Adenoid Cystic Carcinoma Patients Research Articles

Radiosensitization Through Targeting Molecular Alterations in Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck. There are currently no approved systemic agents for ACC and no data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated model systems has hampered research efforts. We report the establishment and propagation of an ACC patient–derived xenograft (PDX), genomic evaluation of cancer-associated mutations, and in vivo response profiles to personalized radiosensitization agents based on next-generation sequencing. An ACC PDX was established and maintained in NOD-SCID gamma (NSG) mice directly from the patient. Common cancer-associated mutations were identified using the Illumina TruSeq Amplicon Cancer panel. PDXs were treated with focal radiation or chemotherapy selected based on the genomic profile of the cancer. Focal radiation was delivered at 5 Gy x 8 fractions twice weekly for 4 weeks. Tumor size was measured over time and comparisons between treatment groups made by repeated measures ANOVA. Target inhibition in vivo was confirmed via western blot of tumor lysates and IHC of FFPE tissue. The histologic and physical characteristics of the primary human tumor are maintained in this ACC PDX. Mutations in the receptor tyrosine kinases (RTKs) cKit and KDR/VEGFR2 were identified. No mutations were identified in EGFR, RAS, or PIK3CA. Several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/mTORC inhibitor, and cetuximab, an EGFR mAB. Target inhibition was confirmed by western blot and IHC. Radiation temporarily halted tumor growth. Treatment with molecularly targeted agents prolonged time to tumor doubling compared to control treatment (p<0.05 for each). Chemoradiation resulted in significant tumor regression which persisted more than 2 months after the end of treatment. PDXs are a powerful model system for investigating potential radiosensitizers based on individual tumor characteristics. Our ACC PDX represents one of only a handful of tools for studying this rare disease. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor-specific genetic biomarkers. Expansion of these studies may be valuable to advance the design of new treatment strategies for ACC.

Phase 2 Study of Apatinib, A Novel VEGFR Inhibitor in Patients With Recurrent and/or Metastatic Adenoid Cystic Carcinoma of the Head and Neck: Preliminary Results

Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with incurable, recurrent/metastatic(R/M) ACC of the head and neck. This multicenter, open-label, single arm study enrolled patients with pathologically confirmed recurrent and/or metastatic ACC of the head and neck for whom at least 1 line of systemic chemotherapy had failed as well as a disease radiographic progression was suggested within three months. The primary endpoint of this study was progression-free survival (PFS). Apatinib was administered as 500 mg daily. Secondary endpoints included best objective response (BOR), disease control rate (DCR), overall survival (OS), and toxicity (Clinical trial information: NCT02775370). Between April 2016 and May 2017, 32 patients were registered and evaluable for efficacy analysis. The median progression-free survival (PFS) of all 32 patients was 4 months (range 1-11 months). Tumor shrinkage was achieved in 24 (75%); 14 (43.8%) had confirmed partial responses (ORR). Seventeen (53.1%) patients had stable disease, 8 of whom had disease stability for > 4 months, DCR was 90.6% (29/32). The recurrent diseases had better response rates than metastatic diseases. Twenty (62.5%) patients experienced dose reduction during treatment. The most common grade 3/4 treatment-related AEs were hypertension (31.3%), hand-foot syndrome (9.4%), proteinuria (12.5%) and fatigue (6.3%). Of three possibly drug-related SAEs recorded in the study, 2 deaths occurred and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization. Apatinib exhibited objective efficacy in R/M ACC patients with manageable toxicity. Further prospective studies that enroll more patients with longer follow-up time are warranted.

