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Dear Editor,
Extramammary Paget disease (EMPD) is a rare adenocarcinoma that originates in the apocrine gland–rich skin and usually affects the perineal skin (primary EMPD) or represents the intraepithelial spread of an underlying visceral carcinoma (secondary EMPD). Approximately half of EMPD cases are confined to the epidermis, which was defined as intraepithelial EMPD, and surgery can provide long-term survival, with positive surgical margins being an important factor causing recurrence. Invasive EMPD carries a high rate of recurrence, metastasis, and mortality. Patients with advanced EMPD may be considered for chemotherapy and targeted therapy. However, unfavorable outcomes emphasize the necessity for novel treatment approaches. At present, therapies are customized to target tumors based on specific molecular aberrations. For example, anti-HER2-targeted therapies and novel HER2-targeted antibody-drug conjugate (ADC) therapies are used.
HER2 is overexpressed/amplified in a wide variety of malignancies, and it is associated with a poor prognosis. Studies evaluating HER2 status in EMPD have been conducted, but they have involved a small sample size. The reported rates of HER2 overexpression range from 15% to 60.87% [
1,
2]. Nonetheless, evidence from larger cohorts and multicenter studies remains scarce. The feasibility of trastuzumab-based targeted therapy for advanced EMPD has been mentioned in several case reports [
3], providing a novel idea for clinical treatment strategy, but adjuvant chemotherapy is still necessary to maximize the curative effect of an anti-HER2 monoclonal antibody.
ADC is a therapeutic drug that contains an antigen-specific antibody and a cytotoxic payload, which has been approved for the treatment of solid tumors. Disitamab vedotin (DV), an innovative anti-HER2 ADC, which consists of cytotoxic agent monomethyl auristatin E and HER2 antibodies (hertuzumab) via a valine-citrulline linker, has been approved for HER2-overexpressing locally advanced or metastatic urothelial carcinoma and gastric cancer in China [
4,
5]. The use of DV is also clinically developed for the treatment of other solid tumors, including biliary tract cancer (NCT04329429), non-small cell lung cancer (NCT04311034), and HER2-positive or HER2-low expressing breast cancer, in China [
6]. However, the application of DV in EMPD has not yet been explored.
In assessing the HER2 status and the efficacy of DV in patients with advanced EMPD harboring HER2 expression, we conducted a retrospective study that included a total of 129 cases diagnosed with EMPD from three medical centers. The baseline characteristics of 129 patients with EMPD are presented in Table S1 and supplemental results. The morphological evaluation confirmed the poor fixation quality of the formalin-fixed paraffin-embedded (FFPE) tissue, and cases with insufficient remaining FFPE tissue for HER2 analysis were excluded from our cohort. Finally, HER2 immunohistochemical (IHC) staining was performed in 102 cases. In addition, we embarked on an initial foray into the assessment of the HER2 fluorescence in-situ hybridization (FISH) status in a total of 46 cases. More details are presented in the supplementary method. Two patients with advanced EMPD who failed to respond to previous chemotherapy received HER2-targeted ADC therapy. The response was assessed using the modified RECIST 1.1 criteria, and re-staging scans were performed at least every 3 months to assess response and progression.
HER2 protein expression was detected in 93.1% (95/102) of cases, with scores of 1+, 2+, and 3+ observed in 47.1% (48/102), 37.3% (38/102), and 8.7% (9/102) of cases, respectively (Fig.1, Table S2). The proportion of HER2 2+ and 3+ scores in invasive EMPD was slightly higher than that of intraepithelial EMPD (53.2% vs. 46.8%). A higher frequency of lymph node metastasis was detected in the subgroup of HER2 2+/3+ compared with HER2 1+/0 (66.7% vs. 33.3%, P = 0.034). Meanwhile, the HER2 status did not show a significant difference among patients with different tumor locations and among primary, recurrent, and metastatic lesions (Fig.1). Furthermore, HER2 gene amplification was found in eight cases (17.39%, 8/46), including all cases with IHC 3+ (5/5, 100%), two with IHC 2+ (2/18, 11.1%), and one with IHC 1+ (1/22, 4.5%, Fig.1). Furthermore, five cases of intraepithelial tumor (7.2%, 5/69), one case of superficially invasive tumor (3.1%, 1/32), and two cases of deeply invasive EMPD (7.1%, 2/28) consisted of HER2-amplified subpopulation. In eight matched cases where primary and metastatic lesions were tested, the HER2 status remained consistent (Fig. S1A–S1F, Table S3).
