DecisionDx-UM is a
prognostic
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stable ...
test that accurately determines the metastatic risk associated with ocular melanoma
tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
of the eye. Ocular melanoma is a term commonly used to describe tumors of the
uvea
The uvea (; Lat. ''uva'', "grape"), also called the ''uveal layer'', ''uveal coat'', ''uveal tract'', ''vascular tunic'' or ''vascular layer'' is the pigmented middle of the three concentric layers that make up an eye.
History and etymolog ...
l tract such as
uveal melanoma
Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the Iris (anatomy), iris, choroid, and ciliary body, but can also be divided into class I (low metastatic risk) and class II (high metasta ...
,
choroidal melanoma,
ciliary body melanoma
Ciliary body melanoma is a type of cancer arising from the coloured part (uvea) of the eye.
About 12% of uveal melanoma arise from the ciliary body.
Clinical features
It occurs most commonly in the sixth decade of life.
* External signs includ ...
, and iris melanoma. The DecisionDx-UM test was clinically validated on these tumors of the uveal tract. DecisionDx-UM assesses the
gene expression profile (GEP) of a subset of genes which are differentially expressed in primary tumor cells compared to cells that have undergone transformation to a
metastatic
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
phenotype.
The test classifies tumors as:
* Class 1A (low metastatic risk),
* Class 1B (long-term metastatic risk),
* Class 2 (immediate, high metastatic risk).
[Harbour, J.W., Retina Times 2011;29: 36-7.]
Also referred to as the gene expression profile, the test has been directly compared to all other
clinical and
pathological
Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
factors, such as
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
3 status (
monosomy
Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.
Human monosomy
Human conditions due to monosomy:
* Turner syndrome – People wit ...
3),
cytopathology
Cytopathology (from Greek , ''kytos'', "a hollow"; , ''pathos'', "fate, harm"; and , '' -logia'') is a branch of pathology that studies and diagnoses diseases on the cellular level. The discipline was founded by George Nicolas Papanicolaou in 1 ...
and tumor size and the DecisionDx-UM test was shown to be more accurate than these other factors.
[Worley, L.A., et al., Clinical Cancer Research, 2007. 13(5): p. 1466-71.] The DecisionDx-UM test has become standard of care in the majority of
ocular oncology
Eye neoplasms can affect all parts of the eye, and can be a benign tumor or a malignant tumor (cancer). Eye cancers can be primary (starts within the eye) or metastatic cancer (spread to the eye from another organ). The two most common cancers t ...
centers in the U.S. and is recommended by the
American Joint Committee on Cancer {{Short description, Organization standardising cancer staging
The American Joint Committee on Cancer (AJCC) is an organization best known for defining and popularizing cancer staging standards, officially the AJCC staging system.
The American Joi ...
(AJCC). The AJCC recommends this testing for all patients with a diagnosis of uveal melanoma as the results are ‘clinically significant’. Accurate results are achieved using both
fine needle aspirate biopsies (FNAB) or
formalin
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section Fo ...
fixed,
paraffin Paraffin may refer to:
Substances
* Paraffin wax, a white or colorless soft solid that is used as a lubricant and for other applications
* Liquid paraffin (drug), a very highly refined mineral oil used in cosmetics and for medical purposes
* Alkan ...
embedded (FFPE) tumor tissue. The prognostic information provided by DecisionDx-UM helps physicians and their patients make individualized decisions about the surveillance and therapeutic options that are most appropriate. The DecisionDx-UM test was exclusively licensed from
Washington University in St. Louis
Washington University in St. Louis (WashU or WUSTL) is a private research university with its main campus in St. Louis County, and Clayton, Missouri. Founded in 1853, the university is named after George Washington. Washington University is r ...
and is only available through Castle
Biosciences
This list of life sciences comprises the branches of science that involve the scientific study of life – such as microorganisms, plants, and animals including human beings. This science is one of the two major branches of natural science, ...
, Incorporated.
Uveal Melanoma
While rare, uveal melanoma (ocular melanoma) is the most common form of eye cancer and the second most common form of
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
. Uveal melanoma tumors arise in the uveal tract of the eye which includes the
iris
Iris most often refers to:
*Iris (anatomy), part of the eye
*Iris (mythology), a Greek goddess
* ''Iris'' (plant), a genus of flowering plants
* Iris (color), an ambiguous color term
Iris or IRIS may also refer to:
Arts and media
Fictional ent ...