Primary Salivary Type Lung Cancers in the National Cancer Database

Primary salivary type lung cancers such as adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC) are uncommon primary lung tumors that, given their rarity, remain incompletely understood. This study aimed to characterize the management and outcomes associated with these less common pulmonary malignancies. Patients in the National Cancer Database diagnosed with primary lung and bronchial (not tracheal) MEC and ACC between 2004 and 2014 were identified. Adjusted mortality risk of surgically managed patients was evaluated in multivariable Cox proportional hazards regression models. In all, 699 MEC patients and 424 ACC patients were identified. The MEC tumors were smaller (mean size 3.1 cm versus 3.8 cm, p < 0.001), less likely to have lymph node metastases (16% versus 38%, p < 0.001), and less likely to undergo pneumonectomy (9% versus 39%, p< 0.001) compared with ACC. Adjusted Cox models of the surgically managed subset of MEC patients identified high tumor grade (hazard ratio [HR] 3.0, 95% confidence interval [CI]: 1.31 to 7.1, p= 0.01), tumor size greater than 4 cm (HR 6.7, 95% CI: 2.0 to 22.0, p= 0.01), and wedge resection (HR 3.7, 95% CI: 1.1 to 12.0, p= 0.03) to be associated with increased risk of death. For ACC patients, incomplete tumor resection, R1 versus R0 (HR 4.0, 95% CI: 1.5 to 10.6, p= 0.006), and distant metastases (HR 12.6, 95% CI: 2.5 to 64.4, p= 0.002) were associated with increased mortality. Pulmonary MEC and ACC appear to have distinct physical and oncologic attributes in the National Cancer Database. Although the overall prognosis appears to be favorable, there are subsets of primary salivary type lung cancers with increased mortality risk, and efforts should be made to completely resect these tumors.

Cellular Subtype May Predict Survival Outcomes in Salivary Adenoid Cystic Carcinoma Patients: A Single-Institution Experience

Background Adenoid cystic carcinoma (ACC) is a biphasic salivary gland malignancy that is characterized by cellular, morphologic, and clinical heterogeneity. ACCs are the second most common salivary gland malignancy, are the most common malignancy of minor salivary glands, and comprise 15 to 25% of all salivary carcinomas. ACC arises from the intercalated ducts, which are composed of inner ductal epithelial and outer myoepithelial cell. The histogenesis of these tumors is uncertain. However, an origin from stem cells with multidirectional differentiation is likely possible. Histologic architecture alone determines the grade of ACC: tubular and cribriform growth patterns are associated with a longer survival time than solid forms are. We are currently starting to understand and get insights into intrinsic subtypes of this cancer directly linked to the dominant myoepithelial (M-ACC) or epithelial (E-ACC) cell type.

Mortality risk after clinical management of recurrent and metastatic adenoid cystic carcinoma

BackgroundManagement of locoregional recurrence (LRR) and distant metastasis (DM) in adenoid cystic carcinoma (ACC) is guided by limited data. We investigated mortality risks in patients diagnosed and treated for recurrent ACC.MethodsA retrospective review of ACC patients treated from 1989 to 2016 identified 36 patients with LRR or DM. High-risk disease was defined as skull base involvement (for LRR) or International Registry of Lung Metastases Group III/IV or extrapulmonary site of metastasis (for DM). Kaplan-Meier method, log-rank tests, and Cox proportional hazards were used for time-to-event analysis.ResultsAmong 20 LRR and 16 DM patients, the median times to recurrence were 51 and 50 months, respectively. The median follow-up post-recurrence was 37.5 months (interquartile range (IQR)16.5–56.5). Post-recurrence 3-year overall survival (OS) was 78.5%, 73.3% for LRR and 85.1% for DM (p = 0.62). High-risk recurrences were associated with worse 3-year OS (68.8% for high-risk and 92.3% for low-risk, χ2 = 10.4, p = 0.001).Among LRR patients, 90% had surgery as part of their treatment. Multimodality therapy, age, and histopathologic features (size, margins, solid histology, lymphovascular or perineural invasion) were not associated with PFS or OS. High-risk LRR was the only variable associated with OS (χ2 = 5.9, p = 0.01).Among DM patients, six were initially managed with observation and ten received surgery, RT, or systemic therapy. Upfront therapy was not associated with improved PFS or OS. High-risk DM was the only variable associated with OS (χ2 = 4.7, p = 0.03).ConclusionsHigh-risk LRR and DM were associated with decreased 3-year OS. More effective therapies are needed for high-risk ACC recurrences.

AKT3 drives adenoid cystic carcinoma development in salivary glands.

Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K‐AKT‐mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.

Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes.

