High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma*

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.

Eccrine Porocarcinoma: A Review of the Literature

“…Moreover, the identified mutational processes were found to be comparable to those observed in melanoma, BCC and SCC, suggesting common mechanisms of tumorigenesis [ 28 ]. In agreement with this study, Westphal et al assessed molecular pathway alterations in EPC and revealed high overall mutational burden, mostly attributable to UV-induced mutational signatures, while they found altered protein expression of p53, as well as significant expression of epidermal growth factor receptor (EGFR) protein and programmed death-ligand-1 (PD-L1) [ 29 ]. The functional relevance of these findings was supported by reports of EPCs responding to anti-PD-1 and anti-EGFR therapy, suggesting that these pathways may serve as oncogenic drivers in EPC [ 30 , 31 ].…”

Diagnosis and Management of Porocarcinoma

“…In the activating mutations, HRAS was detected in 40%. Westphal et al reported the overexpression of the genes EGFR , PAK1 , and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) in PC tumors as assessed by WES, RNA sequencing (RNA-Seq), and comparative genomic hybridization analyses [ 31 ]. Based on this result, they treated the patient with anti-EGFR antibody.…”

Porocarcinoma: Clinical and Histological Features, Immunohistochemistry and Outcomes: A Systematic Review

“…Therapy with cetuximab followed by nivolumab was started, after which disease progression occurred after 7 and 5 months, respectively. MEK inhibitors also inhibited growth and induced apoptosis in the examined PC cell line, making it a potential therapeutic target [ 31 ]. In the last decade, the treatment of melanoma and non-melanoma skin cancer has changed drastically with the implementation of immunotherapies.…”