Paget’s disease: biomarkers differences between extra-mammary and mammary diseases


Zoran Gatalica, Kelsey Poorman, Gino K. In, Denisa Kacerovska, Božo Krušlin, Jude Senerathne, Elena Florento, & Alexandra Leary


Extra-mammary Paget’s disease (E-MPD) is a rare primary cutaneous carcinoma of uncertain etiology (apocrine, Toker cell, anogenital mammary-like
glands) commonly arising in the vulva, while mammary Paget’s disease (MPD) is a frequent manifestation of intra-epidermal dissemination of an underlying invasive breast carcinoma. The postsurgical recurrence rate in E-MPD is 20–40%, and metastatic E-MPD has a poor survival rate. While there is no standard systemic treatment, cases of EMPD 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.


12 patients (14 samples) with vulvar E-MPD and 10 patients with MPD (areolar) Paget’s disease were available for a comprehensive molecular profiling at
Caris Life Sciences (Phoenix, AZ).

Lesions were examined for mutations using NGS DNA sequencing (Illumina NextSeq) on 592 genes, gene copy number amplification (using NGS or in
situ hybridization/ISH), protein expression (immunohistochemistry/IHC), and fusion events (NGS RNA sequencing, Archer FusionPlex) on 54 genes.

Tumor mutational burden (TMB) was calculated based on the total number of somatic nonsynonymous missense mutations identified per megabase of genome coding area. Threshold for TMB-high was set at ≥10. Microsatellite (MS) instability was evaluated on over 7,000 known MSI loci in target regions. The threshold to determine MSI by NGS was determined to be 46 or more loci with insertions or deletions.

Biomarker results were compared between cohorts using Barnard’s Unconditional Test.


Extra-mammary Paget’s disease shows a distinct molecular profile from mammary Paget’s disease, including lower HER2 overexpression (27% v. 88%) and amplification (22% v. 75%), but higher TOP2A amplification (38% v. 17%).

Over-expression of AR in triple (Her2/ER/PR) negative E-MPD (n=5/6) also suggests a role for androgen inhibitor therapy, analogous to its use in triple negative breast cancer and prostate cancer.

Special note should be taken as ARv7 transcripts, resistance mechanism to AR-targeted therapies, are possible in this setting.

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