonspecific, and thus many patients end up undergoing biopsy for benign disease. Proteomics has been proposed as a technique to further evaluate cancer risk in this diagnostic gray zone.
Proteomics
Proteomics involve the use of mass spectrometry to study differences in patterns of protein expression. While patterns of protein expression have been proposed to yield more biologically relevant and clinically useful information than assays of single proteins, many limitations in the use of proteomics exist. (1) In contrast to genomics, in which amplification techniques like polymerase chain reaction (PCR) allow for the investigation of single cells, no technology is available at the protein level. (1) Other issues between studies have been lack of uniform patient inclusion and exclusion criteria, small patient numbers, absence of standardized sample preparations, and limited analytical reproducibility.(1)
Proteomic tests
Correlogic Systems, Inc. developed a serum-based test using proteomics for the early detection of epithelial ovarian cancer called OvaCheck®. The test is based on proteomic patterns detected in the serum, which are further analyzed with the use of a mass spectrometer to profile a population of proteins based on their size and electrical charge. This type of analysis contains thousands of data points, which undergo further sophisticated computer analysis using artificial intelligence-based algorithms to identify a pattern that is consistent with ovarian cancer.
Regulatory status
Originally, the manufacturer had assumed that the test would not be subject to approval by the U.S. Food and Drug Administration (FDA), since the test would be performed exclusively at one reference laboratory and testing materials do not cross state lines (i.e., a “home brew” test). However, in 2004, the FDA determined that the software used to perform the analysis was considered a medical device and under the FDA premarket review jurisdiction. In 2010 Correlogic filed for bankruptcy and in 2011 its assets including the OvaCheck® test were acquired by Vermillion®. The test has since been taken off the market on FDA recommendation.
Related Policies
- Proteomics-Based Testing Related to Ovarian Cancer (Policy #046 in the Pathology Section)
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
Analysis of proteomic patterns in serum for screening and detection of cancer is considered investigational.
(NOTE: On 09/07/2016, the FDA issued a Safety Communication on 'Ovarian Cancer Screening Tests'. The FDA is alerting women about the risks associated with the use of tests being marketed as ovarian cancer screening tests. The Agency is especially concerned about delaying effective preventive treatments for women who show no symptoms, but who are still at increased risk for developing ovarian cancer. Based on currently available information, the FDA recommends against using currently offered tests to screen for ovarian cancer.
Despite extensive research and published studies, there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results. However, over the years, numerous companies have marketed tests that claim to screen for and detect ovarian cancer.
For more information, please refer to the FDA Safety Communication which is available at:http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm519540.htm)
Medicare Coverage:
There is no National Coverage Determination (NCD) for analysis of proteomic patterns in serum for screening and detection of cancer. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for analysis of proteomic patterns in serum for screening and detection of cancer.
PROPRIETARY LABS (Labs that are the sole source for the diagnostic lab test)
For labs which are proprietary (that is, the sole source for the diagnostic lab test involved), Medicare Advantage Products will follow the Medicare Local Coverage Determination of the State where the proprietary lab is located.
Noridian Healthcare Solutions, LLC , (Jurisdiction J-F) has provided limited coverage for proprietary lab MyPath® Melanoma, Myriad Genetic Laboratories, when used for the diagnosis or exclusion of melanoma from a biopsy when LCD LCD L37881 and Article A57627 criteria are met including all of the following:
• The test is ordered by a board-certified dermatopathologist and;
• The specimen is a primary cutaneous melanocytic neoplasm for when diagnosis with a clear distinction between benign or malignant cannot be achieved using clinical and/or histopathological features alone and;
• The individual may be subjected to additional intervention, such as re-excision and/or sentinel lymph node biopsy, as a result of the diagnostic uncertainty.
For additional information and eligibility, refer to Noridian Healthcare Solutions, LLC , (Jurisdiction J-F), LCD L37881 and Article A57627. Local Coverage Determination (LCD): MolDX: myPath Melanoma Assay (L37881) and Noridian Healthcare Solutions, LLC , (Jurisdiction J-F) Local Coverage Article: Billing and Coding: MolDX: myPath Melanoma Assay (A57627). Available to be searched at Local Coverage Determinations (LCDs) by State Index: https://www.cms.gov/medicare-coverage-database/indexes/lcd-state-index.aspx.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[INFORMATIONAL NOTE: The potential role for proteomics for cancer screening and detection has undergone considerable discussion (1-5); however, data in the peer-reviewed literature are inadequate to permit scientific conclusions regarding ovarian, prostate, or other malignancies. The literature has been searched through February 22, 2019.