The 5-year disease-free survival (DFS) and overall survival (OS) rates of patients with EMPD were 61.6% and 74.3%, respectively. With regard to survival, superficially invasive EMPD demonstrated similar outcomes and risk values compared with intraepithelial EMPD (DFS: P = 0.730, hazard ratio (HR) = 0.874; OS: P = 0.995, HR = 1.003, Fig.1 and 1E), both of which were superior to deeply invasive EMPD (DFS: P < 0.001, HR = 3.912; OS: P = 0.005, HR = 2.977) according to univariate analysis.
Patients with EMPD who developed lymph node metastasis had a lower 5-year OS rate of 50.2%, compared with 80.2% for those without metastasis. Lymph node metastasis was identified as an independent risk factor for DFS (P < 0.001; HR = 5.073, 95% confidence interval (CI), 2.226–11.557) and OS (P = 0.047; HR = 2.701, 95% CI, 1.014–7.196, Fig.1 and 1G, Tables S4 and S5). Furthermore, in patients with invasive EMPD, those with a HER2 score of 2+/3+ tended to have worse median survival time compared with those with a score of 1+/0 (OS: not achieve vs. 84.50 months, P = 0.3719, HR = 0.5177, 95% CI = 0.1569–1.710; DFS: not achieve vs. 54.43 months, P = 0.1851, HR = 0.5585, 95% CI = 0.2360–1.322, Fig.1 and 1I).
In our cohort, two cases of EMPD with HER2 expression accepted the treatment with ADC therapy. Case 1 was a 67-year-old man who presented to the hospital in February 2020 for the management of a genital eruption. He reported erythematous, painful, pruritic, eczematous lesions involving the left side of the scrotum. The patient underwent wide resection of the entire scrotal lesion on June 29, 2020. The pathological report revealed EMPD of the scrotum. At the 12-month post-operative visit, the patient reported enlargement of bilateral inguinal lymph nodes. The patient underwent complete bilateral lymphadenectomy in November 2021. Massive metastases were detected in 48/48 left and 9/9 right inguinal lymph nodes. In December 2021, the patient was diagnosed with a spread of cancer to the skin and subcutaneous tissue of the groin and perineum area. Starting in January 2022, the patient received six cycles of nab-paclitaxel, cisplatin, and nedaplatin, after which progression to the skin or subcutaneous metastases was observed with new lesions in the groin and scrotum area. Given the lack of approved drugs and appropriate study options, as well as HER2-positive expression (IHC 2+ score and FISH negative, Fig.1), the multidisciplinary committee recommended ADC therapy for DV in May 2022. A partial response was achieved after 8 weeks of treatment (2 mg/kg every 2 weeks, Fig.1 and 1L). The patient developed finger numbness 14 days after DV infusion. He also had transient diarrhea occasionally (The clinical course is shown in Fig. S2). DV was continued without dose reduction until bone lesions were newly discovered, which occurred after 11.0 months. The patient received subsequent therapy, including chemotherapy, antiangiogenic therapy, and checkpoint inhibitors, and he is still in follow-up.