,
ciliary body
The ciliary body is a part of the eye that includes the ciliary muscle, which controls the shape of the lens, and the ciliary epithelium, which produces the aqueous humor. The aqueous humor is produced in the non-pigmented portion of the ciliar ...
, and
choroid
The choroid, also known as the choroidea or choroid coat, is a part of the uvea, the vascular layer of the eye, and contains connective tissues, and lies between the retina and the sclera. The human choroid is thickest at the far extreme rear ...
. Treatment for the primary eye tumor consists of eye-sparing therapy (
plaque radiotherapy or
proton beam irradiation) or eye removal (
enucleation). Both are highly effective with ‘cure’ rates above 90%. However, as has been well documented in multiple publications including th
Collaborative Ocular Melanoma Study(COMS), in nearly 50% of patients the melanoma has likely already metastasized by the time the primary eye tumor has been diagnosed and treated.
[Archives of Ophthalmology, 2006. 124(12): p. 1684-93.][Diener-West, M., et al., Archives of Ophthalmology, 2001. 119(7): p. 969-82.] The majority of these metastases are microscopic and clinically undetectable at the time of primary tumor diagnosis.
[Harbour, J.W., Clinical overview of uveal melanoma:introduction to tumors of the eye., ed. D.M. Albert, Polans, A.2003: Marcel Dekker. 1-18.] Unfortunately, many of the current diagnostic techniques (including imaging and liver function tests) are not able to accurately detect micrometastases until tumor nodules have grown considerably, and likely become resistant to therapy.
[Finger, P.T., et al., The British Journal of Ophthalmology, 2005. 89(10): p. 1270-4.][Kurli, M., et al., American Journal of Ophthalmology, 2005. 140(2): p. 193-9.]
The lack of accurate prognostic tests to identify which patients are at risk of developing clinically overt metastatic disease has been a significant issue in the management of individual patients with uveal melanoma. Without accurate measures of individual metastatic risk, it is impossible to identify which patients are at high risk for clinical metastasis, which can then lead to either over or under-treatment of any given patient. The DecisionDx-UM test was developed to provide improved individual metastatic risk assessment which allows for more appropriate surveillance and treatment planning.
DecisionDx-UM GEP Assay
Discovery
The gene expression profile measured by DecisionDx-UM was discovered in the laboratory of
J. William Harbour at
Washington University
Washington University in St. Louis (WashU or WUSTL) is a private research university with its main campus in St. Louis County, and Clayton, Missouri. Founded in 1853, the university is named after George Washington. Washington University is r ...
in
St. Louis
St. Louis () is the second-largest city in Missouri, United States. It sits near the confluence of the Mississippi and the Missouri Rivers. In 2020, the city proper had a population of 301,578, while the bi-state metropolitan area, which e ...
.
[Onken, M.D., et al., Cancer research, 2004. 64(20): p. 7205-9.][Onken, M.D., et al., The Journal of molecular diagnostics : JMD, 2010. 12(4): p. 461-8.] The application of microarray analysis to primary untreated uveal melanomas revealed that the tumors clustered into two discreet groups based upon their expression profiles.
Filtering of the differentially expressed gene set led to the identification of a set of genes able to discriminate between Class 1 and Class 2 tumors.
In subsequent experiments, Dr. Harbour’s group assembled microarray information from a larger subset of uveal melanoma tumor samples, and were able to identify candidate discriminatory genes for further analysis.
The genetic expression profiles of those discriminating genes were verified in uveal melanoma tumors using
quantitative polymerase chain reaction
A real-time polymerase chain reaction (real-time PCR, or qPCR) is a laboratory technique of molecular biology based on the polymerase chain reaction (PCR). It monitors the amplification of a targeted DNA molecule during the PCR (i.e., in real ...
(qPCR) methods, and predictive modeling was performed to identify an optimum set of genes able to accurately predict metastatic risk and report class assignments.
[Onken, M.D., et al., The Journal of molecular diagnostics : JMD, 2006. 8(5): p. 567-73.] The final assay evaluated 12 discriminating genes and 3 control genes to determine Class 1 (low risk) and Class 2 (high risk) tumors, and was validated in a 609 patient multicenter study that included FNAB and FFPE samples.
Prognostic Accuracy
The current DecisionDx-UM platform was clinically validated in the COOG study, which included 514 patients with UM treated at 12 ocular oncology centers in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
between 1998 and 2010.
The report provides data showing that DecisionDx-UM has a high technical success rate (>95%).
