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April 15, 2020

Gene Expression Profile Testing for Thin Melanoma: Evidence to Support Clinical Use Remains Thin

Author Affiliations
  • 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 2Department of Internal Medicine, Dell Medical School, The University of Texas at Austin
  • 3LIVESTRONG Cancer Institutes, The University of Texas at Austin
JAMA Dermatol. 2020;156(8):837-838. doi:10.1001/jamadermatol.2020.0894

Cutaneous melanoma incidence in the US is increasing, with an estimated 96 480 cases in 2019 compared with 47 700 in 2000 (https://seer.cancer.gov). Most cutaneous melanomas are limited to the skin (84%), defined as stage I or II disease by the American Joint Committee on Cancer.1 For all stages combined, 5-year mortality rate is 7.8%, but mortality is more likely when cutaneous melanoma has metastasized to lymph nodes or organs (stage III or IV).1

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    1 Comment for this article
    Physicians who use GEP understand how to manage melanoma patients based on risk
    Federico Monzon, M.D. | Castle Biosciences
    The text below was submitted to this journal as a letter to the editor but was rejected with the suggestion to post in this space.

    Dear Editor,

    In regard to the viewpoint from Dr. Kovarik and colleagues1 concerning the evidence to support clinical use of gene expression profiling for melanoma we would like to comment.

    First, we’d like to note that over 4,300 providers used the DecisionDx-Melanoma gene expression profile (31-GEP) for managing melanoma patients within the past 12 months, which runs counter to the argument, made by the authors, that it is difficult for clinicians to
    determine the clinical action that should follow a test result. In fact, management changes made by clinicians based on test results have been reported in a prospective study,2 demonstrating that these clinicians know what to do when patients are stratified as low or high risk. Indeed, clinical guidelines for melanoma indicate that management should be based on risk of recurrence,3 and thus follow up, surveillance imaging and specialty referral are all decisions based on a patient’s individual risk, whether that risk is based on clinical, pathologic or molecular features.

    Kovarik et al. also contend that the 31-GEP test should be validated in a randomized clinical trial (RCT), such as was done for GEP testing for breast cancer, without considering the different intended uses for these tests. The breast cancer GEP was validated as a response predictor with the goal of removing patients from chemotherapy. Any test that predicts response to a therapy should indeed be validated in an RCT. However, under the Strength of Recommendation Taxonomy (SORT) criteria, used by the American Academy of Dermatology (AAD) melanoma guideline, a prognostic test does not require an RCT to achieve the highest level of evidence. This is also reiterated when discussing the sentinel lymph node biopsy prognostic procedure in AAD’s melanoma guideline.4

    Regarding the evidence behind the test, the authors state that the majority of studies have been retrospective or prospective studies without a comparator group. As discussed above, a comparator group is not required in the assessment of prognostic tests. Furthermore, to date, there are three retrospective studies, five prospective studies and two recent meta-analyses, all reporting consistent results and demonstrating that the test is an independent prognostic factor that provides information as an adjunct to staging factors alone.5

    We appreciate the opportunity to comment on this important topic.


    Federico A. Monzon, M.D.
    Chief Medical Officer

    Robert A. Cook, Ph.D.
    Vice President, Research & Development

    Both authors are employed and hold stock options in Castle Biosciences, Inc

    1. Kovarik et al. JAMA Dermatol. 2020 Apr 15. doi: 10.1001/jamadermatol.2020.0894
    2. Dillon LD, et al. SKIN J Cut Med 2018 Mar;2(2):111-121. doi: 10.25251/skin.2.2.3
    3. Coit DG, et al. Cutaneous Melanoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.
    4. Swetter SM, et al. J Am Acad Dermatol. 2019 Jan;80(1):208-250. doi: 10.1016/j.jaad.2018.08.055
    5. Greenhaw BN, et al. J Am Acad Dermatol. 2020 Mar 27. pii: S0190-9622(20)30475-8. doi: 10.1016/j.jaad.2020.03.053
    CONFLICT OF INTEREST: Employee and stock/option holder at Castle Biosciences