Abstract
Background: Salivary ductal carcinoma (SDC) is a high-grade malignancy, and molecular studies show frequent overexpression of human epidermal growth factor receptor 2 (HER2). We reviewed our experience with molecular-targeted therapy using trastuzumab for patients with HER2-positive SDC. Patients and Methods: The records of all patients treated with trastuzumab for HER2-tested SDC at The University of Texas MD Anderson Cancer Center between 1997 and 2011 were reviewed. Results: Thirteen patients with SDC overexpressing HER2 were treated with trastuzumab as a single agent or in combination with chemotherapy. Ten of these had 3+ immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization. Patients underwent therapy in the surgical adjuvant setting (n=2), as a component of combined therapy for advanced disease (n=8), or as single therapy near end of life (n=3). Treatment efficacy via radiographic review for response could not be assessed. Conclusion: Trastuzumab should undergo prospective therapeutic clinical trials, in SDC which will likely require international cooperation.
Salivary gland cancers represent 3-6% of all head and neck cancers in adults and include a variety of histologically-diverse entities with distinct pathogenesis and biological behavior (1, 2). Salivary ductal carcinoma (SDC) is a high-grade epithelial malignancy that most commonly affects the major salivary glands, particularly the parotid gland (1-4). Even though SDC is a rare tumor, its aggressive nature presents a challenge for management.
Histologically, SDC is derived from the main excretory ductal epithelial cells and can emerge de novo or in the setting of carcinoma ex-pleomorphic adenoma (2). SDC was first described by Kleinsasser et al. in 1968, who first noticed the remarkable similarity to ductal carcinoma of the breast, from which SDC acquired its name (5). Furthermore, SDC is associated with an aggressive nature and poor clinical outcome, as is evidenced by a late stage at presentation, high incidence of local and regional recurrence, and distant metastasis (2, 4, 6).
Current treatment for salivary gland tumors is primarily surgical resection with adjuvant radiation therapy. Systemic therapy may be added to radiotherapy for patients with cervical lymph node metastasis, positive surgical margins, or perineural invasion and more often it is used as a single modality for those with distant metastases (2). A variety of agents have been utilized, but no regimen has demonstrated therapeutic superiority (7-10). Combination therapies have been shown to be more active than single-agent chemotherapy; however, responses are rarely durable (7-9). In recent years, molecular markers in salivary gland tumors have been identified as possible targets of therapy and include epithelial growth factor receptor (EGFR), c-kit, and progesterone receptor (PR) (10-12). However, response rates have generally been poor, probably in large part due to patient selection and target choice. One such marker is the human epidermal growth factor receptor 2 (HER2) receptor, which has been shown to be frequently expressed in SDC (2, 4).
Trastuzumab (Herceptin®) is a humanized monoclonal antibody to HER2 that has been widely investigated for the treatment of breast cancer, both as a single agent and in combination with other chemotherapeutic drugs (13-15). Considering the histopathological similarities between breast cancer and SDC, trastuzumab has been suggested as a possible therapeutic option for SDC (2, 4). Owing to the rarity of this disease, however, standardization of treatment protocols is challenging. In this study, we reviewed our single-institutional experience of the management of SDC with trastuzumab to determine the frequency of use, and evidence for responses to therapy.
Patients and Methods
A retrospective case series review was conducted at the University of Texas MD Anderson Cancer Center and was approved by the Institution's Review Board (DR08-0813). All patients treated with trastuzumab for SDC from September 1, 1998 to November 1, 2011 were identified through the pharmacy informatics database and through a departmental database of patients with salivary gland malignancies (n=1500). Patients greater than 18 years of age, with a history of SDC, and treated with trastuzumab were included. Medical records were reviewed for the following data: demographics, performance status, tumor histology, sites of tumor involvement, pathological staging at diagnosis, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) HER2 status, oncological treatment history, trastuzumab dosing and schedule, trastuzumab toxicities, radiographic response, location of progression, progression free survival, and overall survival to the end of March 2012 or date of last contact. Response was assessed via standard RECIST criteria (16). HER2 overexpression was defined as a tumor with an IHC score of 3+, an average HER2 gene/chromosome 17 ratio of greater than 2.2 by FISH, or an average number of HER2 gene copies/cell of 6 or greater. Tumors with an IHC score of 2+ were considered equivocal unless confirmed by FISH to be overexpressing.
All patients were staged according to the American Joint Committee on Cancer (17). All histological specimens were reviewed by a head and neck pathologist. These data were used to describe the clinical course and outcome of patients treated with trastuzumab for salivary gland cancers.
