| Clinical validity and performance—risk of recurrence |
| Gerami et al6 (January 2015) |
Multicenter (6 sites), archival, N=268, Stage I–IV melanoma |
Clear and significant separation of risk between Class 1 and Class 2 result for DFS, DMFS, MSS, OS using KM analysis
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| Gerami et al25 (May 2015) |
Multicenter (7 sites), archival, N=217, Stage I–IV melanoma (all underwent SLNB) |
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| Zager et al5 (February 2018) |
Multicenter (16 sites), archival, N=523 |
GEP was used in combination with SLNB to enhance identification of patients with high-risk melanoma. GEP predicted an additional 29 recurrences and 23 distant metastases, improving sensitivity of recurrences to 88% and distant metastasis to 91% compared to sensitivities of 65% for recurrences and 67% for distant metastases when using SLNB alone. Multivariate analysis demonstrated that GEP, tumor thickness, and SLN status were independent, significant predictors of RFS and DMFS
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| Gastman et al22 (January 2019) |
Multicenter (18 sites), archival, N=690; combined non-overlapping cohort of patients from Gerami6, Gerami,25 and Zager5 that had 31-GEP results, staging information, and survival outcomes; Stage I–III melanoma |
Combined cohort (n=690)
Class 2B result independent and significant predictor of RFS, DMFS, and MSS For combined cohort, NPV is 86% for RFS, 90% for DMFS and 98% for MSS.
Confirmed Node Negative (n=259)
Stage I-IIA (n=393)
Patients managed by dermatology who were considered low risk by AJCC staging and were identified as Class 2B: 43% developed recurrence, 28% developed distant metastasis, and 15% died from their melanoma. GEP result was the strongest and only independent predictor of risk across all end points. Class 2B result most important predictor of RFS and DMFS and Class 2 result was the only significant predictor of MSS. NPV >99% for patients with Stage I–IIA for 5-year MSS.
T1 (≤1mm) Tumors (n=281)
Accounts for 24–30% of melanoma related deaths. GEP is an additional, independent predictor of recurrence in this group. Class 2B result was the only factor significantly associated with RFS in multivariate analysis when considering thickness, mitoses, ulceration, and SLNB positivity NPV >99% for patients with thin tumors for 5-year MSS.
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| Greenhaw et al15 (March 2020) |
Meta-analysis of retrospective and prospective studies, N=1,479, Stage I–III |
GEP consistently identifies melanoma patients at increased risk of metastasis, independent of clinicopathologic features and can be used in conjunction with traditional staging to improve patient risk stratification. Meta-analysis results show that GEP Class 2 result is significantly associated with recurrence and distant metastasis. Combining GEP results with SLNB status improved sensitivity and NPV.
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| Where to use the test—risk of recurrence |
| Marks et al26 (July 2019) |
Multicenter, archival, prospective, N=1,479, based on combined cohorts Gastman8, Greenhaw,15 Hsueh,37 and new archival cohort |
Established a 0.3mm threshold for use of GEP to guide decisions and follow-up for risk of recurrence. Management changes occurred in 25% of cases where a test was ordered for patients ≤1 mm. Class results were correlated with recurrence rates (RFS and DMFS) in large dataset, suggesting appropriate population includes those with tumor thickness ≥0.3mm. First recurrent/distant metastatic event occurred in a 0.3mm tumor, so the RFS and DMFS was 100% for tumors <0.3mm thick
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| Clinical validity and performance—SLNB guidance |
| Vetto et al27 (January 2019) |
Multicenter (26 sites), prospective, n=1,421; limited to T1–T2 tumors, n= 1,065) |
Patients older than 55 with a T1 or T2 tumor and a Class 1A signature have a less than 5% chance of being node positive. Class 2B patients of all ages with a T1 or T2 melanoma have a greater than 10% risk of being SLNB positive and might benefit most from the procedure.
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| Prospective studies—risk of recurrence |
| Hsueh et al28 (January 2017) |
Multicenter (11 sites), prospective, N=322; combination of INTEGRATE and EXPAND studies that include both dermatological and surgical centers |
Multivariate analysis showed Breslow depth, mitotic rate, and GEP Class 2 result as significant predictors of recurrence SLNB identified 6 out of 12 (50%) patients with DM, while GEP identified 10 out of 12 (83%) patients with DM as Class 2. NPV for Class 1 was 98-99% for RFS, DMFS ,and OS.
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| Greenhaw et al.8 (December 2018) |
Single center, retrospective/prospective, N=256, dermatologic practice |
Patients with a GEP Class 2 result were 22 times more likely to metastasize compared to a Class 1 result. NPV 99% Post-study, this practice modified melanoma protocols to include GEP to inform management decisions (Class 1 received less intensive management; Class 2 more intensive)
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| Podlipnik et al29 (February 2019) |
Multicenter (5 sites), prospective, N=86, dermatologic practices in Spain |
Study in Stage IB–IIC patients showed GEP accurately predicts risk of recurrence both independently and combined with AJCC staging. GEP Class 2 was the only significant predictor of recurrence compared to AJCC stage and age (>50 years).
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| Keller et al9 (April 2019) |
Single center, prospective, N=159, surgical oncology practice |
Independent, prospective study with over 3.5 years of follow-up, showing results consistent with previous validation studies. GEP identified 79% of patients who had a recurrence as Class 2 NPV of 95% for recurrence; 99% for distant metastasis Breslow depth, SLN status, and GEP Class 2 shown to be significant predictors of RFS and DMFS by multivariate analysis.
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