Citations

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

Abstract Objective The quality of all clinical MRI is dependent on B0 homogeneity, which is optimized during the shimming part of a prescan or preparatory phase before image acquisition. The purpose of this study was to assess shimming techniques clinically employed for breast MRI across our practice, and to determine factors that correlate with higher image quality for contrast-enhanced breast MRI at 1.5T. Methods One hundred consecutive female patients were retrospectively collected with Institutional Review Board approval. Shimming-related parameters, including shim-box placement and shimming gradient offsets were extracted from prior contrast-enhanced 3D fat-suppressed T1-weighted gradient echo image acquisitions. Three breast radiologists evaluated these images for fat saturation, breast density, overall image quality, and artifacts. Technologist experience was also evaluated for variability of shimming. Generalized linear mixed models were used to compare acquisition parameters between fat saturation. P < 0.05 was considered as statistical significance. Results The percentage of soft tissue inside the field of view (FOV) (ie, Tissue/FOV) in the good fat-saturation group (0.37 ± 0.06) was significantly lower (P < 0.01) than that in the poor fat-saturation group (0.39 ± 0.06). Other shimming-related parameters were found not significantly affecting the fat-saturation outcomes. Technologists with more experience tended to have less variable shimming performance than junior technologists did. Conclusions The quality of clinical MRI and especially breast MRI is highly dependent on shimming. Decreasing Tissue/FOV was associated with good image quality (good fat saturation). Optimization of shimming may require manual shimming or higher-order field-correction strategies.

Background: The CACNA1C -encoded cardiac L-type calcium channel (Cav1.2) is essential for cardiocyte action potential duration (APD). We previously reported the CACNA1C-p.R518C variant associated with prolonged QT intervals, cardiomyopathy, and sudden cardiac death in several pedigrees. Methods: To characterize a patient-derived human induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) CACNA1C-p.R518C model, CACNA1C-p.R518C hiPSC-CMs were generated from a 13-year-old man (QTc, >480 ms) with a family history of sudden cardiac death. An isogenic hiPSC-CM gene-corrected control was created using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9). APD and calcium handling were assessed by live cell imaging with Arclight voltage and Fluo-4 calcium indicators, respectively. The APD and L-type calcium channel biophysical properties were further assessed by whole-cell patch clamp technique. Results: The Bazett formula-corrected, Arclight-measured APD 90 of CACNA1C-p.R518C hiPSC-CMs was significantly longer (622±11 ms; n=92) than the isogenic control hiPSC-CMs (453±5 ms; n=62; P <0.0001). Patch clamp assessment of CACNA1C-p.R518C hiPSC-CMs paced at 1 Hz confirmed a prolonged APD 90 (689±29 ms; n=10) compared with the patient’s isogenic control hiPSC-CMs (434±30 ms; n=8; P <0.05). Fluo-4–measured calcium transient decay time suggested calcium mishandling in CACNA1C-p.R518C. Patch clamp analysis revealed increased L-type calcium channel window current, slow decay time at various voltages, and increased late calcium current for CACNA1C-p.R518C hiPSC-CMs when compared with isogenic control hiPSC-CMs. Conclusions: Using patient-specific hiPSC-CM mutant and isogenic control lines, we demonstrate that the CACNA1C-p.R518C variant is the self-sufficient, monogenetic substrate for the patient’s long-QT syndrome phenotype. These data further bolster the conclusion that CACNA1C is a bona fide, definite evidence long-QT syndrome susceptibility gene.

Background: To assess the differential effect of robotic assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) on survival outcomes in matched analyses performed on a large multicentric cohort. Methods: The study included 9757 patients with urothelial bladder cancer (BCa) treated in a consecutive manner at each of 25 institutions. All patients underwent radical cystectomy with bilateral pelvic lymphadenectomy. To adjust for potential selection bias, propensity score matching 2:1 was performed with two ORC patients matched to one RARC patient. The propensity-matched cohort included 1374 patients. Multivariable competing risk analyses accounting for death of other causes, tested association of surgical technique with recurrence and cancer specific mortality (CSM), before and after propensity score matching. Results: Overall, 767 (7.8%) patients underwent RARC and 8990 (92.2%) ORC. The median follow-up before and after propensity matching was 81 and 102 months, respectively. In the overall population, the 3-year recurrence rates and CSM were 37% vs. 26% and 34% vs. 24% for ORC vs. RARC (all p values > 0.1), respectively. On multivariable Cox regression analyses, RARC and ORC had similar recurrence and CSM rates before and after matching (all p values > 0.1). Conclusions: Patients treated with RARC and ORC have similar survival outcomes. This data is helpful in consulting patients until long term survival outcomes of level one evidence is available.

