Supplementary Materials Appendix S1: Helping Information IJC-146-3196-s001

Supplementary Materials Appendix S1: Helping Information IJC-146-3196-s001. independent cohort of locally advanced SDC patients receiving adjuvant ADT (=?14) after surgical tumor resection, and in most cases a neck dissection (13/14 Estetrol patients) and postoperative radiotherapy (13/14 patients). In conclusion, we are the first to describe that AR pathway activity may predict clinical benefit from ADT in SDC patients, but validation in a prospective study is needed. hybridizationH&Ehematoxylin and eosinHPRT1hypoxanthine phosphoribosyltransferase 1IQRinterquartile rangeLAlocally advancedOSoverall survivalPFSprogression\free survivalR/Mrecurrent/metastaticROCreceiver operating characteristicSDCsalivary duct carcinomasmMIPsingle\molecule molecular inversion probeSRD5A1/2steroid 5 alpha\reductase 1/2 Introduction Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer, which is often androgen receptor (AR) positive (66.7C96.4%).1, 2, 3 Primary treatment consists of a tumor resection, most often in combination with a neck dissection and postoperative radiotherapy. Despite this extensive treatment, the 3\year disease\free survival (DFS) rate is only 27.7% in locally advanced patients.4 In patients with recurrent and/or metastatic (R/M) SDC, androgen deprivation therapy (ADT) is often used as first\line palliative treatment. In retrospective studies, ADT has shown response prices of 17.6C50.0% and an OS of 17?weeks in comparison to 5 weeks in a ideal supportive treatment cohort.5, 6 A recently available prospective stage 2 trial in Japan demonstrated a reply rate of 41.7%, median development\free success (PFS) of 8.8 months and median OS of 30.5 months.7 Due to the efficacy of ADT in R/M SDC individuals, we examined ADT as adjuvant treatment in 22 individuals with locally advanced (LA) AR\positive SDC. Multivariable Cox regression evaluation showed a considerably improved DFS (risk percentage 0.14, 95% CI 0.03C0.75, =?0.022) and Operating-system (hazard percentage 0.06, 95% CI 0.01C0.76, =?0.030) in comparison to 111 settings who didn’t receive adjuvant ADT.4 Besides BA554C12.1 ADT, other treatment plans are for sale to individuals with R/M SDC. Regarding (HER2) gene amplification (29.4C46.4%),1, 2 individuals could be treated with trastuzumab in addition docetaxel, showing a standard response price of 70.2% and median PFS of 8.9 months.8 Double HER2 blockade with docetaxelCtrastuzumabCpertuzumab or in second\range using the antibody\medication conjugate trastuzumab\emtansine also demonstrated promising effects.9, 10, 11 Finally, the high frequency (61.3%) of oncogenic drivers gene mutations gives personalized treatment plans.12 Regardless of the effectiveness of ADT in the palliative and adjuvant setting, ADT is only effective in a subgroup of patients and little is known about primary resistance mechanisms. Although AR expression, determined by immunohistochemistry, is a hallmark of SDC, intratumoral and intertumoral variation of AR expression is frequently observed.13 Therefore, variation in AR mRNA and Estetrol protein levels may cause variable responses. Furthermore, AR\V7, an AR splice variant that lacks the ligand\binding domain and is constitutively active, may cause ADT resistance. In prostate cancer expression is 20\fold higher in castration\resistant prostate cancer (CRPC) compared to hormone\na?ve prostate cancer, though in SDC the presence of has also been shown in hormone\na?ve tumors.14, 15 Another ADT resistance mechanism described in CRPC is increased expression of genes involved in intratumoral androgen synthesis.16 Key enzymes involved in the conversion of androgen precursors, such as dehydroepiandrosterone into dihydrotestosterone are aldo\keto reductase family 1 member C3 (and gene amplification or other tumor\driving gene mutations. The aim of our study was to assess these potential primary ADT resistance mechanisms in a cohort of R/M SDC patients receiving palliative ADT and a cohort of LA SDC patients receiving adjuvant ADT. For those factors that differed significantly between R/M SDC patients with and without clinical benefit Estetrol from ADT, the optimal cut\off value and survival differences were assessed. Subsequently, this cut\off value was used to evaluate DFS differences in the LA cohort. Methods Patients Clinicopathological characteristics and potential ADT resistance mechanisms were assessed in a cohort of R/M AR\positive SDC patients receiving palliative ADT (=?30) and a cohort of LA AR\positive SDC patients receiving adjuvant ADT (=?14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). ADT consisted of bicalutamide or LHRH\analog plus bicalutamide following shared decision making.5 Patients were treated in the Radboud.