Abstract
SummaryBackgroundThe updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high‐risk stage I tumour subsets.ObjectivesTo determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma.MethodsPeritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas.ResultsDecreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7‐year disease‐free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi‐quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low‐risk group (n = 239) vs. 85·4% in the AMLo high‐risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69–9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93–9·56; P = 0·068) in stage IB patients.ConclusionsLoss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high‐risk tumour subsets independently of Breslow depth. What's already known about this topic? There is an unmet clinical need for biomarkers of early‐stage melanoma.Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor.Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation.The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow‐up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs.
Highlights
Melanoma is one of the most devastating skin cancers, with a worldwide incidence that continues to climb [1], [2]
Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 American Joint Committee on Cancer (AJCC) I tumours was associated with 81.5% 7-year disease free survival (DFS) versus 100% survival with maintained AMBRA1; P
Sub-cohort, multivariate analysis revealed the AMLo hazard ratio of 4.04 ((95% CI 1.69-9.66) P = 0.002), is a stronger predictor of DFS than Breslow depth (multivariate analysis 2.97 P = 0.068) in AJCC stage IB patients
Summary
Melanoma is one of the most devastating skin cancers, with a worldwide incidence that continues to climb [1], [2]. The recently updated 8th edition AJCC guidelines came into effect in January 2018 [4], with removal of mitotic count and reduction of Breslow depth for stage IA melanomas to 0.8mm. These criteria are still unable to reliably identify which individuals with seemingly low risk early melanomas are at specific risk of disease progression; occurring in up to 15% of patients with AJCC I melanoma [4, 5]. An urgent unmet need for credible prognostic biomarkers able to identify patients with high risk early stage melanomas, facilitating appropriate counselling and follow up (including guidance on appropriate need for sentinel lymph node biopsy (SLNB)) or access to clinical trials and potentially adjuvant systemic treatment [6, 7], remains
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