scholarly journals Predictive and prognostic biomarker identification in a large cohort of androgen receptor-positive salivary duct carcinoma patients scheduled for combined androgen blockade.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6071-6071
Author(s):  
Gerben Lassche ◽  
Yuichiro Tada ◽  
Carla M.L.- Van Herpen ◽  
Marianne A. Jonker ◽  
Diederick Keizer ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Growth Factor ◽  
Clinical Benefit ◽  
Predictive Value ◽  
Prognostic Value ◽  
Salivary Duct ◽  
Duct Carcinoma ◽  
Pathway Activity ◽  
Combined Androgen Blockade ◽  
Androgen Blockade

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]

scholarly journals Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3527
Author(s):  
Gerben Lassche ◽  
Yuichiro Tada ◽  
Carla M. L. van Herpen ◽  
Marianne A. Jonker ◽  
Toshitaka Nagao ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Clinical Benefit ◽  
Predictive Value ◽  
Target Genes ◽  
Salivary Duct Carcinoma ◽  
Salivary Duct ◽  
Duct Carcinoma ◽  
Expression Levels ◽  
Combined Androgen Blockade ◽  
Androgen Blockade

Patients suffering from recurrent or metastatic (R/M) salivary duct carcinoma (SDC) are often treated with combined androgen blockade (CAB). However, CAB frequently fails, resulting in a worse prognosis. Therefore, biomarkers that can predict treatment failure are urgently needed. mRNA from 76 R/M androgen receptor (AR)-positive SDC patients treated with leuprorelin acetate combined with bicalutamide was extracted from pre-treatment tumor specimens. AR, Notch, MAPK, TGFβ, estrogen receptor (ER), Hedgehog (HH), and PI3K signaling pathway activity scores (PAS) were determined based on the expression levels of target genes. Additionally, 5-alpha reductase type 1 (SRD5A1) expression was determined. These markers were related to clinical benefit (complete/partial response or stable disease ≥6 months) and progression-free and overall survival (PFS/OS). SRD5A1 expression had the highest general predictive value for clinical benefit and positive predictive value (PPV: 85.7%). AR PAS had the highest negative predictive value (NPV: 93.3%). The fitting of a multivariable model led to the identification of SRD5A1, TGFβ, and Notch PAS as the most predictive combination. High AR, high Notch, high ER, low HH PAS, and high SRD5A1 expression were also of prognostic importance regarding PFS and SRD5A1 expression levels for OS. AR, Notch PAS, and SRD5A1 expression have the potential to predict the clinical benefit of CAB treatment in SDC patients. SRD5A1 expression can identify patients that will and AR PAS patients that will not experience clinical benefit (85.7% and 93.3% for PPV and NPV, respectively). The predictive potential of SRD5A1 expression forms a rational basis for including SRD5A1-inhibitors in SDC patients’ treatment.

scholarly journals Analysis of functional androgen receptor-pathway activity to predict response to androgen deprivation therapy in salivary duct carcinoma

2018 ◽  
Vol 29 ◽  
pp. viii385
Author(s):  
W. van Boxtel ◽  
I. van Engen-van Grunsven ◽  
D. van Strijp ◽  
J.B.A. van Zon ◽  
M.J.L. Ligtenberg ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Salivary Duct Carcinoma ◽  
Salivary Duct ◽  
Duct Carcinoma ◽  
Pathway Activity

Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Salivary Duct Carcinoma

2019 ◽  
Vol 37 (2) ◽  
pp. 125-134 ◽  
Author(s):  
Hideaki Takahashi ◽  
Yuichiro Tada ◽  
Takashi Saotome ◽  
Kohei Akazawa ◽  
Hiroya Ojiri ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Growth Factor Receptor ◽  
Salivary Duct ◽  
Duct Carcinoma ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

Purpose Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease’s rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2–positive SDC. Patients and Methods This was a single-center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437). Results Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred. Conclusion Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2–positive SDC, with a manageable toxicity profile.

scholarly journals Reciprocal and Autonomous Glucocorticoid and Androgen Receptor Activation in Salivary Duct Carcinoma

2019 ◽  
Vol 26 (5) ◽  
pp. 1175-1184 ◽  
Author(s):  
Yoshitsugu Mitani ◽  
Sue-Hwa Lin ◽  
Kristen B. Pytynia ◽  
Renata Ferrarotto ◽  
Adel K. El-Naggar
Keyword(s):  
Androgen Receptor ◽  
Receptor Activation ◽  
Salivary Duct Carcinoma ◽  
Salivary Duct ◽  
Duct Carcinoma ◽  
Androgen Receptor Activation
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