Ovarian Cancer
Petricoin and colleagues reported on the technical feasibility of proteomic screening in a test series of serum from 50 patients with and 50 patients without ovarian cancer. (6) The spectra of proteins were analyzed by an iterative searching algorithm that identified a cluster pattern that segregated the patients with cancer from those without. This discovered pattern was then used to classify an independent set of 116 masked serum samples; 50 were from women with ovarian cancer and 66 were from unaffected women or those with nonmalignant conditions. Patients without cancer were considered at high risk, due either to familial breast or cancer syndrome or positivity of BRCA1 or BRCA2 mutations. All 50 with ovarian cancer were correctly identified, including the 18 with Stage I cancer. Of the 66 benign cases, 63 were identified as not being positive for cancer, yielding a sensitivity of 100% and a positive predictive value (PPV) of 94%. The authors noted that while a PPV of 94% may be acceptable for high-risk patients, in the larger population of average-risk patients, the PPV must be close to 100% to avoid a high number of false-positive results, which, in turn, would generate additional workup. One of the key outcomes of an ovarian cancer screening test is the ability to identify Stage I ovarian cancer that is potentially curable with surgery. The described study only included 18 patients with Stage I ovarian cancer. The authors stated that an important future goal is the confirmation of the diagnostic performance of proteomic screening for the prospective detection of Stage I ovarian cancer in trials of both high- and low-risk women.
It should also be noted that the technology used in the Petricoin et al. study (6) is not the same as that proposed for the OvaCheck® test. According to the National Cancer Institute, “The two techniques use different mass spectrometry instrumentation and detection methods, as well as different sample handling and processing methods. Therefore the class of molecules analyzed by these two approaches, and thus the molecules that constitute the diagnostic patterns would be expected to be entirely different.” Other comments and correspondence in the literature (8) also question the statistical analysis used by Petricoin et al. and other technical issues. (9) The results of the Petricoin et al. study have not been reproduced elsewhere. (5)
Prostate Cancer
Ornstein and colleagues reported the results of serum proteomic profiling in 154 men with serum PSA ranging from 2.5 to 15.0 ng/mL. (10) A total of 63 samples (30 malignant, 33 benign) were used as the training set to identify a proteomic pattern that could distinguish benign from malignant disease. The results of the training set were then applied to the remaining 91 samples (i.e., the “testing” set) in a blinded fashion. In this testing set of 63 negative biopsies and 28 positive biopsies, there was 100% sensitivity and 67% specificity. These data imply that if the results of proteomic profiling were used to deselect patients for biopsy; 42 of 63 (67%) patients without prostate cancer could have avoided biopsy. The authors noted that using a training set of only 63 samples may be inadequate and that “before this new technology can be applied in clinical practice, much larger and diverse training and testing sets will be needed.”
McLerran and colleagues selected serum samples from biorepositories from patients with 1) prostate cancer with a Gleason score of 7 or higher; 2) prostate cancer with a Gleason score of less than 7; or 3) negative prostate biopsies with a prostate-specific antigen (PSA) of 10 mcg/L or less and no history of cancer of any kind, a normal digital rectal examination, and no inflammatory disease. They also selected 2 control groups: one with a history of inflammatory disease but no cancer and one with no history of prostate cancer but a history of another type of cancer. (11) Four hundred specimens were analyzed by mass spectrometry after random selection from the 5 groups of patients, with 125 from the group with high Gleason grade, 125 with low Gleason grade, 125 from the biopsy-negative group, and 50 from each of the control groups. The investigators sought to derive a decision algorithm for classification of prostate cancer from the mass spectrometry data but found that they were unable to separate the patients with prostate cancer from biopsy-negative controls. They also were not able to separate patients with high and low Gleason scores. The conclusion was made that in the validation process, this protein-expression profiling approach did not perform well enough to advance to the prospective study stage.
Miscellaneous Cancers
A number of preliminary proteomic studies are available for many cancers including breast, lung, colorectal, gastric, pancreatic, liver, cervical, endometrial, bladder, lymphoma/leukemia, melanoma, and astrocytomas. (1, 12-16)
Ongoing Clinical Trials
National Cancer Institute (NCI) PDQ®/Clinical Trials
As of February 2018, no ongoing Phase III trials with results analyzing proteomic patterns for early detection of cancer were identified.
A prospective longitudinal patient-based pilot study is currently recruiting patients for the use of mass spectroscopy to discover and validate serum proteomic expression profiles diagnostic of early lung cancer. The approach will compare the serum proteomic expression profiles of patients with non-small cell lung cancer compared to healthy heavy smoking adults, as well as differences before and after anatomic pulmonary resection with curative intent. The serum samples will be used to develop a training data set and then a test set for validation using a class prediction model. Candidate proteomic patterns will then serve as a basis for a larger prospective multicenter clinical trial. (NCT00175578)
A prospective cohort study of the NovellusDX early detection test aims to determine if the test is able to discriminate between healthy control patients and those with primary or relapsed lung cancer. The NovellusDX test assesses proteomic changes in the blood which indicate deregulated signaling pathways. The estimated study enrollment is 500 participants with a start date of June 2013 and a completion date of December 2016. (NCT01883388)
Summary
The use of proteomic pattern analysis for the early detection of cancer is currently in clinical trials and testing is not commercially available. There are no published prospective trials that demonstrate that the use of proteomic analysis for screening or detection of disease improves clinical outcomes, and it is therefore considered investigational.
