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

Abstract

Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.

Identification of Predictive Factors for Post-operative Recurrence and Clinical Outcomes of Primary Vulvar Extramammary Paget Disease

“…A recent in vivo study demonstrated that HER2 over-expression was more frequent in patients with invasive EMPD than in those with in situ or microinvasive EMPD. Treatment with T-DXd or T-DM1 was found to eradicate an EMPD patientderived xenograft model with no recurrence observed after 10 weeks (24). HER2-targeted ADCs may be promising treatment options for patients with ERBB2-mutant or HER2-over-in vivo 37: 2618-2627 (2023) 2623 In addition, genomic and immunohistochemical profiling has revealed that the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is frequently mutated in EMPD, and the androgen receptor (AR) is over-expressed in the majority of the cases (37,38).…”

“…Although the prognosis of noninvasive EMPD is favorable (24), once metastasis occurs, the prognosis worsens (25). Some chemotherapeutic regimens have been proposed for metastatic EMPD; however, no standardized treatments have been established.…”

“…Therefore, prospective studies are warranted to identify predictive biomarkers and novel therapies for advanced EMPD. Given the biological resemblance between EMPD and breast carcinoma (1,24), human epidermal growth factor receptor 2 (HER2) is recognized as a therapeutic target in patients with HER2-positive EMPD. HER2 over-expression has been reported in 15-60% of EMPD cases and correlates with EMPD progression (26,27).…”

Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget’s Disease of the Vulva: A Referral Center Experience

“…The Paget cells were round to columnar with an increased nuclear/cytoplasmic (N/C) ratio and vacuolated cytoplasm. Since HER2 is frequently expressed in genital and anal EMPD (15-60% of cases) [8], a cell block was set-up with residual cellularity and HER2 expression explored by immunocytochemistry in four cases in order to support the diagnosis (Figure 3).…”