Clinical Technical Success
Since the initial offering of DecisionDx-UM in December 2009, more than 800 clinical orders have been received for analysis by Castle Biosciences from over 55 ocular oncology centers across the U.S. Technical success and class determination was achieved for 96.2% of the samples.
[Bergstrom, C.S., Hovland, P. G., Stone, J. F., Oelschlager, K., and Cook, R. W., 2011.] Most of the failures were due to improper
biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...
collection and/or handling. Tumor biopsy collection is critical for the successful reporting of metastatic risk Class assignment following DecisionDx-UM testing.
DecisionDx-UM Ordering and Reporting
Castle Biosciences, Incorporated only accepts service orders for DecisionDx-UM from licensed physicians (most commonly ocular oncologists, ophthalmologists, or
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
specialists) who care for patients diagnosed with uveal melanoma. Physicians who are first time customers must contact Castle’s for information and to establish an account. Sample submission requires submission of a DecisionDx-UM Requisition Form to be completed and faxed to Castle. FNAB specimens require use of a specimen collection kit, provided by Castle, to stabilize the sample and reduce the chance of technical failure. This kit must be received by the ordering physician prior to sample collection. Castle staff is available to assist with logistics concerning sample collection and shipping.
Castle provides a report to the ordering physician that will classify the tumor as Class 1A, Class 1B, or Class 2. The report will also describe the statistics associated with the classification, and provide a discriminant value that reflects the confidence regarding the classification. The information provided in the report from Castle identifies how likely a tumor is to metastasize (spread) with this risk being categorized as low (Class 1A), intermediate (Class 1B), or high (Class 2).
Other UM Metastasis Prognostic Factors
Histopathologic Factors and Imaging Techniques
Historically there are several clinical and pathologic features that have been statically associated with metastasis.
[Augsburger, J.J. and J.W. Gamel, Cancer, 1990. 66(7): p. 1596-600.][McLean, I.W., K.S. Keefe, and M.N. Burnier, Ophthalmology, 1997. 104(5): p. 777-80.] Tumor size, tumor location, patient age and
vascular
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
structure have all been reported to correlate with metastatic onset and patient survival.
[Foss, A.J., et al., Cancer research, 1996. 56(13): p. 2900-3.] While generalities regarding the UM patient population at large can be made based on these factors, none, alone or collectively, has demonstrated predictive accuracy with regard to metastatic activity.
Imaging techniques used to detect metastatic activity also have limitations. Systemic metastases are detected by
Positron Emission Tomography
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...
(PET) imaging at the time of the original diagnosis in less than 4% of UM patients
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
(MRI) has recently been reported more sensitive than PET for identifying metastasis from
choroidal melanoma, but MRI requires tumor mass greater than 5mm in size.
[Servois, V., et al., European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2010. 36(2): p. 189-94.] Thus, current imaging technology lacks the sensitivity for detecting
micrometastases
A micrometastasis is a small collection of cancer cells that has been shed from the original tumor and spread to another part of the body through the lymphovascular system. Micrometastases are too few, in size and quantity, to be picked up in a sc ...
that may be present at the time of primary diagnosis of uveal melanoma.
Genetic Factors
Genetic analysis techniques have led to the identification of chromosomal abnormalities associated with metastatic tumor progression in uveal melanoma. Loss of
heterozygosity
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
, loss of entire
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s from chromosomes,
partial chromosomal addition and
chromosomal deletion
In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...
and
single nucleotide polymorphisms
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNP) have been associated with uveal melanoma metastatic lesions.
[Harbour, J.W., et al., Science, 2010. 330(6009): p. 1410-3.][Kilic, E., et al., Investigative ophthalmology & visual science, 2006. 47(9): p. 3703-7.][Onken, M.D., L.A. Worley, and J.W. Harbour, Clinical Cancer Research, 2008. 14(12): p. 3737-45.][Prescher, G., N. Bornfeld, and R. Becher, Journal of the National Cancer Institute, 1990. 82(22): p. 1765-9.][Sisley, K., et al., Genes, Chromosomes & Cancer, 1990. 2(3): p. 205-9.] In particular, chromosomes 1, 3, 6 and 8 have been extensively studied for their association with shorter survival time and development of metastatic disease.