Practice Guidelines and Position Statements
The Society of Gynecologic Oncologists released the following statement in February 2004, which remains unchanged to date (17):
“The Society of Gynecologic Oncologists (SGO) recognizes the importance of accurate early detection biomarkers for ovarian cancer. For this reason SGO reviewed the literature regarding OvaCheck, a serum based diagnostic test for ovarian cancer. In the opinion of SGO, more research is needed to validate the test’s effectiveness before offering it to the public.
SGO is committed to actively following and contributing to this vitally important research. As physicians who care only for women with gynecologic cancer, our hope is that these cancers can either be prevented or detected early. Because no test now exists to routinely detect ovarian cancer in its earliest and most curable stage, we will await the results of further clinical validation of OvaCheck with great interest.”
National Comprehensive Cancer Network (NCCN) Guidelines
The 2018 NCCN guidelines for the common cancers addressed in this policy do not comment on the use of proteomics.]
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Index:
Analysis of Proteomic Patterns in Serum to Identify Cancer
OvaCheck, Screening for Ovarian Cancer
Ovarian Cancer, OvaCheck Test
Prostate Cancer, Proteomics
Proteomics
References:
1. Reymond MA, Schlegel W. Proteomics in cancer. Adv Clin Chem 2007; 44:103-42.
2. Dziadziuszko R, Hirsch FR. Advances in genomic and proteomic studies of non-small-cell lung cancer: clinical and translational research perspective. Clin Lung Cancer 2008; 9(2):78-84.
3. Lin Y, Dynan WS, Lee JR et al. The current state of proteomics in GI oncology. Dig Dis Sci 2009; 54(3):431-57.
4. Lomnytska M, Souchelnytskyi S. Markers of breast and gynecological malignancies: The clinical approach of proteomics-based studies. Proteomics Clin Appl 2007; 1(9):1090-101.
5. Unwin RD, Whetton AD. How will haematologists use proteomics? Blood Rev 2007; 21(6):315-26.
6. Petricoin EF, Ardekani AM, Hitt BA et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002; 359(9306):572-7.
7. Questions and Answers: OvaCheck and NCI/FDA Ovarian Cancer Clinical Trials Using Proteomic Technology. Available online at: www.cancer.gov/templates/content_nav_print.aspx?viewid=38D1A09A-7C41-4A.
8. Diamandis EP. Proteomic patterns in serum and identification of ovarian cancer. Lancet 2002; 360(9327):170; author reply 70-1.
9. Diamandis EP. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst 2004; 96(5):353-6.
10. Ornstein DK, Rayford W, Fusaro VA et al. Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml. J Urol 2004; 172(4 Pt 1):1302-5.
11. McLerran D, Grizzle WE, Feng Z et al. SELDI-TOF MS whole serum proteomic profiling with IMAC surface does not reliably detect prostate cancer. Clin Chem 2008; 54(1):53-60.
12. Bast RC, Jr., Brewer M, Zou C et al. Prevention and early detection of ovarian cancer: mission impossible? Recent Results Cancer Res 2007; 174:91-100.
13. Belluco C, Petricoin EF, Mammano E et al. Serum proteomic analysis identifies a highly sensitive and specific discriminatory pattern in stage 1 breast cancer. Ann Surg Oncol 2007; 14(9):2470-6.
14. Garrisi VM, Abbate I, Quaranta M et al. SELDI-TOF serum proteomics and breast cancer: which perspective? Expert Rev Proteomics 2008; 5(6):779-85.
15. Leman ES, Schoen RE, Weissfeld JL et al. Initial analyses of colon cancer-specific antigen (CCSA)-3 and CCSA-4 as colorectal cancer-associated serum markers. Cancer Res 2007; 67(12):5600-5.
16. Li J, Zhuang Z, Okamoto H et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers. Neurology 2006; 66(5):733-6.
17. Society of Gynecologic Oncologists. Chicago Illinois. Press release February 7, 2004.
18. UpToDate. Overview of gene expression profiling, proteomics, and microRNA profiling in clinical oncology. Literature review current through July 2015.
19. UpToDate. Molecular prognostic tests for prostate cancer. Literature review current through April 2016; topic last updated April 19, 2016.
20. Ross A, D’Amico AV, Freedland S, Molecular prognostic tests for prostate cancer. In: UpToDate, Vogelzang N, Richie JP, Lee WR, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed April 9, 2017.)
21. Ross A, D’Amico AV, Freedland S, Molecular prognostic tests for prostate cancer. In: UpToDate, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed February 28, 2018.)
22. Ross A, D’Amico AV, Freedland S, Molecular prognostic tests for prostate cancer. In: UpToDate,Vogelzang N, Richie JP, Lee WR, Savarese DMF (Eds), UpToDate, Waltham, MA. (Accessed March 6, 2019.)
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