|Year : 2020 | Volume
| Issue : 3 | Page : 194-195
Ado-trastuzumab emtansine (T-DM1) for a case of HER2-amplified metastatic extramammary Paget's disease of scrotum: Clinical next-generation sequencing for precision medicine
Chih-Yu Chen1, Chien-Ping Chiang2, Li-Chun Lin3, Hong-Wei Gao4, Wei-Ming Wang1, Ping-Yin Chang5
1 Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Dermatology, Tri-Service General Hospital; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
3 Department of Medicine, National Defense Medical Center, Taipei, Taiwan
4 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
5 Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
|Date of Submission||12-Jan-2020|
|Date of Decision||20-Feb-2020|
|Date of Acceptance||22-Mar-2020|
|Date of Web Publication||16-Jun-2020|
Dr. Ping-Yin Chang
No. 325, Sec. 2, Chenggong Road, Neihu District, Taipei City 11490
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chen CY, Chiang CP, Lin LC, Gao HW, Wang WM, Chang PY. Ado-trastuzumab emtansine (T-DM1) for a case of HER2-amplified metastatic extramammary Paget's disease of scrotum: Clinical next-generation sequencing for precision medicine. Dermatol Sin 2020;38:194-5
|How to cite this URL:|
Chen CY, Chiang CP, Lin LC, Gao HW, Wang WM, Chang PY. Ado-trastuzumab emtansine (T-DM1) for a case of HER2-amplified metastatic extramammary Paget's disease of scrotum: Clinical next-generation sequencing for precision medicine. Dermatol Sin [serial online] 2020 [cited 2020 Sep 23];38:194-5. Available from: http://www.dermsinica.org/text.asp?2020/38/3/194/286575
A 55-year-old male presented to our outpatient clinic with a 1-year history of a growing reddish lesion in his genital area. Physical examination showed a solitary, stinging, reddish, well-demarcated, 2.5-cm nodule arising from ill-defined erythematous patches [Figure 1]a on his left scrotum. Several palpable lymph nodes in the left inguinal area were also observed. The blood biochemistry was normal. Incisional biopsy revealed poorly differentiated adenocarcinoma [Figure 1]b with apocrine features (upper right inset). The patient underwent debulking surgery, following which numerous Paget's cells were found in the biopsy specimen [Figure 1]c. Immunohistochemistry revealed that the tumor was positive for CK7, GCDFP-15, and HER2/neu [DAKO score 3+, 50%; [Figure 1]d but negative for CK20, CDX2, TTF-1, and PSA. Staging computed tomography (CT) scan revealed multiple hepatic [size, up to 5.4 cm; [Figure 2]a and bony metastases. In addition, bilateral inguinal and para-aortic lymph node metastases were observed. The patient's tumor specimen was sent for comprehensive genomic profiling utilizing next-generation sequencing (NGS), which identified HER2 amplification with copy number of 63, and additional mutations in KRAS, RICTOR, and PARP1 (Foundation Medicine Inc., Cambridge, Massachusetts, USA). The patient was diagnosed with Stage IV HER2-amplified metastatic extramammary Paget's disease (EMPD). Anti-HER2 trastuzumab in combination with paclitaxel and radiotherapy was provided, but disease progressed after 1 year. We changed the antineoplastic agents to ado-trastuzumab emtansine (T-DM1; 3.6 mg/kg), which was provided every 3 weeks for a 21-day cycle. After 1 year of treatment with T-DM1, follow-up CT showed a good response with significant reductions in the size and number of the liver metastases [size, up to 1.4 cm; [Figure 2]b. Regression of the tumor was observed in bilateral inguinal regions and para-aortic spaces. HER2 amplification was not detectable in follow-up liquid biopsy by NGS (Foundation Medicine Inc., Cambridge, Massachusetts, USA). At the time of this report, he has been in active treatment and continues to have clinical response.
