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e15025 Background: Cancers have genomic mutations which drive their malignant phenotype. It has been the dream of precision oncology to identify each principal driving mutation, administer therapy directed at a specific defect and thereby provide the most clinical benefit with least toxicity. Previous reports have emphasized the likelihood of finding a targetable mutation in advanced malignancies, however we question the degree of benefit seen in genomic profiling in community-based hospital systems. There are many hurdles to translating mutations into actual real-world benefit, and the effectiveness of commercial profiling is unknown. Methods: This study reviewed data collected by a Michigan Medical Community Cancer Center from 2003 to 2019. We completed a retrospective chart analysis on patients diagnosed with metastatic malignancies who completed genomic profiling with Tempus or Caris. The amount of benefit and cost efficacy were calculated. Results: A total of 102 patients completed genomic sequencing. Age, diagnosis, date of diagnosis, previous lines of therapy, type of next generation sequencing testing (NGS), molecular targets, and outcomes were recorded. Of the 102 individuals, 19 (18.6%) were referred to a clinical trial and 6 of the referred subjects (5.9%) were eligible and entered trials. Two individuals displayed a clinical response by CT imaging. Both were partial remissions lasting 161 and 56 days. An additional 13 patients (12.7%) had either identified mutational targets or high tumor mutational burden (TMB) which altered their therapies outside of a trial. With the addition of targeted agents, 4 patients (3.9%) displayed clinical benefit. Two of these patients had gastric and endometrial carcinoma with high TMB and were placed on immunotherapy. They experienced 638 and 465 days, respectively, of stable disease with partial response. One patient with breast cancer had an androgen receptor and a progression free survival (PFS) of 310 days on enzalutamide. Another breast cancer patient had a PIK3CA mutation with PFS of 131 days on alpelisib. Based on these results, the calculated price for testing alone was $94,817 for every year of PFS obtained, 63% obtained from immunotherapy in two patients with high TMB. The impact of PFS on the OS and cost per quality life-year could not be calculated from this data. Conclusions: These results are in concordance with the magnitude of targetable mutations seen in other publications. However, it brings into question the clinical benefit of NGS panels in a community hospital system. Genomic sequencing aids in the gathering of genetic information, however, at this time there appears to be little change in overall survival for most patients with advanced malignancies. We acknowledge that this is a moving target, and that the usefulness of NGS panels will improve as more treatments are developed. Future studies are needed to help understand the role of NGS at any given point of time.

e24279Background: Epithelial cancers express various tumor-associated carbohydrate antigens. Diagnostic and prognostic utility of expression of these antigens has been studied in cancers of thyroid...

e23111 Background: Many genomic alterations have been identified that are critical to the malignant phenotype. Some of these, termed “driver mutations”, are critical for tumor proliferation and progression. The landscape of targeted therapy has expanded as well. Next-generation sequencing (NGS) of tumors reveals cancer-related genomic alterations and provides therapeutic recommendations for specific targeted therapy. We analyzed our experience with FoundationOne, a validated NGS genomic profile in a community oncology network. Methods: NGS results from May 2014 to September 2016 from a community oncology network in Western Pennsylvania were analyzed. Medical records were reviewed for primary site, stage, biopsy site, timing of testing, prior treatment, FDA-approved therapy in patient’s and other tumor types and potential clinical trials based upon mutations detected. Endpoints determined were percentage of patients with targetable mutations and those in whom treatment decisions were made based on NGS results. Results: 157 NGS results were available for analysis. 38.2% cases were tested early in the disease course (at diagnosis, during or shortly after first-line treatment) and 61.8% at progression. FDA-approved targeted agent for a specific mutation was found in 14% of the primary tumor type and 19.8% of other tumor types. Clinical trials were available for 93% cases. The NGS results were utilized in treatment decisions in 28 patients of which, 9 were tested early and 19 at disease progression. Of the 28, 11 were initiated on a targeted agent. Median duration of targeted therapy was 2.6 months. 9 patients were on appropriate targeted agent prior to testing. 8 patients were unable to start the targeted agent because of insurance denial, clinical deterioration or patient preference. Conclusions: NGS is a valuable tool for personalizing cancer care. From our experience, the actual number of patients starting a targeted agent based on NGS results is low. It nevertheless can provide additional treatment options and facilitate clinical trial enrollment. Optimal timing of testing (early vs late), financial implications of testing and using targeted therapy and survival benefit of targeted therapy need further studies.

e22176 Background: Most neoplastic cells need oncogenes for maintenance of the malignant phenotype and cell survival. Overexpression of c-Myc has been documented in both high-grade pre-malignancy a...

2061 Background: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant ...

e16028 Background: Castrate resistant prostate cancer (CRPC) is the second leading cause of cancer-related death in men in the developed world. Several new therapies, including taxane-based chemoth...

