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Prognostic Gene-Expression Profiling in Cutaneous Melanoma
abstract
This abstract is available on the publisher's site.
Access this abstract nowImportance
Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.
Objective
To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies.
Evidence Review
The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.
Findings
The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.
Conclusions and Relevance
More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.
Additional Info
Disclosure statements are available on the authors' profiles:
Prognostic Gene Expression Profiling in Cutaneous Melanoma: Identifying the Knowledge Gaps and Assessing the Clinical Benefit
JAMA Dermatol 2020 Jul 29;[EPub Ahead of Print], D Grossman, N Okwundu, EK Bartlett, MA Marchetti, M Othus, DG Coit, RI Hartman, SA Leachman, EG Berry, L Korde, SJ Lee, M Bar-Eli, M Berwick, T Bowles, EI Buchbinder, EM Burton, EY Chu, C Curiel-Lewandrowski, JA Curtis, A Daud, DC Deacon, LK Ferris, JE Gershenwald, KF Grossmann, S Hu-Lieskovan, J Hyngstrom, JM Jeter, RL Judson-Torres, KL Kendra, CC Kim, JM Kirkwood, DH Lawson, PD Leming, GV Long, AA Marghoob, JM Mehnert, ME Ming, KC Nelson, D Polsky, RA Scolyer, EA Smith, VK Sondak, MS Stark, JA Stein, JA Thompson, JF Thompson, SS Venna, ML Wei, SM SwetterFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The national Melanoma Prevention Working Group (MPWG), together with international melanoma specialists, convened to review the three most important gene expression profiling (GEP) tests in melanoma. They have undertaken an analysis of the available data in terms of the prognostic power of such tests. There are currently three major GEP tests that have reported data, in no particular order: DecisionDx (31-GEP by Castle Biosciences), MelaGenix (NeraCare), and the CP-GEP by SkylineDx. Although every GEP test has prognostic power, the MPWG does not support the routine use of GEP in the management of cutaneous melanoma patients at this point in time. In the future, GEP might be able to help select appropriate patients to undergo a sentinel node (SN) procedure or, more importantly, to spare a lot of patients who are low risk from an unnecessary SN procedure. Another potential area of use can be that a GEP might be able to help identify the correct high-risk patients for adjuvant systemic therapy, similar to the current situation for other cancers, such as breast cancer.
This evidence-based review on prognostic melanoma gene expression profiling tests (GEPs; marketed as DecisionDx, Castle Biosciences, and MelaGenix, NeraCare) is written by academic melanoma specialists in the fields of dermatology, surgical oncology, and medical oncology. The review is important because: 1) GEP tests are available for clinical use and are being actively marketed without published guidelines; and 2) there has been substantial controversy in the literature about the tests—a polarization that demonstrates lack of consensus and possible professional bias. This article is a “consensus” (defined as at least 50% agreement) of the Melanoma Prevention Working Group (MPWG) and does not include industry, nonacademic providers, or other related specialties (eg, ophthalmology, which uses melanoma GEP testing as standard of care). These evidence-based guidelines are vital to appropriate clinical transition of GEP testing, yet reflect differing expert opinions, a common characteristic of guidelines created with little prospective data and by individuals from different specialties. The MPWG concludes that the potential value of the test is high, but “there are insufficient data to support routine use,” and “there may be non-scientific elements involved in the adoption of new technologies.” How does one navigate apparent contradictions such as these? The guidelines clearly recommend that melanomas be managed using large evidence-based guidelines (eg, NCCN), but concede that they may be useful in specific cases if current guidelines are insufficient or when additional prognostic information is helpful. GEP test–derived prognostic information may be powerful for patients, but current data do not warrant replacement of sentinel lymph node biopsy with GEP testing. In sum, healthcare providers balance prudence with progress daily and should continue to advocate for their patients, sharing a summary of current evidence from these new guidelines and helping them to make the best-informed decisions about GEP use.
Validity, Value, and Inevitability of Gene Expression Profiling in Melanoma
With advancement in technology—the written word, vaccinations, the internet—dissent inevitably follows, but it is nevertheless disheartening and perplexing that there are still those who oppose advancements despite studies showing effectiveness. The JAMA Dermatology articles reviewed here1,2 presented arguments against 31-GEP testing to assess melanoma prognosis, ignoring 20+ studies demonstrating efficacy and clinical validity.3,4
These JAMA Dermatology articles raise objections about the validity and clinical utility of 31-GEP. However, clinicians have already recognized the value of 31-GEP, ordering over 18,000 tests in the past 12 months.3 In over 20 peer-reviewed studies,3,4 31-GEP has proven capable of assessing melanoma prognosis and augmenting clinical decisions.5 These studies have also shown 31-GEP to identify high-risk melanoma-patient subsets in low-risk groups (thin lesions and sentinel-lymph node biopsy [SLNBx]–negative patients) and to be synergistic when integrated into the AJCC algorithm.5 Multiple studies have actually demonstrated that the results of the tests positively impact management in a risk-appropriate, coordinated, holistic manner, accounting for the entire clinical picture/presentation.4 From these peer-reviewed studies, experts in the field developed appropriate usage guidelines.4
Ironically, the authors of these articles support the use of SLNBx, a controversial procedure with numerous studies suggesting questionable prognostic impact and significant associated morbidity, but reject data from 31-GEP studies (a less costly test with no morbidity). Because of the overwhelming supporting data, this CLIA-approved test is now covered by Medicare for assessing prognosis and determining eligibility for SLNBx.6
For all of these reasons, an objective review of all the associated literature demonstrates that it is no longer a question of “if” or even “when” 31-GEP should be incorporated into clinical practice but rather how best to utilize it.4 As history has shown, every advancement is usually met with opposition. After a careful review of the existing data, truly the only question left here to ask is which side of history would an objective viewer stand?
References