Mutational landscape of advanced extramammary Paget disease with comprehensive genomic profiling tests: A cohort study in a Japanese real-world setting

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy, and unresectable or metastatic cases are challenging to treat due to high recurrence rates with existing chemotherapy.1,2 Previous studies on EMPD genetic alterations have mainly reported the involvement of HER2 overexpression and the PI3K/AKT/mTOR pathway.1,3-5 However, due to its rarity, genetic alterations in metastatic cases remain underresearched. This study aimed to investigate genetic alterations as potential therapeutic targets and their clinical implications in EMPD using comprehensive genomic profiling test results.

This retrospective cohort study used comprehensive genomic profiling test results of patients with primary EMPD submitted in Japan, sourced from the Center for Cancer Genomics and Advanced Therapeutics database, between June 2019 and November 2022. In Japan, comprehensive genomic profiling test can only be used in patients lacking appropriate standard treatment or those with poststandard treatment and in EMPD patients with unresectable or metastatic disease. Patient data were recorded at test submission.

Seventy five patients were registered, most having metastasis (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/3fbmvp6swp/1). Genetic analysis revealed the most frequently altered genes as CDKN2A, CDKN2B, ERBB2, MTAP, TP53, and ERBB3 (Fig 1). Thirteen percent of the cases had high tumor mutation burden. There was no microsatellite instability–high classification.

The Gene Ontology enrichment analysis using Metascape (https://metascape.org/) on the top 32 genes with alterations in 7 or more cases revealed that altered genes were significantly associated with the PI3K signaling pathway (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/3fbmvp6swp/1). These findings, consistent with previous literature, support the involvement of the PI3K/AKT/mTOR pathway in the pathogenesis of EMPD. We did not observe any specific characteristics of genetic alterations associated with previous chemotherapy.

Focusing on oncogenic mutations, CDKN2A, CDKN2B, ERBB2, TP53, ERBB3, and PIK3CA were the most common (Fig 2). Slightly different from previous literature,3 on receptor tyrosine kinases, ERBB3 mutations were observed irrespective of ERBB2 alterations, whereas FGFR1 amplifications were seen exclusively in cases without ERBB2/ERBB3 alterations. PIK3CA, STK11, and PTEN mutations, associated with the PI3K/AKT/mTOR pathway, occurred in a mutually exclusive manner. CDKN2A and TP53 alterations, which are part of the cell cycle pathway, were detected in 81% of the cases. Notably, CDKN2A alteration frequency (68%) was double of that reported in a previous study (34%),3 which might suggest its significant role in EMPD progression given our cohort’s metastatic emphasis.

Actionable genetic alterations with an evidence level of D or higher were identified in 65% of the cases. The treatment recommendations primarily included pembrolizumab for tumor mutation burden–high cases; HER2-targeted therapies for ERBB2 alterations; PI3K, mTOR, or AKT inhibitors for PIK3CA alterations; mTOR inhibitors for PTEN alterations; and FGFR inhibitors for FGFR1 amplifications (Supplementary Table II, available via Mendeley at https://data.mendeley.com/datasets/3fbmvp6swp/1).

In examining correlations between specific mutations and metastatic sites, NBN amplifications and KDR mutations were significantly associated with bone and lung metastasis, respectively (Supplementary Fig 2, available via Mendeley at https://data.mendeley.com/datasets/3fbmvp6swp/1; Fisher exact test, P < .01).

Our study observed oncogenic alterations in receptor tyrosine kinases (ERBB2, ERBB3, and FGFR1) and their downstream PI3K/AKT/mTOR pathway, suggesting their pathogenic involvement and therapeutic potential. Although our cohort primarily comprised metastatic cases in Japan, potentially limiting the findings’ generalizability, our analysis provides valuable insights into EMPD tumorigenesis and potential therapeutic targets.

References

  1. Fukuda, K. ∙ Funakoshi, T. Metastatic extramammary Paget’s disease: pathogenesis and novel therapeutic approach Front Oncol. 2018; 8:38

  2. Hashimoto, H. ∙ Kaku-Ito, Y. ∙ Furue, M. ... The outcome of chemotherapy for metastatic extramammary Paget’s disease J Clin Med. 2021; 10:739

  3. Ishida, Y. ∙ Kakiuchi, N. ∙ Yoshida, K. ... Unbiased detection of driver mutations in extramammary Paget disease Clin Cancer Res. 2021; 27:1756-1765

  4. Stasenko, M. ∙ Jayakumaran, G. ∙ Cowan, R. ... Genomic alterations as potential therapeutic targets in extramammary Paget’s disease of the vulva JCO Precis Oncol. 2020; 4, PO.20.00073

  5. Kiniwa, Y. ∙ Yasuda, J. ∙ Saito, S. ... Identification of genetic alterations in extramammary Paget disease using whole exome analysis J Dermatol Sci. 2019; 94:229-235

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