Human epidermal growth factor receptor 2 amplification as a biomarker for treatment in patients with lymph node‑metastatic penoscrotal extramammary Paget's disease

Abstract

The role of human epidermal growth factor receptor 2 (HER2) amplification as a biomarker for treatment in patients with lymph node (LN)-metastatic penoscrotal extramammary Paget's disease (EMPD) was investigated in the present study. A total of 11 male patients with LN-metastatic penoscrotal EMPD were retrospectively reviewed. Positron emission tomography/computed tomography (PET/CT) was conducted prior to surgery. Immunohistochemistry and fluorescence in situ hybridization were used to evaluate HER2 gene amplification in LN samples. Sanger sequencing was used to investigate HER2 mutations. A literature review of the prevalence of HER2 amplification in EMPD and the efficacy of HER2-targeted therapy was also undertaken. PET/CT is effective in detecting metastatic sites. The sensitivity and specificity of PET/CT was 90.9 and 100.0% for inguinal LNs, and 85.7 and 80.0% for pelvic LNs, respectively. The median time from LN dissection to disease progression was 15.9±1.5 months. Of the 11 patients, 3 (27.3%) indicated HER2 amplification. Patients with HER2 amplification showed shorter median times from disease discovery to LN metastasis (HER2 amplification vs HER2 non-amplification; 15.6 vs. 10.0 months; P=0.50) and from LN dissection to disease progression (HER2 amplification vs. HER2 non-amplification, 16.2 vs. 13.6 months; P=0.11). However, the aforementioned observations were not indicated to be statistically significant. No HER2 mutations were identified. Trastuzumab, a HER2-targeted monoclonal antibody, was administered to 2 of the patients with HER2 amplification. A literature review of the prevalence of HER2 amplification in EMPD and the efficacy of HER2-targeted therapy showed similar results. Altogether, 485 cases of EMPD were reported, 35 of which had metastases. The results in the present study suggest that PET/CT should be used on all metastatic EMPD patients. EMPD may be effectively treated with trastuzumab. The present study and case reports from the literature provide evidence for the benefit of testing for HER2 amplification in this rare disease and highlight the requirement for a multicenter clinical trial to assess the impact of trastuzumab therapy in treating this disease.

<p>Response to Pyrotinib in a Chinese Patient with Bone-Metastatic Scrotal Paget’s Disease Harboring Triple Uncommon HER2 Mutation: A Case Report</p>

“…Previous studies reported that 15-60% of patients with EMPD harbor HER2 amplification or overexpression. 7 And Her2-targeted trastuzumab monotherapy for EMPD patients has been described as clinical benefit with median progression-free survival (mPFS) from 6 to 12-17 months. 13,14 However, the efficacy of HER2-targeted trastuzumab in advanced EMPD patients with HER2 mutation is limited, due to the therapeutic efficacy of trastuzumab is dependent on the HER2 overexpression and gene amplification of HER2.…”

“…13,14 However, the efficacy of HER2-targeted trastuzumab in advanced EMPD patients with HER2 mutation is limited, due to the therapeutic efficacy of trastuzumab is dependent on the HER2 overexpression and gene amplification of HER2. 7 Therefore, trastuzumab combined with paclitaxel is effective, which has been recommended for those EMPD patients with HER2 amplification or overexpression. 9 Figure 2 Next-generation sequencing (NGS) showed HER2 R678Q in exon 17, S310Y in exon 8 and S310F in exon 8; triple HER2 mutations could be observed in tissue and ctDNA.…”

“…5 Besides, previous studies reported that 20.7% of EMPD patients exhibited HER2 amplification and the probability of HER2 amplification was more notable in patients with metastatic EMPD. 6,7 Extensive local excision of the skin and subcutaneous tissue with immediate reconstruction is the main method for the treatment of EMPD. 8 Multidisciplinary comprehensive treatment may be a reasonable choice for invasive Paget's disease.…”

HER2-Targeted Antibody–Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget’s Disease Models: In Vivo and Immunohistochemical Analyses

“…More than 15 case reports have addressed HER2-targeted therapies against EMPD [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Most of the cases are EMPD with HER2 overexpression evaluated by IHC.…”

“…Concerning anti-HER2 treatments for EMPD, Vornicova et al reported the HER2-targeted drug lapatinib to be effective against HER2-positive EMPD [ 13 ]. Further, several case reports have shown the HER2-targeted antibody trastuzumab alone or with cytotoxic chemotherapies to be effective against metastatic or advanced EMPD in ERBB2 -mutant or HER2/ ERBB2 -overexpressed cases ( Supplemental Table S1 ) [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Notably, Nordmann et al reported an EMPD tumor harboring the ERBB2 S310F mutation that was sensitive to anti-HER2 treatment, with the patient achieving a near-complete response by a combination treatment of trastuzumab and carboplatin [ 24 ].…”