|Figure 1: (a) A solitary, stinging, reddish, well-demarcated, 2.5-cm nodule (upper right inset) arising from ill-defined erythematous patches on his left scrotum. (b) Poorly differentiated adenocarcinoma with apocrine features (upper right inset) (H and E, ×400). (c) Characteristic Paget's cells (H and E, ×400). (d) Immunohistochemistry for HER-2 showing positive staining (H and E, ×400)|
Click here to view
|Figure 2: (a) Abdominal computed tomography revealed multiple hepatic metastases (size, up to 5.4 cm, white arrow). (b) After 1 year of T-DM1, follow-up computed tomography showed a good response to the therapy with significant reductions in the size (size, up to 1.4 cm, white arrow) and number of the liver metastases|
Click here to view
EMPD of the penis or scrotum is a rare intraepithelial adenocarcinoma with an estimated incidence of 0.27 per million males annually. A small proportion of the patients develop invasive EMPD beyond the dermis with lymph node and distant metastasis at rates of 37% and 17%, respectively. Wide excision and lymphadenectomy followed by chemotherapy and/or radiotherapy were reported to be associated with variable responses.
HER-2/neu is a cell membrane surface-bound receptor tyrosine kinase that accelerates cell growth and differentiation in EMPD progression. HER2 overexpression was observed in 15%–58% of patients with EMPD. Furthermore, many precision medicine trials have relied on NGS assays of tumor tissue to determine the genomic profile. HER2 amplifications were significantly more frequent in the cases of invasive EMPD than in those of intraepithelial EMPD. Several case reports showed that HER2-amplified EMPD exhibited favorable responses to trastuzumab.
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of trastuzumab covalently linked to the small-molecule cytotoxic microtubule inhibitor emtansine. It is currently approved for the treatment of HER2-amplified metastatic breast cancer. The National Cancer Institute-Molecular Analysis for Therapy Choice included a patient with metastatic EMPD of the scrotum who was treated with the standard T-DM1 dosing of 3.6 mg/kg triweekly. He received >15 months of treatment with a near 80% reduction in the sum of the diameters of the measurable tumors. Another patient with metastatic EPMD of the scrotum treated with T-DM1 was reported to achieve nearly 1 year of overall survival. However, one female with metastatic EMPD of the vulva experienced recurrence after 6 months of treatment with T-DM1. The present study showed an evident therapeutic response with reductions in the size of the tumors and no detection of HER2 amplification in the liquid biopsy. To our best knowledge, this is the first report of T-DM1 therapy for patient with EMPD in Asia. Precision medicine is an emerging approach for disease treatment and accumulating evidence indicates that an antibody-drug conjugate of T-DM1 has a significant effect on EMPD.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ohara K, Fujisawa Y, Yoshino K, Kiyohara Y, Kadono T, Murata Y, et al
. A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis of 301 patients with invasive primary tumors. J Dermatol Sci 2016;83:234-9.
Hegarty PK, Suh J, Fisher MB, Taylor J, Nguyen TH, Ivan D, et al
. Penoscrotal extramammary Paget's disease: The University of Texas M. D. Anderson cancer Center Contemporary Experience. J Urol 2011;186:97-102.
Mochitomi Y, Sakamoto R, Gushi A, Hashiguchi T, Mera K, Matsushita S, et al
. Extramammary Paget's disease/carcinoma successfully treated with a combination chemotherapy: Report of two cases. J Dermatol 2005;32:632-7.
Fukuda K, Funakoshi T. Metastatic extramammary Paget's disease: Pathogenesis and novel therapeutic approach. Front Oncol 2018;8:38.
Tanaka R, Sasajima Y, Tsuda H, Namikawa K, Tsutsumida A, Otsuka F, et al
. Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease. Br J Dermatol 2013;168:1259-66.
Jhaveri KL, Wang XV, Makker V, Luoh SW, Mitchell EP, Zwiebel JA, et al
. Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: Results from the NCI-MATCH trial (EAY131) subprotocol Q. Ann Oncol 2019;30:1821-30.
Shin DS, Sherry T, Kallen ME, Wong S, Drakaki A. Human epidermal growth factor receptor 2 (HER-2/neu)-directed therapy for rare metastatic epithelial tumors with HER-2 amplification. Case Rep Oncol 2016;9:298-304.
Gillian LH, Diana PE, Powen T, Ann KF, Amer KK. Case of metastatic extramammary paget disease of the vulva treated successfully with trastuzumab emtansine. JCO Precis Oncol 2018;2:1-8.
[Figure 1], [Figure 2]