Faculty Bibliography

Gene expression profiling (GEP) is making a significant impact in dermatology by providing molecular insights that complement traditional diagnostic methods for skin cancer and inflammatory dermatoses. GEP evaluates messenger RNA levels to identify disease-specific patterns that can aid in diagnosis, prognostication, and/or treatment planning. Currently, commercially available tests for melanoma and cutaneous squamous cell carcinoma are available. The development of GEP tests follows a stepwise process, including discovery, validation, and clinical implementation. Despite challenges such as cost and the need for further prospective studies, advancements in GEP hold promise for supporting more personalized approaches to patient care.

BACKGROUND:High-risk cutaneous squamous cell carcinomas (HRCSCC) have an increased likelihood of poor outcomes following surgery. Adjuvant radiation therapy (ART) may decrease this risk; however, there is limited data on its efficacy. OBJECTIVE:To evaluate whether ART is associated with reduced risks of local recurrence, locoregional recurrence, nodal metastasis, and disease-specific death in localized, fully resected HRCSCC. METHODS:A retrospective, multicenter cohort study was conducted. Competing risk modeling was performed to evaluate ART, controlling for patient, tumor, and treatment factors. RESULTS:This study included 1,267 HRCSCC, of which 155 (12.2%) received ART. ART was associated with a 50% reduction in the risk of local recurrence (CHR=0.47; 95% CI: 0.23, 0.96; p=0.04), locoregional recurrence (CHR=0.47; 95% CI: 0.26, 0.83; p=0.01), and nodal metastasis (CHR=0.45; 95% CI: 0.21, 0.98; p=0.04). The effect on disease-specific death was small and not statistically significant (CHR=0.83; 95% CI: 0.35, 1.94; p=0.66). In modeling, ART decreased the estimated 5-year cumulative incidence of local recurrence from 11.9% (95% CI, 9.4%-14.0%) to 5.9% (2.8%-9.8%), of locoregional recurrence from 17.8% (15.1%-20.3%) to 9.0% (5.1%-13.6%), and of nodal metastasis from 9.5% (7.3%-11.2%) to 4.6% (1.7%-8.5%). A subset of HRCSCC at greatest risk of poor outcomes was identified and comprised of tumors that were Brigham and Women's Hospital (BWH) stage T3, BWH stage T2 tumors with three risk factors, and/or tumors with lymphovascular invasion. Among these 246 HRCSCC, 74 (30.1%) received ART, and ART was associated with a decreased risk of locoregional recurrence (CHR=0.48; 95% CI: 0.26, 0.89; p=0.02) and nodal metastasis (CHR=0.43; 95% CI: 0.19, 0.97; p=0.04). On modeling, this subgroup experienced greater absolute reductions in the estimated 5-year incidence of locoregional recurrence from 36.6% (95% CI, 30.0%-45.3%) to 20.0% (11.1%, 31.1%) and of nodal metastasis from 21.1% (17.4%-30.9%) to 9.6% (4.2%-18.1%). CONCLUSION/CONCLUSIONS:In this retrospective multicenter cohort of HRCSCC, adjuvant radiation was associated with reduced risks of local recurrence and nodal metastasis. Prospective studies are required to further characterize the effect of adjuvant radiation on HRCSCC.

PURPOSE/OBJECTIVE:Patients with stage II and resected stage III melanomas have variable clinical outcomes, evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease), has created a pressing need to develop biomarkers to accurately distinguish patients at low- versus high-risk for recurrence and death from melanoma. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues/fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would more accurately classify 5-year survival outcomes than clinical factors alone. PATIENTS AND METHODS/METHODS:Using a Nanostring miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium, and examined associations between miRNA expression and melanoma-specific death. RESULTS:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve (AUC) for stage II patients from 0.71 for a 'clinical factors-only' model to 0.81 for a 'clinical plus miRNA' model in an independent test set, an improvement of 0.10 with 95% CI (0.03, 0.19). The improvement was more modest for stage III patients that were included in the analysis. CONCLUSIONS:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models, and potentially aid the selection of melanoma patients for adjuvant treatment and clinical trials.

BACKGROUND:Immunosuppression is associated with a higher risk of developing cutaneous squamous cell carcinoma and more aggressive tumors, but its role as an independent predictor of poor outcomes remains unclear. OBJECTIVE:To determine whether immunosuppression independently predicts poor outcomes in cutaneous squamous cell carcinoma. METHODS:This was a retrospective cohort study with pooled data from 12 international centers. Demographics, immunosuppression status, tumor characteristics, treatment, and outcomes were collected. Univariable and multivariable marginal Fine and Gray competing risk analyses were performed. Subgroup multivariable analyses were performed on the organ transplant and chronic lymphocytic leukemia cohorts. RESULTS:A total of 11,930 patients with 18,760 tumors (14,766 in immunocompetent and 3,994 in immunosuppressed) were included. Immunosuppressed patients had a higher prevalence of high-risk tumor features and poor disease outcomes. On multivariable analysis, immunosuppression was independently associated with local recurrence, distant metastasis, disease-specific death, and major poor outcomes. Organ transplantation was predictive of local recurrence, distant metastasis, and disease-specific death, whereas chronic lymphocytic leukemia independently predicted local recurrence, disease-specific death, and major poor outcomes. LIMITATIONS/CONCLUSIONS:Retrospective design, potential for data heterogeneity. CONCLUSIONS:Immunosuppression is an independent risk factor for major poor outcomes in cutaneous squamous cell carcinoma and should be included in risk nomograms.