TPS773 Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.
Abstract Introduction: Caveolin-1 (Cav1) is associated with basal-like triple-negative (ER-/PR-/Her2-) breast cancers (TNBC). Its biological contribution to this subtype has not been fully explored and controversy persists regarding the molecular role of Cav1 in carcinogenesis. Experimental Procedures: Thirty-four TNBC (17 Cav1+/17 Cav1-) patients molecularly-profiled with a commercial assay (Caris Life Sciences, AZ) were evaluated retrospectively. Cav1 status was determined by immunohistochemistry (caveolin-1 polyclonal; ≥2+ ≥50%). The majority of specimens (28/34) used for profiling were from primary breast sites and contained ≥50% neoplastic cells. The transcriptomes were profiled using Illumina's HumanHT-12 microarray (v4). Data were normalized using mean normalization procedure. Differential expression analysis was performed using R's Limma package. Pathway analysis was carried out using R's signaling pathway impact analysis (SPIA) package with 69 cancer, immunity, and cell signaling related KEGG pathways. Results: Using a cutoff of two-fold and adjusted p-value of 0.05, we identified 954 genes differentially expressed between Cav1+/- TNBC patients. Included in these were 31 genes which were found to be up-regulated by over five- fold and 3 genes down-regulated by over five fold in Cav1+ TNBC. Genes of notable interest for their role in cell signaling, cell adhesion, tumor invasion and metastasis, included an up-regulation of TGFBR2, SPARC, integrins (ITGA11, ITGB5, ITGBL1), cell adhesion proteins (LAMB3, COL5A3) and molecules which facilitate tumor invasion (LAMB3, MMP1, MMP2, MMP9). In addition, genes found to be down-regulated in Cav1+ patients and notable for their roles in promoting epithelial-mesenchymal-transition (EMT) included Claudin 3(CLD3) and CA125/MUC16 (Mucin 16). We also detected an approximately two-fold down-regulation of CDKN2A in Cav1+ patients. Using SPIA pathway analysis, 12 pathways were found to be differentially activated in Cav1+ vs. Cav1- TNBC. The most differentially activated pathways were the focal adhesion pathway (p = 4.51E-18), PI3k-Akt signaling pathway (p = 2.01E-6) and TGF-β and MAPK signaling pathways (p = 0.005, 0.014, respectively). Conclusions: Differential gene expression patterns and pathway analyses provide evidence for distinct profiles for gene expression between Cav1+/- TNBC. Cav1+ TNBC patients exhibit up-regulation of genes important for cell signaling, extracellular matrix remodeling and tumor invasion, and down-regulation of genes that may facilitate EMT and loss of cell cycle control. The focal adhesion pathway, as well as TGF-β, PI3K and MAPK signaling pathways, were identified as differentially activated among Cav1+/- TNBC. Taken together, these data support the role of Cav1+ in identifying a subtype of TNBC that may have a greater risk for invasion and metastasis. The correlation of this subtype with prognosis and drug response should be investigated in future studies. Citation Format: Rebecca A. Feldman, Zoran Gatalica, Semir Vranic, Ryan Bender, Sandeep Reddy, Anatole Ghazalpour. Caveolin-1: Beyond a marker for basal-like breast cancers. [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 3928.
11504 Background: Gene fusions are important mutations in cancer development. In NSCLC, ALK- and ROS1-rearrangements led to creation of agents that block further tumor progression. Some fusions are considered unique to a specific cancer subtype (“translocation-defined” cancer types). The purpose of this study is to report fusion testing results performed at a multi-omic tumor profiling facility to identify novel or uncommon fusions in a variety of tumor types. Methods: In total, 1282 solid tumor specimens were profiled using the ArcherDx FusionPlex Assay at a CLIA-certified laboratory (Caris Life Sciences). Commonly profiled cancer specimens included colorectal adenocarcinoma (n = 243), non-small cell lung carcinoma (n = 215), breast adenocarcinoma (n = 109), and glioblastoma multiforme (n = 76). Results: Overall, 13.4% (172/1282) of specimens analyzed contained a previously reported or novel fusion. Fusions were more frequently detected in glioblastoma multiforme (26.3%, 20/76), soft tissue sarcoma (23.5%, 8/34), prostatic adenocarcinoma (20.0%, 5/25), NSCLC (16.7%, 36/215), gastric adenocarcinoma (15.2%, 5/33) and invasive breast carcinoma (7.3%, 8/109) specimens. A common cis-spliced fusion of two adjacent genes (ADCK4-NUMBL) was identified in 6.1% overall (78/1282), followed by the FGFR3-TACC3 (0.5%, 7/1282). Overall, sixty-five unique fusions were identified. In a sub-analysis of breast carcinomas of common histologic subtypes (e.g. ductal), eight distinct gene fusions were detected (ADCK4-NUMBL, CCDC6-RET, ESR1-ATP2B2, ETV6-RUNX1, FCGR2C-MAST2, FGFR2-CCDC3, FGFR3-TACC3, and PRKCG-PRKCB). Conclusions: Our analysis reveals fusions, such as FGFR, that are potentially targetable and these results could be useful to direct patients to clinical trials for relevant drugs. Our analysis indicates gene fusions are not restricted to special subtypes of breast carcinoma. For example, ETV6 gene rearrangement is not restricted to secretory carcinoma as it was detected in a metastatic ductal carcinoma, NOS. In addition, we report ETV-RUNX1, a well-known fusion associated with childhood ALL, in a breast carcinoma. Further studies are warranted to explore the role of fusions in driving various cancers.
