Abstract
Introduction and Objectives: Extra-mammary Paget disease (E-MPD) is a rare primary cutaneous carcinoma of uncertain etiology (apocrine, anogenital mammary-like glands) commonly arising in the vulva, while mammary Pagetu2019s disease (MPD) is a frequent manifestation of intra-epidermal dissemination of an underlying invasive breast carcinoma. The post-surgical recurrence rate in E-MPD is 20u201340%, and metastatic E-MPD has a poor survival rate. While there is no standard systemic treatment, cases of E-MPD with amplified ERBB2/HER2 have been successfully treated with Trastuzumab, alone or in combinations. However, HER2 amplification is overall rare in E-MPD, and most cases are triple (ER/PR/HER2) negative E-MPD. Methods and Patients: 14 specimens from 12 patients with primary vulvar (E-MPD) and 9 patients with mammary (areolar) Pagetu2019s disease (MPD) were molecularly profiled using immunohistochemistry, in-situ hybridization and massively parallel gene sequencing (NGS) (Caris Life Sciences, Phoenix, AZ) to detect potentially targetable alterations. Total mutational burden (TMB) and microsatellite instability (MSI) were calculated from NGS data. Results: E-MPD comprised approximately 3.5% of all vulvar malignancies in a retrospective database of tumors (Caris Life Sciences). Her2 by IHC was significantly overexpressed in MPD (n=6/7) as compared to E-MPD (n=3/11) (p=0.019). HER2 gene amplification was significantly higher in in MPD (n=5/7) compared to E-MPD (n=1/8) (p=0.035). TOP2A amplification was higher in E-MPD (n=3/7) (one co-amplified with HER2) than in MPD (n=1/7), but the difference was not significant. Androgen receptor (AR) overexpression was seen in both cohorts (n=10/12 E-MPD and n=6/7 MPD). Estrogen receptor (ER) and Progesterone Receptor (PR) were rarely overexpressed in E-MPD (n=3/12 and n=1/12, respectively); overexpression was more common in MPD (n=3/8 and n=2/8, respectively). PIK3CA and TP53 genes were recurrently mutated; PIK3CA mutations were detected in 2 of 7 E-MPD cases and in 3 of 6 MPD cases. TP53 mutations were seen in 3 of 6 E-MPD and 1 of 5 MPD. No gene fusions or EGFRvIII variant transcripts were identified from either cohort (n=8). The ARv7 variant transcript was detected in a single case of E-MPD (n=1/4). No cases of E-MPD expressed PD-L1 in tumor cells (TC 0). TMB in E-MPD varied from 6-12 Mut/Mb, with 2 cases showing TMB>10 Mut/Mb. No patients had MSI. One patient with E-MPD with clinical follow-up data was treated with immune-checkpoint inhibitor therapy, where the best response was stable disease followed by disease progression. Discussion/Conclusions: Extra mammary Pagetu2019s disease shows a molecular profile distinct from mammary Pagetu2019s disease, including lower HER2 over-expression (27% v. 85%) and amplification (12.5% v. 71%), but higher TOP2A gene amplification (42% v. 14%), which may represent a novel therapeutic target in E-MPD. Over-expression of AR in triple- negative E-MPD (Her2-/ER-/PR-; n=5/6) also suggests a role for androgen inhibitor therapy, analogous to its use in triple negative breast cancer and prostate cancer. However, special note should be taken as ARv7 transcripts, a resistance mechanism to AR-targeted therapies, are also possible in this setting. Total mutational burden in E-MPD may indicate a potential biomarker for checkpoint inhibitor therapy in selected cases (TMB>10/Mb).