BACKGROUND
Melanoma is a malignancy that originates from the skin's pigment-producing cells, melanocytes. Although accounting for only about 1% of skin cancers, melanoma causes most skin cancer deaths (American Cancer Society, 2016). The average age of diagnosis is 63 years; however, it is not uncommon to diagnose a person younger than 30 years (American Cancer Society, 2016). The American Cancer Society reports rising rates of melanoma and estimates 76,380 new melanoma cases and 10,130 melanoma deaths in the United States for 2016 (American Cancer Society, 2016).
Cutaneous melanoma is the most common type of melanoma in comparison with noncutaneous types such as ocular and mucosal melanomas. Cutaneous melanoma is categorized as Stages 0-IV by the American Joint Committee on Cancer TNM (primary tumor [T], regional lymph nodes [N], distant metastases [M]) system (Balch et al., 2009). On the basis of the staging, the National Comprehensive Cancer Network (NCCN) provides recommendations regarding initial workup, management, and metastatic surveillance (Coit et al., 2016). For example, Stage 0 and 1a tumor workup may consist solely of wide surgical excision, whereas Stage 4 metastatic tumor workup would consist of biopsy or fine needle aspiration, lactate dehydrogenase levels, and imaging of the chest, abdomen, and brain (Coit et al., 2016). Follow-up may vary from having an annual skin examination by a dermatology provider to additional close surveillance with routine imaging and laboratory monitoring for several years (Coit et al., 2016).
Although the latest NCCN guidelines include important prognostic information such as tumor ulceration, mitotic figures, and sentinel lymph node biopsy (SLNB) status (NCCN, 2017), there is high prognostic variability within a stage classification. Although Stage I or II patients are considered to be at a low risk of recurrent metastasis, the 10-year survival rate ranges from 95% to 40% for Stages IA to IIC (American Cancer Society, 2016), and 20% of these patients die from the disease within 4 years of initial diagnosis (Gerami, Cook, Wilkinson, et al., 2015). Another impacting factor on patient care is that the recommendations are nonspecific, allowing for wide ranges of follow-up with similar management for the various stages (Coit et al., 2016). This results in overmanagement of less biologically aggressive tumors and insufficient evaluation of more aggressive lesions (Berger et al., 2016).
DIAGNOSTIC TEST
The 31-gene expression profile (31-GEP) was the diagnostic test used (DecisionDx-Melanoma; Castle Biosciences, Inc., Friendswood, TX).
DIAGNOSTIC TEST DESCRIPTION
Gene expression profiling provides a personalized, molecular-based diagnostic and prognostic assessment that has become an additive tool in various cancers including breast, uveal myeloma, and thymoma (Gerami, Cook, Wilkinson, et al., 2015). The 31-GEP test incorporates a decade's worth of published genomic analysis to represent a novel cutaneous melanoma genetic signature of 28 discriminating gene targets for metastatic risk and three control genes (Gerami, Cook, Wilkinson, et al., 2015). The profile categorizes tumors as low risk (Class 1) or high risk (Class 2) and is an independent prognostic marker for 5-year risk of metastasis with considerably greater prognostic power than other assays (see Table 1; Gerami, Cook, Wilkinson, et al., 2015).
Before the 31-GEP test, the most accurate prognostic indicator of metastatic spread was SLNB (Gerami, Cook, Russell, et al., 2015). However, as there was a death rate of 20% in Stage I and II American Joint Committee on Cancer patients, two of three node-negative patients die from metastatic disease (Morton et al., 2006). Independently, 31-GEP test classification is more accurate than SLNB (Gerami, Cook, Russell, et al., 2015). The negative predictive value of low-risk (Class 1) 31-GEP was 82% (95% CI [71%, 89%]) versus 67% (95% CI [59%, 74%]) of SLNB (Gerami, Cook, Russell, et al., 2015). The 31-GEP test is particularly powerful at stratifying the lower-risk stages. There was no statistically significant difference in disease-free survival or overall survival of patients with negative SLNB and high-risk (Class 2) 31-GEP versus patients with positive SLNB and high-risk (Class 2) 31-GEP. Therefore, low-risk (Class 1) 31-GEP is more reassuring than a negative SLNB result. The 31-GEP test identifies the true low-risk population or, conversely, the high-risk patients with SLNB negative results (Gerami, Cook, Russell, et al., 2015). According to Berger and colleagues, the test is already appropriately impacting current clinical care with decreased intensity of surveillance in low-risk (Class 1) patients and increased intensity for high-risk (Class 2) patients (Berger et al., 2016). Management changes primarily occurred in the frequency of office visits and positron emission tomography and/or computed tomography imaging (Berger et al., 2016).
However, as discussed in a June 2015 online editorial for the Oncology Times, although the 31-GEP test may stratify patients, it neither is therapeutic nor has been studied in regard to improved survival rates or guiding treatment options (Fuerst, 2015). With a categorization of high risk (Class 2), patients may undergo unnecessary tests and scans that may not alter the outcome. In addition, although the 31-GEP test was shown to be more accurate than SLNB results, Gerami and colleagues do not state that SLNB can be replaced. On the basis of their data, they recommend that the 31-GEP test be used conjunctively with SLNB for the most accurate prognostication (Gerami, Cook, Russell, et al., 2015). Notably, if low-risk (Class 1) 31-GEP patients could forego SLNB, then there is the potential for decreased morbidity and cost savings. An SLNB is an invasive surgical procedure that can cause lymphedema, impaired motion, numbness, and pain (Langer et al., 2007). The procedure costs $12,000-$15,000, whereas the 31-GEP test is noninvasive and ranges from $3,000 to $7,000 (Fuerst, 2015).
IMPORTANT IMPLICATIONS
The 31-GEP test provides a noninvasive, personalized molecular-based assessment of low-risk (Class 1) or high-risk (Class 2) cutaneous melanoma tumor biology (Gerami, Cook, Wilkinson, et al., 2015). The studies showed that the 31-GEP test was more accurate than SLNB in predicting recurrent metastatic risk. However, at this time, the two results should be combined for the most accurate prognostication of patients with cutaneous melanoma (Gerami, Cook, Russell, et al., 2015). Studies show that the 31-GEP is already improving risk-appropriate patient management (Berger et al., 2016). Although it is not yet incorporated in the NCCN staging guidelines, with further validation in larger studies involving the average- to low-risk melanoma patients, the 31-GEP test has significant potential to reduce medical costs, direct tumor treatment, and improve survival rates (Fuerst, 2015).
REFERENCES