DecisionDx-UM: Healthcare Professional Information

The main goals of ocular treatment of uveal melanoma are to reduce the risk of metastasis, prevent local growth and destruction of ocular tissues and preserve as much vision as possible. Treatment of the primary eye tumor is highly effective. The most common treatment is plaque brachytherapy. Brachytherapy involves the temporary placement of a plaque (which delivers targeted radiation) on the eye overlaying the area of the tumor. Proton beam irradiation and enucleation (removal of the eye) are also used. All three of these methods are highly effective at controlling the primary eye tumor.

The primary clinical issue for the management of ocular melanoma is accurately predicting metastatic risk. Approximately half of uveal melanoma tumors will metastasize at some point prior to the diagnosis of the primary eye tumor. However, at the time of diagnosis of the primary eye tumor, metastatic disease will only be detectable in about 3% of patients… an event known as 'micrometastasis'. The need for a tool to help physicians identify the population at high risk for having experienced this 'micrometastatic event' is what drove discovery and development of the DecisionDx-UM gene expression profile test.

The DecisionDx-UM gene expression profile (GEP) test was developed to predict this risk during the first 5-years, regardless of the treatment effectiveness of their primary uveal melanoma tumor. The DecisionDx-UM test identifies the molecular signature of an individual's tumor. Tumors with a low likelihood of having metastasized are termed Class 1 and tumors with a high likelihood of having metastasized are termed Class 2. The DecisionDx-UM test has been compared to all clinical and pathologic prognostic factors, including chromosome 3 (monosomy 3) testing and has been shown to be more accurate and statistically superior to all other clinical and pathologic factors (Worley, 2007, Onken, 2010, Harbour, 2011).

In addition to being more accurate than chromosome 3 (monosomy 3) testing, the DecisionDx-UM test is also technically robust. In the prospective multi-center validation study, technical success was 95% (Onken, 2010). Clinical experience through Castle Biosciences is similar at 96% (analysis of over 800 specimens through September, 2011). In contrast, chromosome 3 (monosomy 3) testing has been documented to technically fail in up to 50% of specimens tested (Young, 2007; Desjardins, 2010).

The DecisionDx-UM test is a proprietary test that has been exclusively licensed from Washington University. Technical and clinical validation were completed in 2009 and the DecisionDx-UM test was made available for routine clinical use in late 2009. The DecisionDx-UM test was clinically validated in a 5-year, prospective, multi-center study of 694 patients.

The DecisionDx-UM test is recommended for clinical use by the American Joint Committee on Cancer as the results were concluded to be "clinically significant" for patient care (AJCC, 2010, version 7; identified as the gene expression profile). The AJCC is the only nationally recognized treatment guideline organization that reviews uveal melanoma. The DecisionDx-UM test has been adopted as standard of care in the majority of ocular oncology clinics (over 55 of an estimated 70 clinics, Castle Biosciences data, Aug 2011).

Prospective Clinical Validation

At the most recent collection point (Nov. 2009) the prospective study included 227 patients with evaluable data for analysis (Onken, 2010). The actual outcomes for metastasis and survival of the predicted low-risk (Class 1) molecular signature and the high-risk (Class 2) molecular signature with a 72 months analysis cut-off are shown in Figure 1 below.

The DecisionDx-UM test is a robust, proprietary, multi-gene expression test that analyzes the molecular signature of your patient's uveal melanoma. The DecisionDx-UM molecular signature enables prospective identification of patients who have a low risk (Class 1 molecular signature) or high risk (Class 2 molecular signature) of developing metastatic disease.

The DecisionDx-UM gene expression profile test is a robust, proprietary, multi-gene assay was discovered at Washington University in St. Louis in the laboratory of Dr. J. William Harbour.

The following information provides background on the assay development and validation studies. Further information can be provided upon request.

As shown in Table 1 below, a number of development considerations have been addressed during the development phase of the DecisionDx-UM test.

Comparison to Other Prognostic Markers (Worley, et al 2007)

A study was undertaken to compare the gene expression profile (molecular signature) to the chromosome 3 marker (monosomy 3). The same study compared the assay to clinical and pathologic factors for predicting metastasis in uveal melanoma. This study of 67 patients treated by enucleation is the largest study using metastatic outcome to compare prognostic factors to date in uveal melanoma. Monosomy 3 was assessed through fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH). The clinicopathologic factors of age, sclera invasion, histopathologic cell type, tumor thickness, gender, largest tumor diameter, and anterior tumor location were also assessed.

