Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy–naïve salivary duct carcinomas

Yang, Richard K.; Zhao, Pei; Lu, Changxue; Luo, Jun; Hu, Rong

doi:10.1016/j.humpath.2018.09.009

Cited by 18 publications

(13 citation statements)

References 16 publications

(29 reference statements)

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“…This case shows the possible heterogeneity in AR expression in SDC metastases and could explain treatment resistance in such cases. Furthermore, we detected AR‐V7 mRNA expression in 95.3% of primary tumor samples, which is more frequent than the 37–70% of AR‐V7 positive SDC cases reported earlier . In CRPC, AR‐V7 expression explains at least in part the resistance to ADT, and AR‐V7 expression is elevated in response to ADT .…”

Section: Discussionsupporting

confidence: 51%

“…Furthermore, we detected AR-V7 mRNA expression in 95.3% of primary tumor samples, which is more frequent than the 37-70% of AR-V7 positive SDC cases reported earlier. 12,15,25 In CRPC, AR-V7 expression explains at least in part the resistance to ADT, 26 and AR-V7 expression is elevated in response to ADT. 14 We found AR-V7 expression prior to ADT.…”

Section: Discussionmentioning

confidence: 99%

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Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Boxtel¹,

Verhaegh

Grunsven

et al. 2019

Intl Journal of Cancer

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Androgen deprivation therapy (ADT) is first‐line palliative treatment in androgen receptor‐positive (AR+) salivary duct carcinoma (SDC), and response rates are 17.6–50.0%. We investigated potential primary ADT resistance mechanisms for their predictive value of clinical benefit from ADT in a cohort of recurrent/metastatic SDC patients receiving palliative ADT (n = 30). We examined mRNA expression of androgen receptor (AR), AR splice variant‐7, intratumoral androgen synthesis enzyme‐encoding genes AKR1C3, CYP17A1, SRD5A1 and SRD5A2, AR protein expression, ERBB2 (HER2) gene amplification and DNA mutations in driver genes. Furthermore, functional AR pathway activity was determined using a previously reported Bayesian model which infers pathway activity from AR target gene expression levels. SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit from ADT compared to those without benefit. Survival analysis showed a trend toward a longer median progression‐free survival for patients with high SRD5A1 expression levels and high AR pathway activity scores. The AR pathway activity analysis, and not SRD5A1 expression, also showed a trend toward better disease‐free survival in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 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.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Boxtel¹,

Verhaegh

Grunsven

et al. 2019

Intl Journal of Cancer

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“…For instance, alterations in phosphoinositide 3‐kinase (PI3K) signaling, either by PIK3CA mutation or PTEN loss, may be involved in resistance to HER2‐targeted therapy . Additionally, the discovery of constitutively active AR splice variants, notably AR splice variant‐7 (AR‐V7), which are implicated in resistance to ADT in prostate cancer, has led to the discovery of these variants in SDC specimens as well . A small study conducted by Cappelletti et al suggests that the presence of AR‐V7 in SDC cells may likewise affect response to ADT, but this requires more extensive investigation.…”

Section: Introductionmentioning

confidence: 99%

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

et al. 2019

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Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant‐7 (AR‐V7) in some SDC cases could result in resistance to anti‐androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next‐generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR‐V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%‐8%) programmed death ligand 1 (PD‐L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre‐treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti‐androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD‐L1, mitogen‐activated protein kinase, and PIK3CA pathways.

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“…In tissue-based studies, the use of the RM7 (RevMab) antibody further established CRPC-specific expression AR-V7 48 , 50 , 55 . Interestingly, AR-V7 protein expression was detected using this well-validated antibody in a subset of cells in small cell prostate carcinoma and some salivary ductal carcinoma specimens from untreated female patients 52 , 56 . These recent studies on AR-V7 protein expression further supported that AR-V7 expression arises specifically in a low androgen environment.…”

Section: Advances In Ar-v Measurement and Detection Methodsmentioning

confidence: 99%

Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations

Brown

Antonarakis

et al. 2020

Prostate Cancer Prostatic Dis

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Background: The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance. Methods: We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics. Results: Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in-situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR variant-7 (AR-V7) remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 co-exists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their co-regulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain. Conclusions: Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.

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Expression pattern of androgen receptor and AR-V7 in androgen-deprivation therapy–naïve salivary duct carcinomas

Cited by 18 publications

References 16 publications

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations

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