The relative rarity of salivary gland adenoid cystic carcinoma (ACC) and its slow growing yet aggressive nature has complicated the development of molecular markers for patient stratification. To analyze molecular differences linked to the protracted disease course of ACC and metastases that form 5 or more years after diagnosis, detailed RNA-sequencing (RNA-seq) analysis was performed on 68 ACC tumor samples, starting with archived, formalin-fixed paraffin-embedded (FFPE) samples up to 25 years old, so that clinical outcomes were available. A statistical peak-finding approach was used to classify the tumors that expressed MYB or MYBL1, which had overlapping gene expression signatures, from a group that expressed neither oncogene and displayed a unique phenotype. Expression of MYB or MYBL1 was closely correlated to the expression of the SOX4 and EN1 genes, suggesting that they are direct targets of Myb proteins in ACC tumors. Unsupervised hierarchical clustering identified a subgroup of approximately 20% of patients with exceptionally poor overall survival (median less than 30 months) and a unique gene expression signature resembling embryonic stem cells. The results provide a strategy for stratifying ACC patients and identifying the high-risk, poor-outcome group that are candidates for personalized therapies.

Cellular subtype may predict survival outcomes in salivary adenoid cystic carcinoma patients-a single-institution experience.

Cellular subtype may predict survival outcomes in salivary adenoid cystic carcinoma patients-a single-institution experience.

Abstract 5187: Potent radiosensitization of adenoid cystic carcinoma in a patient derived xenograft model using the MDM2 inhibitor AMG 232

Abstract Purpose: Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents for ACC and no established data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated preclinical model systems has hampered research efforts. We report the successful establishment and propagation of an ACC patient derived xenograft (PDX), genomic evaluation of cancer associated mutations, and in vivo response to MDM2 inhibition combined with radiotherapy. Because TP53 mutations are seen in &amp;lt;5% of ACCs, we investigated the role of a small molecule MDM2 inhibitor, AMG 232. Methods: An ACC PDX was established and assessed for common cancer-associated mutations using the Illumina TruSeq Amplicon Cancer panel. Xenografts were treated with focal radiation with or without AMG 232. Focal radiation was delivered at 0, 2, 5, or 8 Gy x 8 fractions delivered twice weekly, with AMG 232 (50mg/kg) delivered daily by oral gavage. Tumor size was measured by caliper and comparisons between treatment groups made using a repeated measures ANOVA. A TCD50 was calculated by fitting log-transformed data to a dose-response curve and compared using the extra-sum-of-squares f test. Target inhibition and anti-cancer effect was confirmed via immuno-blotting of tumor lysates, and IHC staining or in situ hybridization of relevant targets within FFPE sections of tumors harvested 2 and 48 hrs post treatment. Results: The histologic characteristics of the primary human tumor are maintained in subsequent murine passages of this ACC PDX. Mutational profiling determined that the PDX was wildtype for TP53. AMG 232 alone resulted in modest slowing of tumor growth. Radiation alone produced a tumor growth delay in a dose dependent manner but did not result in sustained local tumor control. Strikingly, the combination of AMG 232 with RT (including low dose radiation of 2 Gy) produced dramatic tumor shrinkage and potent tumor control three months after the end of treatment. Target inhibition of MDM2 was confirmed by western blot of tumor lysates and IHC of FFPE samples taken 2 hrs post treatment. Antiproliferative and apoptotic effects were confirmed by western blot of tumor lysates and IHC of FFPE samples taken at 48 hrs post treatment. Conclusions: This study suggests that MDM2 inhibition may provide potent radiosensitization in TP53 WT ACC. While additional translational models are warranted, the powerful response profile observed suggests that phase I clinical trial evaluation of this combination is worthy for this challenging malignancy. Citation Format: Amal Javaid, Adam D. Swick, Lauryn Werner, Prashanth Prabakaran, Rong Hu, Kwangok P. Nickel, Irene Ong, Emmanuel Sampene, Justine Bruce, Gregory Hartig, Aaron Wieland, Jude Canon, Paul Harari, Randall Kimple. Potent radiosensitization of adenoid cystic carcinoma in a patient derived xenograft model using the MDM2 inhibitor AMG 232 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5187. doi:10.1158/1538-7445.AM2017-5187

Abstract 3738: Use of tumor mRNA expression for patient selection in a phase I study of the pan-fibroblast growth factor receptor inhibitor BAY 1163877

