Excellent Response to MEK Inhibition in an AGK-BRAF Gene Fusion Driven Carcinoma: Case Report and Literature Review.

BACKGROUND: Soft tissue myoepithelial carcinomas (STMC) are a rare, malignant subgroup of myoepithelial tumors that arise typically in glandular or ductal tissues, but also in the bone and soft and cutaneous tissues. Due to its rarity, there is no consensus regarding the treatment of STMC, including chemotherapy or other systemic agents for metastatic STMC. CASE REPORT: A chemotherapy- and regorafenib-refractory STMC, harboring an AGK-BRAF fusion, was successfully treated using MEK-inhibition with cobimetinib in monotherapy. MEK-inhibition with cobimetinib effectively silenced paradoxical MAP kinase/ERK-signaling pathway activation after regorafenib monotherapy, and resulted in a significant and durable clinical response. CONCLUSION: This effect of MEK-inhibition in STMC harboring an AGK-BRAF fusion has not been previously reported and contributes to the existing, yet limited, knowledge on the treatment of BRAF fusion-driven tumors. Also, our case highlights the importance of next generation sequencing in driving further rational therapeutic choices to provide disease control and palliation.

Anti-androgen for myoepithelial tumor: a potent therapy yet a potential misleader.

Myoepithelial tumor is a rare form of cancer, mainly arising from the salivary glands and extremities. Due to its rarity, no formal treatment guidelines exist. Here we report a case of a male patient diagnosed with metastatic myoepithelial tumor which was successfully treated with an androgen-receptor (AR) antagonist (bicalutamide), based on the results of molecular testing. Six years after the initiation of bicalutamide, patient was diagnosed with metastatic prostate cancer. To our knowledge, this is the first case described in literature that demonstrate the effectiveness of anti-androgens in treating myoepithelial tumor. Vigilance should be maintained when screening these patients for prostate cancer as their 'true' prostate specific antigen levels might be masked by the ongoing endocrine therapy.

Ex vivo assessment of targeted therapies in a rare metastatic epithelial-myoepithelial carcinoma.

Epithelial-myoepithelial carcinoma (EMC) is a rare subtype of salivary gland neoplasms. Since the initial description of the cancer, just over 300 cases have been reported. EMCs occupy a biphasic cellular differentiation-state defined by the constitution of two cell types representing epithelial and myoepithelial lineages, yet the functional consequence of the differentiation-state heterogeneity with respect to therapy resistance of the tumors remains unclear. The reported local recurrence rate of the cases is approximately 30%, and while distant metastases are rare, a significant fraction of these cases are reported to receive no survival benefit from radio- or chemotherapy given in addition to surgery. Moreover, no targeted therapies have been reported for these neoplasms. We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial-myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial-myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage composition of EMC could be an important factor to be assessed when novel treatments are being evaluated for management of metastatic EMC.

A first case report of clinical response to targeted therapy in a patient with primary myoepithelial carcinoma of the lung harboring EGFR exon 19 deletion.

BACKGROUND: Primary myoepithelial carcinoma of the lung is a rare subtype in lung cancer. Comprehensive molecular profiling of myoepithelial carcinoma of the lung is absent, neither was clinical evidence of targeted therapy available for this disease. Therefore, the optimal treatment regimen of this tumor needs to be established. CASE PRESENTATION: Here we present a case of a 68-year-old patient with stage IVB primary myoepithelial carcinoma of the lung who harbored EGFR exon 19 deletion and KRAS mutation and underwent icotinib targeted therapy, achieving partial response (PR) with progression free survival (PFS) of 3 months. CONCLUSION: To our knowledge, this study describes the first documented case of primary myoepithelial carcinoma lung cancer patient harboring EGFR exon 19 deletion and KRAS mutation, and showed clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) treatment in this patient.

Adult soft tissue myoepithelial carcinoma: treatment outcomes and efficacy of chemotherapy.