By Cox univariate proportional hazards, only Class 2 gene expression profile (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were significantly associated with metastasis (Table 2). Kaplan-Meier analysis rendered similar results. When all three significant variables were entered into a Cox multivariate model, only the Class 2 molecular signature exhibited significant association with metastasis.

For sensitivity and specificity analyses, a metastasis group consisted of 18 patients who had developed metastasis, and a non-metastasis group contained 16 patients without metastasis who had at least 3-year follow-up after ocular treatment was selected. Consistent with the statistical outcomes above, the Class 2 molecular signature outperformed all other prognostic variables (Table 3).

Comparisons to chromosome 3 (monosomy 3 as determined by SNP_LOH) and other clinical and pathologic factors have been included in the prospective, multi-center study noted earlier (n=694; Onken, in press). The DecisionDx-UM test superiority in accuracy and statistical significance noted above were replicated in this prospective study.

The DecisionDx-UM test is technically robust. In the prospective multi-center validation study, technical success was 95% (Onken, 2010). Clinical experience through Castle Biosciences is similar at 96% (analysis of over 800 specimens through September, 2011). In contrast, chromosome 3 (monosomy 3) testing has been documented to technically fail in up to 50% of specimens tested (Young, 2007; Desjardins, 2010).

A laboratory report will be generated and provided to each ordering and treating clinician for each processed clinical order. The report will be available through facsimile, mail, and secure web portal.

The laboratory report will contain the predicted classification (Class 1 vs Class 2) for the analyzed tumor specimen as well as the corresponding discriminant value.

The clinical use of the results of the DecisionDx-UM test is a decision that is made between a physician and their patient.

To date, clinical medical record reviews and the literature show that physicians use the results of the DecisionDx-UM test to:

• Develop patient specific surveillance plans. Patients identified as having a high risk of developing metastasis may receive a high intensity surveillance plan that may include more frequent monitoring with advanced imaging testing such as CT or MRI. Patients at a low risk of developing metastasis may receive a less intensive surveillance plan – thus balancing the risks of radiation exposure and increased costs of the advanced imaging testing with the patient's risk of metastasis;
• Initiate referral to a medical oncologist for treatment planning and options which may include adjuvant treatment; and
• Refer appropriate high risk patients to clinical trials.

Patients overwhelmingly want to know their likelihood of developing metastasis. Two studies were recently undertaken to assess a patient's interest in being tested for their risk of metastasis (Beran 2009; Cook, 2009). To eliminate bias, both study designs emphasized that no changes would be made in the patient's treatment plans based on these results. Despite these statements, both studies reported that 97% of patients wanted to know their prognosis.

Many ocular oncologists, retinal surgeons and ophthalmologists currently perform fine-needle aspirate biopsies (FNAB) for cytology purposes. However, given that uveal melanoma is primarily a clinical diagnosis, some clinicians have limited experience in performing FNAB for uveal melanoma.

While Castle Biosciences does not train, certify or accept liability for the FNAB procedure, some clinicians have asked for resources such as procedural videotapes, expert flow charts, and introductions to ocular oncologists who are interested in training others in their FNAB technique. Please contact Castle Biosciences for access to these resources.

AJCC Cancer Staging Manual. 2010. Edge, S.B.; Byrd, D.R.; Compton, C.C.; Fritz, A.G.; Greene, F.L.; Trotti, A. (Eds.) 7th ed.

The DecisionDx-UM test is a proprietary assay that is only available through Castle Biosciences. As noted above, the DecisionDx-UM test identifies patients who have a near term (5-year) low risk versus a high risk of developing metastatic disease regardless of the treatment effectiveness of their primary uveal melanoma tumor.

Based upon the completion of the validation of this gene expression assay and its clinical importance in the management of patients with uveal melanoma, the 7th Edition of the American Joint Committee on Cancer (effective January 1, 2010) recommends the use of the DecisionDx-UM gene expression profile test in patients with uveal melanoma because the results were determined to be "clinically significant" for patient care. The DecisionDx-UM test is also standard of care in the majority of ocular oncology practices. Based upon these facts, we anticipate that insurance companies will reimburse for the cost of the assay.

However, we understand that paying for elements of healthcare can be confusing and overwhelming. As a company, we are sensitive to that fact and are prepared to assist patients through the process of securing payment for services provided by Castle. We will coordinate the submission of insurance claims for Medicare and commercial insurance companies. We will work with the patient's authorized healthcare provider regarding benefits investigation should one be requested, any prior authorization required, and appeals processing. The Castle Patient Assistance Program is available to explore options for patients with balances remaining. This program also has options for uninsured patients. In some cases, institutions may ask us to invoice them directly, also known as client bill.