LAUSR

With strong interest, we read the review article, ‘Trastuzumab deruxtecan in HER-2-positive metastatic breast cancer and beyond’ by Perez et al. The authors summarize the characteristics and recent data regarding the efficacy and safety of trastuzumab deruxtecan (T-DXd), which is emerging as a promising drug in oncologic therapy [1]. Trastuzumab targets HER-2 and is the approved first-line therapy for HER2-positive solid tumors such as gastric cancer and metastatic breast cancer. Perez et al. highlight the newer antibody–drug conjugate T-DXd, which targets HER-2 and may meet an unmet need for patients who develop resistance to trastuzumab [1]. T-Dxd is under active investigation in phase I–II clinical trials for the treatment of other solid tumors, including non-small cell lung cancer as well as HER-2-low tumors [1]. The authors highlight the potential of T-DXd in the management of HER-2 positive cancers [1]. We would like to highlight additional data that support the potential therapeutic role of T-DXd for the treatment of extramammary Paget’s disease (EMPD), another neoplasm with HER-2 expression that was not discussed by Perez et al. EMPD is an intraepithelial adenocarcinoma often involving apocrine gland-bearing locations such as the vulva and perianal area [2]. EMPD is usually associated with a favorable prognosis with surgery or topical agents, leading to an overall five-year survival of 75% to 95% [2], but invasive disease leading to progression and metastasis portends a poorer prognosis [2]. Systemic therapy is often warranted in the presence of metastasis but often with inconsistent results [2]. In addition to surgery and cytotoxic drugs, we would like to suggest that trastuzumab merits further study as a therapy for EMPD and emphasizes other considerations, such as the clinical importance of obtaining HER-2 status and the possibility of combination therapy. HER-2 overexpression in EMPD is linked to amplification of the ERBB2 gene located on chromosome 17q21, as confirmed by fluorescence in situ hybridization [3]. The incidence of HER2 overexpression in EMPD has been found to be 15–65% [4–6]. A meta-analysis found the expression of HER2 to be 32% and 26% in female and male patients, respectively [7]. A retrospective study with a small sample size found that 27.3% (3/11) of patients with EMPD demonstrated HER-2 positivity. Of these three patients, one patient was successfully treated with trastuzumab and paclitaxel combination therapy. Another patient was treated successfully for 5 months without a disease response. HER-3 was later found in this patient’s tumor DNA, which can lead to trastuzumab resistance in breast cancer and EMPD [4]. Another case has also demonstrated the use of trastuzumab and paclitaxel in halting the skin metastases of HER-2-positive EMPD, resulting in necrosis of tumor cells in the dermal nests and lymph vessels as well as halting HER-2 expression [8,9]. After unsuccessful combination of chemotherapy consisting of cisplatin, 5-fluorouracil, and docetaxel administered to a patient with HER-2-positive EMPD involving the lymph nodes, trastuzumab led to partial regression of disease [6]. For cases in which cytotoxic chemotherapy may have had greater adverse effects, such as in elderly patients or those with end-stage renal disease, trastuzumab monotherapy was also found to be effective in two cases of EMPD with moderate to strong HER-2 positivity, with mild-to-moderate side effects such as moderate headaches and fatigue [10,11]. Thus, there have been multiple reports of successful use of trastuzumab in patients with EMPD. Maeda et al. created a preclinical model using mice, which has shown promising results as well. EMPD tissues from the inguinal lymph node metastases of a 78-year-old Japanese female with no significant history were transplanted into mice to create a cell line sharing an identical genomic profile. Specifically, the authors introduced a S310F mutation on the ERBB2 gene, a mutation that was previously shown to be related to HER-2 activation. The use of trastuzumab or laptinab, another HER-2 inhibitor, alone was able to suppress tumor progression. Combination therapy of both trastuzumab and laptinab yielded even greater effects [12]. HER-2 positivity is associated with shorter median time from diagnosis to lymph node metastasis [4]. This finding is supported by Masuguchi et al. demonstrating that strong positivity for HER-2 by immunohistochemistry is associated with invasion and lymph node metastasis (P < 0.02) [13]. A review by Angelico et al. concluded that HER-2 overexpression is found in at least one-third of EMPD lesions and is related to deep invasion, recurrence, nodal metastases, and