No Solid Evidence to Support GEP Testing in Thin Melanoma

When making management decisions in patients with thin melanoma, physicians may attempt to predict these patients’ risk of metastasis by means of an expensive 31-gene expression profile (GEP) test touted to do just that. But so far, there has been no convincing evidence that such a test should be used in this scenario, argue the authors of a recent viewpoint article published in JAMA Dermatology.¹ What’s more, some research has suggested that the test may yield incorrect results in 13% of patients² — an issue that may ultimately impact their outcomes.

The studies that have been conducted so far have not been rigorous enough to justify using such tests in patients with thin melanoma, the authors stated. “What we have are papers that basically give us some data with protocols, and there are no studies that actually are outcome studies, that are randomized, that give us direction on what to do with results,” said Carrie L. Kovarik, MD, an associate professor of dermatology at the Hospital of the University of Pennsylvania in Philadelphia and the lead author of the article.

She noted that such randomized studies have, for example, been conducted in early-stage breast cancer, showing that GEP testing does indeed improve clinical decision-making in this group of patients.³

In thin melanoma, a noninvasive test could, in theory, help identify patients who have a high risk of metastasis and steer their doctors toward a tailored management plan that could potentially save lives. But attempts to develop a GEP test to tackle this task have not yielded strong evidence to support its clinical use, argue the authors of the article.

The 31-gene expression profile (GEP) test that is currently available, developed by Castle Biosciences, classifies patients with regard to their risk of metastasis into 3 categories. Patients in class 1A are estimated to have the lowest risk of metastasis, those in class 1B/2A are estimated to have intermediate risk, and those in class 2B are estimated to have high risk.

The 5-year distant metastasis–free survival (DMFS) rate for patients with stage I/II disease in class 1A is 97% and 65% for patients in class 2B. One common problem that the availability of such information may address is whether to perform a sentinel lymph node biopsy in a specific patient with thin melanoma.

But the authors of the viewpoint article pointed out that most studies that have so far looked at 31-GEP testing in melanoma have been retrospective or prospective, and did not involve a comparator group.⁴ Previous research showed a sensitivity of 21% and a specificity of 90% for DMFS in T1 melanomas, with a positive predictive value for 31-GEP of 10%.² The same research, which involved modeling test characteristics in T1 melanoma based on data from a previous study,⁵ suggested that merely 1% of patients would be given correct information about being at high risk for metastasis, whereas as many as 13% would get an incorrect result — a false positive or false negative — based on the test.²

Incorrect results may have consequences for patients’ outcomes. “You can imagine being told that you have a thin melanoma and a positive test,” Dr Kovarik said. “So in that case you’re really worried that you’re going to get metastatic melanoma, whereas in reality you’re not.” Getting a negative result that should have been positive may, on the other hand, give a patient a false sense of assurance, she added.

And even if a test yields a true result indicating that a patient is at risk for metastasis, it is not clear how physicians should respond to it. “There are no studies telling me what to do,” Dr Kovarik said. “So it puts us in a really tough position.”

The authors also called attention to the high cost of the test, with Medicare coverage of $7193 per test.

Douglas Grossman, MD, PhD, a professor of dermatology at the University of Utah in Salt Lake City, who was not involved in the viewpoint article, agreed with the authors’ stance on GEP testing in thin melanoma. “I agree that we don’t have sufficient evidence yet for use of GEP tests in [patient] management, particularly in the early-stage patients,” he said.

References

1. Kovarik CL, Chu EY, Adamson AS. Gene expression profile testing for thin melanoma: evidence to support clinical use remains thin [published online April 15, 2020]. JAMA Dermatol. doi: 10.1001/jamadermatol.2020.0894
2. Marchetti MA, Bartlett EK, Dusza SW, Bichakjian CK. Use of a prognostic gene expression profile test for T1 cutaneous melanoma: will it help or harm patients? J Am Acad Dermatol. 2019;80(6):e161-e162.
3. Cardoso F, van’t Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729.
4. Berman B, Ceilley R, Cockerell C, et al. Appropriate use criteria for the integration of diagnostic and prognostic gene expression profile assays into the management of cutaneous malignant melanoma: an expert panel consensus-based modified Delphi process assessment. Skin (Los Angeles). 2019;3(5):291-306.
5. Gastman BR, Gerami P, Kurley SJ, et al. Identification of patients at risk of metastasis using a prognostic 31-gene expression profile in subpopulations of melanoma patients with favorable outcomes by standard criteria. J Am Acad Dermatol. 2019;80(1):149-157.e4.