HEADER. A review in the NEJM surveys diagnosis and management of squamous cell carcinoma. Despite recent non-coverage LCDs, gene expression testing shows promise as an independent predictor of metastatic risk, while the review notes that further prospective validation is needed.
Recently, I reported that MolDx had published a draft non coverage LCD for a gene expression test for squamous cell skin cancer (here) and that Novitas had finalized an LCD with non coverage of the same test (here). The draft LCD is in comment to 7/15.
June 15, 2023, the NEJM publishes a review article on the same topic, squamous cell skin cancer, by Ashley Wysong MD, who was also a first author on a pivotal gene expression paper (Wysong, 2021). NEJM conflict of interest disclosures note that Wysong was a grantee from Castle Biosciences, but did not receive salary support from the grant.
Here's the paragraph where the NEJM review intersects with gene expression profiling. It comes after a discussion of staging systems, where, like the carefully written MolDx LCD, the Brigham system is described as newer and more accurate than the AJCC rules.
Staging systems based on clinical and pathological features alone may be limited in their ability to accurately stratify all patients with cutaneous squamous-cell carcinoma. Gene expression profiling, which uses tumor biology as a prognostic factor, has been shown to be an independent predictor of metastatic risk, with a significantly improved positive predictive value, as compared with traditional staging, and similar negative predictive value, sensitivity, and specificity.[Wysong 2021] A 40-gene expression profile test has been developed and validated to stratify cases of primary cutaneous squamous-cell carcinoma into three classes (1, 2A, and 2B), with event rates for the development of metastasis at 3 years of 8.9%, 20.4%, and 60.0%, respectively.[Wysong]
Since this prognostic test was developed on the basis of retrospective cohorts, validation in a prospective study is needed, as well as additional data on how best to integrate gene expression profiling into clinical practice.
To my eye, the closing (underscored) statement in NEJM is not too far off from what MolDx wrote a few weeks ago in the draft LCD:
Analysis of Evidence (Rationale for Determination)
While the 40-GEP is capable of metastatic risk stratification, it is unclear how GEP-results can be consistently or accurately interpreted in the context of baseline clinicopathologic risk as part of a comprehensive risk assessment to change patient management. Along these lines, the literature presented to date suggests, but does not adopt, a consistent and recommended patient management strategy with regard to follow-up frequency, nodal assessment, and adjuvant therapy for Class 1, 2A, and 2B tumors according to which outcomes could be measured. Most patients receive a Class 1 or 2A result while Class 2B results are rare; therefore, it is important to clearly define the difference in management of patients with a Class 1 vs 2A result and the net benefit. To-date, this has not been done. It is also important to examine the impact of changes in patient management as a result on the 40-GEP on clinical outcomes from larger real-world trials (rather than anecdotal case reports), as misclassification can cause patient harm. Finally, test performance has not convincingly demonstrated superiority to currently available staging tools and clinicopathologic factors in the intended use population. The main concerns are further outlined below....
The draft LCD review and comment period is underway and we'll learn in 6 to 12 months how it turns out.