Association of genetic alterations with prognosis in extramammary Paget disease: insights into the involvement of somatic CDKN2A variants in patients with a poor prognosis

Background Previous studies have reported the mutational landscape in extramammary Paget disease (EMPD); however, the prognostic implications of genetic alterations remain unexplored. While CDKN2A loss is known to be associated with tumour progression or poor prognosis in some types of cancer, its significance in EMPD has not been investigated. Objectives To examine the association between common genetic alterations and prognosis in EMPD. Methods A retrospective cohort study was carried out to analyse the data of patients with EMPD registered up to January 2024 in the Center for Cancer Genomics and Advanced Therapeutics database, a nationwide database that records clinical data and comprehensive genomic profiling (CGP) test results in Japan. Results A total of 167 patients with EMPD were recorded in the database, with CDKN2A loss being the most frequent genetic variant. Survival analysis was conducted on data from 127 patients. Survival from the initiation of chemotherapy was analysed, adjusting for length bias inherent in the database with the Kaplan-Meier estimator, an established method of adjustment. Patients with BRCA2-mutant tumours (n = 18) had a worse prognosis than those with BRCA2 wildtype (WT) tumours [n = 109; hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.46-6.01 (P = 0.003)]. Additionally, patients in the CDKN2A mutant group (n = 72) had a significantly worse prognosis compared with those in the CDKN2A WT group [n = 55; HR 1.81, 95% CI 1.06-3.07 (P = 0.029)]. Most CDKN2A variants were pathogenic, primarily characterized by loss, while most BRCA2 variants were variants of uncertain significance. In the survival analysis of CGP enrolment based on Eastern Cooperative Oncology Group performance status (ECOG-PS), patients with an ECOG-PS of 1 at the time of CGP enrolment had a significantly poorer prognosis compared with those with an ECOG-PS of 0 (P = 0.034; median survival time 531 vs. 259 days). Conclusions A somatic CDKN2A variant, mainly exhibiting loss, may be associated with a poor prognosis in EMPD. Patients with EMPD with BRCA2-mutant disease might also have a worse prognosis. In addition, CGP testing before ECOG-PS deteriorates is preferable, considering that the observed median survival of individuals undergoing CGP tests in an ECOG-PS 1 condition was < 9 months.