7567 Background: The MET receptor tyrosine kinase and its ligand are associated with the malignant phenotype. In non-small cell lung cancer (NSCLC) MET expression increases with disease stage and is involved in de novo and acquired resistance to tyrosine kinase inhibitors. Despite this, in early stage NSCLC small data series have failed to demonstrate MET expression to be prognostic. We investigated a large cohort of patients who underwent curative surgical resection at our institution to determine whether MET receptor or gene amplification was prognostic. Methods: Tissue Microarrays (TMAs) were constructed using 1mm cores of FFPE primary NSCLC tissues in triplicate. TMAs were stained with the SP44 clone (Novus Biologicals) and a H-score calculated based on % cells stained and intensity; (%cellsx1)+(%cellsx2)+(%cellsx3) with a minimum of 0 and maximum of 300. The mean of triplicate values was calculated. MET gene amplification was detected using Ventana’s MET DNP probe with ultraView SISH DNP silver detection, performed on Ventana’s XT autostainer. DNA was isolated and subjected to mutational profiling using Sequenom’s LungCarta panel. Results: Data for 508 patients, 352 (69%) male, were available for analysis including 329 pathological node negative (pN0), 67 pN1, 104 pN2 and 8 patients with resected primaries and solitary brain metastases (M1). Most patients were smokers with only 33 (6%) non-smokers. The median MET H-score was 100 and consistent across N0, N1 and N2 patients, although was higher in M1 patients. Median H-scores were significantly higher in adenocarcinoma compared to squamous cell carcinoma (140 vs 91.5, p100) was seen in 227 (45%) patients and associated with significantly improved overall survival (HR 1.28 95% CI 1.04-1.59; p=0.023). In univariate analyses improved survival occurred in all stages and histologies. DNA and multivariate analyses are pending. MET gene copy number amplification was detected in 11 cases. Conclusions: In contradistinction to advanced NSCLC, increased MET receptor expression is associated with improved survival in a large cohort of early stage lung cancer. Further correlation with mutation status and gene rearrangements will be reported.

e13585 Background: mTOR plays a critical role in malignant phenotype in many tumors. Everolimus [RAD001 (40-O-(2-hydroxyethyl)-rapamycin)] is a rapamycin rapalog that is being developed as an antitumor agent and is approved for various cancers. Recently, RAD001 has also been reported to increase the radiosensitization following for amplifying the autophagic pathway; however, it could promote an alternative mechanism that leads to apoptosis. In HNSCC, radiation therapy is a common form of cancer treatment, but locoregional recurrence and/or distant metastasis is the most cause of failure after RT and it results in HNSCC significant morbidity. Evidence from previous studies showed that RAD001 enhanced the cytotoxic effects of radiation in HNSCC cell lines. The molecular mechanism of radiosensitization by RAD001 in HNSCC has not cleared.Our aim is to evaluate the role of molecular mechanism of RAD001-mediated radiosensitization in HNSCC. Methods: Radiosensitivity effects of RAD001 were assays on human oral squamous cell carcinoma cell lines (SCC4 and DuFa). RAD001 (30 and 300 nM)and radiation (0~8 Gy) alone and in combination were evaluated for antitumor activity in the clonogenic assay. Next, we also evaluated the RAD001 on radiation-induced signal transduction by western blot analysis. Results: Here, we show that 300nM RAD001 plus 6 Gy cohort with significant HNSCC cell line growth suppression compared to 6 Gy alone (p=0.004) or 30n MRAD001 plus 6 Gy (p=0.008). RAD001 treatment effectively reduces mTOR downstream effector p-S6 protein compared with the vehicle or irradiated alone. RAD001 + 6 Gy significantly increases p53 and PARP cleavage, which facilitates apoptosis. Unexpectedly, autophagy pathway, such as beclin 1 and LC3II were not affected by RAD001. Addiationlly, we discover that Akt phosphorylation (Ser473) is up-regulated after RAD001/and irradiation of HNSCC cells. Conclusions: These findings suggest radiosensitization by the RAD001 involves the induction of apoptosis in HNSCC. Notwithstanding, Akt signaling is increased under RAD001 and it could attenuate anticancer efficacy instead, contribute to the development of resistance.

e13569 Background: CHOP and CHOP-like chemotherapy are the most used regimens for the treatment of peripheral T-cell lymphomas (PTCLs) despite sub-optimal results. Histone deacetylase inhibitors (HDACIs) have shown class activity in PTCLs. The interaction between the HDACIs (depsipeptide (R), belinostat (B), vorinostat (V) and panobinostat (P)) and a DNMT inhibitor (decitabine (D) was investigated in vitro, in vivo and at the molecular level in T-cell lymphoma and leukemia cell lines (H9, HH, P12, PF-382). Methods: For cytotoxicity assays, luminescence cell viability assay was used (CellTiter-Glo). Drug:drug interactions were analyzed with relative risk ratios (RRR) based on the GraphPad software (RRR50s for B, R, V, P, D and 5-Azacytidine alone were assessed at 24, 48 and 72 hours. In cytotoxicity assays the combination of D plus B, R, V or P at 72 hours showed synergism in all the cell lines (RRRs 0.0007-0.9). All the cell lines were treated with D, B or R for 72 hours and all the combinations showed significantly more apoptosis than the single drug exposures and controls (RRR < 1). In vivo, HH SCID beige mice were treated i.p. for 3 cycles with the vehicle solution, D or B or their combination at increasing dose. The combination cohort showed statistically significant tumor growth inhibition compared to all the other cohorts. Gene expression analysis revealed differentially expressed genes and modulated pathways for each of the single agent treatment and the combination. The effects of the two drugs were largely different (only 39 genes modified in common). Most of the effects induced by the single agent were maintained in the combination group. Interestingly, 944 genes were modulated uniquely by the combination treatment. Conclusions: The combination of a DNMTI and HDACIs is strongly synergistic in vitro, in vivo and at the molecular level in model of T-cell lymphoma and these data will constitute the basis for a phase I-II clinical trials.

e14091 Background: In order to maintain their malignant phenotype, neoplastic cells must neutralize most of their tumor suppressor (TSP) and growth regulatory (GRP) proteins. CRM1, also called expo...

5074 Background: PI3K and its downstream mTOR play a critical role in malignant phenotype in many tumors. PI3K pathway is frequently hyper-activated in endometrial cancer through various PI3K/AKT a...

2098 Background: Historically, recurrent glioblastoma (GBM) has a median survival of three to six months. Since active Ras contribute to malignant phenotype of these brain tumors we are conducting ...

9001 Background: Indeterminate melanocytic lesions represent a therapeutic dilemma and improved diagnostic markers are needed. Expression of microRNAs (miRs) is altered in many tumors, however miR ...

15512 Background: The primary therapy for head and neck cancer consists of combination treatment with radiation and chemotherapy. While this combined modality approach is often curative, a significant fraction of patients have residual viable tumor cells after treatment that can result in progressive disease or relapse. We hypothesize that a significant contribution of cell survival results from interaction of cancer cells with the tumor microenvironment that includes soluble ligands of growth factor receptors and structural ligands of cell surface adhesion molecules. One of the growth factors with reported tumor survival effects is epidermal growth factor (EGF). We investigated the contribution of EGF to the relationship of 1483 head and neck cancer cells with their microenvironment. Methods: We treated 1483 head and neck cancer cells with variable concentrations of EGF from 0.1 to 20 nM and carried out western blots and flow cytometry to determine the expression of relevant integrins. Effects of interventions were evaluated by soft agar colony assays, proliferation and survival in tissue culture and adhesion to culture plates coated with integrin ligands. Results: Western blots demonstrated an EGF-induced increase in the expression of intgerin α5 but no change in the expression of integrins α2 or β1. The presence of dissolved fibronectin, a ligand of integrin α5β1, but not of collagen I, a ligand of integrin α2β1, provided a survival advantage to colonies in soft agar in EGF-treated cells. Experiments are determining whether this survival advantage translates to a shift in the dose-response curve to paclitaxel and ionizing radiation, on activation of caspases 3 and 8 and cleavage of poly (ADP- ribose) polymerase (PARP). These data are being correlated with EGF-induced modulation of adhesion to fibronectin, collagen and control plates. We have constructed adenoviral vectors expressing short hairpin RNA (shRNA) sequences to integrins α5 and α2 to confirm the role of integrin α5 expression in the EGF-induced modulation of survival. Conclusions: These data support a potential contribution to survival of head and neck cancer cells by modulation of integrins by EGF through interaction with their ligands in the microenvironment. No significant financial relationships to disclose.

553 Background: 30 percent of breast cancer patients overexpress the erbB2 (HER 2/neu) tyrosine kinase receptor. Tumors that overexpress this cell-surface receptor exhibit a malignant phenotype and...

9654 Background: Several methods are suited to classify different cancer types by testing RNA or protein expression. There is no method available to screen for DCIS. This study was performed to differentiate normal, premalignant, and malignant cases by protein profiling of human serum samples. In addition, the diagnostic value of SELDI-MS (surface-enhanced laser desorption ionisation -mass spectroscopy) for early diagnosis of DCIS was investigated. Methods: SELDI-MS potentiates quantitative measurement of complex protein mixtures such as blood serum. According to their isoelectric point, proteins of 5 to 200 kDa were separated on a mass spectroscopy sample carrier, and then analysed. Based on the obtained protein profiles, algorithms to predict the sample type were developed. Blood samples from about thirty women were analysed including cases without any breast-related lesion, with lesions of premalignant, and malignant phenotype, respectively. Results: SELDI analysis revealed a good differentiation betwe...