Association of a 40-Gene Expression Profile With Risk of Metastatic Disease Progression of Cutaneous Squamous Cell Carcinoma and Specification of Benefit of Adjuvant Radiation Therapy

Abstract

PurposeAdjuvant radiation therapy (ART) for cutaneous squamous cell carcinoma (cSCC) is recommended based on a number of wide-ranging clinicopathologic features, which encompass a broad array of patients. The 40-gene expression profile (40-GEP) test classifies cSCC tumors into low (Class 1) or higher (Class 2A) or highest (Class 2B) risk of nodal and/or distant metastasis. This study's hypotheses are 1) local recurrence is associated with metastatic disease progression, and 2) 40-GEP, by identifying high risk for metastasis, could predict a metastasis-specific benefit from ART. MethodsSamples were obtained from 920 patients (ART-untreated: 496 Class 1, 335 Class 2A, 33 Class 2B; ART-treated: 11 Class 1, 35 Class 2A, 10 Class 2B) who were matched on clinical risk factors and stratified by ART status, to create 49 matched patient strata. To control for the variety of characteristics and treatment selection bias, randomly sampled pairs of matched ART and non-ART patients comprising 10,000 resampled cohorts were each analyzed for 5-year metastasis-free survival and predicted time to metastatic event. ResultsOf 96 patients experiencing local recurrence, 56.3% experienced metastasis; of those experiencing both, 88.9% had local recurrence before (75.9%) or concurrently (13.0%) with metastasis. After matching for clinicopathological risk, median 5-year disease progression rates for resampled cohorts demonstrated approximately 50% improvement for Class 2B ART-treated as compared to ART-untreated cohorts. Class 2B ART-treated cohorts had a 5-fold delay in predicted time to metastatic event and deceleration of disease progression as compared to ART-untreated cohorts (Kolmogorov-Smirnov test, p<0.01); this was not observed for Class 1 or 2A patients (p>0.05 for each). No risk factor or staging system combined with ART status identified groups that would benefit from ART as well as 40-GEP. Conclusion40-GEP identifies patients at highest risk of nodal/distant metastasis who may derive greatest benefit from ART, as well as patients who may have clinical indications for ART but are at low risk of metastasis. Compared to current guidelines, 40-GEP could provide greater specificity concerning the benefit of ART in individual patients.