Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.

PURPOSE

To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva.

METHODS

We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore.

RESULTS

Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in (n = 9; 35%), (4 mutations and 3 copy number alterations; 27%), and (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression.

CONCLUSION

EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations ( or ) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.