Genetic Test Evaluation

understanding how genetic tests impact patient management

DecisionDx-UM (Castle Biosciences Inc.)

June 9, 2016

Background:
The most common intraocular malignancy in adults is melanoma of the uveal tract (uveal melanoma [UM]), with a reported incidence of 4 to 5 new cases per million people (Blum et al., 2016; Nichols et al., 2016). Males are slightly more likely to be affected than are females. The risk of developing UM increases with age, with a peak incidence at age 70 years. Individuals who are white and have light eye and skin color have a higher risk of developing UM than do other individuals. Melanoma can occur in any part of the uveal tract, including the anterior part (iris) or posterior part (ciliary body and/or choroid). Iris melanoma has the best prognosis and rarely metastasizes, whereas melanomas in the posterior part of the eye are more likely to metastasize (Nichols et al., 2016). The risk of metastasis is 25% by 5 years and 34% by 10 years, with liver involvement found in 90% to 95% of patients with metastasis; lung, bone and subcutaneous tissue involvement occurs less often. Metastasis to the lymph nodes rarely occurs (Pereira et al., 2013; Choudhary et al., 2016).

Tumor staging using the tumor-node-metastasis (TNM) system is used to help determine risk of metastasis. “T” refers to the tumor size (both diameter and thickness) and invasiveness of the tumor. “N” refers to lymph node involvement and “M” to the absence or presence of distant metastasis. Stage I to III tumors have no lymph node involvement and have not metastasized, whereas stage IV tumors have spread to lymph nodes and/or distant sites (NCI, 2016). Additional prognostic factors which have been used include certain histopathologic alterations as well as the presence of chromosomal alterations such as monosomy 3, which is associated with a poorer prognosis (Gill and Char, 2012).

Treatment for UM used to consist of eye removal (enucleation) in all cases of choroidal melanoma, but more recently, radiation therapy of various types has been used for treatment of small tumors, thus sparing the eye. Liver surveillance for metastasis is also part of the treatment plan, although it is unclear what constitutes an adequate surveillance strategy (Choudhary et al., 2016). In addition, once a liver metastasis becomes clinically evident, the survival time is usually only a few months. Approaches to treatment of liver metastasis vary, but each approach is usually associated with limited success (Pereira et al., 2013; Choudhary et al., 2016). Indeed, a recent review stated that there is currently no standard of care treatment for metastatic disease (Blum et al., 2016). However, detection of metastasis prior to development of symptoms could theoretically lead to better outcomes in these patients (Pereira et al., 2013; Kaliki et al., 2015). Prognostic indicators include histopathologic variables as well as determination of chromosomal changes. More recently, the DecisionDx-UM genetic test was developed as a means of determining risk of metastasis in UM patients. This report will examine the analytical and clinical validity of the DecisionDX-UM test along with the reported clinical utility.