Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test

The majority of cutaneous melanoma (CM) patients are diagnosed with early-stage (AJCC stage I or II) disease and are considered to have a favorable prognosis [ 1, 2]. However, two-thirds of all melanoma deaths occur in patients initially included in this “low-risk” group, which indicates that metastatic risk is underestimated for a substantial number of early-stage patients [ 1– 4]. A recent study reporting data from the Surveillance, Epidemiology, and End Results (SEER) program reported that the mortality rate for cutaneous melanoma is increasing faster than the incidence rate, highlighting the need for additional prognostic tools to supplement standard clinicopathologic factors and improve identification of high-risk disease [ 5]. More vigilant follow-up for high-risk melanoma patients, including the addition of imaging and increasing clinical assessment frequency, leads to earlier detection of asymptomatic distant metastatic disease, when tumor burden is lower, and when surgical approaches as well as contemporary therapies have greater benefit [ 5– 11]. Distinguishing those CM patients with high-risk tumor biology from those who are categorized as low risk by TNM staging alone is therefore a clinically important goal.

A prognostic gene expression profile (GEP) test (DecisionDx-Melanoma, Castle Biosciences, Inc.) that evaluates 31 gene targets expressed in the primary melanoma tumor to provide a binary classification of low (class 1) or high (class 2) risk of metastasis within 5 years of the initial diagnosis has been previously reported [ 12]. The test assesses the expression of three control genes, four genes with proven prognostic utility for uveal melanoma tumors [ 13], and 24 gene targets previously reported to be differentially expressed in metastatic compared to primary tumors [ 14– 20]. Performance of the test has been evaluated in several retrospective validation studies, showing that it accurately prognosticates survival independent of clinical or pathologic assessment alone [ 12, 21, 22], and though it was originally developed to identify the distant metastasis risk associated with stage I and II melanoma tumors, the prognostic capability of the test has recently been reported in patients with stage III disease. In order to prospectively evaluate outcomes for a real-world representative cohort of CM patients, two multi-center registry studies (EXPAND and INTEGRATE) were initiated. Here, we present an interim analysis of the survival outcomes for 322 patients enrolled in these registries.

An important unmet clinical need in melanoma is the accurate identification of early-stage patients who harbor a higher risk of developing advanced disease. While Breslow thickness and ulceration are strongly associated with metastasis and outcome, and sentinel lymph node status is a proven prognostic tool that identifies a subset of the patients with high-risk disease, two of three patients who die from melanoma are originally diagnosed with stage I or II tumors [ 24]. As these clinicopathologic staging features are used to drive management decisions, molecular tools that supplement and improve current methods of prognostication should have significant clinical impact.

To improve upon the identification of high-risk stage I and II patients, a gene expression profile test was developed to provide prognostic information based on the expression of 31 genes in the primary melanoma tumor [ 12]. A limitation of this interim analysis could be the impact of the short follow-up time. However, consistent with previous reports, the GEP test was a significant predictor of RFS, DMFS, and OS, in both the larger cohort of 322 patients (Fig. 1), and in 282 stage I and II CM cases (Additional file 1: Figure S1). The risk of metastasis and death was significantly higher for patients with a class 2 result compared to class 1 patients. The GEP accurately identified 80% of the recurrences detected during the study, and only 2% of the patients who were predicted to be low risk (class 1) by the test developed recurrent disease. Although multivariate analysis showed BT to be the only independent prognostic factor for DMFS and OS in this cohort, this is likely to be due to the limited number of events for these two outcomes. In all prior studies the GEP has shown independent prognostic value along with Breslow thickness and SLN status.

In this study, 83% (10 of 12) of patients who developed distant metastases were identified as high risk by the GEP test, compared to only 50% (6 of 12) who had a SLN-positive result. Additionally, we found that the median time to recurrence for those who developed advanced disease was only 1 year. National melanoma guidelines specify that patient management should be tailored to an individual’s probability of recurrence. Frequent follow-up and intensified surveillance with imaging is recommended for patients with high-risk clinicopathologic features, while management of low-risk patients is generally restricted to clinical follow-up at 3–12 month intervals [ 25]. A growing body of evidence supports cross-sectional radiographic imaging as the most effective method for detecting asymptomatic distant metastatic disease in patients with stage II and III melanoma [ 7, 10, 11]. In this study, 6 of 12 patients with distant metastasis were originally diagnosed with stage II disease. Of those, five were identified as class 2, including two patients with stage IIA tumors. While direct evidence of a benefit from surveillance has not been published, considering the rapid time to event observed in this interim analysis, and the accuracy of risk prediction by the GEP test, increased surveillance with imaging for class 2 patients might be useful, especially in those patients who would not be offered surveillance options based on stage.

The advantages of molecular testing for enhanced prognosis are well documented for other diseases, including breast cancer and ocular melanoma [ 26, 27]. Consistent with previous studies, the results from this prospective analysis indicate that the 31-gene GEP test for melanoma, in combination with standard clinicopathologic factors, can strengthen risk determination and improve patient management. Better risk prediction is particularly critical when considering the recent advances in therapeutics for melanoma and the evidence supporting better efficacy of contemporary therapies if treatment is administered when tumor burden is low [ 28, 29].

This constitutes the first report of performance for the prognostic 31-gene GEP test in a prospective population of patients with cutaneous melanoma. In concordance with prior retrospective studies, the test showed robust ability to predict recurrence, distant metastasis and death. While this report encompasses only an interim analysis and, therefore, it is expected that additional events will accrue in this population, the strong statistical association with outcomes even at this early time point provides assurance of the test’s prognostic value.