Abstract
6071 Background: Patients suffering from recurrent or metastatic (R/M) salivary duct carcinoma (SDC) are often treated with combined androgen blockade (CAB). This treatment however frequently fails (response rates: 18-53%), resulting in a worse prognosis. Therefore, biomarkers that have prognostic value and can predict treatment response are urgently needed. Methods: mRNA from 77 R/M androgen receptor (AR) positive SDC patients treated with leuprorelin acetate combined with bicalutamide was extracted from pre-treatment tumor specimens. AR, Notch, Mitogen-Activated Protein Kinase (MAPK), Transforming Growth Factor beta (TGFβ), Estrogen Receptor (ER), Hedgehog (HH) and the Phosphoinositide 3-Kinase (PI3K) signaling pathway activities were calculated based on expression levels of relevant target genes. Besides this, 5-alpha reductase type 1 ( SRD5A1) expression and Human Epidermal growth factor Receptor 2 (HER2) status were determined. Clinical benefit was defined as complete or partial response or stable disease ≥6 months. Results: Of the 7 signaling pathways, AR pathway activity was the best predictor of clinical benefit (AUC 0.67, 95%-CI 0.54-0.80). At a threshold of 47.8, 21% of the patients tested negative, with a negative predictive value of 93%. SRD5A1 expression outperformed the signaling pathways regarding predictive value (AUC 0.78, 95%-CI 0.67-0.88). Fitting of a multivariable model led to the identification of SRD5A1, Notch and TGFβ as most predictive combination (AUC 0.82, 95%-CI 0.72-0.91). AR, Notch, HH and SRD5A1 were also of prognostic importance regarding progression free survival and SRD5A1 expression levels also for overall survival (median of 175.0 weeks for high versus 96.7 weeks for low expression). Conclusions: Our study revealed predictive and/or prognostic value of AR, HH, Notch and TGFβ signaling activities and SRD5A1 expression in SDC patients treated with CAB. AR pathway activity can be used for identifying non-responders. Further clinical validation is required before implementation of these biomarkers in clinical practice. The observed role of SRD5A1 expression in CAB response forms a rational basis for including SRD5A1-inhibitors in the treatment of SDC patients.[Table: see text]
Highlights
Salivary duct carcinoma (SDC) is one of the 22 salivary gland cancer (SGC) subtypes, as recognized by the World Health Organization classification of head and neck tumors [1].salivary duct carcinoma (SDC) distinguishes itself from the other subtypes by its aggressive nature, with estimated 5and 10-year overall survival rates as low as 43% and 26%, respectively [2]
Seventy-six patients with a median age of 65.2 years were treated with combined androgen blockade (CAB) and included in the analysis
Of these 76 patients, 93.4% were male, and the majority of the primary tumors were located in the parotid gland (68.4%)
Summary
Salivary duct carcinoma (SDC) is one of the 22 salivary gland cancer (SGC) subtypes, as recognized by the World Health Organization classification of head and neck tumors [1]. SDC distinguishes itself from the other subtypes by its aggressive nature, with estimated 5and 10-year overall survival rates as low as 43% and 26%, respectively [2]. In the case of metastatic disease, refraining from treatment with antineoplastic agents leads to a median overall survival (OS) of five months when best supportive care is given [5]. This emphasizes the need for systemic, and preferably targeted, therapeutic approaches for these patients. A more promising treatment is targeting androgen receptor (AR) signaling or targeting the human epidermal growth factor receptor 2 (HER2) [6,7,8,9]
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