Prevalence of FOXA1 and ERBB2 activating mutations in extramammary Paget's disease: A retrospective multicenter analysis of 99 cases from Japanese and Taiwanese cohorts

Background: Extramammary Paget's disease (EMPD) occurs in areas where apocrine glands are abundant. EMPD is associated with the known somatic hotspot mutation g.chr14:38064406 G>A in the promoter region of FOXA1 and S310F in ERBB2. Whether EMPD patients in non-Japanese populations have FOXA1 driver mutations remains undetermined, and the relationship between the clinical characteristics of EMPD patients and the presence of somatic FOXA1 driver mutations has yet to be investigated. Objective: To assess the prevalence and clinical significance of the FOXA1 and ERBB2 hotspot somatic mutations. Methods: Surgical specimens from 99 EMPD patients who underwent surgery from January 2013 to March 2024 were collected from five facilities in Japan and Taiwan. To detect the somatic mutations, amplicon sequencing was performed for FOXA1, and ddPCR was conducted for ERBB2. Immunohistochemical analysis for FOXA1 was performed on 38 samples. Results: The frequencies of the FOXA1 (g.chr14:38064406 G>A) mutation and the ERBB2 S310F mutation were 8/93 (8.6 %) and 37/93 (40.0 %), respectively, among the non-fresh-frozen specimens. FOXA1 somatic hotspot mutation-positive cases were found at all five medical institutions. Regardless of the mutational status of the FOXA1 promoter mutation, all examined cases immunohistochemically exhibited strong FOXA1 expression in the Paget cell nuclei. No significant correlation was found between the FOXA1 somatic mutation or the ERBB2 somatic mutation and any clinical parameter. Conclusion: The FOXA1 somatic hotspot mutation was found in both Japanese and Taiwanese EMPD patients. We cannot rule out the possibility that FOXA1 might be a potential target for EMPD therapies in Japan and Taiwan.