Soft tissue myoepithelial carcinomas are a rare, malignant subgroup of myoepithelial tumours mostly arising in the extremities with equal predilection for women and men. The mainstay of management of localised disease is complete surgical resection. Despite optimal treatment, 40-45% of tumours recur. Data regarding the efficacy of systemic therapy for advanced and metastatic disease are lacking. The primary aim of this study was to evaluate the outcome of all patients with soft tissue myoepithelial carcinoma treated at a single referral centre. The secondary aim was to establish the efficacy of systemic therapies in patients with advanced disease. A retrospective review of the prospectively maintained Royal Marsden Sarcoma Unit database was performed to identify soft tissue myoepithelial carcinoma patients treated between 1996 and 2019. Patient baseline characteristics and treatment history were recorded. Response to systemic therapy was evaluated using RECIST 1.1. We identified 24 patients treated at our institution between 1996 and 2019,12 males and 12 females. Median age at presentation was 49.6 years [interquartile range (IQR) 40.5-63.3 years]. Twenty-two out of 24 patients (91.7%) underwent primary surgical resection. Nine patients (37.5%) received systemic treatment. A partial response was documented in one patient treated with doxorubicin. The median progression-free survival for first-line chemotherapy was 9.3 months. Myoepithelial carcinoma frequently recurs after complete surgical resection. Conventional chemotherapy demonstrated some activity in myoepithelial carcinoma, however, more effective systemic therapies are required and enrolment in clinical trial should be encouraged.

Report of a unique case of myoepithelial carcinoma of left parotid gland with metachronous bilateral cavernous sinus metastasis.

Myoepithelial carcinoma (MC) is a rare, locally aggressive malignant neoplasm of the salivary glands. Only few evidences on its metastatic behavior are available in the literature. We herein present a unique case of MC of left parotid gland which metastasized to bilateral cavernous sinuses. The patient was successfully treated with palliative radiotherapy and chemotherapy.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

Soft Tissue Myoepithelial Carcinoma in a Child: Case Report.

BACKGROUND: Myoepithelial carcinoma was only recently recognized to occur primarily in soft tissue. Only a small number has been reported in children. OBSERVATION: We report a rare case of myoepithelial carcinoma of the leg in a 4-month-old boy with a good response to chemotherapy initially. However, he presented secondarily during chemotherapy a local and metastatic progression. CONCLUSIONS: The rarity of the tumor and unusual age of discovery have prompted us to report this case. Our case suggests that this disease can have an aggressive behavior. This is why we advise a rapid and correct diagnosis followed by an aggressive treatment.

Myoepithelial carcinoma of the extremity: Response to isolated limb infusion.

We report our experience with two patients with myoepithelial carcinoma (MEC) of the extremity. An 83-year-old male and a 35-year-old female were treated with standard isolated limb infusion (ILI), using melphalan and dactinomycin. The first patient had a complete response (CR) that was sustained for two and a half years, until he developed a regional lymph node metastasis. The second patient had a 4.7 cm tumor located on her left hand with metastasis to the ipsilateral axillary lymph nodes. Initial treatment consisted of ILI and left axillary lymphadenectomy. The primary tumor regressed and showed signs of central necrosis, measuring 2.8 cm after 1 month. Though she was continuing to respond, a decision was made by her orthopedic surgeon to administer neoadjuvant radiation followed by surgical resection.

Myoepithelial carcinoma treatment in children: a report from the TREP project.

BACKGROUND: Myoepithelial carcinoma (MC) of soft tissues is an aggressive tumor that rarely affects children, for whom no established treatment protocols exist. As part of the TREP (Tumori Rari in Età Pediatrica) project - an Italian network dedicated to children and adolescents with very rare tumors - we present a series of patients with MC, who were treated homogeneously and achieved a satisfactory outcome. PROCEDURE: From 2005 to 2012, seven patients (age 0.5-9.2 years) with a diagnosis of MC were registered in the TREP study. After one patient treated with ifosfamide, cisplatin, and etoposide showed tumor shrinkage and experienced long-term disease remission, all subsequent patients were treated with the same chemotherapy regimen. All patients also received radiotherapy. RESULTS: Initial surgical management involved a biopsy in three cases and tumor resection in 4. Response to initial chemotherapy was evaluable in four patients: two had a partial remission, one a minor response and one stable disease. Four patients received external-beam radiotherapy and three had brachytherapy. Overall, six patients are alive in first complete remission with a median follow-up of 2.5 years (0.9-5.1 years). CONCLUSIONS: Though our experience is limited to a small number of patients, our treatment strategy for patients with MC is appears clinically useful and demonstrates how cooperation within the TREP project has enabled enough data to be collected to propose treatment recommendations for pediatric patients with this very rare tumor.

Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours.

BACKGROUND: Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified. DESIGN: Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology. RESULTS: Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations. CONCLUSION: Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.

[Basal and myoepithelial phenotype of metastatic mammary carcinomas. A prognostic factor in the palliative situation?]. / Basaler und myoepithelialer Phänotyp des invasiven Mammakarzinoms. Prognostischer Faktor in der palliativen Situation?

AIMS: The aim of the present study was to evaluate the prognostic impact of basal and myoepithelial phenotype in breast carcinomas (BBC and MBC) in the palliative situation. METHODS: Paraffin-embedded material from 244 primary breast carcinomas of patients with subsequent metastatic disease was stained immunohistochemically for CK 5/6, CK14, smooth-muscle actin, p63, estrogen receptor and progesterone receptor. BBC was defined as positive for CK5/6 and/or CK14 and MBC as positive for SMA and/or p63. Clinical and pathological data were available for all patients and follow-up data for 96.3% (range 5 days-151 months). RESULTS: Until the end of the follow-up period 90.2% of patients died and 6.1% are still alive. Of the tumours 28.7% could be classified as BBC and 8.2% as MBC. Kaplan Meier analysis revealed a trend for reduced survival after first diagnosis of metastasis (OASM) for BBC and MBC. Differences in survival were significant for BBC (log-rank =5.0; p=0.025), but not for MBC. CK5/6+ and CK14+ double positive tumours (n=18; 7.4%) were identified as a subgroup of BBC associated with reduced OASM (log-rank=8,6; p=0.003). This subgroup, but not BBC or MBC was an independent negative prognostic factor in a multivariate analysis including age, typing, tumour size, grading, axillary nodes, HR, Her2/neu, site of first metastasis and disease-free interval. CONCLUSION: The association of BBC and MBC with reduced OASM in metastatic breast carcinomas is not independent from established prognostic factors. CK5/6+ CK14+ double positive tumours may be a subgroup of BBC with particularly unfavourable outcome.

Epithelial-myoepithelial carcinoma of the submandibular gland with symptomatic lung metastases treated with chemotherapy.

This report concerns a patient with symptomatic lung metastases from an epithelial-myoepithelial carcinoma of the submandibular gland. Although the efficacy of chemotherapy is unknown in this disease, our patient was treated with cisplatin combined with 5-fluorouracil and later with paclitaxel and cyclophosphamide. Chemotherapy allowed disease stabilization and relief of the pulmonary symptoms. This is the first report on the use of chemotherapy in this very rare salivary gland carcinoma.

Radiotherapy and chemotherapy for myoepithelioma of the sellar region.

BACKGROUND: Myoepithelioma might arise in the head and neck area, especially within the salivary glands. It is very uncommon as a primary intracranial tumor. CASE REPORT: A 34-year-old African patient with proliferating myoepithelioma originating in the sellar region is described. After subtotal resection, the tumor recurred locally despite postoperative radiotherapy to a total dose of 54 Gy (Figures 1 and 2). When intracranial metastases developed, chemotherapy with ifosfamide and, later, BCNU was administered. No objective response was obtained with any of the nonsurgical approaches. Uncontrolled intracranial tumor growth led to the patient's death 20 months after the initial diagnosis. CONCLUSION: Most tumors of the sellar region have a favorable prognosis. However, this case of incompletely resected proliferating myoepithelioma showed both local and distant recurrences, which did not respond to further treatment. Thus, complete surgical resection is recommended, whenever technically feasible.

Epithelial-myoepithelial carcinoma of the base of tongue: pathology and management.

Epithelial-myoepithelial carcinoma is a rare tumor which makes up about 0.2% of epithelial neoplasms of the salivary glands; parotid gland being the most common primary site of origin. The tumor may also very rarely originate in minor salivary glands of the base of the tongue. Due to rarity of its occurrence, histogenesis and clear cut therapeutic guidelines are not defined. The present report describes the case of a 48 year old male who was diagnosed to have a tubular variant of epithelial-myoepithelial carcinoma of the base of tongue, Stage T3 N0 M0 (Stage group III). The patient was treated with neoadjuvant chemotherapy followed by radical radiotherapy (Rt) and is alive with no evidence of disease 14 months following end of treatment.