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Multiple new tyrosine kinase inhibitors, immunotherapies and anti-angiogenic therapies are now available for the treatment of advanced hepatocellular carcinoma (HCC). In this article, we reviewed the evidence supporting these new therapies.The combination of atezolizumab and bevacizumab has become a new standard of care for initial systemic therapy in eligible patients, replacing sorafenib in the first line for many patients. Lenvatinib, a multikinase inhibitor, is also a new first line treatment option for patients who are not eligible for immunotherapy. Several additional options for second line treatment were also reviewed in detail in this paper. New systemic therapies for advanced HCC have prolonged overall survival. However, these new therapies are primarily approved for patients with Child-Pugh A classification with few options for patients with Child-Pugh B disease. Further work is needed to expand options for patients with more advanced liver disease and to optimize the sequencing of these new therapies.

There is an urgent need to understand the molecular signaling pathways that drive or mediate the development of hepatocellular carcinoma (HCC). The focal adhesion kinase (FAK) gene, PTK2, is amplified in 16.4% of The Cancer Genome Atlas HCC specimens, and its amplification leads to increased FAK messenger RNA expression. It is not known whether the overexpression of FAK alone is sufficient to induce HCC or whether it must cooperate in some ways with other oncogenes. In this study, we found that 34.8% of human HCC samples with FAK amplification also show β-catenin mutations, suggesting a co-occurrence of FAK overexpression and β-catenin mutations in HCC. We overexpressed FAK alone, constitutively active forms of β-catenin (CAT) alone, or a combination of FAK and CAT in the livers of C57/BL6 mice. We found that overexpression of both FAK and CAT, but neither FAK nor CAT alone, in mouse livers was sufficient to lead to tumorigenesis. We further demonstrated that FAK’s kinase activity is required for FAK/CAT-induced tumorigenesis. Furthermore, we performed RNA sequencing analysis to identify the genes/signaling pathways regulated by FAK, CAT, or FAK/CAT. We found that FAK overexpression dramatically enhances binding of β-catenin to the promoter of androgen receptor (AR), which leads to increased expression of AR in mouse livers. Moreover, ASC-J9, an AR degradation enhancer, suppressed FAK/β-catenin-induced HCC formation. Conclusion: FAK overexpression and β-catenin mutations often co-occur in human HCC tissues. Co-overexpression of FAK and CAT leads to HCC formation in mice through an increased expression of AR. This mouse model will be useful for further studies of the molecular mechanisms in the pathogenesis of HCC and could lead to the identification of new therapeutic targets.

Background Hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related mortality worldwide. Studies have suggested that aspirin (ASA) and statins may be associated with a decrease in incident HCC. Goals We aimed to evaluate the effect of ASA and statin use on the incidence of HCC in a prospective cohort of patients with liver cirrhosis and to identify if there was an increased risk of esophageal variceal hemorrhage (VH) in patients with ASA use. Study We conducted a retrospective study of 521 patients with data collected from July 1, 2012 to December 31, 2017. We used competing risk analysis to assess the association between risk factors and HCC; and the association between ASA and VH. Results ASA use alone was associated with a decreased incidence of HCC in the univariate and multivariate models; [hazard ratio (HR) confidence interval (CI): 0.348 (0.124-0.976); P=0.0448] and [HR (CI): 0.266 (0.094-0.755); P=0.0129, respectively]. The combination of ASA and statin use was associated with a decreased hazard of HCC [HR (CI): 0.15 (0.036-0.624); P=0.0090] and this remained statistically significant in the multivariable model [HR (CI): 0.113 (0.026-0.483); P=0.0033]. Among daily ASA users compared with non-users, there was not a significant increase in risk of VH. Conclusions Daily ASA use was associated with a decrease risk of incident HCC. The combination of daily ASA use and statin use decreased the risk of incident HCC suggesting there is beneficial interaction. Finally, no excess VH was observed in daily ASA users compared with non-users.

