High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma. (18th August 2021)

• Record Type: Journal Article
• Authors: Westphal, D.; Garzarolli, M.; Sergon, M.; Horak, P.; Hutter, B.; Becker, J.C.; Wiegel, M.; Maczey, E.; Blum, S.; Grosche‐Schlee, S.; Rütten, A.; Ugurel, S.; Stenzinger, A.; Glimm, H.; Aust, D.; Baretton, G.; Beissert, S.; Fröhling, S.; Redler, S.; Surowy, H.; Meier, F.
• Is Part Of: British journal of dermatology. Volume 185:Number 6(2021)
• Page Start: 1186
• Page End: 1199
• Publication Date: 2021-08-18
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.20604
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate. Objectives: To investigate the drivers of EPC progression. Methods: We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient‐derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens. Results: mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer‐relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1 / PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen‐activated protein kinase kinase 1; also known as MEK1 ) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient‐derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR‐directed therapy and immune checkpoint inhibition for more than 2 years. Conclusions: Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC. Abstract : What is already known about this topic? Eccrine porocarcinoma (EPC) is a rare skin cancer with a largely unknown aetiology and molecular makeup. In cases not amendable by surgery, no effective treatment is available. What does this study add? Using comprehensive genomic and transcriptomic profiling, aberrations in cancer‐relevant signalling pathways were identified that could not only be validated functionally in a newly established patient‐derived culture model but could also be confirmed in a larger series of retrospective cases. Importantly, these observations were translated into treatment regimens resulting in substantial clinical benefit in a patient with metastatic EPC. What is the translational message? Here, we provide an excellent example of how from‐bedside‐to‐bench and back can work. We not only detected relevant genetic aberrations in EPC, but also confirmed their functional relevance and their transferability to additional cases, culminating in effective treatment of the patient. We thus provide new therapeutic options for EPC and possibly other adnexal carcinomas with similar molecular makeup. Plain language summary available online