Abstract BAY 1163877 is a potent and selective, oral, small molecule pan-FGFR inhibitor with anti-tumor activity in a wide range of cancer types. In vivo profiling in xenograft models identified tumor FGFR mRNA levels as a predictor of drug efficacy. Anti-tumor efficacy was largely independent of the tumor type surveyed or the FGFR isoform being overexpressed. Preclinical models included a patient-derived squamous head and neck cancer (HNSCC) xenograft (PDx) model overexpressing FGFR3 mRNA, a bladder cancer PDx model overexpressing FGFR2 mRNA, and a squamous esophageal cancer PDx model overexpressing FGFR1 mRNA. Against this background, clinical proof-of-concept was assessed by enrolling patients into the stratified expansion cohort of a Phase 1 study of BAY 1163877 (NCT01976741) based on tumor FGFR1-3 mRNA levels. FGFR1-3 mRNA was quantified in archival or newly obtained FFPE tumor biopsies by RNA in situ hybridization (RNAscope, ACD) and digital transcript counting (NanoString). In total, biopsies from &amp;gt; 500 patients were studied for FGFR1-3 mRNA expression levels. Based on preclinical xenograft experiments showing that low to moderate FGFR1-3 mRNA overexpression was not sufficient for a robust drug response, only patients with an RNAscope score of 3 or 4 (range 0-4) or a normalized Nanostring signal of 800 counts were eligible for enrollment. By applying these stringent criteria, FGFR1-3 mRNA positivity was on average observed with a 2- to 3-fold higher prevalence than published data for genetic aberrations of FGFRs in the respective tumor types (including amplifications, translocations, mutations). We further identified FGFR mRNA(+) tumor types in which genetic FGFR aberrations have not been previously reported. FGFR1-3 mRNA positivity ranged from 10% in lung adenocarcinoma to 45% in squamous non-small cell lung cancer (sqNSCLC) and 54% in HNSCC. As of August 2016, 57 FGFR mRNA(+) patients were enrolled and treated with BAY 1163877. Six patients experienced a partial remission (PR) by RECIST v1.1 criteria; including an FGFR3 mRNA(+) HNSCC patient without FGFR3 amplification or translocation, an FGFR1 mRNA(+) adenoid cystic carcinoma patient, and an FGFR1 mRNA(+) sqNSCLC patient (both without FGFR1 gene amplification), as well as an FGFR3 mRNA(+) bladder cancer patient without FGFR3 amplification, mutation or translocation. These results suggest that high FGFR1-3 mRNA expression identifies patients sensitive to FGFR inhibition. This population includes patients with and without genetic aberrations of FGFR1-3 encoding genes. In summary, an mRNA expression-based selection approach may identify a broader patient population with potential benefit from BAY 1163877, including tumor types not previously associated with altered FGFR signaling. Citation Format: Peter Ellinghaus, Matthias Ocker, Sebastian Bender, Christoph Kneip, Stuart Ince, Markus Joerger, Martin Schuler. Use of tumor mRNA expression for patient selection in a phase I study of the pan-fibroblast growth factor receptor inhibitor BAY 1163877 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3738. doi:10.1158/1538-7445.AM2017-3738

Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling.

Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target. Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided. The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04). MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.

Risk factors and prognosis for salivary gland adenoid cystic carcinoma in southern china: A 25-year retrospective study.

Adenoid cystic carcinoma (ACC) is characterized by slow growth, frequent local recurrences, and high incidence of distant metastasis (DM). The aim of this study was to evaluate predictive factors for local-regional (LR) recurrence, DM, and survival in ACC.A retrospective review of the medical records for patients with salivary glands ACC from 1990 to 2015 was performed. The clinical parameters were assessed to identify correlations with the development of LR recurrence, DM, and survival of these patients.Among 228 patients who underwent surgery as definitive treatment, 210 (92.1%) were followed up in the study. DM was detected in 64 (30.5%) patients, LR recurrence was detected in 58 (27.6%) patients. The estimated 5, 10, and 15-year overall survival rates were 84.7%, 70.8%, and 34.0%, respectively. Multivariate analysis revealed that the presence of lymphovascular invasion and a high T classification were very strong adverse factors, which independently influenced LR recurrence, DM, and survival of ACC patients. Positive/close margin and N+ status were independent risk factors for DM and LR recurrence, respectively. Survival of ACC patents was also affected by tumor location.Presence of lymphovascular invasion and a high T classification were very strong adverse factors and independent predictors for ACC patients’ prognosis, which influenced LR control, DM control, and survival.

