Purpose: Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies. Experimental Design: Matched tumor/normal DNA from patients with HCC (N ¼ 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: WNT/b-catenin pathway (45%) and TP53 (33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (n ¼ 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (n ¼ 31), activating alteration WNT/b-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including TSC1/2 (8.5%) inactivating/truncating mutations, FGF19 (6.3%) and MET (1.5%) amplifications, and IDH1 missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics. Conclusions: Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies. See related commentary by Pinyol et al., p. 2021
Purpose: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.Experimental Design: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advancedstage PDAC, who had both germline-and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1,
Page 1 of 27 CancerThis is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version record. Please cite this article as doi:10.1002/cncr.29769.This article is protected by copyright. All rights reserved. Accepted ArticleABSTRACT Advanced hepatocellular carcinoma (HCC) carries a dismal prognosis and the current treatment is limited to sorafenib, an agent with modest benefit. Preclinical data indicate that several immunologic mechanisms are at play to promote HCC development and growth while impairing effective antitumor immune surveillance. Several novel approaches geared at manipulating the immune response to HCC have suggested a therapeutic benefit in early stage clinical trials, indicating a real potential to augment tumor-specific immunity and improve outcomes in this disease. Herein, we review the barriers to an effective immune response against HCC and contemporary clinical investigations that may be "primed"to alter the natural history of HCC.
The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further. Cancer 2019;125:3312-3319.
IMPORTANCE Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC).OBJECTIVE To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. DESIGN, SETTING, AND PARTICIPANTSThis unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-
Lessons Learned. TKM‐080301 showed a favorable toxicity profile at the studied dose. TKM‐080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early‐phase study does not support further evaluation as a single agent. Background. Polo‐like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA‐induced silencing complex and a reduction in cell proliferation. Methods. A 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child‐Pugh score A received TKM‐080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days. Results. The study enrolled 43 patients. The starting dose of TKM‐080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression‐free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months. Conclusion. TKM‐080301 was generally well tolerated. In this early‐phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.
Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.
BACKGROUND: With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs). METHODS: Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected. RESULTS: Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate-penetrance cancer predisposition gene. Among high-penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer. CONCLUSIONS: The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.
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