Results
Twenty-nine patients were identified and their medical records reviewed. Sixteen patients were excluded; three patients with skin primary malignancies expressing HER2, one patient had HER2-positive breast cancer, and 12 had limited chart documentation to adequately evaluate their clinical course and response to trastuzumab. These patients were typically treated at another institution and had come to MD Anderson for a second opinion. Thirteen patients with SDC treated with trastuzumab were reviewed. Demographics and tumor specifics are listed in Table I. The median age of the patients was 58 years (range=28-67 years) and 70% were male. All patients but one had an Eastern Cooperative Oncology Group performance status 0-2 at the time trastuzumab was initiated. Twelve of thirteen (92%) had primary tumors arising in the parotid gland. At the time of diagnosis, seven patients had metastatic disease. As trastuzumab was administered, eleven patients had metastatic disease, documented by magnetic resonance imaging, computed tomography, or bone scan. The most common sites of metastases were the bone and lung.
Treatment for primary disease predominately consisted of surgery (85%) and postoperative radiation (85%). In 11 patients trastuzumab was administered as a single agent (in three patients), or as a component of systemic therapy (eight patients) later in the clinical course for progressive metastatic disease (See Table II). The median number of therapies prior to trastuzumab initiation was one (range, 0-6). Two patients had not received prior chemotherapy and were therefore treated with trastuzumab as a component of adjuvant systemic therapy, administered with cytotoxic chemotherapy after surgical resection of the primary malignancy.
The majority of patients (54%) received trastuzumab every three weeks (8 mg/kg loading dose followed by 4 mg/kg weekly), while 31% received trastuzumab on a weekly schedule (4 mg/kg loading dose followed by 2 mg/kg weekly), and two patients switched between both treatment schedules.
There was no measurable objective response to single-agent treatment; however, three patients achieved partial tumor responses after combined therapy, with duration of 3 to 8 months. The contribution of trastuzumab to this outcome is not quantifiable. Notably, both high-risk patients receiving adjuvant chemotherapy had no tumor recurrence.
Trastuzumab appears to have been well-tolerated. No patients experienced infusion-related reaction. No patients experienced lasting symptomatic or measurable cardiotoxicity. On routine echocardiographic monitoring, one patient (patient 10) was found to have an asymptomatic decline in ejection fraction. The time-to-onset was 259 days following 12 doses of trastuzumab every three week. However, the ejection fraction recovered to baseline upon discontinuation of the drug, with no long-term sequelae.
Discussion
This retrospective chart review describes empirical use of trastuzumab for the treatment of HER2-overexpressing SDCs. Our findings suggest that the administration of trastuzumab is safe. The data are insufficient to assess drug activity, as responding and adjuvant therapy patients also received chemotherapy, typically with platinum-taxane platforms.
SDC is a rare and often aggressive salivary malignancy which shares significant histological similarities with breast cancer (5). Like breast cancer, SDC overexpressed HER2 in 60-80% of tumors tested (2, 4). HER2 is a membrane-bound receptor tyrosine kinase that normally regulates cell growth and differentiation (18). The HER2/neu gene on chromosome 17 encodes the HER2 transmembrane receptor. Amplification of HER2/neu causes a 2 log increase in the number of HER2 receptors expressed on the surface of tumor cells (19). Overexpression markedly increases the cellular growth rate, motility, malignant transformation, and the secretion of vascular endothelial growth factor, which promote an aggressive tumor biology. Clinically, these phenotypic changes result in faster relapses and a worse prognosis compared with tumors expressing HER2 at normal levels (20, 21). The poor prognosis attributed to HER2 overexpression has not only been reported in breast cancer, but accumulating data suggest it is also a negative prognostic factor in SDC (22). With conventional chemotherapy, HER2-positive SDC has a high incidence of recurrence and a predilection to rapidly progress (23). Therefore, novel treatments for aggressive salivary gland cancers, specifically SDC, are warranted.
Blocking HER2 with trastuzumab has led to dramatic improvements in disease-free survival and overall survival in HER2-overexpressing breast cancer (24, 25). Considering the histopathological similarities between breast cancer and SDC, trastuzumab has been suggested as a possible therapeutic option for SDC (5, 14, 22, 26). Thus far, data evaluating the use of trastuzumab in salivary gland cancers are accumulating slowly and erratically.
Our case series shows that results are consistent with previous reports (see table III) showing trastuzumab to be safe and potentially effective in the management of HER2-positive salivary gland cancers (23, 26-32). However, several characteristics should be considered for proper interpretation of our data. Firstly, the present case series was retrospective in design; patients were variably treated; and the contribution of trastuzumab to tumor response outcomes could not be quantified. Prospective trials are needed. To secure adequate numbers, a cooperative group study perhaps on an international level will be needed. Consideration should be given to single-agent study of patients and possibly a randomized phase II study with chemotherapy with/without the antibody. Most would agree that with no established cytotoxic regimen accepted as a standard of care, molecular-targeted therapies will emerge. Dependent upon tumor molecular analyses, putative targets in SDC, which include EGFR, androgen receptor, and HER2, have been proposed as selection factors. Therapeutic investigations of EGFR inhibition, androgen ablation, and trastuzumab are emerging.
Footnotes
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Conflicts of Interest
The Authors declare that they have no conflicts of interest and no funding was obtained for this case series.
- Received March 25, 2013.
- Revision received May 7, 2013.
- Accepted May 10, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved