https://orcid.org/0000-0002-0458-044X
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 [Citation1]. Trastuzumab targets HER-2 and is the approved first-line therapy for HER-2-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 [Citation1]. 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 [Citation1].
The authors highlight the potential of T-DXd in the management of HER-2 positive cancers [Citation1]. 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 [Citation2]. EMPD is usually associated with a favorable prognosis with surgery or topical agents, leading to an overall five-year survival of 75% to 95% [Citation2], but invasive disease leading to progression and metastasis portends a poorer prognosis [Citation2]. Systemic therapy is often warranted in the presence of metastasis but often with inconsistent results [Citation2]. 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 [Citation3]. The incidence of HER-2 overexpression in EMPD has been found to be 15–65% [Citation4–6]. A meta-analysis found the expression of HER2 to be 32% and 26% in female and male patients, respectively [Citation7]. 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 [Citation4]. 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 [Citation8,Citation9]. 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 [Citation6]. 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 [Citation10,Citation11]. 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 [Citation12].
HER-2 positivity is associated with shorter median time from diagnosis to lymph node metastasis [Citation4]. 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) [Citation13]. 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 poor outcomes [Citation7]. In regard to HER-2 congruency, there were no differences in the degree of HER-2 positivity between the primary tumors and lymph node metastases in 85% of cases. However, since some cases showed discrepancies, the authors of this study recommend confirming HER-2 status at both the site of primary tumor and lymph node metastasis [Citation14]. Measures such as ultrasound-guided aspirative cytology and sentinel lymph node biopsy have utility in the early detection of metastases and therapeutic management [Citation7].
Given the overall rarity of EMPD, little is known about prognostic factors and optimal therapy [Citation2]. Thus, there are a limited number of reported cases documenting the use of trastuzumab in EMPD. However, in the context of the relationship between metastatic EMPD and HER-2 and the evolving use of HER-2-targeted therapies, we highlight the potential therapeutic impact and need for further study of trastuzumab and T-Dxd in the treatment of HER-2-positive neoplasms such as EMPD.
Declaration of interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed involvement with Advanced Accelerator Applications, Alphasites, AstraZeneca, Bayer, Best Doctors, Celldex, Curium, Decision Resources, Inc., Defined Health, Eisai Pharmaceuticals, Exelixis, Inc., Genentech, Inc (Roche Holding), Gerson Lehrman Group, Inc., Guidepoint Global, Health Advances, IPSEN Innovation
Lexicon Pharmaceuticals, Inc., MEDACorp (Leerink Swann & Co), PPD, Inc., Pfizer Inc., QED, Quintiles-Iqvia, Schlesinger Associates, Shionogi Pharma, Society for Immunotherapy of Cancer, Sun Biopharma, Taiho, Ultimate Medical Academy and Xcenda, LLC (AmerisourceBergen Corp). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
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References
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