BACKGROUND & AIMS: We investigated whether ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) is involved in development of hepatocellular carcinoma (HCC). METHODS: We analyzed clinical and gene expression data from The Cancer Genome Atlas. Albumin-Cre (Hep(WT)) mice and mice with hepatocyte-specific disruption of Abl1 (Hep(Abl−/−) mice) were given hydrodynamic injections of plasmids encoding the sleeping beauty transposase and transposons with the MET gene and a catenin beta 1 gene with an N-terminal truncation, which induces development of liver tumors. Some mice were then gavaged with the ABL1 inhibitor nilotinib or vehicle (control), daily for 4 weeks. We knocked down ABL1 with short hairpin RNAs in Hep3B and Huh7 HCC cells and analyzed their proliferation and growth as xenograft tumors in mice. We performed RNA sequencing and gene set enrichment analysis of tumors. We knocked down or overexpressed NOTCH1 and MYC in HCC cells and analyzed proliferation. We measured levels of phosphorylated ABL1, MYC, and NOTCH1 by immunohistochemical analysis of an HCC tissue microarray. RESULTS: HCC tissues had higher levels of ABL1 than non-tumor liver tissues, which correlated with shorter survival times of patients. Hep(WT) mice with the MET and catenin beta 1 transposons developed liver tumors and survived a median 64 days; Hep(Abl−/−) mice with these transposons developed tumors that were 50% smaller and survived a median 81 days. Knockdown of ABL1 in human HCC cells reduced proliferation, growth as xenograft tumors in mice, and expression of MYC, which reduced expression of NOTCH1. . Knockdown of NOTCH1 or MYC in HCC cells significantly reduced cell growth. NOTCH1 or MYC overexpression in human HCC cells promoted proliferation and rescued the phenotype caused by ABL1 knockdown. The level of phosphorylated (activated) ABL1 correlated with levels of MYC and NOTCH1 in human HCC specimens. Nilotinib decreased the expression of MYC and NOTCH1 in HCC cell lines, reduced their growth of xenograft tumors in mice, and slowed growth of liver tumors in mice with MET and catenin beta 1 transposons, reducing tumor levels of MYC and NOTCH1. CONCLUSIONS: HCC samples have increased levels of ABL1 compared with non-tumor liver tissues, and increased levels of ABL1 correlate with shorter survival times of patients. Loss or inhibition of ABL1 reduces proliferation of HCC cells and slows growth of liver tumors in mice. Inhibitors of ABL1 might be used for treatment of HCC.

e15169 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (dMMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for cancers with proficient MMR. In an ongoing phase III randomized trial, we will determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR. By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that could serve as ‘immune priming'. Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR are randomized to modified FOLFOX6 for 6 months (12 cycles) alone (control arm) or combined with atezolizumab (840 mg IV q2 wk) with continuation of the antibody as monotherapy for an additional 6 months (total duration of 12 months) [experimental arm]. Patients will be stratified by T, N stage and tumor sidedness. Local testing for MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. One cycle of FOLFOX is allowed pre-registration. The targeted accrual goal of 700 patients and 165 disease-free survival (DFS) events will provide 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint of DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. Results: This study is being conducted by the Alliance for Clinical Trials in Oncology, was approved by NCI CTEP and activated in 09/2017. The study is actively accruing and, as of 02/11/2019, 152 patients are enrolled. We are actively exploring an international collaboration. Conclusions: This is a current clinical trial in progress. Clinical trial information: NCT02912559.

TPS3630 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (MMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for proficient MMR tumors (Le, M, et al, NEJM 2016). We propose a phase III randomized trial to determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech™), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR or microsatellite instability (MSI). By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that may serve as ‘immune priming.’ Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR or MSI will be randomized to modified FOLFOX6 for 6 months (12 cycles) alone or combined with atezolizumab (840 mg IV q2 wk) continued as monotherapy for an additional 6 months (total duration of 12 months). Patients will be stratified by T, N stage and tumor sidedness. Local testing for MSI or MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. The targeted accrual goal of 700 patients provides 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. This study will be conducted by the Alliance for Clinical Trials in Oncology. The protocol has been approved by NCI CTEP and is expected to be activated in mid 2017. Clinical trial information: NCT02912559.

323 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection, aggressive biology and resistance to chemotherapy. Markers for early detection of PDAC and mediators of chemoresistance are poorly understood. GRP78 is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER. Increased GRP78 expression promotes in vitro cancer cell survival, progression, and chemoresistance. This study aims to examine expression of GRP78 protein in PDAC and intraductal papillary mucinous neoplasm (IPMN) compared to normal pancreatic ducts using immunohistochemistry (IHC). Methods: The expression of GRP78 was assessed using IHC in 93 sections of formalin-fixed paraffin-embedded tissue: normal ducts (38), low grade IPMN (IPMN-LG, 26), high grade IPMN (IPMN-HG, 9), and PDAC (20). Immunostaining intensity of GRP78 protein was categorized as no or weak staining (0-1+) and strong staining (2-3+). Fisher’s exact test with two tails was performed using the GraphPad statistical software. Results: GRP78 expression was identified in the cytoplasm of normal pancreatic ducts, IPMN and PDAC with a fine granular pattern. All PDAC and IPMN-HG showed strong expression of GRP78 while the normal ductal cells showed only minimal expression of GRP78. 73% of IPMN-LG expresses GRP78 strongly. Statistical analysis revealed a significant difference in GRP78 expression level between normal ductal cells and all three pathological conditions including PDCA, IPMN-HG and IPMN-LG (all p < 0.0001). Conclusions: This study shows that the expression level of GRP78 is significantly increased in PDAC, IPMN-HG and IPMN-LG compared to normal ductal cells. There appears to be a progressive increase in GRP78 expression from IPMN-LG to IPMN-HG and invasive PDAC. Increased GRP78 expression may be a marker for those at risk of developing PDAC. Changes in GRP78 expression over time and its role in PDAC chemoresistance should be further assessed. [Table: see text]