Abstract Background: HER-2 is a transmembrane receptor that is overexpressed in multiple epithelial tumors. We have previously shown that a first generation HER-2 B-cell peptide vaccine targeting epitopes (628-647) and (316-339) was safe and relatively active. We recently developed a novel B-cell epitope specific vaccine (HER-Vaxx) consisting of epitopes derived from the extracellular domain of HER-2 that correspond to amino acid sequences 597-626 (pertuzumab binding site) and 266-296 (trastuzumab binding site). Methods: This first-in-human Phase 1b study evaluated the safety, optimal immunologic/biologic dose (OID/OBD) and immunogenicity of HER-Vaxx. Using a 3+3 dose escalation design, 3 patients (pts) were treated at each dose level (DL). If &lt;2 pts experience dose-limiting toxicity (DLT), we required an additional 3 pts to be entered at that DL for OID/OBD assessment (defined as the dose level inducing a strong immunogenic response for 5 out of 6 patients). We also required that at least 6 patients at each DL to receive 3 inoculations of the combination vaccines at 3-week intervals and that &lt; 2 of the 6 pts experience DLT before dose escalation. DLs were 1.0 mg (DL1), 1.5 mg (DL2), 2.0 mg (DL3) and 2.5 mg (DL4) of each peptide. Each dose contained 0.025 mg of n-MDP. Results: 49 patients with metastatic and/or recurrent solid tumors and a median of 4 prior lines of chemotherapy received at least one inoculation of HER-vaxx. Common related toxicities include injection site reactions (56% grade 1/2 and 5% grade 3/4). There were no DLTs. The OID/OBD was found to be DL 2 (1.5 mg of each peptide vaccine).A total of 28 patients received ≥ 3 vaccinations including 2 with a partial response and 14 with stable disease. Of those, 6 patients received at least one 6-month boost. The vaccine generated sustained humoral response eliciting HER-2 specific antibodies in the majority of responding patients. Conclusion: We demonstrate that HER-Vaxx is well tolerated and able to generate sustained anti-HER-2 immune response. Given the promise, continuous development of the vaccine is ongoing at the suggested OBD in HER-2 overexpressing tumors. Citation Format: Tanios Bekaii-Saab, Lai Wei, Robert Wesolowski, Daniel Ahn, Christina Wu, Maryam Lustberg, Amir Mortazavi, Bhuvaneswari Ramaswamy, Jay Overholser, Pravin Kaumaya. A Phase Ib of a combination of two chimeric (Trastuzumab-like and Pertuzumab-like) HER-2 B cell peptide vaccine emulsified in ISA 720 and nor-MDP adjuvant in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT017.

Abstract Lung cancer is the deadliest and most frequently diagnosed type of tumor worldwide, with 1.6 million deaths reported annually. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases and carries a poor 5-year survival rate below 15%. Prognoses remain dismal due to the large number of patients diagnosed with advanced stage disease and the development of resistance to current therapies. A better understanding of acquired drug resistance will help to circumvent the progression of lung cancer and make significant strides in improving NSCLC patient treatment. Our recent work demonstrates that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its amino-terminally truncated splice variant (t-DARPP) promote lung tumor growth in orthotopic mouse models. IHC staining of 62 human lung adenocarcinoma tissues showed that t-DARPP expression is elevated with increasing tumor (T) staging score, which represents the size of the primary tumor and whether it has grown into nearby areas, as a metric of tumor progression and growth. Correspondingly, a computational biology analysis of 513 lung adenocarcinoma patients revealed upregulation of t-DARPP isoform expression correlates with advanced T stage and is associated with poor overall survival. We identified a novel physical interaction between DARPP-32 and inhibitory kappa B kinase-α (IKKα) that promotes NSCLC cell migration through activation of non-canonical NF-κB2 signaling. It has been shown that DARPP-32 overexpression inhibits gefitinib-induced apoptosis in gastric cancer and t-DARPP contributes to the trastuzumab resistance phenotype in breast cancer. Our recent findings suggest DARPP-32 and t-DARPP overexpression in NSCLC promotes resistance to specific molecular targeted inhibitors by enabling tumor cells to evade apoptosis via Akt- and Erk-dependent cell survival mechanisms. Current ongoing studies are focused on manipulating expression of DARPP-32 isoforms in lung tumor cells to prevent resistance to targeted therapies in NSCLC patients. Citation Format: SK Kayum Alam, Matteo Astone, Ping Liu, Li Wang, Abbygail M. Coyle, Erin N. Dankert, Dane K. Hoffman, Stephanie R. Hall, Wei Zhang, Rui Kuang, Anja C. Roden, Aaron S. Mansfield, Luke H. Hoeppner. Molecular mechanisms of non-small cell lung cancer growth and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 873.