The cross-contaminated cell lines of adenoid cystic carcinoma: A crucial concern

Adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, characterized by slow growth but high incidence of distant metastasis. Distant metastasis occurs in 25%–50% of ACC patients and more commonly in lungs. However, the molecular mechanism underlying the aggressive growth of ACC remains obscure. Human tumor cell lines are extremely useful in studying cancer biology, under both in vitro and in vivo condition. Unfortunately, the tumor cell lines are susceptible to cross-contamination, by other cell lines, during routine culture. Recent studies have proved that most of the ACC cell lines, established for preclinical research, are either cross-contaminated or nonhuman cells. Here, we review the literature assessing the identity of ACC cell lines, dated up to September 1, 2016, using PubMed, EMBASE, and the China National Knowledge Infrastructure databases with the following keywords: “adenoid cystic carcinoma,” “cell line,” and “characterization” or “contamination.” According to the results, only salivary adenoid cystic carcinoma (SACC)-83/SACC-lung metastasis, the HPV-transformed ACC-112 and the two newly established moderately differentiated adenocarcinoma-ACC-01 and LACC-1 cell lines are authentic ACC cell lines. These results suggest that, in the future, it is crucial to authenticate the ACC cell lines before research.

Maxillofacial rehabilitation of adenoid cystic carcinoma patient using full mouth fixed implant and pharyngeal obturator: a clinical report

Maxillofacial rehabilitation of adenoid cystic carcinoma patient using full mouth fixed implant and pharyngeal obturator: a clinical report

Maxillofacial rehabilitation of adenoid cystic carcinoma patient using full mouth fixed implant and pharyngeal obturator: a clinical report

Maxillofacial rehabilitation of adenoid cystic carcinoma patient using full mouth fixed implant and pharyngeal obturator: a clinical report

Clinical outcomes and prognostic factors of salivary gland adenoid cystic carcinomas: a case control study

To determine whether there was any difference in the clinical and pathologic features, management, and survival outcomes based on tumor site for salivary adenoid cystic carcinoma (ACC). This study is a retrospective chart review of 63 salivary ACC patients. These patients were subclassified into 2 groups, the minor salivary glands group (MiSGG) and the major salivary glands group (MaSGG). With a median follow-up time of 69.6months, the overall 5-year locoregional failure-free survival, distant metastasis-free survival, overall survival (OS), and cancer-specific survival (CSS) rates were 83.1%, 74.9%, 84.7%, and 89.1%, respectively. Compared with MaSGG patients, MiSGG patients were characterized by a trend toward higher T classification (P=.054). In multivariate analysis, age, T classification, and radiotherapy were independent factors for OS, whereas N classification, margin status, and tumor site (minor or major salivary glands) were observed to be independent prognostic factors for CSS. Compared with MaSGG patients, MiSGG patients were characterized by a trend toward higher T classification. Tumor site (minor or major salivary glands) was observed to be an independent prognostic factor for CSS of salivary ACC.

Abstract 3044: Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity

Abstract Background: Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck region. Hallmark characteristics include slow growth rate, peri-neural tumor spread, and a high propensity for late distant metastasis. Surgery and radiation are the mainstays of treatment with no effective systemic agents to date. Due to infrequency, studies of novel therapeutics are not routinely feasible. In addition, whether these tumors can be sensitized to radiation by concurrent chemotherapy is not known. We report here the establishment and examination of ACC patient derived xenografts (PDX) to investigate the efficacy of novel chemotherapies and combinations of chemotherapy and radiation. Methods: PDXs have been established and maintained in NOD-SCID gamma (NSG) mice from both research biopsies and surgical specimens. Common cancer-associated mutations in both the primary patient tumor and PDX were identified using the Illumina TruSeq Amplicon Cancer panel. Well described immunohistochemical markers of ACC were used to compare histological characteristics between the primary tumor and PDX. The ACC PDX was engrafted into the flanks of nude mice and treated with focal radiotherapy (5 Gy x 8 fractions delivered twice weekly), a panel of chemotherapeutic agents, or combination radiochemotherapy. Tumor size was measured over time and comparisons between treatment groups made by the extra-sum-of-squares f test. Results: PDXs established from ACC maintain the histologic and physical characteristics of the primary tumor. Targeted mutational analysis of ACC identified expected alterations based on previously reported large scale sequencing of other human tumors including mutations in the receptor tyrosine kinases(RTKs) cKit and KDR/VEGFR2. Based on identified tumor mutations, several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/mTORC inhibitor, and cetuximab, an EGFR mAB. Treatment with each of these compounds showed varying degrees of growth inhibition without evidence of frank tumor regression. However, combining these drugs with radiation demonstrated significantly improved tumor control in comparison to drug alone. Conclusions: Studies using our PDX model suggest that several molecular targeting agents can significantly augment the impact of radiation on ACC tumor growth. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor specific genetic biomarkers. Expansion of these ACC studies may be valuable to advance the design of new investigational treatment strategies for this challenging tumor. Citation Format: Prashanth Prabakaran, Kwangok P. Nickel, David T. Yang, Lauryn R. Werner, Justine Y. Bruce, Aaron M. Wieland, Timothy M. McCulloch, Gregory K. Hartig, Paul M. Harari, Adam D. Swick, Randall J. Kimple. Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3044.

Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma.

Retrospective analyses were done on 19 lacrimal adenoid cystic carcinoma (ACC) patients who underwent curative treatment between 1997 and 2013. Nine patients (47.4%) had T1-2 disease and ten (52.6%) had T4 disease. Surgical procedures were globe-preserving tumor resection in 11 patients (57.9%), incisional biopsy in five (26.3%), and orbital exenteration was undertaken in three (15.8%). Residual tumor burdens were R0/1 in 12 patients (63.2%) and R2 in seven (36.8%). Radiation therapy (RT) was recommended to all patients, and 16 (84.2%) completed RT (median 60 Gy). After median follow-up of 57.5 months, seven (36.8%) developed progression and three (15.8%) died. Local recurrence occurred in four patients (21.1%), distant metastasis in one (5.3%), and combined local recurrence and distant metastasis in two (10.5%). Progression-free survival and overall survival rates at 5-years were 64.5% and 82.6%, respectively. Among 12 patients following R0/1 resection, two (16.7%) developed local recurrence and none died, while among seven following R2 resection, five (71.4%) developed progression and three (42.9%) died. RT following R0/R1 resection could reduce progression. Globe-preserving surgery and RT seemed optimal strategy for T1-2 disease. Careful attention should to be paid to minimize residual tumor burden at surgery and effort for safe radiation dose escalation would be desired.

Clinical outcomes of adenoid cystic carcinoma of the head and neck: a single institution 20-year experience.

This study reports the clinical outcomes of head and neck adenoid cystic carcinoma treatment over a 20-year period. The treatment outcome of 51 head and neck adenoid cystic carcinoma patients treated between 1992 and 2013 were analysed. Patients were stratified into radical treatment and disease control groups. A total of 40 patients underwent surgery and post-operative radiotherapy. The 10-year disease-specific survival rate was 93 per cent. Eleven patients had tumour recurrence: of these, nine were pulmonary metastases. The 11 patients in the disease control group had a median follow up of 21 months (range, 2-172 months); 5 underwent radical radiotherapy with palliative intent. There was late tumour recurrence in over 25 per cent of patients. Adenoid cystic carcinoma has a high tendency to relapse even after radical excision and adjuvant therapy. However, definitive radiotherapy should still be considered on an individual basis because it may provide local control and prolong patient survival.

The impact of the MYB-NFIB fusion proto-oncogene in vivo

Recurrent fusion of the v-myb avian myelobastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) generates the MYB-NFIB transcription factor, which has been detected in a high percentage of individuals with adenoid cystic carcinoma (ACC). To understand the functional role of this fusion protein in carcinogenesis, we generated a conditional mutant transgenic mouse that expresses MYB-NFIB along with p53 mutation in tissues that give rise to ACC: mammary tissue, salivary glands, or systemically in the whole body. Expression of the oncogene in mammary tissue resulted in hyperplastic glands that developed into adenocarcinoma in 27.3% of animals. Systemic expression of the MYB-NFIB fusion caused more rapid development of this breast phenotype, but mice died due to abnormal proliferation in the glomerular compartment of the kidney, which led to development of glomerulonephritis. These findings suggest the MYB-NFIB fusion is oncogenic and treatments targeting this transcription factor may lead to therapeutic responses in ACC patients.