[Damato, B., J.A. Dopierala, and S.E. Coupland, Clinical Cancer Research, 2010. 16(24): p. 6083-92.][Sisley, K., et al., Genes, Chromosomes & Cancer, 1997. 19(1): p. 22-8.][Prescher, G., et al., Lancet, 1996. 347(9010): p. 1222-5.][Singh, A.D., et al., Archives of Pathology & Laboratory Medicine, 2009. 133(8): p. 1223-7.]
While genetic aberrations in chromosomes 1, 6 and 8 have not independently been able to predict disease progression, cytogenetic profiling of chromosome 3 has uncovered an important genetic region highly associated with metastatic onset in uveal melanoma patients.
Chromosome 3 abnormalities have been analyzed using multiple techniques, including fluorescence in situ hybridization (FISH), chromosomal in situ hybridization (CISH),
array comparative genomic hybridization Comparative genomic hybridization (CGH) is a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The a ...
(aCGH), SNP,
multiplex ligation-dependent probe amplification
Multiplex ligation-dependent probe amplification (MLPA) is a variation of the multiplex polymerase chain reaction that permits amplification of multiple targets with only a single primer pair. It detects copy number changes at the molecular level, ...
(MLPA), and
microsatellite analysis.
[Naus, N.C., et al., Clinical Cancer Research, 2002. 8(2): p. 534-9.][Onken, M.D., et al., Clinical Cancer Research, 2007. 13(10): p. 2923-7.][Sandinha, M.T., M.A. Farquharson, and F. Roberts, The British Journal of Ophthalmology, 2004. 88(12): p. 1527-32.][Tschentscher, F., et al., Cancer genetics and cytogenetics, 2000. 122(1): p. 13-7.]
Despite a wealth of data that has identified the association of chromosome 3
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
with UM metastasis, the clinical application of this data has yet to be realized.
[Damato, B. and S.E. Coupland, Archives of Ophthalmology, 2009. 127(4): p. 423-9.] Reasons for the uncertainty of chromosome 3 clinical use include:
* high false-positive rates (ranging from 5-22%)
* high false-negative rates (ranging from 4-50%)
* high technical failure rates (up to 50%) due to the large tissue requirement for current analysis techniques
* the adverse effects of cellular
heterogeneity
Homogeneity and heterogeneity are concepts often used in the sciences and statistics relating to the uniformity of a substance or organism. A material or image that is homogeneous is uniform in composition or character (i.e. color, shape, siz ...
on
chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
cytogenetic analysis.
[Maat, W., et al., Archives of Pathology & Laboratory Medicine, 2007. 131(1): p. 91-6.][Mensink, H.W., et al., Investigative ophthalmology & visual science, 2009. 50(2): p. 500-4.][Midena, E., et al., European journal of ophthalmology, 2006. 16(3): p. 422-5.][Shields, C.L., et al., Transactions of the American Ophthalmological Society, 2007. 105: p. 43-52; discussion 52-3.][Young, T.A., et al., Ophthalmology, 2007. 114(1): p. 142-6.]
Furthermore, unlike the DecisionDx-UM test, there are no published, peer-reviewed studies that demonstrate clinical validation in an independent set of patients.
Castle Biosciences, Incorporated
Castle Biosciences, Incorporatedis a molecular diagnostics company that develops diagnostic and prognostic assays for rare cancers. Castle’s mission is to serve individuals afflicted with rare cancers by offering accurate prognostic tests which provide information for making critical decisions regarding an individual’s surveillance and treatment regimens. In addition to DecisionDx-UM, Castle offers prognostic tests for
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
(DecisionDx-Melanoma) and
squamous cell carcinoma
Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
(DecisionDx-SCC). Castle is based in
Friendswood, TX, and has operations in
Phoenix, AZ
Phoenix ( ; nv, Hoozdo; es, Fénix or , yuf-x-wal, Banyà:nyuwá) is the capital and most populous city of the U.S. state of Arizona, with 1,608,139 residents as of 2020. It is the fifth-most populous city in the United States, and the onl ...
.
References
External links
The Tumori FoundationThe Ocular Melanoma Foundation. A cancer nonprofit foundation.The Ocular Oncology Service at Washington University in St. Louis{{Webarchive, url=https://web.archive.org/web/20110930072834/http://www.eyetumor.org/ , date=2011-09-30
The Eye Cancer NetworkOCU-MEL - Ocular Melanoma e-mail list for patients, caregivers and healthcare professionalsAll NCI-approved clinical trials for uveal melanoma that has spread to the liverA phase III clinical trial for uveal melanoma that has spread to the liverEyeMelanoma.org
Diagnostic ophthalmology
Medical tests