Case 2 was a 63-year-old man who presented to the hospital with a 5-year history of scaling and erythematous plaques in the scrotum in October 2019. A subsequent biopsy revealed EMPD. The patient underwent wide resection in December 2019. In January 2021, the patient complained of the presence of a mass on the right inguinal area. The pathological report revealed Paget disease and HER2 expression (IHC 1+ score and FISH negative, Fig.1). Starting July 2021, the patient received six cycles of docetaxel and 5-Fu. In April 2022, the positron emission tomography scan showed multiple lymph node metastases. The patient started DV in August 2022. A partial response was achieved after 8 weeks of treatment (2 mg/kg every 2 weeks, Fig.1 and 1O). The patient developed hand and foot numbness 18 days after the initiation of DV infusion; he also complained of hair loss and constipation. Imaging 7 months after starting DV showed liver metastasis. The patient added an anti-PD-1 agent based on DV, and the liver metastasis was stable in the subsequent scans 3 months thereafter (The clinical course is shown in Fig. S2).
In the two EMPD cases with HER2 expression that responded to HER2-targeted ADC therapy, the IHC stain of HER2 was positive with 1+ and 2+ scores in both patients, while subsequent FISH testing was negative. After the failure of previous paclitaxel-based chemotherapy, both patients achieved a partial response with DV, which antibody disitamab targets different epitopes of the
HER2 receptor and has a better molecular affinity for the HER2 target than trastuzumab. This result might demonstrate that HER2 expression is therapeutically targetable by DV for patients with EMPD. Our finding might have implications for the use of drugs targeting HER2 expression, even at low levels. Therefore, we hypothesize that ADC therapy can be applied to advanced EMPD patients with different HER2 expression levels, which is similar to its performance in gastric cancer [
7]. Nevertheless, a comprehensive evaluation of targeted therapies has been conducted because of their rarity. Further research and clinical trials are necessary to evaluate the efficacy and safety of ADC therapy in a larger cohort of patients with EMPD, which could provide a new treatment option for this rare and challenging malignancy.
Recently, the use of HER2-targeted agent, with trastuzumab alone, or in combination with different cytotoxic agents, was considered as an effective and safe method for patients with HER2-overexpressing advanced EMPD. Notably, this method could achieve long-term tumor control through trastuzumab-based therapies in a few case reports [
8]. On the contrary, while the US Food and Drug Administration has approved several ADC regimens for the treatment of solid tumors, including HER2-positive metastatic breast cancer, gastric cancer, and non-small cell lung cancer, no sufficient studies have investigated the efficacy of HER2-targeted ADC in patients with EMPD. However, there have been reports of a complete response to trastuzumab emtansine (HER2-targeted ADC) in a scrotal EMPD patient with HER2 overexpression/amplification, as well as promising results from preclinical EMPD models with HER2-targeted ADC [
9,
10].
The rarity of EMPD has limited the availability of studies with large sample sizes and comprehensive data on HER2 expression. The multicenter nature of this study, involving three clinical research centers in China, is a notable strength as it provides the largest sample size to date for evaluating HER2 expression in EMPD. One of the unique aspects of this study is its focus on the low HER2 expression level in EMPD, which has not been extensively investigated in previous studies. The findings indicate that a significant proportion of EMPD cases exhibit HER2 expression, with low levels of HER2 expression being more prevalent. This observation is significant. The identification of HER2 expression, including low and high levels, in EMPD further supports the potential use of HER2-targeted ADC therapies such as DV in these patients. The study indicates that even patients with low HER2 expression level in EMPD may benefit from HER2-targeted therapy, expanding the potential pool of candidates who could benefit from this treatment approach.
In conclusion, our study highlights the potential application of HER2-targeted ADC therapy in the treatment of EMPD. The high frequency of HER2 expression in EMPD indicates that it can be considered as a routine treatment target. The use of DV, an innovative anti-HER2 ADC, showed promising results in patients with HER2 expression, including those with low levels. This finding provides a new perspective on the treatment of EMPD and warrants further investigation through larger clinical studies. By expanding our understanding of targeted therapies for EMPD, we can potentially improve the outcomes and prognosis for patients with this rare and challenging malignancy.
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