Abstract Epithelial ovarian cancer (EOC) is the most common gynecological cancer, and ranks fifth in cancer deaths among women in the United States. Previous studies have identified several circulating proteins biomarkers for EOC risk, such as CA125 antigen and insulin-like growth factor-1 (IGF-1). However, previous studies on protein biomarkers for EOC were limited with small sample sizes, and only a few proteins investigated. In this study, we integrated genomics and proteomics data to search for novel circulating protein biomarkers for EOC risk. We constructed study instruments using genetic variants for protein quantitative trait loci (pQTL) for over 1,400 circulating proteins. Beta coefficients and standard errors of the selected pQTL variants in relation to EOC risk were obtained from 25,509 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). An inverse-variance weighted method was used to evaluate the association of these genetically predicted protein levels and risk of overall and serous EOC. We identified 35 protein biomarkers, for which their genetically predicted levels were significantly associated with the risk of either overall or serous EOC (false discovery rate &lt;0.05). There are 25 proteins showing significant associations with both overall and serous EOC; most of the associations were stronger for serous EOC than overall EOC. The association for 31 proteins could be attributed, in part, to variants at ABO 9q34.2, a known ovarian cancer susceptibility locus. Five ABO locus-related proteins are in the PI3K-Akt signaling pathway, including insulin-like growth factor 1 receptor, hepatocyte growth factor receptor, interleukin-3 receptor subunit alpha, insulin receptor, and vascular endothelial growth factor receptor 2. Four of these proteins are also in the Rap1 and Ras signaling pathway. These five proteins are all inversely associated with the risk of overall EOC, with odds ratios ranging from 0.64 to 0.93 per unit increase in genetic risk scores (p values: 7.55×10-7 to 5.66×10-2). Four EOC associated proteins which were not influenced by variants in 9q34.2 are microfibrillar-associated protein 2, protein delta homolog 1, semenogelin-2, and netrin-G1, all of which showed significant associations with overall EOC, but not the serous subtype. Our study identifies potential novel biomarkers for ovarian cancer and suggests that genetic variants at locus 9q34.2 may play a role in the relation between levels of these proteins and risk of ovarian cancer. Citation Format: Guochong Jia, Xiang Shu, Xiao-Ou Shu, Jirong Long, Qiuyin Cai, Kirsten B. Moysich, Ellen L. Goode, Thomas A. Sellers, Wei Zheng. Genetically predicted concentration of circulating proteins and epithelial ovarian cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 598.

Abstract CLL is a clinically heterogeneous disease with wide ranging disease course. A novel CLL-IPI based on Rai/Binet stage, IGHV-mutation status, TP53 mutation/deletion, B2M level, and age was developed to stratify patients into 4 risk groups, with a c-statistic of 0.75. Next-generation sequencing has identified ~60 genes recurrently mutated in CLL, some of which are associated with poor overall survival, whereas the clinical effect of most genes is still unknown. Herein, we examine whether somatic mutations in these putative driver genes are associated with time to first treatment (TTT), and whether they add prognostic value beyond CLL-IPI. Based on the 2008 International Workshop CLL criteria, we identified 100 CLL and 96 high-count monoclonal B-cell lymphocytosis (MBL) newly diagnosed from the Mayo Clinic CLL biobank. Pre-treatment peripheral blood mononuclear cells were collected &lt;2 years of diagnosis and tumor DNA was extracted from sorted CD5+/CD19+. We sequenced the coding regions of 61 recurrently mutated CLL driver genes using a custom SureSelect panel, with 24 samples per flow cell in Illumina HiSeq 4000. The average coverage depth was &gt;1000X. Somatic mutations were called using MuTect2 in tumor-only mode. To remove germline variants, variants were eliminated based on minor allele frequencies &gt;0.01%, identified in 1000 Genomes Project, ExAC and/or ESP6500 databases, unless present in known mutation hotspots or COSMIC. After filtering, high/moderate impact mutations were analyzed using Cox regression, to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test for associations with TTT. Among 196 patients the most commonly mutated genes were TP53 (11%), ATM (10%), SF3B1 (10%), NOTCH1 (9%), CHD2 (8%), and BIRC3 (7%). The median follow-up was 8.7 years, and 73 patients were subsequently treated. ATM (HR=3.27, CI:1.8-6.1, P=0.0002) and NOTCH1 (HR=2.41, CI:1.3-4.6, P=0.008) were associated with TTT. When evaluating the total number of mutated genes, we found 32%, 29%, and 39% patients had ≥2, 1, or 0 genes mutated, respectively, and this was associated with shorter TTT (HR=1.74, CI:1.3-2.4, P=0.0005) adjusting for sex and CLL-IPI with a c-statistic=0.8 (CI: 0.75-0.84). When stratified by CLL-IPI, the association held for low (N=99, HR=1.88, CI:1.1-3.4, P=0.03) and intermediate risk (N=54, HR=1.87, CI:1.1-3.2, P=0.03) but not high/very high risk (N=35, HR=1.07, CI:0.6-1.9, P=0.83). We demonstrated that the total number of CLL putative driver genes with high or moderate impact mutations provided prognostic information in newly diagnosed CLL/MBL beyond CLL-IPI. Moreover, even among those with low or intermediate CLL-IPI risk, the total number of somatic mutations separated those patients who progressed. Sequencing the CLL driver genes at time of diagnosis could be a potential biomarker for outcome prediction. Citation Format: Geffen Kleinstern, Daniel R. O’Brien, Brian F. Kabat, Kari G. Chaffee, Aaron D. Norman, Timothy G. Call, Sameer A. Parikh, Jose F. Leis, Wei Ding, James R. Cerhan, Neil E. Kay, Susan L. Slager, Esteban Braggio. Somatic mutations within chronic lymphocytic leukemia (CLL) putative driver genes are associated with outcomes beyond the CLL international prognostic index (CLL-IPI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4466.

