Profiling of 149 Salivary Duct Carcinomas, Carcinoma Ex Pleomorphic Adenomas, and Adenocarcinomas, Not Otherwise Specified Reveals Actionable Genomic Alterations

Wang, Kai; Russell, J S; McDermott, Jessica D.; Elvin, Julia A.; Khaira, Depinder; Johnson, Adrienne; Jennings, Timothy A.; Ali, Siraj M.; Murray, Molly; Marshall, Carrie B.; Oldham, Dwight S.; Washburn, Donna; Wong, Stuart J.; Chmielecki, Juliann; Yelensky, Roman; Lipson, Doron; Miller, Vincent A.; Stephens, Philip J.; Serracino, Hilary S.; Ross, Jeffrey S.; Bowles, Daniel W.

doi:10.1158/1078-0432.ccr-15-2568

Cited by 108 publications

(128 citation statements)

References 52 publications

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“…In salivary tumours, p53 mutations are commonly identified, and that identification is consistent in cxpa 20 . Anomalies in cyclin-dependent kinases and inhibitors cox2 and fgf2 have also been identified in other studies [21][22][23] . Although potential targets have been identified (MYC, HMGA2, MDM2, COX2, and FGF2) for which inhibitors are in development, none has been reported as attempted for patient management.…”

Section: Discussionsupporting

confidence: 61%

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

Chooback

Shen²,

Jones³

et al. 2017

Current Oncology

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The most common benign salivary tumour is a pleomorphic adenoma. Transformation to malignancy, carcinoma ex pleomorphic adenoma (cxpa), occurs in 6% of cases. Management focuses on surgical resection and radiotherapy; however, rare cases require systemic management. We present the case of a 60-year-old woman with a cxpa of the left parotid gland who required systemic therapy for locally recurrent disease. Treatment options were guided by the literature concerning malignant salivary gland tumour and by whole-genome and transcriptome sequencing of the tumour. The patient received multiple systemic agents during the course of her disease, with cyclophosphamide-doxorubicin-cisplatin providing the best control (partial response). Genomeand transcriptome-directed therapy, including sorafenib and vismodegib, were utilized with limited clinical benefit. Malignant transformation in cxpa is a complex process, and therapy directed at a single tumour pathway might not be sufficient to control disease.

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Section: Discussionsupporting

confidence: 61%

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

Chooback

Shen²,

Jones³

et al. 2017

Current Oncology

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“…More importantly, 91.5% of these patients had at least one aberration that was potentially targetable by an FDAapproved drug or an investigational agent in a clinical trial, showing that research on targeted therapies based on molecular profiling is worthwhile [81]. A study of 149 patients also had similar results, with further alterations in RAS, ERBB2, NOTCH1, NF1, and RET, showing diverse genetic alterations that may lead to novel treatment options [69]. The molecular targets and the signaling pathways activated by the previously described translocations for MEC, AdCC, and SC are also of potential therapeutic use.…”

Section: Clinical Relevance Of Heterogeneitymentioning

confidence: 88%

“…In addition, ERBB2 overexpression and amplification similar to those which occur in SDC [68,69], copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) [70], MDM2 amplification [71,72], loss of heterozygosity, and microsatellite alterations in the p53 and RB genes and at chromosomal location 5q [73] are all secondary genetic alterations detected in CPA and may be of importance for disease progression from PA.…”

Section: Pa and Its Progression: An Example Of Recurrent Genetic Altementioning

confidence: 99%

Salivary Gland Neoplasms: Does Morphological Diversity Reflect Tumor Heterogeneity

Rito¹,

Fonseca²

2017

Pathobiology

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Salivary gland tumor classification encompasses a vast list of benign and malignant neoplasms. Their morphological diversity is recognized not only between different entities but also within individual tumors. Tumor categories as described by the World Health Organization reflect, in part, a true genetic heterogeneity (e.g., translocations involving CRTC1 and CRTC3-MAML2 genes in mucoepidermoid carcinoma and MYB-NFIB fusion in adenoid cystic carcinoma). Carcinoma ex pleomorphic adenoma shows diversity in its histological appearance, but recurrent rearrangements on PLAG1 and HMGA2 are common to its benign precursor. More recently, new categories have been defined, like secretory carcinoma with the t(12;15) (p13;q25) ETV6-NTRK3 translocation and clear-cell carcinoma with EWSR1-ATF1 fusion. Recent studies on cribriform adenocarcinoma of minor salivary gland origin and epithelial-myoepithelial carcinoma point to a correlation with their morphological features. All of these advances show that the search of a histogenetic and genetic basis for salivary gland tumors is helping to clarify morphological categories and unraveling new ones. Nevertheless, currently morphology is still the hallmark of tumor classification and the gold standard. The therapeutic options for advanced tumors remain very limited but the discovery of translocation-generated gene fusions and increased knowledge of the genomic information of salivary gland tumors is creating opportunities for the development of specific targeted therapies.

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“…One of the most frequently altered pathways is the PI3K/AKT/mTOR pathway, with many SDC specimens showing mutations and copy number variations in PIK3CA , PTEN , RICTOR , AKT1 , AKT3 , and/or PIK3R1 [57–60]. As with other tumor types, TP53 mutations, HRAS/NRAS mutations and alterations in cyclin D1/CDK pathways are also found with relative frequency in SDC [4, 50, 57, 59, 61, 62]. A few studies have demonstrated loss of p16 expression [3, 4, 18].…”

Section: Mutational Landscape Of Sdcmentioning

confidence: 99%

“…A few studies have demonstrated loss of p16 expression [3, 4, 18]. Combinations of alterations in more than one of these pathways is also relatively common in SDC [50, 57, 61]. Other less common gene expression patterns and genomic alterations have been found in small numbers of studies including few tumors, and their significance is unclear [3, 27, 31, 50, 61, 63–67].…”

Section: Mutational Landscape Of Sdcmentioning

confidence: 99%

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

2017

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Salivary duct carcinoma (SDC) is a rare, aggressive salivary malignancy that is often diagnosed at an advanced stage. Previously, little was known about outcomes of this disease due to its rarity. In the past several years, much has been learned about salivary duct carcinoma after publication of outcomes from several large single-institution series and national database searches. Recent studies of genomic alterations have helped elucidate the biology and pathogenesis of this aggressive disease. Here we review outcomes of the disease, effects of treatment, prognostic factors, and genomic alterations in SDC. Studies of targeted therapy and promising future directions are also discussed.

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Profiling of 149 Salivary Duct Carcinomas, Carcinoma Ex Pleomorphic Adenomas, and Adenocarcinomas, Not Otherwise Specified Reveals Actionable Genomic Alterations

Abstract: CGP of salivary adenocarcinoma, NOS, SDCs, ca ex PA, and carcinoma, NOS revealed diverse GAs that may lead to novel treatment options. Clin Cancer Res; 22(24); 6061-8. ©2016 AACR.

Cited by 108 publications

References 52 publications

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

Carcinoma Ex Pleomorphic Adenoma: Case Report and Options for Systemic Therapy

Salivary Gland Neoplasms: Does Morphological Diversity Reflect Tumor Heterogeneity

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

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