11521 Background: The role of genomic and protein biomarkers in the selection of treatments of advanced cancer is limited by the availability of outcome data following biomarker selected treatment. TNT has been used as a clinical endpoint by the FDA and reflects the clinical decision making process integrating efficacy and toxicity components. We hypothesized that TNT is a meaningful surrogate endpoint correlating to overall survival (OS) for biomarker selected treatments. Methods: We studied 4729 unselected patients (2009-2015), heterogeneous in cancer type, stage, and line of therapy, who were referred for panomic testing utilizing IHC, PCR, ISH, NGS and RNAseq technologies. Treatment data were retrospectively obtained from the International Oncology Network database. TNT was defined as the interval between start of first treatment after tissue collection and next line of treatment. An unselected subset of 952 patients OS data was used to validate TNT as a meaningful clinical surrogate endpoint. Patients were considered “matched” (M) when the biomarker and treatment were consistent and “unmatched” (U) when they were not. The first regimen of treatment was often delivered without knowledge of biomarker results, minimizing selection bias between groups. Results: A significant improvement was observed between M (n=3011) and U (n=1718) cohorts [HR 0.85 (CI:(0.78,0.93), p<0.001)]. The median TNT was 15% longer in the M v U cohorts (248 v 215 days). Improved OS (HR of 0.69 (CI: (0.56,0.84), p<0.001)) was observed between M (n= 505) and U (n=447), with a median increase of more than 1 year (M = 1069 and U = 686 days). Conclusions: Concordance of TNT and OS for patients with biomarker-associated therapies validates the clinical utility of TNT as a surrogate endpoint that can be assessed using EMR extracted data. Additionally, this analysis demonstrates that patients receiving therapies that match their biomarker profile achieve a longer time until subsequent therapy is used. TNT reflects results of a therapeutic medical decision and thus should be further evaluated against PFS or DFI to determine the best surrogate for OS.
A three-dimensional (3D) pillared-layer metal–organic framework, [Cd(bipy)0.5(Himdc)](DMF)]n (1), (bipy =4,4′-bipyridine and Himdc = 4,5-imidazoledicarboxylate) has been synthesized and structurally characterized. The highly rigid and stable framework contains a 3D channel structure with highly polar pore surfaces decorated with pendant oxygen atoms of the Himdc linkers. The desolvated framework [Cd(bipy)0.5(Himdc)]n (1′) is found to exhibit permanent porosity with high H2 and CO2 storage capacities. Two H2 molecules occluded per unit formula of 1′ and the corresponding heat of H2 adsorption (ΔHH2) is about ∼9.0 kJ/mol. The high value of ΔHH2 stems from the preferential electrostatic interaction of H2 with the pendent oxygen atoms of Himdc and aromatic bipy linkers as determined from first-principles density functional theory (DFT) based calculations. Similarly, DFT studies indicate CO2 to preferentially interact electrostatically (Cδ+···Oδ-) with the uncoordinated pendent oxygen of Himdc. It also interacts with bipy through C–H···O bonding, thus rationalizing the high heat (ΔHCO2 ∼ 35.4 kJ/mol) of CO2 uptake. Our work unveiled that better H2 or CO2 storage materials can be developed through the immobilization of reactive hetero atoms (O, N) at the pore surfaces in a metal–organic framework.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
56 Background: NCCN guidelines state “regorafenib (Stivarga) [REG], and Trifluridine+Tipiracil (Lonsurf) [LON] are treatment options for patients who have progressed through all available regimens”. Available clinical trial data has not established whether recycling of prior regimens (oxaliplatin/irinotecan/5FU) with exchange of biologics (bevacizumab, ziv-aflibercept, cetuximab, panitumumab) is superior to changing class of therapy with oral well tolerated agents such as REG and LON. Methods: Data from a pre-authorization platform used by multiple commercial insurance companies in the US (Eviti) was analyzed. 6325 treatment plans of advanced CRC patients were evaluated. Analysis for request for use of REG and LON was limited to third-line and later of therapy in patients with a diagnosis of advanced CRC patients. Results: Of 394 treatment plans beyond second-line of therapy, REG was preferred over LON (239 v 155). Excluding growth factors, anti-emetics, and leucovorin, REG and LON were the 9th and 13th most frequently requested drugs in this clinical setting. Irinotecan was the most commonly requested drug in this setting at >10x the frequency of REG. Ramucirumab was requested more often than REG, and Pembrolizumab, Nivolumab, and Ziv-aflibercept were more requested than LON. HEOR models that included expected supportive care drugs and medication complication management fees estimated the cost of REG at $62,515 per patient versus LON at $26,596 with similar duration of therapy. Conclusions: Therapeutic preferences exist in third-line and later treatment of advanced CRC patients which cannot be fully explained by clinical trial outcome differences, HEOR cost differences, or NCCN guideline preferences. Recycling of chemotherapy and biologics in the late line setting is common and occurs more frequently than switching to a drug regimen with an alternative mechanism of action.
