Comparison of the biomarkers for targeted therapies in primary extra-mammary and mammary Paget's disease.
BACKGROUND
Primary Extra-mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known.


METHODS
Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy-relevant protein biomarkers).


RESULTS
Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD-L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a "high" tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable.


CONCLUSIONS
EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD-L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.
['Gatalica|Zoran|Z|', 'Vranic|Semir|S|0000-0001-9743-7265', 'Krušlin|Božo|B|', 'Poorman|Kelsey|K|', 'Stafford|Phillip|P|', 'Kacerovska|Denisa|D|', 'Senarathne|Wijendra|W|', 'Florento|Elena|E|', 'Contreras|Elma|E|', 'Leary|Alexandra|A|', 'Choi|April|A|', 'In|Gino K|GK|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D000971:Antineoplastic Combined Chemotherapy Protocols D014408:Biomarkers, Tumor D001940:Breast D001943:Breast Neoplasms D056915:DNA Copy Number Variations D005260:Female D005784:Gene Amplification D006801:Humans D008297:Male D053842:Microsatellite Instability D008875:Middle Aged D058990:Molecular Targeted Therapy D009154:Mutation D010145:Paget Disease, Extramammary D010144:Paget's Disease, Mammary D057285:Precision Medicine D012189:Retrospective Studies D012611:Scrotum D017422:Sequence Analysis, DNA D012867:Skin D012878:Skin Neoplasms D014844:Vulva
targeted therapy extra-mammary Paget's disease immune therapy molecular profiling