Abstract Background: The methylthioadenosine phosphorylase (MTAP) gene encodes an essential enzyme for the salvage pathway of adenosine synthesis and is frequently lost in different types of cancer including urothelial bladder carcinoma. Therefore, MTAP-deficient tumors are theoretically very sensitive to anti-folate agents such as pemetrexed that can effectively block the de novo pathway of adenosine synthesis and as a result, create a state of synthetic lethality. We thus hypothesize that tumor MTAP gene deficiency is associated with response to pemetrexed therapy in bladder cancer. Methods: In this study, we investigated MTAP gene deficiency rates in the TCGA database and confirmed MTAP protein loss by immunohistochemistry using a tumor tissue microarray containing bladder tumor tissues from 151 patients. We then performed in vitro and in vivo studies using MTAP-proficient and MTAP-deficient human bladder cancer cell lines. Functional loss of MTAP was verified with mass spectrometry, which detects its substrate methylthioadenosine (MTA) levels. We also correlated these pre-clinical studies with clinical response data on patients with metastatic bladder cancer treated with pemetrexed. Results: We identified that 27.8% bladder cancer patients have MTAP protein deficiency, which is consistent with exome sequencing data from the TCGA database. In vitro data showed MTAP-deficient human bladder cancer cell lines were significantly more sensitive to pemetrexed, with IC50 at least 40 times lower than MTAP-proficient cell lines. Subsequent knockdown of the MTAP gene in MTAP-proficient cell lines increased sensitivities to pemetrexed treatment. Consistent with the in vitro data, pemetrexed significantly inhibited the growth of MTAP-deficient or knockdown xenograft tumors but not MTAP-proficient tumors. Furthermore, 4 of 4 (100%) patients with MTAP-deficient metastatic bladder cancer responded to pemetrexed treatment, whereas only 1 of 11 (9%) patients with MTAP-proficient metastatic bladder cancer responded to pemetrexed. Conclusion: Our data demonstrate that MTAP gene loss in urothelial bladder cancer leads to a metabolic state of synthetic lethality with pemetrexed therapy. Therefore, bladder tumor MTAP loss should be further investigated as a potential biomarker for selection of patients for anti-folate therapy. Citation Format: Jianfeng Chen, Omar Alhalabi, Guangchun Han, Wei-Lien Wang, Xin-Qiao Zhang, Jian H. Song, Lidia P. Lopez, Sumankalai Ramachandran, Anh G. Hoang, Tyrone Garnett, Matthew Campbell, Amishi Y. Shah, Jennifer Wang, Arlene O. Siefker-Radtke, Shi-Ming Tu, Mark Titus, Charles C. Guo, Gary E. Gallick, Eleni Efstathiou, William F. Benedict, Christopher J. Logothetis, Thai H. Ho, Linghua Wang, Jianjun Gao. MTAP gene deficiency creates vulnerability to anti-folate therapy in urothelial bladder carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 385.